Compounds involved in cooperative binding and uses thereof

Abstract

The present disclosure features macrocyclic compounds alone and in combination with other therapeutic agents, as well as pharmaceutical compositions and protein conjugates thereof, which have the ability to modulate biological processes, including the inhibition of RAS and RAS-RAF, and their use in the treatment of cancer.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application Nos. 62 / 783,816, filed December 21, 2018, 62 / 894,493, filed August 30, 2019, and 62 / 930,489, filed November 4, 2019, each of which is incorporated herein by reference. The present disclosure relates to compounds that participate in cooperative binding and uses thereof. [Background technology]

[0002] The vast majority of small molecule drugs act by binding to functionally important pockets on target proteins, thereby modulating their activity. For example, cholesterol-lowering drugs such as statins bind to the enzyme active site of HMG-CoA reductase, thereby preventing the enzyme from binding its substrate. The high number of known drug / target interaction pairs may lead some to mistakenly believe that small molecule modulators for most, if not all, proteins are feasible given reasonable time, effort, and resources. This perception is far from the truth. Current estimates suggest that only about 10% of all human proteins are amenable to small molecule targeting. The other 90% are currently considered intractable or intractable for such small molecule drug discovery. Such targets are commonly referred to as "undruggable." These undruggable targets represent a vast and largely untapped reservoir of medically important human proteins. Therefore, there is great interest in creating new molecular modalities that have the ability to modulate the function of such undruggable targets.

[0003] It is well established in the literature that RAS proteins (KRAS, HRAS, and NRAS) play pivotal roles in various human cancers and are therefore suitable targets for anticancer therapy. Dysregulation of RAS proteins through activating mutations, overexpression, or upstream activation is common in human tumors, and activating RAS mutations are found in approximately 30% of human cancers. Among RAS proteins, KRAS is the most frequently mutated, making it an important target for cancer therapy. Despite significant small molecule drug discovery efforts directed against RAS over the past few decades, no drugs directly targeting RAS are currently available for clinical use.

[0004] Covalent drugs are covalently bound to their biological targets. Covalent drugs have a long history in medicine, and they will continue to impact drug discovery and human health into the future. Biological targets with nucleophilic reactive groups (such as -SH, -OH, -NH2, -COOH, and others) are potentially suitable for covalent drug discovery approaches. Summary of the Invention

[0005] The present disclosure features compounds (e.g., macrocycles) of Formula I that have the ability to modulate biological processes, for example, by binding to a presenter protein, such as a member of the cyclophilin A ("CYPA") family, and to a target protein that is a mutant RAS protein in which an amino acid in the wild-type amino acid sequence has been mutated to a cysteine (e.g., KRAS G12C, KRAS G13C, NRAS G12C, NRAS G13C, HRAS G12C, and HRAS G13C). In some embodiments, provided compounds may be useful in treating diseases and disorders in which these RAS mutants play a role, such as cancer.

[0006] In an aspect, the present disclosure provides a compound of structural formula (I): [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: Q is a bicyclic arylene, bicyclic heteroarylene, or bicyclic heterocyclylene, wherein the first ring in Q is bonded to X and the second ring in Q is bonded to Z, and Q is optionally substituted; X is a bond; a straight-chain C1-C3 alkylene optionally substituted with 1 to 3 substituents independently selected from fluoro, —CN, —C1-C3 alkyl, and —O—C1-C3 alkyl; —O—; —S(O) 0-2 -; * -CH2-O-; * -CH2-S(O) 0-2 -; * -O-CH2-; or * -CH2-S(O) 0-2 - and " * " is when X is -C(R 4 )(R 5 )- and the moiety bonded to Y is -O-, -NH-, or -N(C1-C3 alkyl)-; the Z ring is phenyl or a 6-membered heteroaryl; R 1 is an optionally substituted C1-C6 alkyl, -(CH2) 0-1 -(optionally substituted C-C cycloalkyl), -(CH) 0-1 -(optionally substituted aryl), or optionally substituted heterocyclyl; R 2 teeth, [ka] and Ring A is a 4- to 8-membered cycloalkyl or a 4- to 8-membered heterocyclyl; W is -N(R 12 )-, -O-, or -C(R 12a )(R 12b )- and Each R Aare each independently fluoro; chloro; —CN; —OH; —NH; —C1-C3 alkyl optionally substituted with CN, OH, NH2, or —O—C1-C3 alkyl; —O—C1-C3 alkyl; or —NH—C1-C3 alkyl; R 9 is, if present, —N(C-C alkylene-H)—, —N(C(O)—(C-C alkylene-H)—, —C(C-C alkylene-H)(C-C alkylene-H)—, or —C(C-C alkylene-H)(C(O)—C-C alkylene-H)—, and R 9 each alkylene moiety is optionally substituted by one or more substituents, each substituent independently selected from halo, —CN, —OH, —C1-C3 alkyl, and —O—C1-C3 alkyl; R 10 is, if present, C-C alkylene optionally substituted by one or more substituents, each substituent being independently selected from halo, —CN, —OH, —C-C alkyl, and —O—C-C alkyl; R 11 is —N(C-C alkylene-H)—, —N(C(O)—(C-C alkylene-H)—, —C(C-C alkylene-H)(C-C alkylene-H)—, —C(C-C alkylene-H)(C(O)—C-C alkylene-H)—, or a nitrogen-containing saturated heterocyclyl; R 11 each alkylene moiety is optionally substituted by one or more substituents, each substituent independently selected from halo, —CN, —OH, —C1-C3 alkyl, and —O—C1-C3 alkyl; R 12 is hydrogen or -C1-C3 alkyl, or R 12 is one R A together with the atoms to which they are respectively attached and any intervening atoms, form an optionally substituted 5- to 8-membered heterocyclyl fused or spirofused to ring A, or R 12 is R 10 Any methylene unit in or R11 any methylene units therein, taken together with the atoms to which they are respectively attached, and any intervening atoms, form an optionally substituted 5- to 8-membered heterocyclyl; R 12a and R 12b are each independently hydrogen or -C1-C3 alkyl, or R 12a and R 12b together with the carbon atoms to which they are attached form a 3- to 6-membered cycloalkyl ring, R 13 is O, S, N—CN, or NO—C1-C3 alkyl; WH is [ka] and Each R 14 are independently hydrogen; —CN; or —C1-C3 alkyl optionally substituted by one or more substituents independently selected from —OH, —O—C1-C3 alkyl, —NH2, —NH(C1-C3 alkyl), —N(C1-C3 alkyl)2, or optionally substituted 4- to 7-membered saturated heterocyclyl; R 15 is —C1-C3 alkyl optionally substituted by one or more substituents independently selected from —OH, —O—C1-C3 alkyl, —NH2, —NH(C1-C3 alkyl), —N(C1-C3 alkyl)2, or an optionally substituted 4- to 7-membered saturated heterocyclyl; R 16 is hydrogen; or —C1-C3 alkyl optionally substituted by one or more substituents independently selected from —OH, —O—C1-C3 alkyl, —NH2, —NH(C1-C3 alkyl), —N(C1-C3 alkyl)2, or an optionally substituted 4- to 7-membered saturated heterocyclyl; R 14 is R 9 Or R 11taken together with the atom to which they are attached and any intervening atoms, form an optionally substituted 5- to 8-membered ring system; or R 16 is R 9 Or R 11 taken together with the atom to which they are attached and any intervening atoms, form an optionally substituted 5- to 8-membered ring system; R 3 is hydrogen, halogen, C1-C3 alkyl, or C1-C3 hydroxyalkyl; R 4 is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R 5 is hydrogen, halogen, —OH, —CN, —O—(optionally substituted C1-C3 alkyl), optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, —(CH2) 0-1 -aryl, -(CH2) 0-1 -heteroaryl, -(CH2) 0-1 -cycloalkyl, or -(CH2) 0-1 -heterocyclyl, or R 4 and R 5 taken together form =CH2, an optionally substituted C3-C6 cycloalkyl, or a 3- to 7-membered saturated heterocyclyl; or R 5 is a ring atom in Q, R 4 together with the carbon atom to which is bonded and X, form a 4- to 9-membered saturated or unsaturated heterocyclyl fused with Q; R 6 is hydrogen or -CH3, Each R 7 are independently halo, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, -OH, -O-C1-C3 alkyl, -O-C1-C3 haloalkyl, -NR n1 R n2 , -NR n1 OR n2, -ONR n1 R n2 , or -NR n1 NR n2 R n3 and R n1 is H, C1-C3 alkyl, C1-C3 heteroalkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, or C1-C3 aminoalkyl; R n1 One of the methylene units of [ka] is optionally replaced by R n2 is H, C1-C3 alkyl, C1-C3 heteroalkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, or C1-C3 aminoalkyl; R n2 One of the methylene units of [ka] is optionally replaced by R n3 is H, C1-C3 alkyl, C1-C3 heteroalkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, or C1-C3 aminoalkyl; R n3 One of the methylene units of [ka] is optionally replaced by Each R 8 are independently halo, C1-C3 alkyl, or C1-C3 haloalkyl; n is 0, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, or 3; r is 0, 1, 2, 3, or 4.

[0007] In some embodiments, Y is -O-. In some embodiments, Y is -NH-. In some embodiments, Y is -N(C1-C3 alkyl)-.

[0008] In some embodiments, WH is [ka] In some embodiments, WH is [ka] In some embodiments, WH is [ka] In some embodiments, WH is [ka] In some embodiments, WH is [ka] is.

[0009] In some embodiments, Z is phenyl or pyridyl. In some embodiments, Z is phenyl. In some embodiments, Z is 3-hydroxyphen-1,5-diyl. In some embodiments, Z is 6-membered heteroaryl. In some embodiments, Z is pyridyl.

[0010] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6.

[0011] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0012] In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4.

[0013] In some embodiments, R 3 is H. In some embodiments, R 3 is halogen. In some embodiments, R 3 is C1-C3 alkyl. In some embodiments, R 3 is C1-C3 hydroxyalkyl.

[0014] In some embodiments, X is -CH2-. In some embodiments, X is a bond.

[0015] In some embodiments, the compound has formula (Ia): [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof; During the ceremony: X is a bond, -O-, -CH2-, -CH(CH3)-, * -CH2-O-, or -CH2-CH2-, * " is a string where X is C(R 4 )(R 5 ) and represents the part that is combined with Y is —O— or —NH—; R 1 is -C1-C4 alkyl, -(CH2) 0-1 -(C3-C6 cycloalkyl), or -C4-C6 cycloalkyl; R 2 teeth, [ka] and Ring A is a 4- to 8-membered cycloalkyl or a 4- to 8-membered saturated heterocyclyl; Each R A are each independently fluoro; chloro; —CN; —OH; —NH; —C1-C3 alkyl optionally substituted with CN, OH, NH2, or —O—C1-C3 alkyl; —O—C1-C3 alkyl; or —NH—C1-C3 alkyl; n is 0, 1, 2, 3, 4, 5, or 6; R 9 is, if present, —N(C-C alkylene-H)—, —N(C(O)—(C-C alkylene-H)—, —C(C-C alkylene-H)(C-C alkylene-H)—, or —C(C-C alkylene-H)(C(O)—C-C alkylene-H)—, and R 9 each alkylene moiety is optionally substituted by one or more substituents independently selected from halo, —CN, —OH, —C1-C3 alkyl, and —O—C1-C3 alkyl; R 10 is, if present, C-C alkylene optionally substituted by one or more substituents independently selected from halo, —CN, —OH, —C-C alkyl, and —O—C-C alkyl; R 11 is —N(C-C alkylene-H)—, —N(C(O)—(C-C alkylene-H)—, —C(C-C alkylene-H)(C-C alkylene-H)—, or —C(C-C alkylene-H)(C(O)—C-C alkylene-H)—, and R 11 each alkylene moiety is optionally substituted by one or more substituents independently selected from halo, —CN, —OH, —C1-C3 alkyl, and —O—C1-C3 alkyl; R 12 is hydrogen or -C1-C3 alkyl, or R 12 is one RA together with the atoms to which they are respectively attached and any intervening atoms, form an optionally substituted 5- to 8-membered heterocyclyl fused to ring A, or R 12 is R 10 Any methylene unit in or R 11 any methylene units therein, taken together with the atoms to which they are respectively attached, and any intervening atoms, form an optionally substituted 5- to 8-membered heterocyclyl; WH is [ka] and Each R 14 are independently hydrogen, —CN, —C1-C3 alkyl, —C1-C3 hydroxyalkyl, or —O—C1-C3 alkyl; R 15 is —C1-C3 alkyl, —C1-C3 hydroxyalkyl, or —C1-C3 alkylene-O—C1-C3 alkyl; R 16 is hydrogen, —C1-C3 alkyl, —C1-C3 hydroxyalkyl, or —C1-C3 alkylene-O—C1-C3 alkyl; or R 14 is R 9 Or R 11 taken together with the atom to which they are attached and any intervening atoms, form an optionally substituted 5- to 8-membered ring system; or R 16 is R 9 Or R 11 taken together with the atom to which they are attached and any intervening atoms, form an optionally substituted 5- to 8-membered ring system; R 4 is hydrogen, halo, or C1-C3 alkyl; R 5 is hydrogen, halo, -OH, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 alkylene-O-C1-C3 alkyl, C1-C3 haloalkyl, -(CH2) 0-1-C3-C6 cycloalkyl, C1-C3 cyanoalkyl, or -(CH2) 0-1 -aryl(benzyl), or R 4 and R 5 taken together to form =CH2 or C3-C6 cycloalkyl, or R 5 together with the ring atoms of Q, the carbon atom to which it is attached, and X, form a 5- to 7-membered saturated heterocyclyl; R 7 is -OH, -NH2, or C1-C3 haloalkyl; Q is a bicyclic arylene, a bicyclic heteroarylene, or a bicyclic heterocyclylene; the first ring in Q is bonded to X and the second ring in Q is bonded to Z; Q is ═O; —CN; —C1-C5 alkyl optionally substituted by one or more independently selected halo, CN, OH, —O—(C1-C3 alkyl), —C(O)—(C1-C3 alkyl), —O—(C2-C3 alkynyl), —(C3-C6 cycloalkyl), or 4-7 membered saturated heterocyclyl; —O—(C1-C3 alkyl optionally substituted by one or more independently selected halo; C2-C5 alkenyl optionally substituted by -CN or -OH; C2-C3 alkynyl; -S(O)2-C1-C3 alkyl; -(CH2) optionally substituted by one or more independently selected halo, =O, -CN, C1-C3 alkyl optionally substituted by -CN or -O-C1-C3 alkyl, -C(O)-saturated heterocyclyl, -O-saturated heterocyclyl, O-cycloalkyl, or -O-aryl. 0-1 -C3-C6 cycloalkyl; -C1-C3 alkyl optionally substituted by one or more independently selected halo, -CN, -CN, or -O-C1-C3 alkyl, -C(O)-saturated heterocyclyl, -O-saturated heterocyclyl, O-cycloalkyl, or -O-aryl; 0-1-heteroaryl; -(CH) optionally substituted by one or more independently selected halo, =O, -CN, C-C alkyl optionally substituted by -CN or -O-C-C alkyl, -C(O)-saturated heterocyclyl, -O-saturated heterocyclyl, O-cycloalkyl, or -O-aryl. 0-1 -heterocyclyl; -(CH) optionally substituted by one or more independently selected halo, -CN, -CN, or -O-C-C alkyl, -C(O)-saturated heterocyclyl, -O-saturated heterocyclyl, O-cycloalkyl, or -O-aryl. 0-1 optionally substituted by one or more independently selected substituents selected from: -aryl; -C(O)-NH-(C1-C3 alkyl); -C(O)-N(C1-C3 alkyl)2; C2-C3 alkenylene =NO-(C1-C3 alkyl) optionally substituted by C3-C6 cycloalkyl; or Two substituents on the same ring atom or adjacent ring atoms of Q are joined to form a 5- to 7-membered monocyclic ring or a 6- to 12-membered bicyclic ring optionally substituted with one or more independently selected halo, ═O, —CN, C1-C3 alkyl, or —O—C1-C3 alkyl, and are fused to Q.

[0016] In some embodiments, the compound has formula (Ib): [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0017] In some embodiments, the compound has formula (Ic): [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0018] In some embodiments, Q is a 5,6 bicyclic heteroarylene, a 5,6 bicyclic heterocyclylene, a 6,6 bicyclic heteroarylene, or a 6,6 bicyclic heterocyclylene, and Q is optionally substituted. In some embodiments, Q is a 5,6 bicyclic heteroarylene and Q is optionally substituted. In some embodiments, Q is a 5,6 bicyclic heterocyclylene and Q is optionally substituted. In some embodiments, Q is a 6,6 bicyclic heteroarylene and Q is optionally substituted. In some embodiments, Q is a 6,6 bicyclic heterocyclylene and Q is optionally substituted.

[0019] In some embodiments, Q is [ka] is selected from the group consisting of During the ceremony: V1, V2, V3, and V4 are each independently C, CH, or N; R Q1 is -S(O)2-R Q11 , -C(O)-R Q11 , -S(O)2-N(R Q11 )R Q12 , -C(O)-N(R Q11 )R Q12 , C1-C 10 Alkyl, C3-C 10 cycloalkyl, 4- to 14-membered heterocyclyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; or R Q1 taken together with the nitrogen atom to which it is attached and adjacent ring atoms, forms an optionally substituted 4- to 8-membered ring, which ring is optionally further fused to a 5- or 6-membered ring; R Q11 and R Q12 are each independently C1-C 10 Alkyl, C3-C 10cycloalkyl, 4- to 14-membered heterocyclyl, aryl, or heteroaryl; R Q11 and R Q12 are each optionally replaced by, or R Q11 and R Q12 together with the nitrogen atom to which they are both attached form an optionally substituted 4- to 8-membered ring, and R Q11 and R Q12 The ring formed by joining together is optionally fused to another 5- or 6-membered ring.

[0020] In some embodiments, Q is ═O; halo; —OH; —CN; one or more independently selected halo, CN, OH, —O—(C1-C3 alkyl), —C(O)—(C1-C3 alkyl), —OC(O)—N(C1-C3 alkyl), —O—(C2-C3 alkynyl), —(C3-C6 cycloalkyl), 5-6 membered heteroaryl optionally substituted with one or more C1-C3 alkyl, or —C1-C5 alkyl optionally substituted with 4-7 membered saturated heterocyclyl; optionally substituted with one or more independently selected halo. -O-(C1-C3 alkyl); -C2-C5 alkenyl optionally substituted by one or more independently selected -CN or -OH; C2-C3 alkynyl optionally substituted by heteroaryl; -S(O)2-C1-C3 alkyl; -C1-C3 alkyl optionally substituted by one or more independently selected halo, =O, -CN, -CN or -O-C1-C3 alkyl, -C(O)-saturated heterocyclyl, -O-saturated heterocyclyl, O-cycloalkyl, or -O-aryl. 0-1 -C3-C6 cycloalkyl; -C1-C3 alkyl optionally substituted by one or more independently selected halo, -CN, -CN, or -O-C1-C3 alkyl, -C(O)-saturated heterocyclyl, -O-saturated heterocyclyl, O-cycloalkyl, or -O-aryl; 0-1-heteroaryl; -(CH) optionally substituted by one or more independently selected halo, =O, -CN, C-C alkyl optionally substituted by -CN or -O-C-C alkyl, -C(O)-saturated heterocyclyl, -O-saturated heterocyclyl, O-cycloalkyl, or -O-aryl. 0-1 -heterocyclyl; -(CH) optionally substituted by one or more independently selected halo, -CN, -C1-C3 alkyl optionally substituted with -CN, -C(O)-O-C1-C3 alkyl, -C1-C3 alkylene-O-C1-C3 alkyl, -O-C1-C3 alkyl, NO2, -C(O)-saturated heterocyclyl, -CH2-saturated heterocyclyl, -O-saturated heterocyclyl, O-cycloalkyl, or -O-aryl. 0-1 -aryl; -CH2-O-heteroaryl, -C(O)-NH-(C1-C3 alkyl); -C(O)-N(C1-C3 alkyl)2; C2-C3 alkenylene =NO-(C1-C3 alkyl) optionally substituted with C3-C6 cycloalkyl; or two substituents on Q taken together form a 5-7 membered monocyclic or 6-12 membered bicyclic ring optionally substituted with one or more independently selected halo, ═O, —CN, C1-C3 alkyl, or —O—C1-C3 alkyl, and fused to Q; " ** " represents the portion where Q is attached to the Z ring.

[0021] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] is.

[0022] In some embodiments, Q is chloro, fluoro, -CN, -CH3, -CF3, -CHF2, -CH2CH3, -CH2-CN, -(CH2)2-CN, -OCH3, -CH2-O-CH3, -(CH2)2-O-CH3, -CH2-O-CH2-CN, -CH(CN)-CH3, -C(O)-N(CH3)2, -C(O)-NH-CH3, -C(O)-CH3, -S(O)2CH3, -C( CH3)=NO-CH(CH3)2, -C(CH3)=NO-CH3, -C≡C-CH3, -C≡CH, -CH=CH-CN, -CH2-O-CH2-C≡CH, -C(CH3)(CN)CH2CN, -CH2-OC(O)-N(CH3)2, 1-(cyclopentyl)-1-cyanoethan-1-yl, 1-(tetrahydrofuran-3-yl)-1-cyanoethan-1-yl, 1-(tetrahydropyran-3-yl)-1-cyanoethan-1-yl, (1-methylpyrazol-4-yl)-1-cyanoethan-1-yl, 1,3-dimethoxy-2-cyanopropan-2-yl, 1,4-dimethylpyrazol-5-yl, 1-cyanocyclobutyl, 1-cyanocyclopropyl, 1-cyanocyclopentyl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 1-methylpiperidin-4-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-5-yl, (1-methylpyrazol-4-yl)cyanomethyl, 1-oxoindolin-5-yl, 1-oxoisoindolin-4-yl, 1-oxoisoindolin-6-yl, 2-(2-methoxyethan-1-yl)phenyl, 3-(1,1-dioxothiomorpholin-1-ylmethyl)phenyl, 2-(tetrahydropyran-4-yloxy)phenyl, 2,2-difluoro-benzo[d][1,3]dioxol-4-yl, 2-chlorophenyl, 2-cyano-2-tetrahydrofuran-3-ylpropanyl, 2-cyano-3-chlorophenyl, 2-cyano-3-fluorophenyl, 2-cyano-3-methoxyphenyl, 2-cyano-4-fluorophenyl, 2-cyano-4-chlorophenyl, 2-cyano-4-methoxybutan-2-yl, 2-cyano-5-chlorophenyl, 2-cyano-5-fluorophenyl, 2-cyano-5-methoxyphenyl, 2-cyano-5 -(methoxymethyl)phenyl, 2-cyano-6-chlorophenyl, 2-cyano-6-fluorophenyl, 2-cyano-6-bromophenyl, 2-cyano-6-(methoxymethyl)phenyl, 2-cyano-6-(tetrahydropyran-4-yloxy)phenyl, 2-cyanomethylphenyl, 2-cyanophenyl, 2-cyanopropan-2-yl, 2-cyclopentylphenyl, 2-difluoromethoxyphenyl, 2-fluorophenyl, 2-methoxy-6-cyanophenyl, 2-methoxyphenyl, 2-methoxycarbonylphenyl, 2-(methoxymethyl)phenyl, 2-nitrophenyl, 2-oxopyrrolidin-1-yl, 2-phenoxyphenyl, 3-(2-methoxyethan-1-yl)phenyl, 3-methoxycarbonylphenyl, 3,5-difluoro-4-(pyrrolidin-1-ylcarbonyl)phenyl, 3-cyano-2-methylpropan-2-yl, 3-cyanomethylphenyl, 3-cyanopentan-3-yl, 3-cyanophenyl, 3-hydroxy-2-methylbutan-2-yl, 3-hydroxy-3-methyl-but-1-yn-1-yl, 3-methoxy-2-methylbutan-2-yl, 3-methoxyphenyl, 3-methoxymethyl-5-methylisoxazol-4-yl, 3-oxo-2-methylbutan-2-yl, 3-(tetrahydropyran-4-yl)-2-cyanopropan-2-yl, 4-cyanophenyl, 4-cyanotetrahydropyran-4-yl, 4-methoxyphenyl, benzo[d][1,3]dioxol-4-yl, benzo[d]oxazol-7-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-7-yl, cyclobutyl, cyclopropyl, cyclopropylcyanomethyl, morpholin-4-ylmethyl, N-methoxycyclopropanecarbimidoyl, phenyl, pyrazol-1-ylmethyl, pyridin-2-yl, pyridin-2-ylmethyl, pyridin-2-yloxymethyl, pyridin optionally further substituted by 1 to 4 substituents independently selected from tetrahydrofuran-3-yl, pyridin-3-yl-ethynyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, pyridin-4-yl-ethynyl, tetrahydrofuran-3-ylmethyl, tetrahydrofuran-3-ylcyanomethyl, tetrahydropyridin-4-yl, tetrahydropyran-4-ylmethyl, 2-(tetrahydropyran-4-yl)ethan-1-yl, tetrahydropyran-4-ylcyanomethyl, or tetrahydropyran-4-yl; or two substituents attached to the same carbon atom taken together form =O, 2,3-dihydrobenzofuran-3,3-diyl, 2,3-dihydrofuro[2,3-b]pyridine-3,3-diyl, tetrahydropyran-3,3-diyl, 6,7-dihydro-5H-cyclopenta[c]pyridine-6,6-diyl, or tetrahydropyran-4,4-diyl; or Two substituents attached to adjacent carbon atoms together form 4-cyanobenzene-1,2-diyl, 3-cyanobenzene-1,2-diyl, 5-methyl-5-cyanotetrahydropyran-3,4-diyl, 3-cyanocyclohexane-1,2-diyl, 3-methoxybenzene-1,2-diyl, benzene-1,2-diyl, 3-oxocyclohexyl-1,2-diyl, 3-cyanocyclopentane-1,2-diyl, or pyridine-3,4-diyl.

[0023] In some embodiments, Q is [ka] is selected from the group consisting of During the ceremony: V1, V2, V3, and V4 are each independently CH, N, C(F), C(CH3), C(OH), C(OCH3), or C(CN); V5, V6, and V7 are each independently C(R 17a )(R 17b ) or C(=O), and R 17a and R 17b are each independently selected from hydrogen, halo, —C1-C3 alkyl, —C1-C3 haloalkyl, —O—C1-C3 alkyl, —O—C1-C3 haloalkyl; and no more than two of V5, V6, and V7 are C(═O); R NQ1 is hydrogen, optionally substituted -S(O)2-R Q11 , -C(O)-R Q11 , -S(O)2-N(R Q11 )R Q12 , -C(O)-N(R Q11 )R Q12 , C1-C 10 Alkyl, C3-C 10 cycloalkyl, 4- to 14-membered heterocyclyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; Each R Q2 are independently hydrogen, CN, optionally substituted -S(O)-R Q11 , -C(O)-R Q11 , -S(O)2-N(R Q11 )R Q12 , -C(O)-N(R Q11 )R Q12 , C1-C 10 Alkyl, C3-C 10 cycloalkyl, 4- to 14-membered heterocyclyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; or R NQ1 and one R Q2taken together with the atoms to which they are attached form an optionally substituted 4- to 8-membered ring, and R NQ1 and one R Q2 The ring formed by combining these is optionally further fused with a 5- to 6-membered ring, Each R Q3 are independently hydrogen, CN, optionally substituted -S(O)-R Q11 , -C(O)-R Q11 , -S(O)2-N(R Q11 )R Q12 , -C(O)-N(R Q11 )R Q12 , C1-C 10 Alkyl, C3-C 10 cycloalkyl, 4- to 14-membered heterocyclyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; or Two Rs bonded to the same atom Q3 together form =CH, =O, =S, or =NR V4 Forming, or Two Rs bonded to the same atom Q3 taken together with the atoms to which they are attached form an optionally substituted 4- to 8-membered ring, and each R Q3 The ring formed by joining together is optionally further fused with a 5- to 6-membered ring, or R NQ1 and one R Q3 taken together with the atoms to which they are attached form an optionally substituted 4- to 8-membered ring, and R NQ1 and R Q3 The ring formed by combining these is optionally further fused with a 5- to 6-membered ring, R Q11 and R Q12 are each independently C1-C 10 Alkyl, C3-C 10 cycloalkyl, 4- to 14-membered heterocyclyl, aryl, or heteroaryl; R Q11 and R Q12 are each optionally replaced by, or R Q11 and R Q12 taken together with the atoms to which they are attached form an optionally substituted 4- to 8-membered ring, and R Q11 and R Q12 The ring formed by joining together is optionally further fused to another 5- or 6-membered ring, " ** " represents the portion where Q is attached to the Z ring.

[0024] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] is.

[0025] In some embodiments, Q is [ka] In some embodiments, Q is selected from the group consisting of: [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] is.

[0026] In some embodiments, the compound has the formula (Id): [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0027] In some embodiments, the compound has formula (Ie): [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0028] In some embodiments, the compound has the formula (Ig): [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, and Q a is a 4- to 9-membered saturated heterocyclyl.

[0029] In some embodiments, the compound has the formula (Ij): [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, and Q ais a 4- to 9-membered saturated heterocyclyl.

[0030] In some embodiments, the compound has the formula (Ik): [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, and Q a is a 4- to 9-membered saturated heterocyclyl.

[0031] In some embodiments, the compound has the formula (Ik'): [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, and Q a is a 4- to 9-membered saturated heterocyclyl.

[0032] In some embodiments, R 9 is absent, and ring A is a 4- to 8-membered heterocyclyl, or R 11 is -N(C-C alkylene-H)- or -N(C(O)-(C-C alkylene-H)-, and R 11 is optionally substituted with one or more substituents independently selected from halo, -CN, -OH, -C1-C3 alkyl, and -O-C1-C3 alkyl.

[0033] In some embodiments, W is —N(R 12 )- and R 13 is =O.

[0034] In some embodiments, the compound has the formula (IL): [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, and R 18 is Br or Cl.

[0035] In some embodiments, the compound has the formula (Im): [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, and R 14 is H.

[0036] In some embodiments, Q is [ka] is selected from the group consisting of During the ceremony: "1" indicates the moiety where Q is attached to X, and Q is optionally further substituted. In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] is.

[0037] In some embodiments, Q is [ka] is selected from the group consisting of During the ceremony: R is -CH2CH3, -CH2CH-OCH3, -CH2CHF2, -CH2-CN, CH2(CH3)2-CN, -C(CH3)2-CH2CN, -CH2CH2-CN, cyclohexyl, cyclobutyl, cyclopropyl, pyridin-4-yl, tetrahydropyran-4-yl, tetrahydropyran-4-ylmethyl, oxetan-3-ylmethyl, 2-cyano-5-methoxyphenyl, 2-cyano-5-methoxymethylphenyl, 2-cyano-6-(methoxymethyl)phenyl, 2-cyano-6-bromophenyl, 2-methoxyethan-1-yl, 2-cyanopropan-2-yl, 2-tetrahydropyran-4-ylethan-1-yl, 3-cyanopentan-3-yl, 2-cyano-4-methoxybutan-2-yl, or R is [ka] and R 23 is hydrogen or fluoro, R 24is hydrogen, chloro, -CN, -CH3, -CH2CH3, -CHF2, -CF3, -CH2-CN, -CH(CN)-CH3, -C(CH3)2-CN, -C(CH2CH3 )2-CN, -CH2-CH2-CN, -C(CH3)=NO-CH(CH3)2, -C(CH3)=NO-CH3, -C(O)-N(CH3)2, -C(O)-NH-CH 3, -OCH3, -CH2-O-CH3, -C≡CH, -C≡C-CH3, -S(O)2CH3, 1-(cyclopentyl)-1-cyanoethan-1-yl, 1-(tetrahydropyran-4-yl)-1-cyanoethan-1-yl, 1-(tetrahydrofuran-3-yl)-1-cyanoethan-1-yl, 1,3-dimethoxy-2-cyanopropane-2 -yl, 1,4-dimethylpyrazol-5-yl, 1-cyanocyclobutyl, 1-cyanocyclopropyl, 1-cyanocyclopentyl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-ylcyanomethyl, 1-methylpiperidin-4-yl, 1-methylpyrazol-5-yl, 1-oxoindolin-5-yl, 1-oxoisoindolin-4-yl, 1-oxoisoindolin-6-yl, 2-(2-methoxyethan-1-yl)phenyl, 2-(methoxymethyl)phenyl, 2-(tetrahydropyran-4-yloxy)phenyl, 2,2-difluoro-benzo[d][1,3]dioxol-4-yl, 2,3-dicyanopropan-2-yl, 2-chlorophenyl, 2-cyano-3-(tetrahydropyran-4-yl)propan-2-yl, 2-cyano-3-chlorophenyl, 2-cyano-3-fluorophenyl, 2-cyano-3-methoxyphenyl, 2-cyano-4-fluorophenyl, 2-cyano-4-chlorophenyl, 2-cyano-5-chlorophenyl, 2-cyano-5-fluorophenyl, 2-cyano-5-methoxyphenyl, 2-cyano-6-chlorophenyl, 2-cyano-6-fluorophenyl, 2-cyano-6-(tetrahydropyran-4-yloxy)phenyl, 2-cyanomethylphenyl, 2-cyanophenyl, 2-cyanopropan-2-yl, 2-cyclopentylphenyl, 2-difluoromethoxyphenyl, 2-fluorophenyl, 2-methoxy-6-cyanophenyl, 2-methoxyphenyl, 2-methoxycarbonylphenyl, 2-Nitrophenyl, 2-oxopyrrolidin-1-yl, 2-phenoxyphenyl, 3-(1,1-dioxothiomorpholin-4-ylmethyl)phenyl, 3-(2-methoxyethan-1-yl)phenyl, 3,5-difluoro-4-(pyrrolidin-1-ylcarbonyl)phenyl, 3-cyano-2-methylpropan-2-yl, 3-cyanomethylphenyl, 3-cyanopentan-3-yl, 3-cyanophenyl, 3-hydro oxy-2-methylbutan-2-yl, 3-hydroxy-3-methyl-but-1-yn-1-yl, 3-methoxy-2-methylbutan-2-yl, 3-methoxymethyl-5-methylisoxazol-4-yl, 3-methoxyphenyl, 3-methoxycarbonylphenyl, 3-oxo-2-methylbutan-2-yl, 4-cyanophenyl, 4-cyanotetrahydropyran-4-yl, 4-methoxyphenyl, benzo[d][1,3]dioxol-4-yl, benzo[d]oxazol-7-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-7-yl, cyclobutyl, cyclopropyl, cyclopropylcyanomethyl, N-methoxycyclopropanecarbimidoyl, phenyl, pyridin-2-ylmethyl, pyridin-3-yl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, tetrahydrofuran-3-ylmethyl, tetrahydrofuran-3-ylcyanomethyl, tetrahydropyran-4-yl, or tetrahydropyran-4-ylcyanomethyl, R 27 is hydrogen, -CH3, -CHF2, -CH2CH3, -CH2-O-CH3, -CH2CN, -CN, -CH2-O-CH2-CN, -C(O)-N(CH3)2, -C(O)-NH-CH3, -CH2-O-CH2-C≡CH, 2-methoxyphenyl, 3-methoxyphenyl, 2,2-difluorobenzo[d][1,3]dioxol-4-yl, 2-cyanophenyl, 3-cyanophenyl, phenyl, 2-benzylmethyl ether, 2-(2-methoxyethyl)benzene, 2-(2-difluoromethoxyethyl)benzene, 2-(2-dimethylmethoxyethyl)benzene, pyridin-3-yl, pyridin-2-yl, pyridin-3-ylmethyl, or tetrahydropyridin-4-yl; R 24 and R 27 together to form 4-cyanobenzene-1,2-diyl, 3-cyanobenzene-1,2-diyl, 5-methyl-5-cyanotetrahydropyran-3,4-diyl, 3-cyanocyclohexane-1,2-diyl, 3-methoxybenzene-1,2-diyl, benzene-1,2-diyl, 3-oxocyclohexyl-1,2-diyl, 3-cyanocyclopentane-1,2-diyl, or pyridine-3,4-diyl, R 28 is hydrogen, -CH3, or -CH2-O-CH3, R29 is hydrogen, acetyl, CN, -CH2-CN, -CH2-CH2-CN, -CH2-O-CH3, -CH=CH-CN, -CH2-OC(O)-N(CH3)2, morpholin-4-ylmethyl, pyrazol-1-ylmethyl, pyridin-3-yl, pyridin-3-ylethynyl, pyridin-2-yloxymethyl, or 2-cyanopropan-2-yl, or R 28 and R 29 taken together form 2,3-dihydrobenzofuran-3,3-diyl, 2,3-dihydrofuro[2,3-b]pyridine-3,3-diyl, tetrahydropyran-3,3-diyl, 6,7-dihydro-5H-cyclopenta[c]pyridin-6-yl, tetrahydropyran-4,4-diyl, or 4-methoxycyclohexane. [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] is.

[0038] In some embodiments, R 1 is -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -CH(CH3)CH2CH3, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxybenzyl, or tetrahydropyran-4-yl.

[0039] In some embodiments, R 9 is absent and the A ring is a nitrogen-containing saturated heterocyclyl.

[0040] In some embodiments, R 2 Among them, [ka] The part represented by [ka] and R 2 Each ring system in is optionally substituted with up to four substituents independently selected from fluoro; chloro; -CN; -OH; -NH; -C1-C3 alkyl optionally substituted with CN, OH, NH2, or -O-C1-C3 alkyl; -O-C1-C3 alkyl; and -NH-C1-C3 alkyl.

[0041] In some embodiments, R 2 Some of the [ka] In some embodiments, R 2 Some of the [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] is.

[0042] In some embodiments, R 2wherein the moiety represented by WH is -C(O)-C≡C-CH3, -C(O)-CH=CH2, -S(O)-CH=CH2, -C(O)-CH2Cl, -C(O)-CH(CH3)Cl, or -C(O)-CH(Cl)-CH2-O-CH3; or R 2 Among them, -R 11 The moiety represented by -WH is R 11 is one R 14 When combined with [ka] is.

[0043] In some embodiments, R 2are 1-(2-chloro-3-methoxypropanoyl)azetidin-3-yl-N-methylcarboxamide, 1-(2-chloroacetyl)azetidin-3-ylcarboxamide, 1-(2-chloroacetyl)azetidin-3-yl-N-ethylcarboxamide, 1-(2-chloroacetyl)azetidin-3-yl-N-methylcarboxamide, 1-(2-chloroacetyl)piperidin-3-yl-N-methylcarboxamide, 1-(2-chloroacetyl)piperidin-4-yl-N-methylcarboxamide, 1-(2-chloroacetyl)pyrrolidine-3- yl-N-methylcarboxamide, 1-(2-chloropropanoyl)-piperidin-4-yl-N-methylcarboxamide, 1-(2-chloropropanoyl)-3-fluoroazetidin-3-yl-N-methylcarboxamide, 1-(2-chloropropanoyl)azetidin-3-yl-N-methylcarboxamide, 1-(2-chloropropanoyl)pyrrolidin-3-yl-N-methylcarboxamide, 1-(2-chloropropanoyl)pyrrolidin-3-yl-N-methylcarboxamide, 1-(but-2-ynoyl)-4-fluoropiperidin-4-ylcarbonylmethylamino, 1-(but-2-ynoyl)azetidin-2-yl-N- Methylcarboxamide, 1-(but-2-ynoyl)azetidin-3-yl-N-methylcarboxamide, 1-(but-2-ynoyl)-piperidin-3-ylcarbonylmethylamino, 1-(but-2-ynoyl)-piperidin-4-ylcarbonylmethylamino, 1-(but-2-ynoyl)pyrrolidin-2-ylcarbonyl-N-methylamino, 1-(but-2-ynoyl)pyrrolidin-3-ylcarbonyl-N-methylamino, 1-acryloyl-2-oxo-imidazolidin-3-yl, 1-acryloyl-3-fluoroazetidin-3-yl 1-acryloyl-N-methylcarboxamide, 1-acryloyl-3-fluoropyrrolidin-3-yl-N-methylcarboxamide, 1-acryloyl-4-fluoropiperidin-4-ylcarbonylmethylamino, 1-acryloylazetidin-2-yl-N-methylcarboxamide, 1-acryloylazetidin-3-yl-N-methylcarboxamide, 1-acryloyl-piperidin-3-ylcarbonylmethylamino, 1-acryloyl-piperidin-4-ylcarbonylmethylamino, 1-acryloylpyrrolidin-2-yl-N-methylcarboxamide,1-Acryloylpyrrolidin-3-yl-N-methylcarboxamide, 1-oxo-7-(2-chloroacetyl)-2,7-diazaspiro[4.3]octan-2-yl, 1-oxo-7-(2-chloroacetyl)-2,7-diazaspiro[4.4]nonan-2-yl, 1-oxo-2-(2-chloroacetyl)-2,7-diazaspiro[4.5]decan-7-yl, 1-oxo-7-(2-chloroacetyl)-2,7-diazaspiro[4.5]decan-2-yl, 1-oxo-7-(2-chloropropanoyl)-2,7-diazaspiro[4.3]octan-2-yl ]octan-2-yl, 1-oxo-7-(but-2-ynoyl)-2,7-diazaspiro[4.4]nonan-2-yl, 1-oxo-7-acryloyl-2,7-diazaspiro[4.3]octan-2-yl, 1-oxo-7-acryloyl-2,7-diazaspiro[4.4]nonan-2-yl, 1-oxo-7-acryloyl-2,7-diazaspiro[4.5]decan-2-yl, 1-oxo-8-(2-chloroacetyl)-2,8-diazaspiro[4.5]decan-2-yl, 1-oxo-8-(but-2-ynoyl)-2,8-diazaspiro Pyrro[4.5]decan-2-yl, 1-oxo-8-acryloyl-2,8-diazaspiro[4.5]decan-2-yl, 1-vinylsulfonyl-2-oxoimidazolidin-3-yl, 1-vinylsulfonylazetidin-3-yl-N-methylcarboxamide, 2-(1-acryloylpiperidin-4-yl)-N-methylacetamide, 2-(but-2-ynoyl)-5-oxo-2,6-diazaspiro[3.4]octan-6-yl, 2,5-dioxo-3,4-dimethyl-2,5-dihydropyrrol-1-yl-N-methylacetamide , 2-acryloyl-2-azabicyclo[2.1.1]hexan-4-yl-N-methylcarboxamide, 2-chloroacetamidomethyl-N-methylcarboxamide, 2-oxo-2,5-dihydro-1H-pyrrol-1-yl-N-methylacetamide, 2-oxo-3-(2-chloroacetamido)pyrrolidin-1-yl, 2-oxo-3-(N-methyl-2-chloroacetamido)pyrrolidin-1-yl, 2-oxo-3-(N-methylacrylamide)pyrrolidin-1-yl, 2-oxo-3-acrylamidopyrrolidin-1-yl,2-oxo-4-(2-chloroacetyl)piperazin-1-yl, 2-oxo-4-acryloylpiperazin-1-yl, 2-oxo-4-vinylsulfonylpiperazin-1-yl, 2-oxocyclopent-3-en-1-yl-N-methylacetamide, 3-(4-(dimethylamino)but-2-enamido)phenyl-N-methylcarboxamide, 4-(butyl) 4-Acryloylpiperazin-1-yl-N-methylcarboxamide, 4-acryloylpiperazin-1-yl-N-methylcarboxamide, 6-oxo-2-(2-chloroacetyl)-2,7-diazaspiro[4.5]decan-7-yl, and 6-oxo-2-acryloyl-2,7-diazaspiro[4.5]decan-7-yl.

[0044] In some embodiments, R 4 is hydrogen, fluoro, or -CH3, and R 5 is hydrogen, fluoro, chloro, -OH, -CH3, -CH2CH3, -CH(CH3)2, -CH2OH, -CH2OCH3, -CH2F, -CHF2, CH2CN, -CH2-cyclopropyl, cyclopropyl, pyridyl, phenyl, or -CH2-phenyl; R 5 any phenyl moiety in R is optionally substituted with up to four substituents independently selected from halo, —CN, and —O—C1-C3 alkyl; 4 and R 5 taken together form =CH2 or cyclopropyl or cyclobutyl or cyclopentyl or cyclohexyl, or R 5 together with the carbon atom to which it is attached, the ring atoms of Q, and X form an oxazepane.

[0045] In some embodiments, R 7 is —OH, —NH, or —CHF. In some embodiments, R 7 is -OH.

[0046] In some embodiments, the compound has the structure of any of Compounds 1-418 or Compounds 1-461, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0047] In some aspects, the disclosure features a pharmaceutical composition including any compound of the invention, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0048] In one aspect, the disclosure features a complex including a presenter protein, a RAS protein, and any compound of the invention, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or any pharmaceutical composition comprising such a compound described herein.

[0049] In some embodiments, the RAS protein is KRAS. In some embodiments, the RAS protein is NRAS. In some embodiments, the RAS protein is HRAS. In some embodiments, the RAS protein is KRAS G12C. In some embodiments, the RAS protein is KRAS G13C. In some embodiments, the RAS protein is NRAS G12C. In some embodiments, the RAS protein is NRAS G13C. In some embodiments, the RAS protein is HRAS G12C. In some embodiments, the RAS protein is HRAS G13C.

[0050] In some embodiments, the presenter protein is cyclophilin. In some embodiments, the presenter protein is CYPA, CYPB, CYPC, CYP40, CYPE, CYPD, NKTR, SRCyp, CYPH, CWC27, CYPL1, CYP60, CYPJ, PPIL4, PPIL6, RANBP2, or PPWD1. In some embodiments, the presenter protein is CYPA.

[0051] In some aspects, the disclosure features a method for producing a complex, the method comprising contacting a presenter protein and a KRAS G12C protein with a compound of the invention under conditions suitable for complex formation. In some embodiments, the disclosure features a method for producing a complex, the method comprising contacting a presenter protein with a KRAS G13C protein, an NRAS G12C protein, an NRAS G13C protein, an HRAS G12C protein, or an HRAS G13C protein with a compound of the invention under conditions suitable for complex formation. In some embodiments, the presenter protein is a cyclophilin protein. In some embodiments, the presenter protein is PP1A, CYPA, CYPB, CYPC, CYP40, CYPE, CYPD, NKTR, SRCyp, CYPH, CWC27, CYPL1, CYP60, CYPJ, PPIL4, PPIL6, RANBP2, or PPWD1. In some embodiments, the presenter protein is CYPA.

[0052] In some aspects, the disclosure features a method for producing a complex, the method comprising contacting a presenter protein and a KRAS G12C protein with a compound of the invention capable of forming a complex with the presenter protein and the KRAS G12C protein under conditions suitable for allowing complex formation. In some aspects, the disclosure features a method for producing a complex, the method comprising contacting a presenter protein and a KRAS G13C protein, an NRAS G12C protein, an NRAS G13C protein, an HRAS G12C protein, or an HRAS G13C protein with the compound of the invention capable of forming a complex with the presenter protein and the RAS protein under conditions suitable for allowing complex formation. In some embodiments, the presenter protein is a cyclophilin protein. In some embodiments, the presenter protein is PP1A, CYPA, CYPB, CYPC, CYP40, CYPE, CYPD, NKTR, SRCyp, CYPH, CWC27, CYPL1, CYP60, CYPJ, PPIL4, PPIL6, RANBP2, or PPWD1. In some embodiments, the presenter protein is CYPA.

[0053] In some aspects, the disclosure features a method of treating cancer in a subject in need thereof, the method including administering to the subject an effective amount of a compound of the invention or any pharmaceutical composition including such a compound.

[0054] In some embodiments, the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, or small cell lung cancer.

[0055] In one aspect, the disclosure features a method for inhibiting KRAS G12C protein in a cell, the method comprising contacting the cell with an effective amount of a compound of the invention or any pharmaceutical composition comprising such a compound. In one aspect, the disclosure features a method for inhibiting KRAS G13C protein, NRAS G12C protein, NRAS G13C protein, HRAS G12C protein, or HRAS G13C protein in a cell, the method comprising contacting the cell with an effective amount of a compound of the invention or any pharmaceutical composition comprising such a compound. In some embodiments, the cell is a cancer cell.

[0056] In certain aspects, the disclosure features a method of treating a KRAS G12C protein-associated disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the invention or any pharmaceutical composition comprising such a compound. In certain aspects, the disclosure features a method of treating a KRAS G13C protein-associated disorder, an NRAS G12C protein-associated disorder, an NRAS G13C protein-associated disorder, an HRAS G12C protein-associated disorder, or an HRAS G13C protein-associated disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the invention or any pharmaceutical composition comprising such a compound.

[0057] In some embodiments, the cells are cancer cells. In some embodiments, the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, or small cell lung cancer. In some embodiments, the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, small cell lung cancer, acute myeloid leukemia, multiple myeloma, thyroid adenocarcinoma, myelodysplastic syndrome, or squamous cell lung carcinoma.

[0058] In one aspect, the disclosure features a method for inhibiting RAF-RAS binding in a cell, the method comprising contacting the cell with an effective amount of a compound of the invention or any pharmaceutical composition containing such a compound. In some embodiments, the cell is a cancer cell. In some embodiments, the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, or small cell lung cancer. In some embodiments, the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, small cell lung cancer, acute myeloid leukemia, multiple myeloma, thyroid adenocarcinoma, myelodysplastic syndrome, or squamous cell lung carcinoma.

[0059] In some aspects, the disclosure features the use of a compound of the invention, any pharmaceutical composition comprising such a compound, or any conjugate described herein, to treat cancer in a subject in need thereof.

[0060] In certain aspects, the disclosure features the use of any compound of the present invention, any pharmaceutical composition comprising such a compound, or any conjugate described herein, for treating a KRAS G12C protein-associated disorder in a subject in need thereof. In certain aspects, the disclosure features the use of a compound of the present invention, any pharmaceutical composition comprising such a compound, or any conjugate described herein, for treating a KRAS G13C protein-associated disorder, an NRAS G12C protein-associated disorder, an NRAS G13C protein-associated disorder, an HRAS G12C protein-associated disorder, or an HRAS G13C protein-associated disorder in a subject in need thereof.

[0061] In some embodiments, the method may further include administering an additional therapeutic agent (e.g., an anti-cancer agent). In some embodiments, the additional therapeutic agent is a HER2 inhibitor, an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, or a combination thereof.

[0062] In some embodiments, the additional therapeutic agent is an SHP2 inhibitor. SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene that contributes to multiple cellular functions, including proliferation, differentiation, cell cycle maintenance, and migration. SHP2 has two N-terminal Src homology 2 domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal tail. These two SH2 domains control the intracellular localization and functional regulation of SHP2. The molecule exists in an inactive, autoinhibited conformation stabilized by a binding network involving residues from both the N-SH2 and PTP domains. Upon stimulation (e.g., by cytokines or growth factors acting through receptor tyrosine kinases (RTKs)), SHP2 is enzymatically activated by exposure of the catalytic site.

[0063] SHP2 is involved in signal transduction through the RAS-mitogen-activated protein kinase (MAPK) pathway, the JAK-STAT pathway, or the phosphoinositol 3-kinase-AKT pathway. Mutations in the PTPN11 gene, resulting in SHP2 mutations, have been identified in several human developmental disorders (e.g., Noonan syndrome and Leopard syndrome) and human cancers (e.g., juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and cancers of the breast, lung, and colon). Some of these mutations destabilize the autoinhibitory conformation of SHP2, promoting its autoactivation or enhancing growth factor-stimulated activation of SHP2. Therefore, SHP2 is an attractive target for developing novel therapeutics to treat various diseases, including cancer. SHP2 inhibitors (e.g., RMC-4550 or SHP099) have been shown in vitro to suppress the growth of multiple cancer cell lines (e.g., pancreatic, lung, ovarian, and breast cancers) when combined with RAS pathway inhibitors (e.g., MEK inhibitors). Therefore, combination therapy using SHP2 inhibitors with RAS pathway inhibitors may be a general strategy for preventing tumor resistance in a wide range of malignancies.

[0064] Examples of such SHP2 inhibitors known in the art include, but are not limited to, those described in Chen et al. Mol Pharmacol. 2006, 70, 562, Sarver et al., J. Med. Chem. 2017, 62, 1793, Xie et al., J. Med. Chem. 2017, 60, 113734, and Igbe et al. al., Oncotarget, 2017, 8, 113734, and PCT applications WO2015107493, WO2015107494, WO201507495, WO2016203404, WO2016203405, WO2016203406, WO2011022440, WO2017156397, and WO2017079723 , WO2017211303, WO2012041524, WO2017211303, WO2019051084, WO2017211303, US2016003 0594, US20110281942, WO2010011666, WO2014113584, WO2014176488, WO2017100279, WO20 19051469, US8637684, WO2007117699, WO2015003094, WO2005094314, WO2008124815, WO20 09049098, WO2009135000, WO2016191328, WO2016196591, WO2017078499, WO2017210134, W WO2018013597, WO2018129402, WO2018130928, WO20181309928, WO2018136264, WO2018136265, WO2018160731, WO2018172984, and WO2010121212, each of which is incorporated herein by reference.

[0065] In some embodiments, the SHP2 inhibitor binds to the active site. In some embodiments, the SHP2 inhibitor is a mixed, irreversible inhibitor. In some embodiments, the SHP2 inhibitor binds to an allosteric site, e.g., a non-covalent allosteric inhibitor. In some embodiments, the SHP2 inhibitor is a covalent SHP2 inhibitor (such as an inhibitor that targets a cysteine residue (C333) located outside the active site of the phosphatase). In some embodiments, the SHP2 inhibitor is a reversible inhibitor. In some embodiments, the SHP2 inhibitor is an irreversible inhibitor. In some embodiments, the SHP2 inhibitor is SHP099. In some embodiments, the SHP2 inhibitor is TNO155. In some embodiments, the SHP2 inhibitor is RMC-4550. In some embodiments, the SHP2 inhibitor is RCM-4630. In some embodiments, the SHP2 inhibitor is JAB-3068.

[0066] chemical terms It will be understood by those of skill in the art that certain compounds described herein can exist in one or more different isomeric (e.g., stereoisomers, geometric isomers, tautomers) and / or isotopic forms (e.g., in which one or more atoms are replaced by a different isotope of that atom, such as hydrogen replaced by deuterium). Unless otherwise specified or apparent from context, the depicted structures can be understood to represent any such isomeric or isotopic forms individually or in combination.

[0067] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). Unless otherwise specified, all stereoisomers (such as enantiomers and diastereomers) are intended. Compounds of the present disclosure containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods are known in the art on how to prepare optically active forms from optically active starting materials, such as by resolving racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in this disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and can be isolated as a mixture of isomers or as separated isomeric forms.

[0068] In some embodiments, one or more of the compounds presented herein may exist in different tautomeric forms. Unless explicitly excluded, as will be clear from the context, reference to such a compound encompasses all such tautomeric forms. In some embodiments, a tautomeric form results from the interchange of a single bond with an adjacent double bond, accompanied by the displacement of a proton. In certain embodiments, a tautomeric form may be a prototropic tautomer, which is an isomeric protonation state having the same empirical formula and total charge as the referenced form. Examples of moieties with prototropic tautomeric forms are ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position in a heterocyclic system (such as 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole). In some embodiments, tautomeric forms are in equilibrium or can be sterically locked into one form by appropriate substitution. In certain embodiments, tautomeric forms arise as a result of acetal interconversion (e.g., the interconversions shown in the following scheme). [ka]

[0069] Those skilled in the art will understand that in some embodiments, compounds described herein that contain isotopes can be prepared and / or utilized in accordance with the present invention. "Isotopes" refer to atoms having the same atomic number but different mass numbers due to different numbers of neutrons in their nuclei. For example, isotopes of hydrogen include tritium and deuterium. In some embodiments, isotopic substitution (e.g., replacement of hydrogen with deuterium) can alter the physicochemical properties of a molecule, such as metabolism, distribution of metabolites, and / or racemization rate of a chiral center.

[0070] As is known in the art, many chemical entities (e.g., many organic molecules and / or many small molecules) can exist in a variety of different solid forms, such as amorphous forms and / or crystalline forms (e.g., polymorphs, hydrates, solvates, etc.). In some embodiments, such entities can be utilized in any form, including any solid form. In some embodiments, such entities are utilized in a particular form (e.g., a particular solid form).

[0071] In some embodiments, the compounds described and / or illustrated herein may be provided and / or utilized in salt form.

[0072] In certain embodiments, the compounds described and / or illustrated herein may be provided and / or utilized in the form of a hydrate or solvate.

[0073] The term "compound(s) of the invention" or the like is intended to encompass salt (e.g., pharmaceutically acceptable salt) forms, hydrate forms, and solvate forms of such compounds, as well as enantiomers, stereoisomers, or tautomers thereof. In some embodiments, "compound(s) of the invention" or the like may refer to the compound and its pharmaceutically acceptable salts. Examples of compounds of the invention include, but are not limited to, those depicted in Figure 1.

[0074] Substituents for compounds of the present disclosure are disclosed in groups or ranges at various points herein. It is expressly intended that the present disclosure include any and all individual subcombinations of the members of such groups and ranges. For example, the term "C1-C6 alkyl" is expressly intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. Furthermore, when a compound includes more than one position where a substituent is disclosed in a group or range, unless otherwise specified, the present disclosure is intended to cover each individual compound as well as groups of compounds (e.g., general formulas and subgeneric formulas) including any and all individual subcombinations of the members at each position.

[0075] As used herein, phrases of the form "optionally substituted X" (e.g., optionally substituted alkyl) are intended to be equivalent to "X, X is optionally substituted" (e.g., "alkyl, the alkyl is optionally substituted"). It is not intended to imply that the feature "X" (e.g., alkyl) itself is optional. As described herein, certain target compounds may contain one or more "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more of the hydrogens of the specified moiety has been replaced with a suitable substituent (e.g., any of the substituents or groups described herein). Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when multiple positions in any given structure may be substituted with multiple substituents selected from a particular group, the substituents may be the same or different at every position. Combinations of substituents contemplated by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that is substantially unchanged when subjected to conditions that allow for its production, detection, and, in certain embodiments, recovery, purification, and use for one or more of the purposes disclosed herein.

[0076] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are, independently, deuterium, halogen, -(CH) 0-4 R ○ , -(CH2) 0-4 OR ○ , -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR°, -(CH2) 0-4 CH(OR ○ )2, -(CH2) 0-4 SR ○ , -(CH2) 0-4 Ph (which may be substituted with R°), —(CH2) 0-4 O(CH2) 0-1Ph (which may be substituted with R°), -CH=CHPh (which may be substituted with R°), -(CH2) 0-4 O(CH2) 0-1 -pyridyl (which may be substituted by R°), 4-8 membered saturated or unsaturated heterocyclyl (e.g., pyridyl), 3-8 membered saturated or unsaturated cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl), -NO2, -CN, -N3, -(CH2) 0-4 N(R ○ )2, -(CH2) 0-4 N(R ○ )C(O)R ○ , -N(R ○ )C(S)R ○ , -(CH2) 0-4 N(R ○ )C(O)NR ○ 2, -N(R ○ )C(S)NR ○ 2, -(CH2) 0-4 N(R ○ )C(O)OR ○ , -N(R ○ )N(R ○ )C(O)R ○ , -N(R ○ )N(R ○ )C(O)NR ○ 2, -N(R ○ )N(R ○ )C(O)OR ○ , -(CH2) 0-4 C(O)R ○ , -C(S)R ○ , -(CH2) 0-4 C(O)OR ○ , -(CH2) 0-4 -C(O)-N(R o )2, -(CH2) 0-4 -C(O)-N(R o )-S(O)2-R o , -C(NCN)NR°2, -(CH2) 0-4 C(O)SR ○ , -(CH2) 0-4 C(O)OSiR ○ 3. -(CH2) 0-4 OC(O)R ○ , -OC(O)(CH2) 0-4 SR○ , -SC(S)SR°, -(CH2) 0-4 SC(O)R ○ , -(CH2) 0-4 C(O)NR ○ 2. -C(S)NR ○ 2, -C(S)SR°, -(CH2) 0-4 OC(O)NR ○ 2. -C(O)N(OR ○ )R ○ , -C(O)C(O)R ○ , -C(O)CHC(O)R ○ , -C(NOR ○ )R ○ , -(CH2) 0-4 SSR ○ , -(CH2) 0-4 S(O)2R ○ , -(CH2) 0-4 S(O)2OR ○ , -(CH2) 0-4 OS(O)2R ○ , -S(O)NR ○ 2, -(CH2) 0-4 S(O)R ○ , -N(R ○ )S(O)NR ○ 2, -N(R ○ )S(O)2R ○ , -N(OR ○ )R ○ , -C(NOR°)NR°2, -C(NH)NR ○ 2. -P(O)2R ○ , -P(O)R ○ 2, -P(O)(OR°)2, -OP(O)R ○ 2. -OP(O)(OR ○ )2, -OP(O)(OR°)R°, -SiR ○ 3, -(C 1-4 Straight chain alkylene or C 1-4 Branched alkylene)ON(R ○ )2, or -(C 1-4 Straight chain alkylene or C 1-4 Branched alkylene)C(O)ON(R ○ )2, and each R ○ may be substituted as defined below, and each R ○are independently hydrogen, -C1-6 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (5-6 membered heteroaryl ring), or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definition, two independently occurring R ○ taken together with their intervening atom(s) form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which can be substituted as defined below.

[0077] R ○ an appropriate monovalent substituent (or two independently occurring R ○ Suitable monovalent substituents for the ring formed by -(CH2) taken together with their intervening atoms are independently halogen, -(CH2) 0-2 R · ,-(Halo R · ), -(CH2) 0-2 OH, -(CH2) 0-2 OR · , -(CH2) 0-2 CH(OR · )2, -O(HaloR · ), -CN, -N3, -(CH2) 0-2 C(O)R · , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR · , -(CH2) 0-2 SR · , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR · , -(CH2) 0-2 NR · 2, -NO2, -SiR · 3. -OSiR · 3. -C(O)SR · , -(C 1-4 Straight chain alkylene or C 1-4Branched alkylene)C(O)OR · , or -SSR · where each R · is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and each R · is C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 R is independently selected from Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. ○ Suitable divalent substituents for a saturated carbon atom of include ═O and ═S.

[0078] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include ═O, ═S, ═NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 Each R contains S- and exists independently * is hydrogen, C 1-6 aliphatic (which may be substituted as defined below), or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to adjacent substitutable carbons of an "optionally substituted" group include -O(CR * 2) 2-3 Each R, including O-, is present independently * is hydrogen, C 1-6 aliphatic (which may be substituted as defined below), or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0079] R* Suitable substituents for the aliphatic group include halogen, -R · ,-(Halo R · ), -OH, -OR · , -O(HaloR · ), -CN, -C(O)OH, -C(O)OR · , -NH2, -NHR · , -NR · 2, or -NO2, and each R · is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and each R · independently C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0080] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † Each R † are independently hydrogen, C aliphatic (which may be substituted as defined below), unsubstituted -OPh, or an unsubstituted 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definition, two independently occurring R †taken together with their intervening atom(s) form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0081] R † Suitable substituents for the aliphatic group are independently halogen, -R · ,-(Halo R · ), -OH, -OR · , -O(HaloR · ), -CN, -C(O)OH, -C(O)OR · , -NH2, -NHR · , -NR · 2, or -NO2, and each R · is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and each R · independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. † Suitable divalent substituents for a saturated carbon atom of include ═O and ═S.

[0082] The term "alkyl," as used herein, refers to a saturated hydrocarbon group containing 1 to 20 (e.g., 1 to 10 or 1 to 6) carbons. In some embodiments, an alkyl group is unbranched (i.e., straight-chain). In some embodiments, an alkyl group is branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl and iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl, and neopentyl.

[0083] The term "alkylene," as used herein, refers to a divalent saturated hydrocarbon group obtained by removing two hydrogen atoms from a straight- or branched-chain saturated hydrocarbon, and is exemplified by methylene, ethylene, isopropylene, and the like. x -C y The term "alkylene" refers to an alkylene group having x to y carbons. Examples of values of x are 1, 2, 3, 4, 5, and 6, and examples of values of y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C-C alkylene, C-C 10 Alkylene, C2-C 20 Alkylene, C2-C6 alkylene, C2-C 10 Alkylene, or C2-C 20 In some embodiments, the alkylene can be further substituted with 1, 2, 3, or 4 substituents as defined herein for an alkyl group.

[0084] The term "alkenyl," as used herein, refers to a straight- or branched-chain monovalent group (containing 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) unless otherwise specified) containing one or more carbon-carbon double bonds, and is exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. Alkenyl includes both cis and trans isomers. The term "alkenylene," as used herein, refers to a straight- or branched-chain divalent group (containing 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) unless otherwise specified) containing one or more carbon-carbon double bonds.

[0085] The term "alkynyl," as used herein, refers to a straight- or branched-chain monovalent group containing 2 to 20 carbon atoms (e.g., 2 to 4, 2 to 6, or 2 to 10 carbons) containing a carbon-carbon triple bond and is exemplified by ethynyl, 1-propynyl, and the like.

[0086] As used herein, the term "amino" refers to -N(R † )2.

[0087] As used herein, the term "amino acid" refers to a molecule having a side chain, an amino group, and an acidic group (e.g., a carboxy group (-COH) or a sulfo group (-SOH)), where the amino acid is attached to the parent molecular group by the side chain, the amino group, or the acidic group (e.g., the side chain). As used herein, the term "amino acid" in its broadest sense refers to any compound and / or substance that can be incorporated into a polypeptide chain, where this incorporation occurs, for example, through the formation of one or more peptide bonds. In some embodiments, an amino acid has the general structure HN-C(H)(R)-COOH. In some embodiments, an amino acid is a naturally occurring amino acid. In some embodiments, an amino acid is a synthetic amino acid. In some embodiments, an amino acid is a D-amino acid. In some embodiments, an amino acid is an L-amino acid. A "standard amino acid" refers to any of the 20 standard L-amino acids commonly found in naturally occurring peptides. A "non-standard amino acid" refers to any amino acid other than the standard amino acids, whether it is synthetically prepared or obtained from a natural source. In some embodiments, amino acids, including the carboxy-terminal and / or amino-terminal amino acids in a polypeptide, may contain structural modifications compared to the general structure described above. For example, in some embodiments, amino acids may be modified by methylation, amidation, acetylation, and / or substitution compared to the general structure. In some embodiments, such modifications may, for example, alter the circulating half-life of a polypeptide containing such modified amino acids compared to one containing the otherwise identical unmodified amino acid. In some embodiments, such modifications do not significantly alter the relative activity of a polypeptide containing such modified amino acids compared to one containing the otherwise identical unmodified amino acid. As will be clear from the context, in some embodiments, the term "amino acid" is used to refer to a free amino acid, and in some embodiments, to an amino acid residue of a polypeptide. In some embodiments, an amino acid is attached to a parent molecular group by linking a side chain or amino group to a carbonyl group.In some embodiments, the amino acid is an α-amino acid. In certain embodiments, the amino acid is a β-amino acid. In some embodiments, the amino acid is a γ-amino acid. Exemplary side chains include optionally substituted alkyl, aryl, heterocyclyl, alkaryl, alkheterocyclyl, aminoalkyl, carbamoylalkyl, and carboxyalkyl. Exemplary amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, optionally substituted hydroxylnorvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.

[0088] The term "aryl," as used herein, represents a monovalent monocyclic, bicyclic, or polycyclic ring system formed by carbon atoms, wherein each ring is aromatic. Examples of aryl groups are phenyl, naphthyl, phenanthrenyl, and anthracenyl. An aryl ring can be attached to its pendant group at any heteroatom or carbon ring atom that results in a stable structure, and any ring atom can be optionally substituted unless otherwise specified.

[0089] As used herein, the term "C" represents a bond. For example, part of the term -N(C(O)-(C-C alkylene-H)- includes -N(C(O)-(C alkylene-H)-, which is also represented by -N(C(O)-H)-.

[0090] As used herein, the terms "carbocyclic" and "carbocyclyl" refer to an optionally substituted monovalent C-C 12 Monocyclic ring structure, C3-C 12 Bicyclic ring structure, or C3-C 12"Carbocyclyl" refers to a tricyclic ring structure in which all rings are formed by carbon atoms and at least one ring is non-aromatic. Carbocyclic structures include cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Examples of carbocyclyl groups include cyclohexyl, cyclohexenyl, cyclooctynyl, 1,2-dihydronaphthyl (e.g., [ka] ), 1,2,3,4-tetrahydronaphthyl (e.g., [ka] ), fluorenyl (e.g., [ka] ), indenyl (e.g., [ka] ), indanyl (e.g., [ka] ), decalinyl, and the like. A carbocyclic ring can be attached to its pendant group at any heteroatom or carbon ring atom that results in a stable structure, and any ring atom can be optionally substituted unless otherwise specified.

[0091] The term "carbonyl" as used herein refers to a C(O) group, which may also be represented as C=O.

[0092] The term "carboxy" as used herein means -CO2H or the unprotonated counterpart.

[0093] As used herein, the term "cyano" refers to a -CN group.

[0094] The term "cycloalkyl," as used herein, refers to a monovalent cyclic saturated hydrocarbon group (containing 3 to 8 carbons, unless otherwise specified) and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicycloheptyl, and the like.

[0095] The term "diyl" when used in the name of a compound refers to a divalent radical.

[0096] As used herein, the term "diastereomers" means stereoisomers that are not mirror images of one another and are not superimposable with respect to one another.

[0097] As used herein, the term "enantiomer" refers to each individual optically active form of a compound of the invention, which form has an optical purity or enantiomeric excess (as determined by standard methods in the art) of at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90%, and more preferably at least 98%.

[0098] The term "halo" as used herein refers to a halogen selected from bromine, chlorine, iodine, or fluorine.

[0099] As used herein, the term "heteroaryl" refers to a monovalent monocyclic or polycyclic ring system containing at least one complete aromatic ring and at least one ring heteroatom selected from N, O, or S, i.e., the monocyclic or polycyclic ring system contains 4n+2 pi electrons within the monocyclic or polycyclic ring system. Examples of unsubstituted heteroaryl groups are those containing 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. The term "heteroaryl" includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heteroaromatic rings are fused to one or more aryl or carbocyclic rings (e.g., phenyl or cyclohexane rings). Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, thiazolyl, quinolinyl (e.g., [ka] ), tetrahydroquinolinyl (e.g., [ka] ), 4-azaindolyl (e.g., [ka] ), and the like. The heteroaryl ring may be any ring with its pendant groups that results in a stable structure. Attachment is possible at any heteroatom or carbon ring atom, and any ring atom can be optionally substituted unless otherwise specified. In some embodiments, the heteroaryl is substituted with 1, 2, 3, or 4 substituents.

[0100] As used herein, the term "heteroarylene" refers to a divalent heteroaromatic monocyclic or polycyclic ring system containing at least one complete aromatic ring and at least one ring heteroatom selected from N, O, or S. The term "heteroarylene" includes divalent bicyclic, tricyclic, and tetracyclic groups in which any of the above heteroaromatic rings are fused to one or more aryl or carbocyclic rings. A heteroarylene ring can be attached to its pendant group at any heteroatom or carbon ring atom that results in a stable structure, and all ring atoms can be optionally substituted unless otherwise specified. In certain embodiments, a heteroarylene is substituted with one, two, three, or four substituents.

[0101] As used herein, the term "heterocyclyl" refers to a monovalent monocyclic, bicyclic, or polycyclic ring system in which at least one ring is non-aromatic and the non-aromatic ring contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Five-membered rings have zero to two double bonds, and six- and seven-membered rings have zero to three double bonds. Examples of unsubstituted heterocyclyl groups are those containing 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. The term "heterocyclyl" also refers to heterocyclic compounds having bridged polycyclic structures in which one or more carbons and / or heteroatoms bridge two non-adjacent members of a monocyclic ring (e.g., a quinuclidinyl group). The term "heterocyclyl" includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings are fused with one or more aromatic, carbocyclic, heteroaromatic, or heterocyclic rings (e.g., aryl, cyclohexane, cyclohexene, cyclopentane, cyclopentene, pyridine, or pyrrolidine rings). Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl (e.g., [ka] ), decahydroquinolinyl (e.g., [ka] ), dihydropyrrolopyridines (e.g., [ka] ), decahydronaphthyridinyl (e.g., [ka] ), and the like. A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon ring atom that results in a stable structure, and any ring atom can be optionally substituted unless otherwise specified.

[0102] As used herein, the term "heterocyclylene" refers to a divalent monocyclic, bicyclic, or polycyclic ring system in which at least one ring is non-aromatic and the non-aromatic ring contains one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The term "heterocyclylene" includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or more aromatic, carbocyclic, heteroaromatic, or heterocyclic rings. The heterocyclylene ring can be attached to its pendant group at any heteroatom or carbon ring atom that results in a stable structure, and all ring atoms can be optionally substituted unless otherwise specified.

[0103] The term "haloalkyl," as used herein, refers to an alkyl moiety having one or more carbon atoms substituted with one or more of the same or different halo moieties.

[0104] The term "hydroxyalkyl," as used herein, refers to an alkyl moiety having one or more carbon atoms replaced by one or more --OH moieties.

[0105] As used herein, the term "isomer" refers to any tautomer, stereoisomer, enantiomer, or diastereomer of any compound of the invention. It will be recognized that compounds of the invention may possess one or more chiral centers and / or double bonds and may therefore exist as stereoisomers (double bond isomers (i.e., geometric E / Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers, etc.). In accordance with the present invention, the chemical structures depicted herein, and thus the compounds of the invention, encompass all corresponding stereoisomers, i.e., stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure forms), as well as enantiomeric mixtures and diastereomers. The term "enantiomeric mixtures" encompasses both stereoisomeric mixtures (e.g., racemates) and mixtures of stereoisomers. Enantiomeric and stereoisomeric mixtures of the compounds of the present invention can typically be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high-performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and stereoisomers can also be obtained from stereoisomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0106] As used herein, the term "methylene unit" refers to a divalent -CH2- moiety.

[0107] The term "nitro" as used herein refers to the group --NO.sub.2.

[0108] The term "oxo" as used herein refers to =O.

[0109] As used herein, the term "nitrogen-containing saturated heterocyclyl" refers to a heterocyclyl moiety that does not contain a double bond in the ring and that contains at least one nitrogen atom. Examples of "nitrogen-containing saturated heterocyclyl" include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and the like.

[0110] As used herein, the term "spirocyclyl" refers to a C2-C7 alkylene diradical bonded at both ends to the same carbon atom of a parent group to form a spirocyclic group, and also to a C1-C6 heteroalkylene diradical bonded at both ends to the same atom. The heteroalkylene radical forming the spirocyclyl group can contain one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the spirocyclyl group contains one to seven carbon atoms, excluding the carbon atom to which the diradical is attached. The spirocyclyl groups of the present invention are optionally substituted with one, two, three, or four of the substituents provided herein as optional substituents for the cycloalkyl and / or heterocyclyl groups.

[0111] The term "stereoisomer," as used herein, refers to all of the different possible isomeric and conformational forms that a compound (e.g., a compound of any formula described herein) may possess, and specifically refers to all of the stereochemically and conformationally possible isomeric forms of the basic molecular structure, diastereomers, enantiomers, and / or conformers. Some of the compounds of the present invention may exist in different tautomeric forms, all of the latter being included within the scope of the present invention.

[0112] The term "sulfonyl," as used herein, refers to the group -S(O)2-.

[0113] definition In this application, unless otherwise clear from the context, (i) the term "a" may be understood to mean "at least one," (ii) the term "or" may be understood to mean "and / or," (iii) the terms "comprising" and "including," whether used alone or in combination with one or more additional elements or steps, may be understood to encompass the recited elements or steps, (iv) the terms "about" and "approximately" may be understood to allow for standard variations that would be appreciated by one of ordinary skill in the art, and (v) when ranges are given, endpoints are included.

[0114] As used herein, the term "adjacent," in the context of describing adjacent atoms, refers to divalent atoms that are directly joined by a covalent bond.

[0115] As used herein, the term "administration" refers to administering a composition (e.g., a compound, conjugate, or preparation comprising a compound or conjugate described herein) to a subject or system. Administration to an animal subject (e.g., a human) can be by any suitable route. For example, in some embodiments, administration can be bronchial (including by intrabronchial instillation), buccal, intraintestinal, intradermal, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, and vitreous.

[0116] As known to those skilled in the art, "affinity" is a measure of the tightness with which a particular ligand binds to its partner. Affinity can be measured in a variety of ways. In some embodiments, affinity is measured by a quantitative assay. In some such embodiments, the binding partner concentration can be fixed so that the ligand concentration is in excess to mimic physiological conditions. Alternatively, or additionally, in some embodiments, the binding partner concentration and / or the ligand concentration can be varied. In some such embodiments, affinity can be compared to a reference under comparable conditions (e.g., concentrations).

[0117] As used herein, the term "animal" refers to any member of the animal kingdom. In some embodiments, "animal" refers to a human at any stage of development. In some embodiments, "animal" refers to a non-human animal at any stage of development. In some embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, a cow, a primate, and / or a pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, and / or worms. In some embodiments, the animal may be a transgenic animal, a genetically engineered animal, and / or a clone.

[0118] As used herein, the term "antagonist" refers to a compound that i) inhibits, reduces, or reduces the action of a target protein (e.g., a eukaryotic target protein (such as a mammalian target protein or a fungal target protein) or a prokaryotic target protein (such as a bacterial target protein)), and / or ii) inhibits, reduces, decreases, or delays one or more biological events. Antagonists can be direct (in which case the antagonist exerts its effect directly on its target) or indirect (in which case the antagonist exerts its effect by something other than binding to its target, e.g., by interacting with a regulator of the target protein (e.g., a eukaryotic target protein (such as a mammalian target protein or a fungal target protein) or a prokaryotic target protein (such as a bacterial target protein)), resulting in, e.g., a change in the level or activity of the target protein).

[0119] As used herein, the terms "approximately" and "about" are each intended to encompass normal statistical variations that would be understood by one of ordinary skill in the art as appropriate to the relevant circumstances. In certain embodiments, the terms "approximately" or "about" each refer to a range of values that is within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction of the stated value (above or below the stated value), unless otherwise specified or unless otherwise apparent from the context (e.g., where such value is assumed to exceed 100% of possible values).

[0120] As the term is used herein, two events or entities are "associated" with one another when the presence, level, and / or form of one correlates with that of the other. For example, a particular entity (e.g., a polypeptide) is considered to be associated with a particular disease, disorder, or condition if its presence, level, and / or form correlates with the incidence and / or prevalence of such disease, disorder, or condition (e.g., across a relevant population). In some embodiments, two or more entities are physically "associated" with one another when they directly or indirectly interact with one another, thereby bringing them into physical proximity and maintaining that proximity. In some embodiments, two or more entities that are physically associated with one another are covalently linked to one another. In some embodiments, two or more entities that are physically associated with one another are not covalently linked to one another, but are non-covalently linked, for example, by hydrogen bonds, van der Waals interactions, hydrophobic interactions, magnetism, and combinations thereof.

[0121] It will be understood that the term "binding," as used herein, typically refers to an association (e.g., non-covalent or covalent) between two or more entities. "Direct" binding involves physical contact between the entities or moieties. Indirect binding involves a physical interaction through physical contact with one or more intermediate entities. Binding between two or more entities can typically be assessed in any of a variety of contexts, including when the interacting entities or moieties are tested in isolation or in the context of a more complex system (e.g., covalently or otherwise associated with a carrier entity and / or in a biological system or cell).

[0122] The affinity of molecule X for its partner Y is generally expressed as the dissociation constant (K D ) Affinity can be measured by common methods known in the art, including those described herein. Below are described specific examples and exemplary embodiments for measuring binding affinity. As used herein, "K" refers to the affinity of a molecule to which the molecule is attached. DThe term "" is intended to refer to the dissociation equilibrium constant of a particular compound-protein or complex-protein interaction. Typically, compounds of the present invention have a dissociation equilibrium constant of about 10 -6 The dissociation equilibrium constant (K D )(approximately 10 -7 Less than M, approximately 10 -8 Less than M, approximately 10 -9 Less than M or about 10 -10 M or even lower), and D is obtained, for example, by surface plasmon resonance (SPR) technology using the presenter protein as an analyte and the compound as a ligand. -6 The dissociation equilibrium constant (K D )(approximately 10 -7 Less than M, approximately 10 -8 Less than M, approximately 10 -9 Less than M or about 10 -10 M or even lower), and D is obtained, for example, when determined by surface plasmon resonance (SPR) technology using the target protein as the analyte and the complex as the ligand.

[0123] As used herein, the term "combination therapy" refers to a situation in which a subject is exposed to two or more therapeutic regimens (e.g., two or more compounds (such as compounds of the invention)) simultaneously. In some embodiments, the two or more compounds may be administered simultaneously. In some embodiments, such compounds may be administered sequentially. In some embodiments, such compounds are administered in overlapping dosing regimens.

[0124] As used herein, the term "equivalent" refers to two or more compounds, entities, circumstances, sets of conditions, etc. that may not be identical to one another but are sufficiently similar to permit comparisons between them so that reasonable conclusions can be drawn based on observed differences or similarities. In some embodiments, equivalent sets of conditions, circumstances, individuals, or populations are characterized by the presence of multiple substantially identical characteristics and one or a few different characteristics. Given the context, one of ordinary skill in the art will understand the level of identity required in any given situation for two or more such compounds, entities, circumstances, sets of conditions, etc. to be considered equivalent. For example, one of ordinary skill in the art will understand that sets of conditions, individuals, or populations are equivalent to one another if they have substantially identical characteristics and are characterized by the number and type of characteristics sufficient to warrant a reasonable conclusion that differences in results or observed phenomena under or with different sets of conditions, individuals, or populations are caused by or indicate different variations in those characteristics.

[0125] The term "complex" as used herein refers to a group of two or more compounds and / or proteins bound together through binding interactions (e.g., non-covalent interactions, such as hydrophobic, electrostatic, van der Waals, or π-effect interactions). An example of a complex is a "presenter protein / compound complex," which comprises a compound of the invention bound to a presenter protein.

[0126] As used herein, the term "corresponding to" is often used to designate a structural element or moiety in a compound of interest that shares a position (e.g., in three-dimensional space or relative to another element or moiety) with one present in an appropriate reference compound. For example, in some embodiments, the term is used to refer to the position / identity of a residue in a polymer (such as an amino acid residue in a polypeptide or a nucleotide residue in a nucleic acid). For simplicity, residues in such polymers are often designated using a standard numbering system based on the reference related polymer, such that a residue in a first polymer that "corresponds to" a residue at position 190 in the reference polymer, for example, need not actually be the 190th residue in the first polymer, but will correspond to the residue found at position 190 in the reference polymer. Those skilled in the art will understand and will readily understand how to identify "corresponding" amino acids, including using one or more commercially available algorithms specifically designed for comparison of polymer sequences.

[0127] Many of the methodologies described herein include a "determining" step. Those skilled in the art will understand from reading this specification that such "determining" may utilize or be accomplished by using any of a variety of techniques available to those of skill in the art (e.g., including specific techniques explicitly mentioned herein). In some embodiments, the determining involves physical manipulation of the sample. In some embodiments, the determining involves consideration and / or manipulation of data or information, for example, using a computer or other processing device suitable for performing relevant analyses. In some embodiments, the determining involves obtaining relevant information and / or materials from a source. In some embodiments, the determining involves comparing one or more characteristics of the sample or entity to an equivalent reference.

[0128] As used herein, the term "dosage form" refers to a physically discrete unit of active compound (e.g., therapeutic or diagnostic agent) for administration to a subject. Each unit contains a predetermined amount of active agent. In some embodiments, such amount is a unit dosage (or total amount) suitable for administration according to a dosing regimen (i.e., a therapeutic dosing regimen) determined to correlate with achieving a desired or beneficial result when administered to a relevant population. Those skilled in the art will understand that the total amount of therapeutic composition or compound to be administered to a particular subject will be determined by one or more attending physicians and may involve the administration of multiple dosage forms.

[0129] As used herein, the term "dosing regimen" refers to the individual administration of a series of unit doses (typically multiple) to a subject, the administrations typically being spaced apart. In some embodiments, a given therapeutic compound has a recommended dosing regimen, and such a dosing regimen can include one or more doses. In some embodiments, a dosing regimen includes multiple doses, each separated from the other by periods of equal length. In some embodiments, a dosing regimen includes multiple doses, and the individual doses are separated by at least two different periods. In some embodiments, all doses included in a dosing regimen are of the same unit dosage. In some embodiments, different doses included in a dosing regimen are of different amounts. In some embodiments, a dosing regimen uses a first dose at a first dosage level, followed by one or more additional doses at a second dosage level that is different from the first dosage level. In some embodiments, a dosing regimen uses a first dose at a first dosage level, followed by one or more additional doses at a second dosage level that is the same as the first dosage level. In some embodiments, the dosing regimen correlates with a desired or beneficial outcome when administered to the entire relevant population (ie, is a therapeutic dosing regimen).

[0130] As used herein, the term "macrocycle" refers to a small molecule compound containing a ring with nine or more ring atoms. In some embodiments, a macrocycle is a small molecule in which more than 25% (e.g., more than 30%, more than 35%, more than 40%, more than 45%) of the non-hydrogen atoms present in the small molecule are contained in a single ring structure or a fused ring structure.

[0131] The term "modulator" is used to refer to an entity whose presence or level in a system in which an activity of interest is observed correlates with the level and / or nature of that activity, relative to that observed under otherwise equivalent conditions in its absence. In some embodiments, a modulator is an activator, in that its presence increases activity relative to that observed under otherwise equivalent conditions in its absence. In some embodiments, a modulator is an antagonist or inhibitor, in that its presence decreases activity relative to otherwise equivalent conditions in its absence. In some embodiments, a modulator interacts directly with a target entity having the activity of interest. In some embodiments, a modulator interacts indirectly with a target entity having the activity of interest (i.e., interacts directly with an intermediate compound that interacts with the target entity). In some embodiments, a modulator affects the level of a target entity of interest. Alternatively or additionally, in some embodiments, a modulator affects the activity of a target entity of interest without affecting the level of the target entity. In some embodiments, a modulator affects both the level and activity of a target entity of interest, such that the observed difference in activity is not entirely explained by or is disproportionate to the observed difference in level, hi some embodiments, the modulator is an allosteric modulator (such as an allosteric agonist).

[0132] As used herein, the term "mutant RAS protein" refers to a RAS protein (e.g., KRAS, NRAS, HRAS) that contains at least one mutation in which a non-cysteine amino acid in the corresponding wild-type RAS protein is mutated to a cysteine.

[0133] As used herein, the term "pharmaceutical composition" refers to an active compound formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the active compound is present in a unit dosage suitable for administration in a therapeutic regimen that, when administered to a relevant population, achieves a statistically significant probability of achieving a predetermined therapeutic effect. In some embodiments, pharmaceutical compositions can be specially formulated for administration in solid or liquid form, including those suitable for oral administration (e.g., liquid oral doses (aqueous or non-aqueous solutions or suspensions), tablets (e.g., buccal, sublingual, and those targeted for systemic absorption), boluses, powders, granules, pastes for application to the tongue), parenteral administration (e.g., by subcutaneous, intramuscular, intravenous, or epidural injection (e.g., as a sterile solution or suspension or sustained release formulation)), topical application (e.g., as a cream, ointment, or controlled release patch or spray applied to the skin, lungs, or buccal cavity), vaginal or rectal administration (e.g., as a pessary, cream, or foam), sublingual, ocular, transdermal, or intranasal, pulmonary, and other mucosal surfaces.

[0134] As used herein, "pharmaceutically acceptable excipient" refers to any inactive ingredient (e.g., a medium capable of suspending or dissolving an active compound) that is non-toxic and non-inflammatory in a subject. Typical excipients include, for example, anti-adhesives, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, bulking agents (diluents), film-forming or coating agents, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or hydration water. Excipients include, but are not limited to, optionally substituted butylated hydroxyl toluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxyl propyl cellulose, optionally substituted hydroxyl propyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. Those skilled in the art are familiar with the wide variety of agents and materials useful as excipients.

[0135] As used herein, the term "pharmaceutically acceptable salt" refers to the above salt of the compound described herein, which is suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive toxicity, irritation, allergic response, and the like, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. Such salts can be prepared in situ during the final isolation and purification of the compound described herein, or can be prepared separately by reacting the free base group with a suitable organic acid.

[0136] The compounds of the present invention may have ionizable groups that allow them to be prepared as pharmaceutically acceptable salts. These salts may be acid addition salts with inorganic or organic acids, or when the compounds of the present invention are in acidic form, they may be prepared from inorganic or organic bases. In many cases, compounds are prepared or used as pharmaceutically acceptable salts prepared as the addition product of a pharmaceutically acceptable acid or base. Suitable pharmaceutically acceptable acids and bases are well known in the art, and include, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, lactic acid, citric acid, or tartaric acid for the formation of acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines, and the like for the formation of base salts. Methods for preparing suitable salts are well established in the art.

[0137] Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, and optionally substituted 2-hydroxyethanesulfonates. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

[0138] The term "presenter protein" refers to a protein that, upon binding to a small molecule, forms a complex that binds to and modulates the activity of a target protein (e.g., a eukaryotic target protein (such as a mammalian target protein or a fungal target protein) or a prokaryotic target protein (such as a bacterial target protein)). In some embodiments, the presenter protein is a relatively abundant protein (e.g., the presenter protein is sufficiently abundant that its participation in a ternary complex does not substantially affect the biological role of the presenter protein in the cell and / or the viability or other attributes of the cell). In certain embodiments, the presenter protein is a protein that has chaperone activity within the cell. In some embodiments, the presenter protein is a protein that has multiple natural interaction partners within the cell. In certain embodiments, the presenter protein is known to form a binary complex upon binding to a small molecule that is known or suspected to bind to and modulate the biological activity of the target protein.

[0139] The term "pure" means substantially pure or free from undesired components (e.g., other compounds and / or other cell lysate components), contaminating materials, contamination, or imperfections.

[0140] The term "reference" is often used herein to describe a standard or control compound, individual, population, sample, sequence, or value to which a compound, individual, population, sample, sequence, or value of interest is compared. In some embodiments, the reference compound, reference individual, reference population, reference sample, reference sequence, or reference value is tested and / or determined substantially simultaneously with the testing or determination of the compound, individual, population, sample, sequence, or value of interest. In some embodiments, the reference compound, reference individual, reference population, reference sample, reference sequence, or reference value is a historical reference, and such historical reference is optionally embodied in a tangible medium. Typically, as one of skill in the art will understand, the reference compound, reference individual, reference population, reference sample, reference sequence, or reference value is determined or characterized under conditions equivalent to those used to determine or characterize the compound, individual, population, sample, sequence, or value of interest.

[0141] The term "small molecule" refers to a low molecular weight organic and / or inorganic compound. Generally, a "small molecule" is a molecule less than about 5 kilodaltons (kD) in size. In some embodiments, a small molecule is less than about 4 kD, less than 3 kD, less than about 2 kD, or less than about 1 kD. In some embodiments, a small molecule is less than about 800 daltons (D), less than about 600 D, less than about 500 D, less than about 400 D, less than about 300 D, less than about 200 D, or less than about 100 D. In some embodiments, a small molecule is less than about 2000 g / mol, less than about 1500 g / mol, less than about 1000 g / mol, less than about 800 g / mol, or less than about 500 g / mol. In some embodiments, a small molecule is not a polymer. In some embodiments, a small molecule does not comprise a polymeric moiety. In some embodiments, a small molecule is not a protein or polypeptide (e.g., not an oligopeptide or peptide). In some embodiments, the small molecule is not a polynucleotide (e.g., not an oligonucleotide). In some embodiments, the small molecule is not a polysaccharide. In some embodiments, the small molecule does not comprise a polysaccharide (e.g., is not a glycoprotein, proteoglycan, glycolipid, etc.). In some embodiments, the small molecule is not a lipid. In some embodiments, the small molecule is a regulatory compound. In some embodiments, the small molecule is biologically active. In some embodiments, the small molecule is detectable (e.g., comprises at least one detectable moiety). In some embodiments, the small molecule is a therapeutic agent.

[0142] Those skilled in the art will understand, upon reading this disclosure, that certain small molecule compounds described herein can be provided and / or utilized in any of a variety of forms. These forms include, for example, salt forms, protected forms, prodrug forms, ester forms, isomeric forms (e.g., optical and / or structural isomers), isotopic forms, etc. In some embodiments, a reference to a particular compound may refer to a specific form of that compound. In some embodiments, a reference to a particular compound may refer to that compound in any form. In some embodiments, if a compound is naturally occurring or found in nature, the compound may be provided and / or utilized in accordance with the present invention in a form that differs from the form in which it naturally occurs or is found in nature. Those skilled in the art will understand that a compound preparation that includes one or more individual forms at levels, amounts, or ratios that differ from that of a reference preparation or reference source (e.g., a natural source) of the compound may be considered a different form of the compound described herein. Thus, in some embodiments, for example, a preparation of a single stereoisomer of a compound may be considered a different compound form from a racemic mixture of the compound. A particular salt of a compound may be considered to be a different form from another salt form of the compound. A preparation containing one conformational isomer of the double bond ((Z) or (E)) may be considered to be a different form from a preparation containing the other conformational isomer of the double bond ((E) or (Z)). A preparation in which one or more atoms are isotopes different from the isotopes present in the reference preparation may be considered to be a different form. Similarly in other cases.

[0143] As used herein, the terms "specific binding" or "specific for" or "specific for" refer to an interaction occurring between a binder and a target entity. As one of skill in the art would understand, an interaction occurs selectively in the presence of another interaction (e.g., a K of less than 10 μM (e.g., less than 5 μM, less than 1 μM, less than 500 nM, less than 200 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 25 nM, less than 10 nM). DA specific interaction is considered "specific" if binding occurs at a specific binding site (e.g., an epitope, cleft, binding site) on the target entity. In many embodiments, the specific interaction is dependent on the presence of a particular structural feature of the target entity (e.g., an epitope, cleft, binding site). It will be understood that specificity need not be absolute. In some embodiments, specificity may be assessed relative to that of the binder for one or more other potential target entities (e.g., competitors). In some embodiments, specificity is assessed relative to that of a specific reference binder. In some embodiments, specificity is assessed relative to that of a non-specific reference binder.

[0144] The term "specific," when used in reference to a compound having activity, is understood by those skilled in the art to mean that the compound discriminates between potential target entities or target states. For example, in some embodiments, a compound is said to "specifically" bind to a target if it selectively binds to the compound's target in the presence of one or more competing targets. In many embodiments, the specific interaction is dependent on the presence of a particular structural feature (e.g., an epitope, cleft, binding site) of the target entity. It will be understood that specificity need not be absolute. In some embodiments, specificity can be assessed relative to that of a binding agent for one or more other potential target entities (e.g., competitors). In some embodiments, specificity is assessed relative to that of a specific reference binding agent. In some embodiments, specificity is assessed relative to that of a nonspecific reference binding agent. In some embodiments, an agent or entity, under conditions in which it binds to its target entity, does not detectably bind to competing targets. In some embodiments, a binding agent binds to its target entity with an increased on-rate, a slower off-rate, an increased affinity, reduced dissociation, and / or increased stability compared to another competing target(s).

[0145] A "therapeutic regimen" refers to a dosing regimen whose administration to an entire relevant population correlates with a desired or beneficial therapeutic outcome.

[0146] The term "therapeutically effective amount" refers to an amount sufficient to treat a disease, disorder, and / or condition when administered in accordance with a therapeutic dosing regimen to a population suffering from or susceptible to such a disease, disorder, and / or condition. In some embodiments, a therapeutically effective amount is an amount that reduces the incidence and / or severity of a disease, disorder, and / or condition and / or delays the onset of one or more of its symptoms. Those skilled in the art will appreciate that the term "therapeutically effective amount" does not necessarily require that successful treatment be achieved in a particular individual. Rather, a therapeutically effective amount may be an amount that, when administered to patients in need of such treatment, provides a particular desired pharmacological response in a substantial number of subjects. It will be clearly understood that certain subjects may, in fact, be "resistant" to a "therapeutically effective amount." By way of example only, bioavailability in resistant subjects may be low, resulting in a failure to achieve clinical benefit. In some embodiments, reference to a therapeutically effective amount may be a reference to the amount measured in one or more specific tissues (e.g., tissues affected by a disease, disorder, or condition) or bodily fluids (e.g., blood, saliva, serum, sweat, tears, urine, etc.). One of skill in the art will understand that in some embodiments, a therapeutically effective amount may be formulated and / or administered in a single dose. In some embodiments, a therapeutically effective amount may be formulated and / or administered in multiple doses, for example, as part of a dosing regimen.

[0147] The term "treatment" (also used as "treat" or "treating"), in its broadest sense, refers to any administration of a substance (e.g., a provided composition) that partially or completely alleviates, improves, alleviates, suppresses, delays the onset of, reduces the severity of, and / or reduces the incidence of one or more of the symptoms, characteristics, and / or causes of a particular disease, disorder, and / or condition. In some embodiments, such treatment may be administered to subjects who do not exhibit signs of the associated disease, disorder, and / or condition and / or who exhibit only early signs of such disease, disorder, and / or condition. Alternatively or additionally, in some embodiments, treatment may be administered to subjects who exhibit one or more established signs of the associated disease, disorder, and / or condition. In some embodiments, treatment may be administered to subjects who have been diagnosed with the associated disease, disorder, and / or condition. In some embodiments, treatment may be administered to subjects who have been found to have one or more susceptibility factors that statistically correlate with an increased risk of developing the associated disease, disorder, and / or condition.

[0148] The term "variant" refers to an entity that has significant structural identity with a reference entity but that differs structurally from the reference entity in the presence or level of one or more chemical moieties relative to the reference entity. In many embodiments, a variant also differs functionally from the reference entity. Generally, whether a particular entity is appropriately considered a "variant" of a reference entity is based on its degree of structural identity with the reference entity. As one of skill in the art will understand, both biological and chemical reference entities have certain characteristic structural elements. A variant, by definition, is a different chemical entity that shares one or more such characteristic structural elements. To name just a few examples, a small molecule can have a characteristic core structural element (e.g., a hexahydropyridazine core) and / or one or more characteristic pendant moieties; such that variants of a small molecule share such core structural elements and characteristic pendant moieties but differ in other pendant moieties and / or the type of bond (e.g., single or double bond, E or Z) present within the core. Polypeptides can have characteristic sequence elements composed of multiple amino acids whose positions relative to each other in linear or three-dimensional space are defined and / or contribute to a specific biological function. Nucleic acids can have characteristic sequence elements composed of multiple nucleotide residues whose positions relative to each other in linear or three-dimensional space are defined. For example, a variant polypeptide can differ from a reference polypeptide as a result of one or more differences in amino acid sequence and / or one or more differences in chemical moieties (e.g., carbohydrates, lipids, etc.) covalently attached to the polypeptide backbone. In some embodiments, a variant polypeptide exhibits at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, or at least 99% overall sequence identity with the reference polypeptide. Alternatively or additionally, in some embodiments, a variant polypeptide does not share at least one characteristic sequence element with the reference polypeptide.In some embodiments, the reference polypeptide has one or more biological activities. In some embodiments, a variant polypeptide shares one or more of the biological activities of the reference polypeptide. In some embodiments, a variant polypeptide does not have one or more of the biological activities of the reference polypeptide. In some embodiments, a variant polypeptide has a reduced level of one or more biological activities compared to the reference polypeptide. In many embodiments, a polypeptide of interest is considered a "variant" of a parent or reference polypeptide if it has an amino acid sequence identical to that of the parent, except for minor sequence changes at specific positions. Typically, a variant replaces less than 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, or 2% of the residues compared to the parent. In some embodiments, a variant replaces 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 residue compared to the parent. In many cases, a variant replaces a very small number (e.g., fewer than 5, fewer than 4, fewer than 3, fewer than 2, or fewer than 1) of functional residues (i.e., residues responsible for a particular biological activity). Furthermore, the number of additions or deletions in a variant compared to the parent is typically 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer; often, a variant has no additions or deletions at all. Furthermore, for any additions or deletions, the number of residues is typically less than about 25, less than about 20, less than about 19, less than about 18, less than about 17, less than about 16, less than about 15, less than about 14, less than about 13, less than about 10, less than about 9, less than about 8, less than about 7, or less than about 6, and generally less than about 5, less than about 4, less than about 3, or less than about 2. In some embodiments, the parent or reference polypeptide is one found in nature. As one of skill in the art will appreciate, it may be common for multiple naturally occurring variants of a particular polypeptide of interest.

[0149] The term "wild-type" refers to an entity having a structure and / or activity found in nature under a "normal" (as opposed to mutant, diseased, altered, etc.) state or condition. Those skilled in the art will appreciate that wild-type genes and polypeptides often exist in multiple alternative forms (e.g., alleles). [Brief explanation of the drawings]

[0150] [Figure 1-1] Compounds 1-418 of the present invention, general schemes for their preparation or specific examples illustrating their synthesis, and their mass spectrometry and / or NMR values are shown. Compounds 419-461 in Figure 1 are additional compounds of the present invention, which were prepared using similar methodologies. [Figure 1-2] Continued from Figure 1. [Figure 1-3] Continued from Figure 1. [Figure 1-4] Continued from Figure 1. [Figure 1-5] Continued from Figure 1. [Figure 1-6] Continued from Figure 1. [Figure 1-7] Continued from Figure 1. [Figure 1-8] Continued from Figure 1. [Figure 1-9] Continued from Figure 1. [Figure 1-10] Continued from Figure 1. [Figure 1-11] Continued from Figure 1. [Figure 1-12] Continued from Figure 1. [Figure 1-13] Continued from Figure 1. [Figure 1-14] Continued from Figure 1. [Figure 1-15] Continued from Figure 1. [Figure 1-16] Continued from Figure 1. [Figure 1-17] Continued from Figure 1. [Figure 1-18] Continued from Figure 1. [Figure 1-19] Continued from Figure 1. [Figure 1-20] Continued from Figure 1. [Figure 1-21]Continued from Figure 1. [Figure 1-22] Continued from Figure 1. [Figure 1-23] Continued from Figure 1. [Figure 1-24] Continued from Figure 1. [Figure 1-25] Continued from Figure 1. [Figure 1-26] Continued from Figure 1. [Figure 1-27] Continued from Figure 1. [Figure 1-28] Continued from Figure 1. [Figure 1-29] Continued from Figure 1. [Figure 1-30] Continued from Figure 1. [Figure 1-31] Continued from Figure 1. [Figure 1-32] Continued from Figure 1. [Figure 1-33] Continued from Figure 1. [Figure 1-34] Continued from Figure 1. [Figure 1-35] Continued from Figure 1. [Figure 1-36] Continued from Figure 1. [Figure 1-37] Continued from Figure 1. [Figure 1-38] Continued from Figure 1. [Figure 1-39] Continued from Figure 1. [Figure 1-40] Continued from Figure 1. [Figure 1-41] Continued from Figure 1. [Figure 1-42] Continued from Figure 1. [Figure 1-43] Continued from Figure 1. [Figure 1-44] Continued from Figure 1. [Figure 1-45] Continued from Figure 1. [Figure 1-46] Continued from Figure 1. [Figure 1-47] Continued from Figure 1. [Figure 1-48] Continued from Figure 1. [Figure 1-49] Continued from Figure 1. [Figure 1-50] Continued from Figure 1. [Figure 1-51] Continued from Figure 1. [Figure 1-52] Continued from Figure 1. [Figure 1-53] Continued from Figure 1. [Figure 1-54] Continued from Figure 1. [Figure 1-55] Continued from Figure 1. [Figure 1-56] Continued from Figure 1. [Figure 1-57] Continued from Figure 1. [Figure 1-58] Continued from Figure 1. [Figure 1-59] Continued from Figure 1. [Figure 1-60] Continued from Figure 1. [Figure 1-61] Continued from Figure 1. [Figure 1-62] Continued from Figure 1. [Figure 1-63] Continued from Figure 1. [Figure 1-64] Continued from Figure 1. [Figure 1-65] Continued from Figure 1. [Figure 1-66] Continued from Figure 1. [Figure 1-67] Continued from Figure 1. [Figure 1-68] Continued from Figure 1. [Figure 1-69] Continued from Figure 1. [Figure 1-70] Continued from Figure 1. [Figure 1-71] Continued from Figure 1. [Figure 1-72] Continued from Figure 1. [Figure 1-73] Continued from Figure 1. [Figure 1-74] Continued from Figure 1. [Figure 1-75] Continued from Figure 1. [Figure 1-76] Continued from Figure 1. [Figure 1-77] Continued from Figure 1. [Figure 1-78] Continued from Figure 1. [Figure 1-79] Continued from Figure 1. [Figure 1-80] Continued from Figure 1. [Figure 1-81] Continued from Figure 1. [Figure 1-82] Continued from Figure 1. [Figure 1-83] Continued from Figure 1. [Figure 1-84] Continued from Figure 1. [Figure 1-85] Continued from Figure 1. [Figure 1-86] Continued from Figure 1. [Figure 1-87] Continued from Figure 1. [Figure 1-88] Continued from Figure 1. [Figure 1-89] Continued from Figure 1. [Figure 1-90] Continued from Figure 1. [Figure 1-91] Continued from Figure 1. [Figure 1-92] Continued from Figure 1. [Figure 1-93] Continued from Figure 1. [Figure 1-94] Continued from Figure 1. [Figure 1-95] Continued from Figure 1. [Figure 1-96] Continued from Figure 1. [Figure 1-97] Continued from Figure 1. [Figure 1-98] Continued from Figure 1. [Figure 1-99] Continued from Figure 1. [Figure 1-100] Continued from Figure 1. [Figure 1-101] Continued from Figure 1. [Figure 1-102] Continued from Figure 1. [Figure 1-103] Continued from Figure 1. [Figure 1-104] Continued from Figure 1. [Figure 1-105] Continued from Figure 1. [Figure 1-106] Continued from Figure 1. [Figure 1-107] Continued from Figure 1. [Figure 1-108] Continued from Figure 1. [Figure 1-109] Continued from Figure 1. [Figure 1-110] Continued from Figure 1. [Figure 1-111] Continued from Figure 1. [Figure 1-112] Continued from Figure 1. [Figure 1-113] Continued from Figure 1. [Figure 1-114] Continued from Figure 1. [Figure 1-115] Continued from Figure 1. DETAILED DESCRIPTION OF THE INVENTION

[0151] compound The present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0152] The present disclosure features a complex including a presenter protein, a compound of the invention (e.g., a compound of Formula (I) or any of Compounds 1-461), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, and a target protein.

[0153] The present disclosure features compounds (e.g., compounds of Formula (I) or any of Compounds 1-461) capable of modulating biological processes, for example, by binding to a presenter protein (e.g., a member of the cyclophilin family) and a target protein (e.g., a member of the RAS family). In some embodiments, the target protein and / or presenter protein are intracellular proteins. In some embodiments, the target protein and / or presenter protein are mammalian proteins. In some embodiments, provided compounds are included in a presenter protein-compound-target protein ternary complex within a cell (e.g., a mammalian cell). In some embodiments, provided compounds may be useful in the treatment of diseases and disorders (e.g., cancer, inflammation, or infectious diseases).

[0154] Compound synthesis The following general reaction schemes illustrate examples of methods for preparing compounds of Formula I or pharmaceutically acceptable salts thereof.

[0155] Coupling agents useful in such schemes include, but are not limited to, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), ethyl-(N',N'-dimethylamino)propylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt) / EDC, (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBROP), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU ... O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TATU), O-(6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate Examples of suitable fluorochemicals include tetramethyluronium hexafluorophosphate (HCTU), carbonyldiimidazole (CDI), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU®), 1-propanephosphonic anhydride (T3P®), a combination of 2,2′-dipyridyl disulfide and triphenylphosphine, and the like known to those skilled in the art.

[0156] The coupling is typically achieved in an organic solvent (such as, but not limited to, N,N-dimethylformamide (DMF), dichloromethane (DCM), acetonitrile, and tetrahydrofuran (THF)) in the presence of a base (such as, but not limited to, diisopropylethylamine, triethylamine, and N-methylmorpholine).

[0157] The coupling reaction can be carried out in the presence or absence of DMAP (catalytic, stoichiometric, or superstoichiometric, more specifically, catalytic amounts) at temperatures ranging from −78° C. to about 120° C., specifically, from −20° C. to 50° C., more specifically, from −5° C. to 30° C.

[0158] Cross-coupling reactions useful in the synthesis of compounds of the present invention include, but are not limited to, Suzuki coupling, Negishi coupling, Stille coupling, Kumada coupling, and Hiyama coupling.

[0159] Cross-coupling reactions generally require a metal catalyst or a mixture of metal catalysts. Suitable metal catalysts include, but are not limited to, palladium, copper, nickel, iron, silver, gold, or a combination of two or more of these catalysts. Suitable palladium catalysts include, but are not limited to, palladium on carbon (Pd / C), palladium acetate (Pd(OAc)), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh)), bis(triphenylphosphine)palladium(II) dichloride (PdCl(PPh)), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride ((dppf)PdCl), and tris(dibenzylideneacetone)dipalladium(0) (Pd(dba)). Suitable copper catalysts include, but are not limited to, CuCl, CuBr, CuI, CuO, CuOTf, Cu(MeCN)PF, CuTC (copper(I) thiophene-2-carboxylate), Cu(OAc), and Cu(OTf). Suitable nickel catalysts include, but are not limited to, bis(cyclooctadiene)nickel(0), bis(triphenylphosphine)nickel chloride, [1,2-bis(diphenylphosphino)ethane]dichloronickel(II) ((dppe)NiCl), [1,1'-bis(diphenylphosphino)ferrocene]dichloronickel(II) ((dppf)NiCl), and [1,3-bis(diphenylphosphino)propane]dichloronickel(II) ((1,3-dppp)NiCl). Suitable iron catalysts include, but are not limited to, FeCl2, FeCl3, Fe(acac)3, and Fe(OAc)2. Suitable silver catalysts include, but are not limited to, Ag(OAc), AgOTf, AgPF6, and AgClO4. Suitable gold catalysts include, but are not limited to, chloro(triphenylphosphine)gold(I) ((Ph3P)AuCl), chloro[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]gold(I), methyl(triphenylphosphine)gold(I), chloro[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene]gold(I), and chloro(trimethylphosphine)gold(I).

[0160] The cross-coupling reaction may be carried out in a suitable solvent at a temperature between -78°C and 250°C, more particularly between 0°C and 120°C.

[0161] Suitable solvents for the cross-coupling reaction can be, but are not limited to, MeOH, EtOH, isopropanol, tert-butanol, HO, DMF, DMSO, THF, 1,4-dioxane, 1,2-dimethoxyethane, or a mixture of two or more of these solvents.

[0162] Cross-coupling reactions can be carried out under conventional heating conditions or in a microwave reactor. Certain cross-coupling reactions are carried out under a nitrogen or argon atmosphere. Other cross-coupling reactions may require the presence of air or oxygen. Additionally, some cross-coupling reactions may require a base. Suitable bases include, but are not limited to, AgO, K2CO3, tBuOK, tBuONa, Cs2CO3, and K3PO4.

[0163] Reactive group for Suzuki cross-coupling reaction (B in the following scheme) 1 and B 2 (referred to herein as "boronic acid moieties") are typically (1) boronic acid, boronic ester, or trifluoroborate moieties (such as, but not limited to, -B(OH)2, -B(OMe)2, -B(OEt)2, -B(OPr-i)2, -B(pinacolato), and -BF3K); (2) halogen or sulfonate ester groups (such as, but not limited to, Cl, Br, I, -OSCF3, -OSCHMe-p, and -OSCH5).

[0164] In these schemes, a variety of protecting groups (PG) are used. Suitable amine protecting groups include, but are not limited to, tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), p-methoxybenzylcarbonyl (Moz), allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), benzoyl (Bz), acetyl (Ac), methanesulfonyl (Ms), trifluoromethanesulfonyl (Tf), p-toluenesulfonyl (Ts), and 4-nitrobenzenesulfonyl (Nosyl). In certain embodiments, the amine protecting group is tert-butyloxycarbonyl (Boc). Suitable alcohol protecting groups include, but are not limited to, silyl groups (including, but not limited to, -SiMe, -SiEt, -Si(iso-Pr), -SiMe(tert-Bu), -SiPh(tert-Bu), -SEM (2-(trimethylsilyl)ethoxymethyl)), ether groups (including, but not limited to, -MOM (methoxymethyl), -MEM (2-methoxyethoxymethyl), -BOM (benzyloxymethyl), -PMBM (p-methoxybenzyloxymethyl), and -THP (tetrahydropyranyl)), and ester groups (including, but not limited to, acetate (Ac), formate, pivaloate (Pv), and benzoate). In certain embodiments, the alcohol protecting group is acetyl. Some protecting groups are alkyl groups or any aryl group (including but not limited to methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, p-methoxybenzyl, allyl, phenyl, and p-nitrophenyl). In some embodiments, the alkyl or aryl protecting group is methyl.

[0165] Removal of protecting groups can be carried out under basic or acidic conditions, depending on the nature of the protecting group. The conditions applicable to specific protecting groups are well known in the art. Suitable bases for removing protecting groups include, but are not limited to, LiOH, NaOH, KOH, CsOH, Li2CO3, Na2CO3, K2CO3, Cs2CO3, and CsF. Suitable acids for removing protecting groups include, but are not limited to, HCl, HBr, HI, H2SO4, HNO3, and CF3CO2H. Certain protecting groups can also be removed using conditions or reagents, such as trimethyltin hydroxide, ammonium cerium nitrate, and oxalyl chloride.

[0166] Removal of the protecting group is typically carried out in a suitable solvent at a temperature of −78° C. to about 150° C., specifically at a temperature of 0° C. to 120° C., more specifically at a temperature of 0° C. to 25° C. Suitable solvents for such reactions include, but are not limited to, MeOH, EtOH, isopropanol, tert-butanol, HO, dichloromethane, ethyl acetate, DMF, DMSO, THF, 1,4-dioxane, and 1,2-dimethoxyethane.

[0167] Variables (Q, X, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , p, and r, etc.) have the meanings indicated in Formula I.

[0168] Dipeptide A-1 can be prepared as shown in Scheme 1 below, where the structural variables are as previously described. [ka]

[0169] In a typical procedure, intermediate AA is reacted with intermediate AB in the presence of a coupling agent.

[0170] Method A Method A can be used to prepare compounds of formula I as shown below in Scheme 2: The structural variables of formula I are as defined above. [ka]

[0171] Step 1: Intermediate A-3 is synthesized from intermediate A-1 and intermediate A-2 via a cross-coupling reaction. In some embodiments, the cross-coupling reaction is a Suzuki coupling reaction. PG 1 is a suitable amine protecting group. In certain embodiments, PG 1 is tert-butyloxycarbonyl (Boc).

[0172] Step 2: PG 2 is an alkyl or aryl protecting group. In some embodiments, PG 2 is methyl. Intermediate A-4 is PG 2 It can be synthesized from A-3 using a deprotection reaction to hydrolyze the containing ester to its corresponding acid.

[0173] Step 3: Macrocyclization of intermediate A-4 to give intermediate A-5 is achieved by a cross-coupling reaction.

[0174] Alternatively, this cyclization reaction can be carried out by converting the acidic group (—COH) in the precursor to the corresponding acid chloride (—COCl) using a chlorinating agent (including, but not limited to, thionyl chloride, PCl3, PCl5, and oxalyl chloride (using DMF as a catalyst)) in a suitable solvent at a temperature of −78° C. to 120° C. (preferably 0° C.). Suitable solvents include, but are not limited to, DMF, dichloromethane, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, toluene, and 1,4-dioxane. After the acid chloride is formed, the solvent can be removed under reduced pressure and replaced with another solvent. Such solvents include, but are not limited to, N,N-dimethylformamide, dichloromethane, 1,2-dimethoxyethane, acetonitrile, tetrahydrofuran, and 1,2-dichloroethane. A base (including but not limited to pyridine, diisopropylethylamine, triethylamine, N-methylmorpholine, and the like) is then added to form the cyclized product. The reaction temperature range is -78°C to 120°C, preferably -20°C to 50°C.

[0175] Step 4: Intermediate A6 is synthesized by PG 1 It is synthesized from intermediate A-5 by removing

[0176] Step 5: Compounds of Formula I are synthesized from intermediates A-6 and A-7 via an amide formation reaction using a cross-coupling reaction.

[0177] Alternatively, those skilled in the art will appreciate that intermediate A-7 can be converted to its acyl chloride or acyl fluoride or activated ester or anhydride and reacted with intermediate A-6 to synthesize compounds of formula I. Examples of these types of reactions are available in the literature, such as Compendium of Organic Synthetic Methods, Vol. I-VI (Wiley-Interscience), or Comprehensive Organic Transformations by RC Larock (Wiley-Interscience).

[0178] Method B Method B can alternatively be used to synthesize compounds of formula I as shown below in Scheme 3. The structural variables of formula I are as defined above. [ka]

[0179] Step 1: PG 11 is a suitable alcohol protecting group (when Y=O) or amine protecting group (when Y=NH or N(C1-C3 alkyl)).

[0180] Intermediate B-2 is synthesized from intermediate A-1 and intermediate B-1 via a cross-coupling reaction.

[0181] Step 2: Intermediate A-3 is synthesized by PG 11 It can be synthesized from intermediate B-2 by removing a group from the alcoholic oxygen atom to which it is attached or from the amino nitrogen atom to which it is attached.

[0182] Steps 3-6: The conversion of intermediate A-3 to Formula I is detailed in the description of Method A.

[0183] Method C Method C can alternatively be used to synthesize compounds of formula I as shown below in Scheme 4. The structural variables of formula I are as defined above. [ka]

[0184] Step 1: Intermediate C-1 is synthesized by PG 2 It can be synthesized from A-1 using a deprotection reaction to hydrolyze the containing ester to its corresponding acid.

[0185] Step 2: Intermediate C-2 can be synthesized from C-1 by forming an amide using a cross-coupling reaction.

[0186] Alternatively, those skilled in the art will appreciate that intermediate A-7 can be converted to its acyl chloride, acyl fluoride, activated ester, or anhydride and reacted with intermediate A-2 to synthesize compounds of formula I. Examples of these types of reactions are available in the literature, such as "Compendium of Organic Synthetic Methods, Vol. I-VI (Wiley-Interscience)" or "Comprehensive Organic Transformations" by RC Larock (Wiley-Interscience)

[0187] Step 3: Macrocycle A-5 can be synthesized from intermediate C-2 using a cross-coupling reaction. In some embodiments, the cross-coupling reaction is a Suzuki coupling reaction.

[0188] Steps 4-5: Conversion of macrocycle A-5 to Formula I is detailed in the description of Method A.

[0189] protein Presenter Protein The presenter protein can bind to the compound of the present invention to form a complex, and this complex can bind to the mutant RAS target protein and regulate its activity. The presenter protein is a member of the cyclophilin A family (e.g., CYPA, CYPB, CYPC, CYP40, CYPE, CYPD, NKTR, SRCyp, CYPH, CWC27, CYPL1, CYP60, CYPJ, PPIL4, PPIL6, RANBP2, PPWD1, PPIAL4A, PPIAL4B, PPIAL4C, PPIAL4D, or PPIAL4G).

[0190] The "cyclophilin family" is a family of proteins that bind to cyclosporine. Genes encoding proteins in this family include PPIA, PPIB, PPIC, PPID, PPIE, PPIF, PPIG, PPIH, SDCCAG-10, PPIL1, PPIL2, PPIL3, PPIL4, P270, PPWD1, and COAS-2. Examples of cyclophilins include CYPA, CYPB, CYPC, CYP40, CYPE, CYPD, NKTR, SRCyp, CYPH, CWC27, CYPL1, CYP60, CYPJ, PPIL4, PPIL6, RANBP2, PPWD1, PPIAL4A, PPIAL4B, PPIAL4C, PPIAL4D, and PPIAL4G.

[0191] Exemplary presenter proteins are those encoded by the genes set forth in Table 1 or their homologs. In some embodiments, the reference presenter protein is one encoded by a gene set forth in Table 1. Furthermore, those skilled in the art can readily refer to Table 1 to identify sequences characteristic of presenter proteins in general and / or sequences characteristic of particular subsets of presenter proteins. [Table 1]

[0192] Target protein Target proteins (e.g., eukaryotic target proteins (such as mammalian target proteins)) are proteins that mediate disease states or symptoms of disease states. Therefore, modulating (inhibiting or enhancing) their activity can achieve a desired therapeutic effect. Target proteins useful in the complexes and methods of the present invention include those that are not naturally associated with a presenter protein, such as those that have an affinity for the presenter protein of greater than 1 μM, preferably greater than 5 μM, and more preferably greater than 10 μM, in the absence of a binary complex with a compound of the present invention. Alternatively, target proteins that are not naturally associated with a presenter protein have an affinity for the compound of the present invention of greater than 1 μM, preferably greater than 5 μM, and more preferably greater than 10 μM, in the absence of a binary complex. In yet other cases, target proteins that are not naturally associated with a presenter protein are other than calcineurin or mTOR.

[0193] The target protein can be naturally occurring, e.g., wild-type, or it can differ from the wild-type protein but still retain biological function, e.g., as a mutant, splice variant, or biologically active fragment.

[0194] In some embodiments, the target protein is a RAS family protein.

[0195] In some embodiments, the target protein is a KRAS protein. In some embodiments, the KRAS protein is a KRAS G12C protein. In some embodiments, the KRAS protein is a KRAS G13C protein.

[0196] In some embodiments, the target protein is an NRAS protein. In some embodiments, the NRAS protein is an NRAS G12C protein. In some embodiments, the NRAS protein is an NRAS G13C protein.

[0197] In some embodiments, the target protein is an HRAS protein. In some embodiments, the HRAS protein is an HRAS G12C protein. In some embodiments, the HRAS protein is an HRAS G13C protein.

[0198] Complex Presenter protein / compound complex In one aspect, the present invention provides a complex comprising a compound of the present invention, a presenter protein that is a member of the CYPA family, and a mutant RAS protein.

[0199] In a related aspect, the disclosure features a method for producing the above-described complex, the method comprising contacting a presenter protein that is a member of the CYPA family and a mutant RAS protein with a compound of the invention (or any pharmaceutical composition containing such a compound) under conditions suitable to allow complex formation.

[0200] In some embodiments of any of the above two aspects, the mutant RAS protein is KRAS G12C, NRAS G12C, or HRAS G12C.In some embodiments, the mutant RAS protein is KRAS G13C, NRAS G13C, or HRAS G13C.In some embodiments, the mutant RAS protein is KRAS G12C.

[0201] In some embodiments of either of the above two aspects, the presenter protein is CYPA, CYPB, CYPC, CYP40, CYPE, CYPD, NKTR, SRCyp, CYPH, CWC27, CYPL1, CYP60, CYPJ, PPIL4, PPIL6, RANBP2, or PPWD1. In some embodiments, the presenter protein is CYPA.

[0202] In some embodiments, the presenter protein / compound / target protein complex of the present invention inhibits the naturally occurring interaction between a target protein and a ligand (such as a protein or small molecule that specifically binds to the target protein).

[0203] In some embodiments, the presenter protein / compound / target protein complex of the invention inhibits BRAF binding to mutant RAS (e.g., KRAS G12C, KRAS G13C, NRAS G12C, NRAS G13C, HRAS G12C, or HRAS G13C).

[0204] kit In some embodiments, the present invention relates to a kit for conveniently and efficiently carrying out a method according to the present invention. Generally, a pharmaceutical pack or kit includes one or more containers filled with one or more of the components of the pharmaceutical composition of the present invention. Such kits are particularly suitable for delivering solid oral forms (such as tablets or capsules). Such kits preferably include a number of unit doses and may also include a card on which the doses are arranged in the order of their intended use. If desired, for example, if the subject is suffering from Alzheimer's disease, a memory aid can be provided (e.g., in the form of numbers, letters, or other labels, or with a calendar refill) to designate the days in the treatment schedule on which the doses can be administered. Alternatively, a kit for daily administration of a dose can be provided by including a placebo dose or calcium supplement, either in a form similar to or different from the dose of the pharmaceutical composition. Optionally, such container(s) may be accompanied by a notice in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceutical products, which notice reflects approval by such agency of the manufacture, use, or sale for human administration.

[0205] Pharmaceutical Composition For use in treating human and animal subjects, the compounds of the present invention can be formulated as pharmaceutical or veterinary compositions. Depending on the subject to be treated, the mode of administration, and the type of treatment desired (e.g., prevention, prophylaxis, or therapy), the compounds will be formulated in a manner consistent with these parameters. A summary of such techniques is provided in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Williams & Wilkins, (2005), and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, each of which is incorporated herein by reference.

[0206] The total amount of the compounds described herein present can be 1 to 95% by weight of the total weight of the composition. The compositions can be provided in a dosage form suitable for intraarticular, oral, parenteral (e.g., intravenous, intramuscular), rectal, intradermal, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intravesical, intraurethral, intrathecal, epidural, aural, or ocular administration, or in a dosage form suitable for injection, inhalation, or direct contact with the nasal, urogenital, genital, or oral mucosa. Thus, the pharmaceutical composition can be in the form of, for example, a tablet, capsule, pill, powder, granule, suspension, emulsion, solution, gel (including hydrogel), paste, ointment, cream, plaster, liquid oral preparation, osmotic delivery device, suppository, enema, injectable solution, deposit, spray, preparation suitable for iontophoretic delivery, or aerosol. The compositions may be formulated in accordance with conventional pharmaceutical practice.

[0207] Generally, for use in therapy, the compounds described herein can be used alone or in combination with one or more other active agents. One example of another pharmaceutical agent to be combined with the compounds described herein would include pharmaceutical agents for treating the same indication. Another example of a pharmaceutical agent that may be combined with the compounds described herein would include pharmaceutical agents for treating different, but related, or associated symptoms or indications. Depending on the mode of administration, the compound will be formulated into a suitable composition to enable enhanced delivery. Each compound in the combination therapy can be formulated in various ways known in the art. For example, the first and second agents of the combination therapy can be formulated together or separately. Desirably, the first and second agents are formulated together for simultaneous or near-simultaneous administration.

[0208] The compounds of the present invention can be prepared and used as pharmaceutical compositions comprising an effective amount of a compound described herein and a pharmaceutically acceptable carrier or excipient, as is well known in the art. In some embodiments, the composition comprises at least two different pharmaceutically acceptable excipients or carriers.

[0209] The formulation can be prepared in a manner suitable for systemic administration or local or topical administration. Systemic formulations include those designed for injection (e.g., intramuscular, intravenous, or subcutaneous injection). Alternatively, systemic formulations can be prepared for transdermal, transmucosal, or oral administration. The formulation will generally include a diluent, and optionally, adjuvants, buffers, preservatives, and the like. The compound can also be administered in a liposomal composition or as a microemulsion.

[0210] For injection, the preparations can be prepared in conventional forms, either as liquid solutions or suspensions, or as solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable pharmaceutical additives include, for example, water, saline, dextrose, glycerol, and the like. Such compositions can also contain varying amounts of nontoxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and the like (e.g., sodium acetate, sorbitan monolaurate, etc.).

[0211] Various sustained drug release systems have also been devised, see, for example, U.S. Patent No. 5,624,677, which is incorporated herein by reference.

[0212] Systemic administration can also include relatively non-invasive methods, such as using suppositories, transdermal patches, transmucosal delivery, and intranasal administration. Oral administration of the compounds of the present invention is also suitable. Suitable forms include syrups, capsules, and tablets, as understood in the art.

[0213] Each compound of the combination therapy can be formulated in a variety of ways known in the art, as described herein, For example, the first and second agents of the combination therapy can be formulated together or separately.

[0214] Individually or separately formulated drugs can be packaged together as a kit. Examples include, but are not limited to, a kit containing two pills, a kit containing a pill and a powder, a kit containing a suppository and a liquid in a vial, a kit containing two topical creams, etc. The kit can include optional components useful for administering a unit dose to a subject, such as a vial for reconstituting a powder form, a syringe for injection, a customized IV delivery system, an inhaler, etc. Furthermore, a unit dose kit can include instructions for preparing and administering the composition. The kit can be manufactured as a single-use unit dose for a single subject, or as a multiple-use kit for a specific subject (either a fixed dose or where the potency of the individual compounds may vary over the course of treatment), or the kit can contain multiple doses suitable for administration to multiple subjects ("bulk packaging"). The components of the kit can be packaged together in cartons, blister packs, bottles, tubes, and the like.

[0215] Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. Such excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugars, mannitol, microcrystalline cellulose, starches (including potato starch), calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate), granulating and disintegrating agents (e.g., cellulose derivatives (including microcrystalline cellulose), starches (including potato starch), croscarmellose sodium, alginate esters, or alginic acid), binders (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethylcellulose, methylcellulose, optionally substituted hydroxylpropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol), and lubricants, glidants, and anti-adherents (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients may be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.

[0216] Two or more compounds may be mixed together and contained in a tablet, capsule, or other vehicle, or may be distributed. In one example, a first compound is contained in the interior of a tablet and a second compound is contained on the outside, so that a substantial portion of the second compound is released before the first compound is released.

[0217] Formulations for oral use may be provided as chewable tablets, or as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin, or olive oil). Powders, granules, and pellets can be prepared in a conventional manner using the ingredients described above for tablets and capsules, for example, using a mixer, fluidized bed apparatus, or spray-drying equipment.

[0218] Dissolution or diffusion-controlled release can be achieved by using a suitable coating on the compound's tablet, capsule, pellet, or granule formulation, or by incorporating the compound into a suitable matrix. Controlled-release coatings can include one or more of the coating materials described above and / or, for example, shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resin, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, optionally substituted 2-hydroxyl methacrylate, methacrylate hydrogel, 1,3 butylene glycol, ethylene glycol methacrylate, and / or polyethylene glycol. In controlled release matrix formulations, the matrix material may also include, for example, hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and / or halogenated fluorocarbons.

[0219] Liquid forms into which the compounds and compositions of the present invention may be incorporated for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions containing edible oils (such as cottonseed oil, sesame oil, coconut oil, or peanut oil), as well as elixirs and similar pharmaceutical vehicles.

[0220] Generally, when administered to humans, the oral dose of any of the combination compounds of the present invention will depend on the properties of such compounds, and those skilled in the art can easily determine such oral dose.Typically, such dose is usually about 0.001 mg to 2000 mg / day, preferably about 1 mg to 1000 mg / day, more preferably about 5 mg to 500 mg / day.A dose of up to 200 mg / day may be required.

[0221] Each drug in the combination therapy described herein can be administered independently 1 to 4 times daily for 1 day to 1 year, or even for the life of the subject. Chronic, long-term administration may also be indicated.

[0222] The following examples are intended to illustrate the synthesis of a representative number of compounds and their use in forming a ternary complex between CYPA and KRAS G12C. Therefore, these examples are intended to be illustrative and not limiting of the present invention. Additional compounds not specifically exemplified can be synthesized using conventional methods in combination with the methods described herein. Furthermore, other RAS proteins (such as KRAS G13C, NRAS G12C, NRAS G13C, HRAS G12C, or HRAS G13C) can also be used to form a ternary complex.

[0223] Treatment method In some embodiments, the present invention discloses a method for treating a disease or disorder characterized by aberrant RAS activity due to a RAS mutant. In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, small cell lung cancer, acute myeloid leukemia, multiple myeloma, thyroid adenocarcinoma, myelodysplastic syndrome, or lung squamous cell carcinoma. In some embodiments, the aberrant RAS activity is due to a RAS G12C mutation. In some embodiments, the aberrant RAS activity is due to a RAS G13C mutation. In some embodiments, the aberrant RAS activity is due to a KRAS G12C mutation. In some embodiments, the aberrant RAS activity is due to a KRAS G13C mutation. In some embodiments, the aberrant RAS activity is due to an HRAS G12C mutation. In some embodiments, the aberrant RAS activity is due to an HRAS G13C mutation. In some embodiments, the aberrant RAS activity is due to an HRAS G12C mutation. In some embodiments, the aberrant RAS activity is due to an HRAS G13C mutation. In some embodiments, the aberrant RAS activity is due to an HRAS G12C mutation. In some embodiments, the aberrant RAS activity is due to an HRAS G13C mutation.

[0224] In some embodiments, the present invention discloses a method for treating a disease or disorder characterized by aberrant or unwanted BRAF-RAS binding, the method comprising contacting a cell with a compound of the present invention (or any pharmaceutical composition containing such a compound). In some embodiments, the disease is characterized by aberrant or unwanted binding between BRAF and a mutant RAS protein. In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, small cell lung cancer, acute myeloid leukemia, multiple myeloma, thyroid adenocarcinoma, myelodysplastic syndrome, or lung squamous cell carcinoma. In some embodiments, the aberrant RAS activity is due to a RAS G12C mutation. In some embodiments, the aberrant RAS activity is due to a RAS G13C mutation. In some embodiments, the aberrant RAS activity is due to a KRAS G12C mutation. In some embodiments, the aberrant RAS activity is due to a KRAS G13C mutation. In some embodiments, the aberrant RAS activity is due to an NRAS G12C mutation. In some embodiments, the aberrant RAS activity is due to an NRAS G13C mutation. In some embodiments, the aberrant RAS activity is due to an HRAS G12C mutation. In some embodiments, the aberrant RAS activity is due to an HRAS G13C mutation.

[0225] In some embodiments, the present invention discloses a method for treating a disease or disorder characterized by aberrant or undesirable pERK expression, the method comprising contacting a cell with an effective amount of a compound of the present invention (or any pharmaceutical composition containing such a compound). In some embodiments, the aberrant or undesirable pERK expression is induced by a mutant RAS protein. In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, small cell lung cancer, acute myeloid leukemia, multiple myeloma, thyroid adenocarcinoma, myelodysplastic syndrome, or lung squamous cell carcinoma. In some embodiments, the mutant RAS that induces pERK expression has a G12C mutation. In some embodiments, the mutant RAS that induces pERK expression has a G13C mutation. In some embodiments, the mutant RAS activity is due to a KRAS G12C mutation. In some embodiments, the mutant RAS activity is due to a KRAS G13C mutation. In some embodiments, the mutant RAS activity is due to an NRAS G12C mutation. In some embodiments, the mutant RAS that induces pERK expression is due to an NRAS G13C mutation. In some embodiments, the mutant RAS activity is due to a KRAS G12C mutation. In some embodiments, the mutant RAS that induces pERK expression is due to a KRAS G13C mutation.

[0226] In some embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising such compounds or salts, and methods provided herein can be used to treat various cancers, including tumors (such as lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc.). More specifically, cancers that can be treated by the compounds of the present invention or salts thereof, pharmaceutical compositions comprising such compounds or salts, and methods of the present invention include, but are not limited to, tumor types (such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate, and thyroid carcinomas and sarcomas). Other cancers include, for example, the following: Heart, for example: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung, for example: bronchial carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitin hamartoma, mesothelioma, Gastrointestinal, for example: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), Genitourinary system, for example: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma), Liver, for example: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, Biliary tract, for example: gallbladder cancer, ampullary cancer, bile duct cancer, Bone, for example: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (cartilaginous exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; Nervous system, for example: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, neurofibromatosis type 1, meningioma, glioma, sarcoma), Gynecological system, for example: uterus (endometrial cancer, uterine cancer, endometrial cancer of the uterine corpus), cervix (cervical cancer, preneoplastic cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma), fallopian tube (carcinoma), Hematological system, for example: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), Skin, for example: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, and Adrenal gland, for example: neuroblastoma.

[0227] Also provided is a method for inhibiting Ras protein in cells, comprising contacting cells with an effective amount of the compound of the present invention or its pharmaceutically acceptable salt.Also provided is a method for inhibiting RAF-Ras binding, comprising contacting cells with an effective amount of the compound of the present invention or its pharmaceutically acceptable salt.Cells can be cancer cells.Cancer cells can be any type of cancer described herein.

[0228] Combination therapy It will be understood that the compounds and pharmaceutical compositions of the present invention can be formulated and used in combination therapy, i.e., such compounds and pharmaceutical compositions can be formulated with one or more other desired therapeutic agents or administered simultaneously with, before, or after one or more other desired therapeutic agents or medical procedures. The specific therapeutic (therapeutic agent or treatment) combination to be used in a combination regimen will take into account the compatibility of the desired therapeutic agents and / or procedures and the desired therapeutic effect to be achieved. It will also be understood that the treatments used can achieve the desired effect for the same disorder or can achieve different effects (e.g., control of any adverse effects).

[0229] In some embodiments of the methods described herein, the method may further include an additional therapeutic agent. For example, in the methods of the present invention, the compound of the present invention may be used alone or in combination with one or more additional therapies (e.g., non-drug therapies or therapeutic agents). The dose of one or more of the additional therapies (e.g., non-drug therapies or therapeutic agents) may be reduced from the standard dose when administered alone. For example, the dose may be empirically determined from the drug combination and permutation, or may be estimated by isobologram analysis (e.g., Black et al., Neurology 65:S3-S6 (2005)).

[0230] The compounds of the present invention can be administered before, after, or simultaneously with one or more such additional treatments. When a dose of a compound of the present invention is combined with a dose of one or more additional treatments (e.g., non-drug treatments or therapeutic agents), a therapeutic effect (e.g., a synergistic or additive therapeutic effect) is obtained. The compounds of the present invention and the additional treatments (e.g., anticancer agents) can be administered together (e.g., in a unit pharmaceutical composition) or separately, and if administered separately, can be administered simultaneously or sequentially. Such sequential administration can be performed close in time or separated in time.

[0231] In some embodiments, the additional treatment is the administration of a side effect limiting agent (e.g., an agent intended to reduce the incidence or severity of the side effects of the treatment). For example, in some embodiments, the compounds of the present invention can also be used in combination with a therapeutic agent that treats nausea. Examples of agents that can be used to treat nausea include dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof.

[0232] In some embodiments, the one or more additional therapies include a non-drug treatment (e.g., surgery or radiation therapy). In some embodiments, the one or more additional therapies include a therapeutic agent (e.g., a compound or biologic that is an anti-angiogenic agent, a signal transduction inhibitor, an anti-proliferative agent, a glycolysis inhibitor, or an autophagy inhibitor). In some embodiments, the one or more additional therapies include a non-drug treatment (e.g., surgery or radiation therapy) and a therapeutic agent (e.g., a compound or biologic that is an anti-angiogenic agent, a signal transduction inhibitor, an anti-proliferative agent, a glycolysis inhibitor, or an autophagy inhibitor). In other embodiments, the one or more additional therapies include two therapeutic agents. In yet other embodiments, the one or more additional therapies include three therapeutic agents. In some embodiments, the one or more additional therapies include four or more therapeutic agents.

[0233] Non-drug treatment Examples of non-drug treatments include, but are not limited to, radiation therapy, cryotherapy, hyperthermia, surgery (eg, surgical removal of tumor tissue), and T cell adoptive transfer (ACT) therapy.

[0234] In some embodiments, the compounds of the present invention may be used as adjuvant therapy after surgery, hi some embodiments, the compounds of the present invention may be used as neoadjuvant therapy before surgery.

[0235] Radiation therapy can be used to inhibit abnormal cell growth or treat hyperproliferative disorders (such as cancer) in a subject (e.g., a mammal (e.g., a human)). Techniques for administering radiation therapy are known in the art. Radiation therapy can be administered by one of several methods or a combination of methods (including, but not limited to, external beam radiation therapy, internal beam radiation therapy, interstitial beam radiation therapy, stereotactic radiotherapy, systemic radiotherapy, radiotherapy, and permanent or temporary interstitial brachytherapy). As used herein, the term "brachytherapy" refers to radiation therapy delivered by spatially confined radioactive material inserted into the body or near the site of a tumor or proliferative tissue disease. The term is intended to include, but is not limited to, exposure to radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioactive isotopes of Lu). Radiation sources suitable for use as cell conditioners of the present invention include both solid and liquid sources. By way of non-limiting example, the radiation source can be a radionuclide (such as I-125, I-131, Yb-169, Ir-192 (as a solid source), I-125 (as a solid source)) or other radionuclide that emits photons, beta particles, gamma rays, or other therapeutic radiation. The radioactive material can also be a fluid prepared from any solution of radionuclide(s) (e.g., a solution of I-125 or I-131). Alternatively, a radioactive fluid can be produced using a slurry of a suitable fluid containing small particles of a solid radionuclide (such as Au-198 or Y-90). Furthermore, the radionuclide(s) can be embodied in a gel or radioactive microspheres.

[0236] In some embodiments, the compounds of the present invention can enhance the sensitivity of abnormal cells to treatment with radiation for the purpose of killing or inhibiting the proliferation of such cells. Thus, the present invention further relates to a method for enhancing the sensitivity of abnormal cells in a mammal to treatment with radiation, the method comprising administering to the mammal a compound of the present invention in an amount effective to enhance the sensitivity of the abnormal cells to treatment with radiation. The amount of the compound in this method can be determined according to the means for ascertaining the effective amount of such compounds described herein. In some embodiments, the compounds of the present invention can be used as adjuvant therapy after radiation therapy or neoadjuvant therapy before radiation therapy.

[0237] In some embodiments, the non-drug treatment is T cell adoptive transfer (ACT) therapy. In some embodiments, the T cells are activated T cells. The T cells can be modified to express a chimeric antigen receptor (CAR). CAR-modified T (CAR-T) cells can be generated by any method known in the art. For example, CAR-T cells can be generated by introducing an appropriate expression vector encoding a CAR into T cells. Prior to expanding and genetically modifying the T cells, a source of T cells is obtained from a subject. T cells can be obtained from many sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from an infection site, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments of the present invention, any number of T cell lines available in the art can be used. In some embodiments, the T cells are autologous T cells. Activation and expansion of T cells can occur either before or after genetically modifying the T cells to express a desired protein (e.g., a CAR), and this activation and expansion is generally described in, e.g., U.S. Patent Nos. 6,352,694, 6,534,055, 6,905,680, 6,692,964, 5,858,358, 6,858,358, and 6,858,358. The method is carried out using the methods described in US Pat. Nos. 87,466, 6,905,681, 7,144,575, 7,067,318, 7,172,869, 7,232,566, 7,175,843, 7,572,631, 5,883,223, 6,905,874, 6,797,514, and 6,867,041.

[0238] therapeutic agent The therapeutic agent can be a compound used in the treatment of cancer or a condition associated therewith.

[0239] For example, the therapeutic agent can be a steroid. Thus, in some embodiments, the one or more additional therapies include a steroid. Suitable steroids include, but are not limited to, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fiucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluocortin acetate, fluocortin butyl, fluocortolone, fluorometholone, fluperolone ... These may include ruprednidene, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednivar, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts or derivatives thereof.

[0240] Additional examples of therapeutic agents that can be used in combination therapy with the compounds of the invention include compounds described in the following patents: U.S. Patent Nos. 6,258,812, 6,630,500, 6,515,004, 6,713,485, 5,521,184, 5,770,599, 5,747,498, 5,990,141, 6,235,764, and 8,623,885. and international patent applications WO01 / 37820, WO01 / 32651, WO02 / 68406, WO02 / 66470, WO02 / 55501, WO04 / 05279, WO04 / 07481, WO04 / 07458, WO04 / 09784, WO02 / 59110, WO99 / 45009, WO00 / 59509, WO99 / 61422, WO00 / 12089, and WO00 / 02871.

[0241] The therapeutic agent can be a biologic (e.g., a cytokine, such as an interferon or an interleukin (IL-2, etc.)) used in the treatment of cancer or symptoms associated therewith. In some embodiments, the biologic is an immunoglobulin-based biologic (e.g., a monoclonal antibody (e.g., a humanized antibody, fully human antibody, Fc fusion protein, or functional fragment thereof)) that agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important to cancer. Antibody-drug conjugates are also included.

[0242] The therapeutic agent can be a T cell checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody, such as a monoclonal antibody). The antibody can be, for example, a humanized antibody or a fully human antibody. In some embodiments, the checkpoint inhibitor is a fusion protein (e.g., an Fc receptor fusion protein). In some embodiments, the checkpoint inhibitor is an agent (e.g., an antibody) that interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent (e.g., an antibody) that interacts with a ligand of a checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA-4 antibody or fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PDL-1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL-2 (e.g., a PDL-2 / Ig fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, a B-7 family ligand, or a combination thereof.In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), PD-L1 antibodies (e.g., avelumab, durvalumab, atezolizumab, pidilizumab, JNJ-63723283 (JNJ), BGB-A317 (BeiGene & Celgene) etc.) or Preusser, M. et. al. (2015) Nat. Rev. Neurol. (including, but not limited to, ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MED14736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, 1-7F9, and KW-6002).

[0243] The therapeutic agent can be an anti-TIGIT antibody (such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A, or OMP-313M32 (etigilimab)).

[0244] The therapeutic agent can be an agent for treating cancer or a condition associated therewith (e.g., a cytotoxic agent, a non-peptide small molecule, or other compound useful in treating cancer or a condition associated therewith (collectively, "anti-cancer agent"). The anti-cancer agent can be, for example, a chemotherapeutic agent or a targeted therapeutic agent.

[0245] Anticancer drugs include mitotic inhibitors, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione-substituted ureas, methylhydrazine derivatives, adrenocortical suppressants, corticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Other anticancer drugs include leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. In some embodiments, the one or more additional treatments include two or more anticancer drugs. Two or more anticancer drugs can be used in a cocktail to be administered in combination, or can be used in separate administration.Suitable dosing regimens for combined anticancer drugs are known in the art and are described, for example, in Saltz et al., Proc.Am.Soc.Clin.Oncol.18:233a (1999) and Douillard et al., Lancet 355(9209):1041-1047 (2000).

[0246] Other examples of anti-cancer drugs include, but are not limited to, Gleevec® (imatinib mesylate), Kyprolis® (carfilzomib), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), alkylating agents (such as thiotepa and cyclophosphamide), alkyl sulfonates (such as busulfan, improsulfan, and piposulfan), aziridines (benzodopa, carboquone, mesylate), and the like. uredopa, and uredopa), ethyleneimines and methylamelamines (including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine), acetogenins (especially bullatacin and bullatacinone), camptothecins (including the synthetic analog topotecan), bryostatin, kallistatin, CC-1065 (and its adzes). synthetic analogs of methicone, carzelesin, and biceresin), cryptophycins (specifically, cryptophycin 1 and cryptophycin 8), dolastatins, duocarmycins (including synthetic analogs (KW-2189 and CB1-TM1)), eleutherobin, pancratistatin, sarcodictyin A, spongistatins, nitrogen mustards (chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, amine, mechlorethamine oxide hydrochloride, melphalan, novoenbiquin, phenesterine, prednimustine, trofosfamide, uracil mustard, etc.), nitrosoureas (such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine), antibiotics (such as enediyne antibiotics (e.g., calicheamicins, such as calicheamicin gamma II and calicheamicin omega II (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994))), dynemycins (such as dynemycin A), bisphosphonates (such as clodronate), esperamicin, neocarzinostatin chromophore and related enediyne antibiotic chromophores, aclacinomycin,Actinomycin, autramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, caminomycin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, adriamycin (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marceloma isin, mitomycin (such as mitomycin C), mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rhodrubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, antimetabolites (such as methotrexate and 5-fluorouracil (5-FU)), folic acid analogs (such as denopterin, pteropterin, trimetrexate), purine analogs (such as fludarabine, 6-methylpropional thiamiprine, thioguanine, etc.), pyrimidine analogues (ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, etc.), androgens (calsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone, etc.), adrenocortical inhibitors (aminoglutethimide, mitotane, trilostane, etc.), folic acid supplements (folinic acid, etc.), aceglatone, aldophosphamide glycosides, aminolevulinic acid, enilu Rasil, amsacrine, Bestravsil, bisantrene, edatraxate, defofamine, demecolcine, diaziquone, elfotimine, elliptinium acetate, epothilone (epothilone B, etc.), etoglucide, gallium nitrate, hydroxyurea, lentinan, lonidamine, maytansinoids (maytansine and ansamitocin, etc.), mitoguazone, mitoxantrone, mopidamol, nitracrine, pentostatin, fenamet, pirarubicin, losoxantrone,Podophyllic acid, 2-ethylhydrazide, procarbazine, PSK® polysaccharide complex (JHS Natural Products, Eugene, OR), razoxane, rhizoxin, schizophyllan, spirogermanium, tenuazonic acid, triazicon, 2,2',2''-trichlorotriethylamine, trichothecenes (such as T-2 toxin, verracurin A, roridin A, and anguidine), urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside ("Ara"). -C"), cyclophosphamide, thiotepa, taxoids (e.g., Taxol® (paclitaxel), Abraxane® (a cremophor-free albumin-bound nanoparticle formulation of paclitaxel), and Taxotere® (doxetaxel)), chloranbucil, tamoxifen (Nolvadex™), raloxifene, aromatase-inhibiting 4(5)-imidazoles, 4-hydroxybenzoates, Cytamoxifen, trioxifene, keoxifene, LY117018, onapristone, toremifene (Fareston®), flutamide, nilutamide, bicalutamide, leuprolide, goserelin, chlorambucil, Gemzar® gemcitabine, 6-thioguanine, mercaptopurine, platinum coordination complexes (such as cisplatin, oxaliplatin, and carboplatin), vinblastine, platinum, etoposide (VP-16), ifosfamide, mitoxantrone , vincristine, Navelbine® (vinorelbine), novantrone, teniposide, edatrexate, daunomycin, aminopterin, ibandronate, irinotecan (e.g., CPT-11), the topoisomerase inhibitor RFS2000, difluoromethylornithine (DMFO), retinoids (such as retinoic acid), esperamicin, capecitabine (e.g., Xeloda®), and pharmaceutically acceptable salts of any of the above.

[0247] Additional examples of anti-cancer drugs include, but are not limited to, trastuzumab (Herceptin®), bevacizumab (Avastin®), cetuximab (Erbitux®), rituximab (Rituxan®), Taxol®, Arimidex®, ABVD, avicin, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alpha Radin, alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxin, antineoplastic agents (e.g., cell cycle non-specific antineoplastic agents and other antineoplastic agents described herein), antitumor herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW2992, biricodar, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapeutic ), calyculin, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, eribulin, exatecan, exisulind, ferruginol, forodesin, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucanton, lurtotecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxin These include cell, PAC-1, pawpaw, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, and zosquidar.

[0248] Further examples of anti-cancer drugs include, but are not limited to, natural products (e.g., vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), epidipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin), mitomycin, enzymes (e.g., enzymes that metabolize L-asparagine systemically and do not metabolize asparagine themselves), and steroids (e.g., steroids that metabolize L-asparagine systemically and do not metabolize asparagine themselves). L-asparaginase, which eliminates cells that do not have the ability to synthesize glutamate), antiplatelet agents, antiproliferative / antimitotic alkylating agents, such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide and analogs, melphalan, and chlorambucil), ethyleneimines and methylmelamines (e.g., hexamethylmelamine and thiotepa), CDK inhibitors (e.g., CDK4 / 6 inhibitors (e.g., palbociclib), seliciclib, UCN-01, P1446A-05, PD-0332991, dinaciclib, P27-00, AT-751), 9, RGB286638, and SCH727965), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogs, and streptozocin), trazene-dacarbazine (DTIC), antiproliferative / antimitotic antimetabolites (folic acid analogs, pyrimidine analogs (e.g., fluorouracil, floxuridine, and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastomose, thiazolinone ... trozole, exemestane, and letrozole), and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidan, suberoylanilide hydroxamic acid, vorinostat, LBH589, romidepsin, ACY-1215, and panobinostat), mTOR inhibitors (e.g., bistusertib, temsirolimus, everolimus, ridaforolimus,and sirolimus), KSP (Eg5) inhibitors (e.g., Array520), DNA binders (e.g., Zalypsis®), PI3K inhibitors (PI3K delta inhibitors (e.g., GS-1101 and TGR-1202), PI3K delta inhibitors and PI3K gamma inhibitors (e.g., CAL-130), copanlisib, alpelisib, and idelalisib), multikinase inhibitors (e.g., TG02 and sorafenib), hormones (e.g., estrogen) and hormone agonists (such as luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide, and triptorelin)), BAFF-neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNT0328), telomerase inhibitors (e.g., GRN163L), auroraquinone (AQP), and enzyme inhibitors (e.g., MLN8237), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38)), anti-CS1 (e.g., elotuzumab), HSP90 inhibitors (e.g., 17AAG and KOS953), P13K / Akt inhibitors (e.g., perifosine), Akt inhibitors (e.g., GSK-2141795), PKC inhibitors (e.g., enzastaurin), FTIs (e.g., Zarnestra), (trademark), anti-CD138 (e.g., BT062), Torcl / 2-specific kinase inhibitors (e.g., INK128), agents targeting the ER / UPR (e.g., MKC-3946), cFMS inhibitors (e.g., ARRY-382), JAK1 / 2 inhibitors (e.g., CYT387), PARP inhibitors (e.g., olaparib and veliparib (ABT-888)), and BCL-2 antagonists.

[0249] In some embodiments, the anti-cancer agent is selected from mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, Navelbine®, sorafenib, or any analog or derivative of the foregoing.

[0250] In some embodiments, the anti-cancer agent is a HER2 inhibitor. Examples of HER2 inhibitors include, but are not limited to, monoclonal antibodies (such as trastuzumab (Herceptin®) and pertuzumab (Perjeta®)), small molecule tyrosine kinase inhibitors (such as afatinib, gefitinib (Iressa®), erlotinib (Tarceva®), pilitinib, CP-654577, CP-724714, canertinib (CI1033), HKI-272, lapatinib (GW-572016), Tykerb®), PKI-166, AEE788, BMS-599626, HKI-357, BIBW2992, ARRY-334543, JNJ-26483327, and JNJ-26483327).

[0251] In some embodiments, the anticancer agent is an ALK inhibitor. Examples of ALK inhibitors include, but are not limited to, ceritinib, TAE-684 (NVP-TAE694), PF02341066 (crizotinib or 1066), alectinib, brigatinib, entrectinib, ensartinib (X-396), lorlatinib, ASP3026, CEP-37440, 4SC-203, TL-398, PLB1003, TSR-011, CT-707, TPX-0005, and AP26113. Additional examples of ALK kinase inhibitors are described in Examples 3-39 of WO05016894.

[0252] In some embodiments, the anti-cancer agent is an inhibitor of a downstream member of a receptor tyrosine kinase (RTK) / growth factor receptor (e.g., an SHP2 inhibitor (e.g., SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068), an SOS1 inhibitor (e.g., BI-1701963, BI-3406), a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, or an mTOR inhibitor (e.g., an mTORC1 inhibitor). In some embodiments, the anti-cancer agent is an additional Ras inhibitor (e.g., AMG510, MRTX1257, MRTX849, JNJ4699157, LY3499446, ARS-3248, or ARS-1620), or a Ras vaccine, or another therapeutic modality designed to directly or indirectly reduce the oncogenic activity of Ras.

[0253] In some embodiments, therapeutic agents that can be used in combination with compounds of the invention are inhibitors of the MAP kinase (MAPK) pathway (i.e., "MAPK inhibitors"). MAPK inhibitors include, but are not limited to, one or more of the MAPK inhibitors described in Cancers (Basel) 2015 Sep;7(3):1758-1784. For example, MAPK inhibitors include trametinib, binimetinib, selumetinib, cobimetinib, LErafAON (NeoPharm), ISIS5132, vemurafenib, pimasertib, TAK733, RO4987655 (CH4987655), CI-1040, PD-0325901, CH5126766, MAP855, AZD6244, refametinib (RDEA119 / BAY86-9766), GDC-0973 / XL581, AZD8330 (ARRY-424704 / ARRY-704), and RO5126766 (Roche, PLoS One. 2014 Nov. 25;9(11)), and GSK1120212 (i.e., JTP-74057, described in Clin Cancer Res. 2011 Mar 1;17(5):989-1000). The MAPK inhibitor can be PLX8394, LXH254, GDC-5573, or LY3009120.

[0254] In some embodiments, the anticancer drug is a disruptor or inhibitor of the RAS-RAF-ERK signaling pathway, the PI3K-AKT-TOR signaling pathway, or the PI3K-AKT signaling pathway. The PI3K / AKT inhibitor may include, but is not limited to, one or more of the PI3K / AKT inhibitors listed in Cancers (Basel) 2015 Sep;7(3):1758-1784. For example, the PI3K / AKT inhibitor may be selected from one or more of NVP-BEZ235, BGT226, XL765 / SAR245409, SF1126, GDC-0980, PI-103, PF-04691502, PKI-587, and GSK2126458.

[0255] In some embodiments, the anti-cancer agent is a PD-1 antagonist or a PD-L1 antagonist.

[0256] In some embodiments, the additional therapeutic agent includes an ALK inhibitor, a HER family inhibitor, an EGFR inhibitor, an IGF-1R inhibitor, a MEK inhibitor, a PI3K inhibitor, an AKT inhibitor, a TOR inhibitor, an MCL-1 inhibitor, a BCL-2 inhibitor, an SHP2 inhibitor, a proteasome inhibitor, and an immunotherapy. In some embodiments, the therapeutic agent can be a pan-RTK inhibitor (such as afatinib).

[0257] IGF-1R inhibitors include linsitinib or a pharmaceutically acceptable salt thereof.

[0258] EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNA. Useful antibody inhibitors of EGFR include cetuximab (Erbitux®), panitumumab (Vectibix®), zalutumumab, nimotuzumab, and matuzumab. Other antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block the activation of EGFR by its natural ligand. Examples of antibody-based EGFR inhibitors include, but are not limited to, those described in Modjtahedi et al., Br. J. Cancer 1993, 67:247-253; Teramoto et al., Cancer 1996, 77:639-645; Goldstein et al., Clin. Cancer Res. 1995, 1:1311-1318; Huang et al., 1999, Cancer Res. 15:59(8):1935-40; and Yang et al., Cancer Res. 1999, 59:1236-1243. The EGFR inhibitor can be the monoclonal antibody Mab E7.6.3 (Yang, 1999, supra) or Mab C225 (ATCC Accession No. HB-8508), or an antibody or antibody fragment having the binding specificity thereof.

[0259] Small molecule antagonists of EGFR include gefitinib (Iressa®), erlotinib (Tarceva®), and lapatinib (TykerB®). See, e.g., Yan et al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005, 39(4):565-8, and Paez et al., EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004, 304(5676):1497-500. Further examples of small molecule EGFR inhibitors include, but are not limited to, any of the EGFR inhibitors described in the following patent publications, and all pharmaceutically acceptable salts of such EGFR inhibitors: EP 0520722, EP 0566226, WO 96 / 33980, U.S. Pat. No. 5,747,498, WO 96 / 30347, EP 0787772, WO 97 / 30034, WO 97 / 30044, WO 97 / 38994, WO 97 / 49688, EP 837063, WO 98 / 02434, WO 97 / 38983, WO 95 / 19774, WO 95 / 19970, WO 97 / 13771, WO 98 / 02437, WO 98 / 02437, WO 98 / 02438, WO 98 / 02439 ... 438, WO97 / 32881, DE19629652, WO98 / 33798, WO97 / 32880, WO97 / 32880, EP682027, WO 97 / 02266, WO97 / 27199, WO98 / 07726, WO97 / 34895, WO96 / 31510, WO98 / 14449, WO98 / 14 450, WO98 / 14451, WO95 / 09847, WO97 / 19065, WO98 / 17662, U.S. Patent No. 5,789,427, U.S. Patent No. 5,650,415, U.S. Patent No. 5,656,643, WO99 / 35146, WO99 / 35132, WO99 / 07701, and WO92 / 20642.Additional examples of small molecule EGFR inhibitors include, but are not limited to, any of the EGFR inhibitors described in Traxler et al., Exp. Opin. Ther. Patents 1998, 8(12):1599-1625. In some embodiments, the therapeutic agent is lapatinib, neratinib, or afatinib.

[0260] MEK inhibitors include, but are not limited to, pimasertib, selumetinib, cobimetinib (Cotellic®), trametinib (Mekinist®), and binimetinib (Mektovi®). In some embodiments, the MEK inhibitor targets a MEK mutation that is a Class I MEK1 mutation selected from D67N, P124L, P124S, and L177V. In some embodiments, the MEK mutation is a Class II MEK1 mutation selected from ΔE51-Q58, ΔF53-Q58, E203K, L177M, C121S, F53L, K57E, Q56P, and K57N.

[0261] PI3K inhibitors include, but are not limited to, wortmannin, 17-hydroxywortmannin analogs described in WO 06 / 044453, 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as pictilisib or GDC-0941, described in WO 09 / 036082 and WO 09 / 055730), 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidomethyl]-2,3-dihydro-2-methyl-4-oxo-3-methyl-2 ... (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (described in WO08 / 070740), LY294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (Axon Medchem), PI103 hydrochloride (3-[4-(4-morpholinylpyrido-[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol hydrochloride (available from Axon Medchem), PIK75 (2-methyl-5-nitro-2-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-1-methylhydrazide-benzenesulfonic acid, monohydrochloride) (available from Axon Medchem), PIK90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl)-nicotinamide (available from Axon Medchem), Medchem), AS-252424 (5-[1-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione (available from Axon Medchem), TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrinidin-4-one (available from Axon Medchem), XL-765, and XL-147. Other PI3K inhibitors include demethoxyviridine, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomid529, GSK1059615, ZSTK474, PWT33597, IC87114, TGI00-115, CAL263, PI-103, GNE-477, CUDC-907, and AEZS-136.

[0262] AKT inhibitors include, but are not limited to, Akt-1-1 (inhibits Akt1) (Barnett et al., Biochem. J. 2005, 385(Pt. 2):399-408), Akt-1-1,2 (inhibits Akt1 and 2) (Barnett et al., Biochem. J. 2005, 385(Pt. 2):399-408), API-59CJ-Ome (e.g., Jin et al., Br. J. Cancer 2004, 91:1808-12), 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO05 / 011700), indole-3-carbinol and its derivatives (e.g., U.S. Pat. No. 6,656,963, Sarkar and Li J Nutr. 2004, 134(12) Suppl):3493S-3498S), perifosine (e.g., disrupts membrane localization of Akt; Dasmahapatra et al. Clin. Cancer Res. 2004, 10(15):5242-52), phosphatidylinositol ether lipid analogs (e.g., Gills and Dennis Expert. Opin. Investig. Drugs 2004, 13:787-97), and triciribine (TCN or API-2 or NCI identifier: NSC154020, Yang et al., Cancer Res. 2004, 64:4394-9).

[0263] mTOR inhibitors include, but are not limited to, ATP-competitive mTORC1 / mTORC2 inhibitors, such as PI-103, PP242, PP30, Torin 1, FKBP12 enhancers, 4H-1-benzopyran-4-one derivatives, and rapamycin (also known as sirolimus) and its derivatives, including derivatives of rapamycin such as temsirolimus (Torisel®), everolimus, (Afinitor®, WO 94 / 09010), ridaforolimus (also known as deforolimus or AP23573), rapalogs (such as those disclosed in WO 98 / 02441 and WO 01 / 14387, e.g., AP23464 and AP23841), 40-(2-hydroxyethyl)rapamycin, 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (such as CC1779), 40-epi-(tetrazolyl)-rapamycin (also known as ABT578), 32-deoxorapamycin, 16-pentynyloxy-32(S)-dihydrorapanycin, derivatives disclosed in WO 05 / 005434, U.S. Pat. Nos. 5,258,389, 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842, and 5, 256,790, as well as those disclosed in WO94 / 090101, WO92 / 05179, WO93 / 111130, WO94 / 02136, WO94 / 02485, WO95 / 14023, WO94 / 02136, WO95 / 16691, WO96 / 41807, WO96 / 41807, and WO2018204416, as well as phosphorus-containing rapamycin derivatives (e.g., WO05 / 016252). In some embodiments, the mTOR inhibitor is a bivalent inhibitor (such as RMC-5552).

[0264] BRAF inhibitors that can be used in combination with the compounds of the invention include, for example, vemurafenib, dabrafenib, and encorafenib. BRAF can include a Class 3 BRAF mutation. In some embodiments, the Class 3 BRAF mutation is selected from one or more of the following amino acid substitutions in human BRAF: D287H, P367R, V459L, G466V, G466E, G466A, S467L, G469E, N581S, N581I, D594N, D594G, D594A, D594H, F595L, G596D, G596R, and A762E.

[0265] MCL-1 inhibitors include, but are not limited to, AMG-176, MIK665, and S63845. The myeloid cell leukemia-1 (MCL-1) protein is an important anti-apoptotic member of the B-cell lymphoma-2 (BCL-2) protein family. Overexpression of MCL-1 is closely associated with tumor progression and resistance, not only to conventional chemotherapy but also to targeted therapeutic agents, including BCL-2 inhibitors (such as ABT-263).

[0266] In some embodiments, the additional therapeutic agent is selected from the group consisting of a HER2 family inhibitor, a SHP2 inhibitor, a CDK4 / 6 inhibitor, an mTOR inhibitor, an SOS1 inhibitor, or a PD-L1 inhibitor. See, e.g., Hallin et al., Cancer Discovery, DOI:10.1158 / 2159-8290 (October 28, 2019) and Canon et al., Nature, 575:217 (2019).

[0267] Proteasome inhibitors include, but are not limited to, carfilzomib (Kyprolis®), bortezomib (Velcade®), and oprozomib.

[0268] Immunotherapies include, but are not limited to, monoclonal antibodies, immunomodulatory imides (IMiDs), GITR agonists, genetically engineered T cells (e.g., CAR-T cells), bispecific antibodies (e.g., BiTEs), and anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAG1, and anti-OX40 agents.

[0269] Immunomodulatory drugs (IMiDs) are a class of immunomodulators (drugs that modulate the immune response) that contain an imide group. The IMiD class includes thalidomide and its analogs (lenalidomide, pomalidomide, and apremilast).

[0270] Examples of anti-PD-1 antibodies and methods of their use are described in Goldberg et al., Blood 2007, 110(1):186-192, Thompson et al., Clin. Cancer Res. 2007, 13(6):1757-1761, and WO06 / 121168 A1), as well as elsewhere herein.

[0271] GITR agonists include, but are not limited to, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies) (such as the GITR fusion proteins described in U.S. Pat. No. 6,111,090, U.S. Pat. No. 8,586,023, WO2010 / 003118, and WO2011 / 090754), or antibodies described in, for example, U.S. Pat. No. 7,025,962, EP1947183, U.S. Pat. No. 7,812,135, U.S. Pat. No. 8,388,967, and the like. Nos. 8,591,886, 7,618,632, EP 1866339, and WO2011 / 028683, WO2013 / 039954, WO05 / 007190, WO07 / 133822, WO05 / 055808, WO99 / 40196, WO01 / 03720, W99 / 20758, WO06 / 083289, WO05 / 115451, and WO2011 / 051726.

[0272] Another example of a therapeutic agent that can be used in combination with the compounds of the present invention is an anti-angiogenic agent. Anti-angiogenic agents include, but are not limited to, in vitro synthetically prepared chemical compositions, antibodies, antigen-binding regions, radionuclides, and combinations and conjugates thereof. Anti-angiogenic agents can be agonists, antagonists, allosteric modulators, toxins, or more generally, agents that act to inhibit or stimulate their targets (e.g., activate or inhibit receptors or enzymes), thereby promoting cell death or inhibiting cell proliferation. In some embodiments, one or more additional treatments include an anti-angiogenic agent.

[0273] The antiangiogenic agent may be an MMP-2 (matrix metalloproteinase 2) inhibitor, an MMP-9 (matrix metalloproteinase 9) inhibitor, and a COX-II (cyclooxygenase 11) inhibitor. Examples of antiangiogenic agents include, but are not limited to, rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include alecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are those disclosed in WO96 / 33172, WO96 / 27583, WO98 / 07697, WO98 / 03516, WO98 / 34918, WO98 / 34915, WO98 / 33768, WO98 / 30566, WO90 / 05719, WO99 / 52910, WO99 / 52 889, WO99 / 29667, WO99007675, EP0606046, EP0780386, EP1786785, EP1181017, EP0818442, EP1004578, and US20090012085, as well as U.S. Patent Nos. 5,863,949 and 5,861,510. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1, and more preferably those that selectively inhibit MMP-2 or MMP-9 relative to other matrix metalloproteinases (i.e., MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors are AG-3340, RO32-3555, and RS13-0830.

[0274] Other examples of anti-angiogenic agents include KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen-binding regions that specifically bind to kinase domain receptors), anti-VEGF agents (e.g., antibodies or antigen-binding regions that specifically bind to VEGF (e.g., bevacizumab) or soluble VEGF receptors or their ligand-binding regions (e.g., VEGF-TRAP™)), and anti-VEGF receptor agents (e.g., antibodies or antigen-binding regions that specifically bind to VEGF receptors), EGFR inhibitors (e.g., antibodies or antigen-binding regions that specifically bind to EGFR), and anti-VEGF receptor agents (e.g., antibodies or antigen-binding regions that specifically bind to VEGF). or antigen-binding region) (Vectibix® (panitumumab), erlotinib (Tarceva®, etc.), anti-Ang1 and anti-Ang2 agents (e.g., antibodies or antigen-binding regions that specifically bind to or specifically bind to its receptor (e.g., Tie2 / Tek)), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind to Tie2 kinase). Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (US2003 / 0 162712, US 6,413,932), anti-TWEAK agents (e.g., specifically binding antibodies or antigen-binding regions or soluble TWEAK receptor antagonists; see US 6,727,225), ADAM disintegrin domains that antagonize integrin binding to its ligands (US 2002 / 0042368), specifically binding anti-eph receptor and / or anti-ephrin antibodies or antigen-binding regions (US 5,981,245, US 5,728,813, US 5,969,110 , 6,596,852, 6,232,447, 6,057,124, and their patent family members), as well as anti-PDGF-BB antagonists (e.g., antibodies or antigen-binding regions that specifically bind) and antibodies or antigen-binding regions that specifically bind to PDGF-BB ligands, and PDGFR kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind to PDGFR kinases). Additional anti-angiogenic agents include SD-7784 (Pfizer, USA), cilengitide (Merck KGaA, Germany,EPO 0770622), pegaptanib octasodium (Gilead Sciences, USA), alphastatin (BioActa, UK), M-PGA (Celgene, USA, US 5712291), ilomastat (Arriva, USA, US 5892112), emaxanib (Pfizer, USA, US 5792783), vatalanib (Novartis, Switzerland), 2-methoxyestradiol (EntreMed, USA), TLC ELL-12 (Elan, Ireland), anecortave acetate (Alcon, USA), alpha-D148 Mab (Amgen, USA), CEP-7055 (Cephalon, USA), anti-Vn Mab (Crucell, Netherlands), DAC antiangiogenic agent (ConjuChem, Canada), angiocidin (InKine Pharmaceutical, USA), KM-2550 (Kyowa Hakko, Japan), SU-0879 (Pfizer, USA), CGP-79787 (Novartis, Switzerland, EP 0970070), ARGENT technology (Ariad, USA), YIGSR-Stealth (Johnson & Johnson, USA), fibrinogen-E fragment (BioActa, UK), angiogenesis inhibitor (Trigen, UK), TBC-1635 (Encysive Pharmaceuticals, USA), SC-236 (Pfizer, USA), ABT-567 (Abbott, USA), metastatin (EntreMed, USA), maspin (Sosei, Japan), 2-methoxyestradiol (Oncology Sciences Corporation, USA), ER-68203-00 (IV AX, USA), BeneFin (Lane Labs, USA), Tz-93 (Tsumura, Japan), TAN-1120 (Takeda, Japan), FR-111142 (Fujisawa, Japan, JP 02233610), platelet factor 4 (RepliGen, USA, EP 407122), vascular endothelial growth factor antagonist (Borean, Denmark), bevacizumab (pINN) (Genentech,USA), angiogenesis inhibitors (SUGEN, USA), XL784 (Exelixis, USA), XL647 (Exelixis, USA), MAb, alpha5beta3 integrin, second generation (Applied Molecular Evolution, USA and MedImmune, USA), enzastaurin hydrochloride (Lilly, USA), CEP7055 (Cephalon, USA and Sanofi-Synthelabo, France), BC1 (Genoa Institute of Cancer Research, Italy), rBPI21 and BPI-derived antiangiogenic agents (XOMA, USA), PI88 (Progen, Australia), cilengitide (Merck KGaA, Germany; Munich Technical University, Germany, Scripps Clinic and Research Foundation, USA), AVE8062 (Ajinomoto, Japan), AS1404 (Cancer Research Laboratory, New New Zealand), SG292 (Telios, USA), endostatin (Boston Children's Hospital, USA), ATN161 (Attenuon, USA), 2-methoxyestradiol (Boston Children's Hospital, USA), ZD6474 (AstraZeneca, UK), ZD6126 (Angiogene Pharmaceuticals, UK), PPI2458 (Praecis, USA), AZD9935 (AstraZeneca, UK), AZD2171 (AstraZeneca, UK), vatalanib (pINN) (Novartis, Switzerland and Schering AG, Germany), tissue factor pathway inhibitor (EntreMed, USA), pegaptanib (Pinn) (Gilead Sciences, USA), xanthorrhizol (Yonsei University, South Korea), vaccine, gene-based, VEGF-2 (Scripps Clinic and Research Foundation, USA), SPV5.2 (Supratek,Canada), SDX103 (University of California at San Diego, USA), PX478 (ProlX, USA), metastatin (EntreMed, USA), troponin I (Harvard University, USA), SU6668 (SUGEN, USA), OXI4503 (OXiGENE, USA), o-guanidine (Dimensional Pharmaceuticals, USA), motuporamine C (British Columbia University, Canada), CDP791 (Celltech Group, UK), atiprimod (pINN) (GlaxoSmithKline, UK), E7820 (Eisai, Japan), CYC381 (Harvard University, USA), AE941 (Aeterna, Canada), vaccine, angiogenic agent (EntreMed, USA), urokinase-type plasminogen activator inhibitor (Dendreon, USA), oglufanide (pINN) (Melmotte, USA), HIF-1 alpha inhibitor (Xenova, UK), CEP5214 (Cephalon, USA), BAY RES 2622 (Bayer, Germany), angiocidin (InKine, USA), A6 (Angstrom, USA), KR31372 (Korea Research Institute of Chemical Technology, South Korea) Korea), GW2286 (GlaxoSmithKline, UK), EHT0101 (ExonHit, France), CP868596 (Pfizer, USA), CP564959 (OSI, USA), CP547632 (Pfizer, USA), 786034 (GlaxoSmithKline, UK), KRN633 (Kirin Brewery, Japan), drug delivery system, intraocular, 2-methoxyestradiol; Anginex (Maastricht University, Netherlands, and University of Minnesota, USA), ABT510 (Abbott, USA), AAL993 (Novartis, Switzerland), VEGI (ProteomTech,(USA), tumor necrosis factor-alpha inhibitors; SU11248 (Pfizer, USA and SUGEN USA), ABT518 (Abbott, USA), YH16 (Yantai Rongchang, China), S-3APG (Boston Children's Hospital, USA and EntreMed, USA), MAb, KDR (ImClone Systems, USA), MAb, alpha5beta (Protein Design, USA), KDR kinase inhibitor (Celltech Group, UK and Johnson & Johnson, USA), GFB116 (University of South Florida, USA and Yale University, USA), CS706 (Sankyo, Japan), combretastatin A4 prodrug (Arizona State University, USA), chondroitinase AC (IBEX, Canada), BAY RES 2690 (Bayer, Germany), AGM1470 (Harvard) University, USA, Takeda, Japan, and TAP, USA), AG13925 (Agouron, USA), tetrathiomolybdate (University of Michigan, USA), GCS100 (Wayne State University, USA), CV247 (Ivy Medical, UK), CKD732 (Chong Kun Dang, South Korea), irsogladine (Nippon Shinyaku, Japan), RG13577 (Aventis, France), WX360 (Wilex, Germany), squalamine (Genaera, USA), RPI4610 (Sirna, USA), heparanase inhibitor (InSight, Israel), KL3106 (Kolon, South Korea), honokiol (Emory University, USA), ZK CDK (Schering AG, Germany), ZK Angio (Schering AG, Germany), ZK229561 (Novartis, Switzerland, and Schering AG, Germany), XMP300 (XOMA, USA), VGA1102 (Taisho,Japan), VE-cadherin-2 antagonist (ImClone Systems, USA), vasostatin (National Institutes of Health, USA), Flk-1 (ImClone Systems, USA), TZ93 (Tsumura, Japan), tumstatin (Beth Israel Hospital, USA), truncated soluble FLT1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA), Tie-2 ligand (R, egeneron, USA), and thrombospondin 1 inhibitor (Allegheny Health, Education and Research Foundation, USA).

[0275] Another example of a therapeutic agent that can be used in combination with the compounds of the invention includes agents (e.g., antibodies, antigen-binding regions, or soluble receptors) that specifically bind to and inhibit the activity of growth factors, such as antagonists of hepatocyte growth factor (HGF, also known as scatter factor), and antibodies or antigen-binding regions that specifically bind to its receptor (c-Met).

[0276] Another example of a therapeutic agent that can be used in combination with the compounds of the present invention is an autophagy inhibitor. Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1, 5-amino-4-imidazolecarboxamide riboside (AICAR), okadaic acid, autophagy-inhibiting algal toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that increase cAMP levels (such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine). In addition, antisense or siRNA inhibitors that inhibit the expression of proteins (including, but not limited to, ATG5 (involved in autophagy)) can also be used. In some embodiments, one or more additional treatments include an autophagy inhibitor.

[0277] Another example of a therapeutic agent that can be used in combination with the compound of the present invention is an anti-neoplastic agent. In some embodiments, one or more additional treatments include an anti-neoplastic agent. Examples of anti-neoplastic agents include, but are not limited to, acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ancer, ancestim, aruglavin, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, and cytarabine. Oxfosfate, DA3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alpha, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emiteflu, epirubicin, epoetin beta, Etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin, gimeracil / oteracil / tegafur combination, glycopin, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronate, idarubicin, (imiquimod, interferon alpha, natural interferon alpha, interferon alfa) Fa-2, interferon alpha-2a, interferon alpha-2b, interferon alpha-Nl, interferon alpha-n3, interferon alphacon-1, natural interferon alpha, interferon beta, interferon beta-1a, interferon beta-1b, interferon gamma, natural interferon gamma-1a, interferon gamma-1b, interleukin-1 beta, iobenguane, irinotecan, irsogladine, lanreotide,LC9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon, leuprorelin, levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, millimostim, mismatched double-stranded RNA, mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartograstim, nedaplatin, nilutamide, no Scapine, novel erythropoiesis stimulator, NSC631570, octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronate, pegaspargase, peginterferon alfa-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonal antibody, polyethylene glycol interferon alfa-2a, porfimer sodium, raloxifene, raltitrexed, rasburiembodiment, etidronate Sodium Re186, R1I retinamide, rituximab, romurtide, samarium (Sm-153) lexidronam, sargramostim, sizofiran, sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa, topotecan, toremifene, tositumomab-iodine-131, trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, triphosphatase Tolerin, natural tumor necrosis factor alpha, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, viridine, zinostatin stimalamer, or zoledronic acid, abarelix, AE941 (Aeterna), ambamustine, antisense oligonucleotides, bcl-2 (Genta), APC8015 (Dendreon), decitabine, dexaminoglutethimide, diazicon, EL532 (Elan), EM800 (Endorecherche), eniluracil,Etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, galocitabine, gastrin-17 immunogen, HLA-B7 gene therapy (Vical), granulocyte-macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM862 (Cytran), interleukin-2, iproxifen, LDI200 (Milkhaus), religistim, lintuzumab, CA125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), idiotype 105AD7 MAb (CRC Technology), idiotype CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techni clone), polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), marimastat, menogaril, mitumomab, motexafine gadolinium, MX6 (Galderma), nelarabine, nolatrexed, P30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL172 (SR Pharma), SU5416 (SUGEN), TA077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, ethyl etiopropyl prurigenin, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma tumor lysate vaccine (New York Medical College), viral melanoma cell lysate vaccine (Royal Newcastle Hospital), or Valspodar.

[0278] Additional examples of therapeutic agents that may be combined with the compounds of the invention include ipilimumab (Yervoy®), tremelimumab, galiximab, nivolumab (also known as BMS-936558 (Opdivo®)), pembrolizumab (Keytruda®), avelumab (Bavencio®), AMP224, BMS-936559, MPDL3280A (also known as RG7446), MEDI-570, AMG557, MGA271, IMP321, BMS-663513, PF-05082566, CDX-1127, anti-OX40 (Providence HealthServices), huMAbOX40L, atacicept, CP-870893, lucatumumab, dacetuzumab, muromonab-CD3, ipilumumab, MEDI4736 (Imfinzi®), MSB0010718C, AMP224, adalimumab (Humira®), ado-trastuzumab emtansine (Kadcyla®), aflibercept (Eylea®), alemtuzumab (Campath®), basiliximab (Simulect®) , belimumab (Benlysta®), basiliximab (Simulect®), belimumab (Benlysta®), brentuximab vedotin (Adcetris®), canakinumab (Ilaris®), certolizumab pegol (Cimzia®), daclizumab (Zenapax®), daratumumab (Darzalex®), denosumab (Prolia®), eculizumab (Soliris®), efalizumab (Raptiva®), (R)), gemtuzumab ozogamicin (Mylotarg®), golimumab (Simponi®), ibritumomab tiuxetan (Zevalin®), infliximab (Remicade®), motavizumab (Numax®), natalizumab (Tysabri®), obinutuzumab (Gazyva®), ofatumumab (Arzerra®), omalizumab (Xolair®), palivizumab (Synagis®), Pertz These include tuzumab (Perjeta®), pertuzumab (Perjeta®), ranibizumab (Lucentis®), raxibacumab (Abthrax®), tocilizumab (Actemra®), tositumomab, tositumomab-i-131, tositumomab and tositumomab-i-131 (Bexxar®), ustekinumab (Stelara®), AMG102, AMG386, AMG479, AMG655, AMG706, AMG745, and AMG951.

[0279] The compounds described herein may be used in combination with other suitable agents disclosed herein or other suitable agents, depending on the condition being treated. Thus, in some embodiments, one or more of the compounds disclosed herein are administered in combination with other therapies described herein. When used in combination therapy, the compounds described herein may be administered simultaneously with the second agent or separately from the second agent. This combination may include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compounds described herein and any of the agents described herein may be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds of the present invention and any of the therapies described herein may be administered simultaneously, with both agents present in separate formulations. In another alternative, the compounds disclosed herein may be administered followed by any of the therapies described herein, or vice versa. In some embodiments of separate administration protocols, the compounds of the present invention and any of the therapies described herein are administered minutes, hours, or days apart.

[0280] In some embodiments of any of the methods described herein, the first treatment (e.g., a compound of the invention) and one or more additional treatments are administered simultaneously or separately, in any order. The first therapeutic agent may be administered immediately before or immediately after, up to 1 hour before, up to 2 hours before, up to 3 hours before, up to 4 hours before, up to 5 hours before, up to 6 hours before, up to 7 hours before, up to 8 hours before, up to 9 hours before, up to 10 hours before, up to 11 hours before, up to 12 hours after, up to 13 hours before, or up to 14 hours after the one or more additional treatments. It may be administered up to 16 hours before or after, administered up to 17 hours before or after, administered up to 18 hours before or after, administered up to 19 hours before or after, administered up to 20 hours before or after, administered up to 21 hours before or after, administered up to 22 hours before or after, administered up to 23 hours before or after, administered up to 24 hours before or after, or administered up to 1 to 7 days before or after, administered up to 1 to 14 days before or after, administered up to 21 days before or after, or administered up to 30 days before or after. [Example]

[0281] Materials and Methods In some aspects, the present invention includes the intermediates, examples, and synthetic methods described herein in all of their embodiments.

[0282] The compounds of formula I can be prepared by the methods described below, which may involve synthetic methods known in the field of organic chemistry or may involve modifications and derivatizations known to those skilled in the art. The starting materials used herein are commercially available or can be prepared by conventional methods known in the art, such as those disclosed in standard reference books (e.g., Compendium of Organic Synthetic Methods, Vol. I-Vl (Wiley-Interscience) or Comprehensive Organic Transformations by RC Larock (Wiley-Interscience)). Preferred methods include, but are not limited to, those described below.

[0283] During any of the synthetic sequences described below, it may be necessary and / or desirable to protect sensitive or reactive groups present on any of the molecules in question. This can be achieved by means of conventional protecting groups such as those described in T.W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons (1981), T.W. Greene and P.G.M.Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons (1991), T.W. Greene and P.G.M.Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons (1999), T.W. Greene and P.G.M.Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons (2006), and T.W. Greene and P.G.M.Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons (2014), which are incorporated herein by reference in their entireties.

[0284] The compounds of Formula I, or pharmaceutically acceptable salts thereof, and intermediates used in the synthesis of the compounds of the invention may be prepared in accordance with the reaction schemes discussed hereinafter and by ordinary skill in the art.

[0285] Unless otherwise specified, the substituents in the schemes are as defined above. Isolation and purification of the products are achieved by standard procedures, which are known to a chemist of ordinary skill.

[0286] Where reference is made to general or exemplary synthetic procedures, those skilled in the art can readily determine appropriate reagents by inferring from such general or exemplary procedures, even if not shown. Some general procedures are provided as examples for the preparation of specific compounds. Those skilled in the art can readily apply such procedures to the synthesis of other compounds. Although unsubstituted positions are shown in structures shown in or referred to in the general procedures, the fact that such positions are shown unsubstituted is for convenience and does not exclude substitutions described elsewhere in this specification. Specific groups that may be present as R groups in the general procedures or as optional substituents not shown refer to those described elsewhere in this document, including the claims, summary, and detailed description.

[0287] The processes for preparing the compounds of the present invention are preferably carried out at about atmospheric pressure, although superatmospheric or subatmospheric pressures can be used if desired. Substantially equimolar amounts of reactants are preferably used, although greater or lesser amounts can be used.

[0288] Unless otherwise noted, all materials and reagents were obtained from commercial suppliers and used without further purification. Reactions were monitored by thin-layer chromatography (TLC) on silica gel 60 F254 (0.2 mm) precoated on aluminum foil or glass substrates and visualized using UV light or appropriate TLC stains. Flash chromatography was performed using either an Agela Technologies CombiFlash with CHEETAH Purification System or an ISCO CombiFlash Rf 200 Organic Purification System. Preparative TLC was performed on Xinnuo Silica Gel 10–40 μm, 20 × 20 cm plates (with a thickness equivalent to 1000 μm).

[0289] 1 H NMR (300 MHz or 400 MHz) spectra were recorded at room temperature on a Bruker or Varian instrument, using TMS or the residual solvent peak as the internal standard. The position of the singlet or multiplet is given in (δ), and the coupling constants (J) are given in absolute values in Hertz (Hz). 1 Multiplicities in H NMR spectra are abbreviated as follows: d (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), mc (centred multiplet), br or broad (broadened).

[0290] NMR data are generally collected in deuterated solvents (such as DMSO-d6, CD3OD, CDCl3, or acetonitrile-d3), although the deuteration state of the solvent may or may not be explicitly indicated in the NMR data section.

[0291] Preparative HPLC purifications were performed on a Waters® Mass-Directed Purification System equipped with a 2545 binary gradient module or a 2525 binary gradient module, a 2767 sample manager, a column fluidics organizer (CFO), a 2489 photodiode array detector, a 515 pump for creating makeup flow to the detector, a reagent manager, a 515 pump for at-column dilution, a Zspray™ single quadrupole mass detector with a Z-spray electrospray interface, and controlled by MassLynx™ version 4.1 with FractionLynx™ software. The mobile phase was water and acetonitrile containing 0.1% formic acid or 0.01 M NH4HCO3 unless otherwise noted. The flow rate was 25 mL / min. After column flow, a 1:1000 LC packings flow splitter allowed a small portion of the eluate to be transferred to the UV detector, followed by 10% for the ZQ MS. The electrospray source capillary voltage was set to 3.0 kV, the cone voltage to 30 V, the ion source temperature to 110 °C, the desolvation temperature to 350 °C, the desolvation gas flow to 600 L / h, and the cone gas flow to 60 L / h. The analyzer multiplier setting was set to 550 for preparative analysis.

[0292] Analytical LCMS data were recorded on an LCMS01, LCMS02, UPLC01, or UPLC0 instrument, unless otherwise stated, with a mobile phase of acetonitrile (B) and HPLC-grade water (A) in the presence of either 0.05% formic acid or 0.05% TFA.

[0293] LCMS01 is a Shimadzu LC-20ADXR HPLC equipped with an SPD-M20A detector and an LCMS-2020 for ionization. The following conditions are used on this system with a run time of 5 or 3 minutes:

[0294] Run time: 5 min. Ascentis Express C18 column, 2 μm, 3.0 × 50 mm. Flow rate: 1.5 mL / min. Run time: 5 min. Gradient profile: 0.01 min B5%; 3.00 min B100%; 4.60 min B100%; 4.90 min B5%; 5.00 min B0%. Electrospray ionization was performed in positive (ES+) or negative (ES-) mode on the LCMS-2020 instrument.

[0295] Run time 3 min: Ascentis Express C18 column, 2 μm, 3.0 × 50 mm. Flow rate was 1.5 mL / min, run time was 3 min, gradient profile was 0.01 min B 5%, 2.00 min B 100%, 2.70 min B 100%, 2.75 min B 5%, 3.00 min B 0%.

[0296] The Agilent LCMS is an Agilent 1260 HPLC equipped with a 6120 / 6125 single quadrupole mass detector, ESI for ionization. The following conditions are used on this system with a run time of 2.5 minutes:

[0297] Conditions: Waters CORTECS C18+ column, 2.7 μm, 4.6 × 30 mm. Flow rate was 1.8 mL / min, run time was 2.5 min, gradient profile was 0.00 min B 5%; 1.00 min B 95%; 2.0 min B 95%; 2.1 min B 5%; 2.5 min B 5%. Electrospray ionization was performed in positive (ES+) or negative (ES-) mode on the Premier XE MS.

[0298] UPLC01 was an Agilent Technologies 1260 Infinity II coupled with a DAD (G4212-60008) detector. A Waters T3 column (4.6 x 100 mm) was heated to 60°C, and detection was performed at 254 nm and 220 nm with electrospray ionization in positive mode. Table 2 below shows the mobile phase gradient (solvent A: 0.05% TFA in water; solvent B: acetonitrile with 0.05% TFA) and flow rates for the analytical UPLC program. [Table 2]

[0299] UPLC02 combines an ACQUITY Sample Manager with a PDA detector. An ACQUITY UPLC® BEH C18 1.7 pm 2.1 x 50 mm column was heated to 45°C, and detection was performed at 254 / 214 nm. Table 3 below shows the mobile phase gradient (Solvent A: 0.05% TFA in water; Solvent B: acetonitrile with 0.05% TFA) and flow rates for the analytical UPLC program. [Table 3]

[0300] Example 1 - Synthesis of intermediates A. Methyl (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoyl)hexahydropyridazine-3-carboxylate [ka] Step A To a solution of (S)-methyl 2-(tert-butoxycarbonylamino)-3-(3-hydroxyphenyl)propanoate (10.0 g, 33.9 mmol) in dichloromethane (100 mL) was added imidazole (4.6 g, 67.8 mmol) and TIPSCl (7.8 g, 40.7 mmol). The mixture was stirred for 16 h, then diluted with dichloromethane (200 mL) and washed with HO (3 x 150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by silica gel chromatography (0 → 10% ethyl acetate in petroleum ether) to give methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-((triisopropylsilyl)oxy)phenyl)propanoate (98% yield) as a colorless oil. ESI-MS m / z = 474.2 [M+Na] +

[0301] Step B Methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-((triisopropylsilyl)oxy)phenyl)propanoate (7.5 g, 16.6 mmol), bis(pinacolato)diborane (6.3 g, 24.9 mmol), [Ir(OMe)(COD)] (1.1 g, 1.66 mmol), and 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (1.3 g, 4.98 mmol) were mixed in a flask. After purging with argon, tetrahydrofuran (75 mL) was added. The flask was sealed, heated to 80 °C, and stirred for 16 hours. The mixture was concentrated under reduced pressure and purified by silica gel chromatography (0% to 20% ethyl acetate in petroleum ether) to give methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoate (78% yield) as a white solid. ESI-MS m / z = 600.4 [M+Na] + .

[0302] Step C To a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoate (4.95 g, 6.88 mmol) in methanol (53 mL) at 0° C. was added a solution of lithium hydroxide (840 mg, 34.4 mmol) in water (35 mL). The mixture was stirred at 0° C. for 2 hours and then acidified with 1 M aqueous hydrochloric acid until the pH of the mixture reached approximately 5. The resulting solution was extracted with ethyl acetate (2×250 mL) and washed with brine (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoic acid as a white solid. This solid was used in the next step without further purification. ESI-MS m / z = 581.4 [M+NH4] + .

[0303] Step D To a solution of methyl (S)-hexahydropyridazine-3-carboxylate trifluoroacetate (6.48 g, 45.0 mmol) in dichloromethane (200 mL) at 0° C. was added N-methylmorpholine (40.99 g, 405.2 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoic acid (24.0 g, 42.6 mmol) in dichloromethane (50 mL), HOBt (1.21 g, 9.01 mmol), and EDCI (12.9 g, 67.55 mmol). The mixture was stirred at 20°C for 16 hours, then diluted with dichloromethane (200 mL) and washed with water (3 x 150 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was purified by silica gel chromatography (0% to 20% ethyl acetate in petroleum ether) to give methyl (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoyl)hexahydropyridazine-3-carboxylate (71% yield) as a yellow oil. ESI-MS m / z = 690.5 [M+H] +

[0304] B. Methyl (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoyl)hexahydropyridazine-3-carboxylate [ka] Step A A solution of (R)-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc(II) iodide (20.0 mL, 25 mmol, 1.0 equiv.), Pd(PPh3)2Cl2 (1.75 g, 2.5 mmol, 0.1 equiv.), and 3-bromo-5-iodopyridine (7.1 g, 25 mmol, 1.0 equiv.) in DMF (10 mL) was stirred at 50 °C for 15 h. The reaction was quenched by adding ice water (300 mL), and the solution was extracted with ethyl acetate (3 x 200 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (PE → petroleum ether / ethyl acetate = 1:1) to give methyl (S)-3-(5-bromopyridin-3-yl)-2-((tert-butoxycarbonyl)amino)propanoate (3.1 g, 35% yield) as a yellow solid. ESI-MS m / z = 359.1 [M+H] + .

[0305] Step B To a solution of methyl (S)-3-(5-bromopyridin-3-yl)-2-((tert-butoxycarbonyl)amino)propanoate (1.8 g, 5.0 mmol, 1.0 equiv) in MeOH (20 mL) was added LiOH (600 mg, 25.0 mmol, 5.0 equiv) in HO (5 mL) at 0 °C. The mixture was stirred at 0 °C for 5 h. The mixture was acidified with 1 M HCl to a pH of approximately 5, and the mixture was extracted with ethyl acetate (2 x 100 mL). The organic layer was washed with brine (3 x 100 mL), dried over anhydrous sodium sulfate, and concentrated to give a residue. The crude product (1.73 g) was used directly in the next step without further purification. ESI-MS m / z = 345.0 [M+H] + .

[0306] Step C A solution of (S)-3-(5-bromopyridin-3-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid (1.73 g, 5.0 mmol, 1.0 equiv.), HATU (2.85 g, 7.5 mmol, 1.5 equiv.), and DIPEA (3.23 g, 25 mmol, 5.0 equiv.) in DMF (15 mL) was stirred at 0 °C for 30 min. Methyl (S)-hexahydropyridazine-3-carboxylate (2.23 g, 6.0 mmol, 1.2 equiv., TFA salt) in DMF (5 mL) was then added dropwise. After 2 h, the reaction was quenched by adding ice water (100 mL), and the solution was extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (dichloromethane → dichloromethane / MeOH = 20:1) to give methyl (S)-1-((S)-3-(5-bromopyridin-3-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate (1.51 g, 64% yield) as an oil. ESI-MS m / z = 471.1 [M+H] + .

[0307] The following intermediates were synthesized according to the procedure described for the preparation of Intermediate B, using the appropriate building blocks and modifying the reaction conditions (such as reagents, reagent ratios, temperature, and reaction time) as needed. [Table 4]

[0308] C. Methyl (S)-1-((S)-3-(6-bromo-4-((tert-butoxycarbonyl)oxy)pyridin-2-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate [ka] Step A A solution of (R)-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc(II) iodide (20.0 mL, 24 mmol, 2.0 equiv.), Pd(PPh3)2Cl2 (1.68 g, 2.4 mmol, 0.2 equiv.), and 2,6-dibromo-4-methoxypyridine (3.2 g, 12 mmol, 1.0 equiv.) in DMF (10 mL) was stirred at 65 °C for 2 h. The reaction was quenched by adding ice water (300 mL), and the solution was extracted with ethyl acetate (3 x 200 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (dichloromethane → dichloromethane / MeOH = 40:1) to give methyl (S)-3-(6-bromo-4-methoxypyridin-2-yl)-2-((tert-butoxycarbonyl)amino)propanoate (2.4 g, 51% yield) as a yellow oil. ESI-MS m / z = 389.0 [M+H] + .

[0309] Step B A solution of methyl (S)-3-(6-bromo-4-methoxypyridin-2-yl)-2-((tert-butoxycarbonyl)amino)propanoate (2.4 g, 6.17 mmol, 1.0 equiv) in HBr (40% aqueous solution) (20 mL) was stirred at 130° C. for 16 h. The mixture was concentrated to give the crude residue (2.1 g) as a yellow solid. This solid was used in the next step without further purification. ESI-MS m / z = 261.0 [M+H] + .

[0310] Step C To a stirred solution of (S)-2-amino-3-(6-bromo-4-hydroxypyridin-2-yl)propanoic acid (2.1 g, 6.17 mmol, 1.0 equiv) in THF (100 mL) was added DMAP (753 mg, 6.17 mmol, 1.0 equiv) and TEA (1.2 g, 12.34 mmol, 2.0 equiv), followed by (Boc)O (2.69 g, 12.34 mmol, 2.0 equiv). The mixture was stirred for 5 h, and then the solution was concentrated to give a residue. The residue was purified by silica gel chromatography (dichloromethane → dichloromethane / MeOH = 20:1) to give (S)-3-(6-bromo-4-((tert-butoxycarbonyl)oxy)pyridin-2-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid (2.15 g, 76% yield) as a yellow oil. ESI-MS m / z = 460.1 [M+H] + .

[0311] Step D A solution of (S)-3-(3-bromo-5-(difluoromethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (2.15 g, 4.66 mmol, 1.0 equiv.), HATU (2.66 g, 6.99 mmol, 1.5 equiv.), and DIEA (3.00 g, 23.3 mmol, 5.0 equiv.) in DMF (15 mL) was stirred at 5 °C for 30 min. Methyl (S)-hexahydropyridazine-3-carboxylate (1.44 g, 5.6 mmol, 1.2 equiv., TFA salt) in DMF (5 mL) was added dropwise. After 2 h, the reaction was quenched by adding ice water (100 mL), and the solution was extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (dichloromethane → dichloromethane / MeOH = 40:1) to give methyl (S)-1-((S)-3-(6-bromo-4-((tert-butoxycarbonyl)oxy)pyridin-2-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate (2.05 g, 75% yield) as a yellow oil. ESI-MS m / z = 587.1 [M+H] + .

[0312] D. 2-(6-bromo-1-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-3-yl)-2-methylpropanenitrile [ka] Step A To a solution of tert-butyl 6-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate (1.3 g, 3.88 mmol, 1.0 equiv.) in THF (25 mL) was added LiHMDS (9.7 mL, 9.7 mmol, 2.5 equiv.) at −78°C. Then, MeI (1.38 g, 9.72 mmol, 2.51 equiv.) was added dropwise at −78°C. The resulting mixture was gradually warmed to room temperature and stirred for 16 h. The reaction was quenched by adding saturated aqueous NH4Cl (10 mL). The resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, washed with brine (100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (eluting with petroleum ether / dichloromethane (5:1)) to give tert-butyl 6-bromo-3-(1-cyano-1-methylethyl)-1H-indole-1-carboxylate (1.2 g, 81%) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 8.41 (s, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.51-7.39 (m, 2H), 1.85 (s, 6H), 1.70 (s, 9H).

[0313] Step B To a stirred solution of tert-butyl 6-bromo-3-(1-cyano-1-methylethyl)-1H-indole-1-carboxylate (1.1 g, 3.03 mmol, 1.0 equiv) in dichloromethane (20 mL) was added TFA (10 mL, 134.63 mmol, 44.5 equiv) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. The mixture was then concentrated under reduced pressure. The resulting mixture was diluted with water (200 mL). The mixture was basified with saturated aqueous NaHCO3 to pH 8. The resulting solution was extracted with ethyl acetate (3 x 200 mL). The organic layers were combined, washed with brine (100 mL), and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude 2-(6-bromo-1H-indol-3-yl)-2-methylpropanenitrile (750 mg, 89% yield) was used directly in the next step without further purification. ESI-MS m / z = 263.1 [M+H] + .

[0314] The following intermediates were synthesized according to the procedure described for the preparation of intermediate D, using the appropriate building blocks and modifying the reaction conditions (such as reagents, reagent ratios, temperature, and reaction time) as needed. [Table 5]

[0315] E. 3-(6-Bromo-1H-indol-3-yl)-3-methylbutan-2-one [ka] To a stirred solution of 2-(6-bromo-1H-indol-3-yl)-2-methylpropanenitrile (3.5 g, 0.013 mmol, 1.0 equiv) in THF (50 mL) was added MeLi (1 M, 10 equiv, 35 mL) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 3 h. To the mixture was added aqueous HCl (1 L) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched by adding aqueous NaHCO (500 mL) at room temperature. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (2 x 300 mL). The organic layers were combined, washed with water (2 x 200 mL), and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting with EA / PE (1:20 → 1:12)) to give 3-(6-bromo-1H-indol-3-yl)-3-methylbutan-2-one (2 g, 48% yield) as a brown solid. ESI-MS m / z = 280.1 [M+H] + .

[0316] F: 6-bromo-1H-indole-3-carboxamide [ka] Step A To a solution of 6-bromo-1H-indole-3-carboxylic acid (2.88 g, 12.0 mmol, 1.0 equiv) in dichloromethane (10 mL) and DMF (10 mL) at 0° C. was added oxalyl dichloride (4.57 g, 36.0 mmol, 3.0 equiv) dropwise. The mixture was stirred at 0° C. for 2 hours. This mixture was used directly in the next step.

[0317] Step B NH3 ·To a solution of HO (8.16 g, 120.0 mmol, 10.0 equiv., 25% NH) in HO (20 mL) was added 6-bromo-1H-indole-3-carbonyl chloride (reaction solvent from Step A) dropwise at 0 °C. The mixture was stirred at 0 °C for 2 h. The mixture was poured into water and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate, and concentrated to give a residue. The residue was purified by silica gel chromatography (dichloromethane → dichloromethane / MeOH = 20:1) to give 6-bromo-1H-indole-3-carboxamide (2.45 g, 85% yield) as a white solid. ESI-MS m / z = 241.0 [M+H] + .

[0318] The following intermediates were synthesized according to the procedure described for the preparation of Intermediate F, using the appropriate building blocks and modifying the reaction conditions (such as reagents, reagent ratios, temperature, and reaction time) as needed. [Table 6]

[0319] G: 6-bromo-3-(methylsulfonyl)-1H-indole [ka] 6-Bromo-1H-indole (1.0 g, 5.13 mmol, 1.0 equiv.) and tert-BuOK (1.15 g, 10.3 mmol, 2.0 equiv.) in THF (15 mL) were stirred at room temperature for 30 min. EtB solution (10.3 mL, 10.3 mmol, 2 equiv., 1 M in THF) was added dropwise over 30 min. Methanesulfonyl chloride (1.2 g, 10.3 mmol, 2.0 equiv.) was added at −15 °C, and the solution was maintained at that temperature for 24 h. The reaction was quenched by adding 30 mL of saturated aqueous NH4Cl. The resulting solution was extracted with ethyl acetate (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (MeCN aqueous solution 5% → 95% in the presence of 0.05% FA) to give 6-bromo-3-(methylsulfonyl)-1H-indole (620 mg, 44% yield) as a pale green solid. ESI-MS m / z = 274.0, 276.0 [M+H] + .

[0320] H: 6-bromo-2-methyl-1H-indole-3-carbonitrile [ka] To a mixture of 6-bromo-2-methyl-1H-indole-3-carbaldehyde (3.2 g, 13.4 mmol, 1.0 equiv.), hydroxylamine hydrochloride (1.0 g, 14.8 mmol, 1.1 equiv.), and EtN (1.5 g, 14.8 mmol, 1.1 equiv.) in DMF (30 mL) was added T3P® (4.7 g, 14.8 mmol, 1.1 equiv., 50% in ethyl acetate). The mixture was stirred at 100 °C for 3 h, then poured into saturated aqueous NaHCO (200 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with HO (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 6-bromo-2-methyl-1H-indole-3-carbonitrile (1.5 g, 45% yield) as a white solid. ESI-MS m / z = 235.0 [M+H] + .

[0321] I: 6-Bromo-1-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile [ka] Step A To a stirred solution of 6-bromo-1H-pyrrolo[2,3-b]pyridine (6.0 g, 30 mmol, 1.0 equiv) in DMF (10 mL) at 0 °C, phosphorus oxychloride (90 mmol, 8.4 mL, 3.0 equiv) was added, and the resulting mixture was stirred at room temperature. After stirring for 1 h, the reaction mixture was poured into cold saturated aqueous NaHCO3 and stirred for 30 min. The reaction mixture was extracted with ethyl acetate (3 times). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 6-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (6.0 g, 87% yield) as a white solid. ESI-MS m / z = 225.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H), 9.94 (s, 1H), 8.51 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H), 7.49 - 7.47 (d, J = 8.2 Hz, 1H).

[0322] Step B To a mixture of 6-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (2.24 g, 10 mmol, 1.0 equiv.), hydroxylamine hydrochloride (764 mg, 11 mmol, 1.1 equiv.), and triethylamine (1.11 g, 11 mmol, 1.1 equiv.) in DMF (30 mL) was added T3P® (3.5 g, 11 mmol, 1.1 equiv., 50% solution in ethyl acetate). The mixture was stirred at 100° C. for 3 hours. The mixture was cooled, poured into aqueous sodium bicarbonate (200 mL), and extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the product 6-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (2.0 g, 91% yield) as a white solid. ESI-MS m / z = 222.1 [M+H] + .

[0323] J: 6-bromo-4-hydroxy-1-naphthonitrile [ka] Step A A solution containing 7-bromonaphthalen-1-ol (100 mg, 0.448 mmol, 1 equiv.), MeCN (10 mL), pTsOH (77.0 mg, 0.45 mmol, 1.0 equiv.), and N-iodosuccinimide (101.0 mg, 0.45 mmol, 1.0 equiv.) was stirred at 25 °C for 14 h. The residue was purified by silica gel chromatography (ethyl acetate / petroleum ether (5:1)) to give 7-bromo-4-iodonaphthalen-1-ol (130 mg, 83% yield). ESI-MS m / z = 347.0 [MH] - .

[0324] Step B A solution containing 7-bromo-4-iodonaphthalen-1-ol (2.20 g, 6.30 mmol, 1.0 equiv), acetonitrile (40 mL), zinc dicarbonitrile (1.10 g, 9.46 mmol, 1.5 equiv), and Pd(dba)2 (220 mg, 0.383 mmol, 0.06 equiv) was stirred at 70 °C for 16 h. The residue was applied to a silica gel column and eluted with ethyl acetate / hexane (5:1) to give 6-bromo-4-hydroxynaphthalene-1-carbonitrile (700 mg, 45% yield). ESI-MS m / z = 246.0 [MH] - .

[0325] K: 8-bromo-5-ethyl-1,3,4,5-tetrahydro-2H-benzo[b][1,4]diazepin-2-one [ka] Step A To a stirred solution of 4-bromo-2-fluoro-1-nitrobenzene (5.0 g, 22.7 mmol, 1.0 equiv.) in DMF (50 mL) was added dropwise K2CO3 (6.33 g, 45.5 mmol, 2.0 equiv.) and methyl 3-(ethylamino)propanoate (3.9 g, 29.7 mmol, 1.3 equiv.). After stirring the resulting mixture for 16 h, the mixture was diluted with 100 mL of water and extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with brine (3 x 100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with petroleum ether (20:1 → 12:1)) to give methyl 3-((4-bromo-2-nitrophenyl)(ethyl)amino)propanoate (6.53 g, 85% yield) as a red oil. ES m / z = 333.1 [M+H] + .

[0326] Step B To a stirred solution of 3-((4-bromo-2-nitrophenyl)(ethyl)amino)propanoate (6.52 g, 19.688 mmol, 1 equiv.) in methanol (60 mL) were added acetic acid (23.7 g, 394.6 mmol, 20 equiv.) and zinc (6.4 g, 99 mmol, 5.0 equiv.) in portions at room temperature. The resulting mixture was stirred at room temperature for 2 h. The precipitated solid was collected by filtration and washed with MeOH (160 mL). The resulting filtrate was stirred at 80 °C overnight. The mixture was neutralized to pH 7 with saturated aqueous NaHCO3. The precipitated solid was filtered off and washed with ethyl acetate (3 x 10 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (eluting with petroleum ether / ethyl acetate (10:1 → 3:1)) to give 8-bromo-5-ethyl-1,3,4,5-tetrahydro-2H-benzo[b][1,4]diazepin-2-one (2.8 g, 50% yield) as a brown solid. ESI-MS m / z = 269.0 [M+H] + .

[0327] L: 6-bromo-3-(3,6-dihydro-2H-pyran-4-yl)-1H-indole [ka] Step A To a stirred solution of NaH (60% dispersion in oil, 0.4 g, 16.67 mmol, 1.25 equiv) in DMF (40 mL) was added 6-bromo-3-iodo-1H-indole (4.3 g, 13.36 mmol, 1 equiv) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 1 h, and then 4-methylbenzene-1-sulfonyl chloride (5.6 g, 29.38 mmol, 2.2 equiv) was added dropwise at 0 °C. The mixture was stirred at room temperature for an additional 16 h. The reaction mixture was poured into ice water. The aqueous layer was extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, washed with brine (3 x 50 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and 6-bromo-3-iodo-1-tosyl-1H-indole was used directly in the next step without further purification. 1 H NMR (300 MHz, CDCl3) δ 8.17 (d, J = 1.5 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.67 (s, 1H), 7.44 (dd, J = 8.4, 1.6 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 1H), 2.40 (s, 3H).

[0328] Step B A solution of 6-bromo-3-iodo-1-tosyl-1H-indole (3.0 g, 6.30 mmol, 1 equiv.), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.0 g, 18.90 mmol, 3 equiv.), Pd(dppf)Cl (0.3 g, 0.41 mmol, 0.07 equiv.), and KCO (4.4 g, 31.84 mmol, 5.05 equiv.) in dioxane (30 mL) and HO (6 mL) was stirred at 60 °C for 3 h. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with brine (3 x 30 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with petroleum ether / ethyl acetate (10:1)) to give 6-bromo-3-(3,6-dihydro-2H-pyran-4-yl)-1-tosyl-1H-indole (2.1 g, 77% yield) as a yellow solid. 1 H NMR (300 MHz, CDCl3) δ 8.21 (d, J = 1.7 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.6 Hz, 1H), 7.49 (s, 1H), 7.42-7.37 (m, 1H), 7.30 (s, 1H), 7.27 (s, 1H), 6.22 (s, 1H), 4.37 (q, J = 2.6 Hz, 2H), 3.98 (t, J = 5.5 Hz, 2H), 2.53 (dd, J = 4.8, 2.2 Hz, 2H), 2.39 (s, 3H).

[0329] Step C A solution of 6-bromo-3-(3,6-dihydro-2H-pyran-4-yl)-1-tosyl-1H-indole (2.1 g, 4.86 mmol, 1 equiv.) and KOH (2.7 g, 48.12 mmol, 9.91 equiv.) in MeOH (40 mL) and HO (10 mL) was stirred at 65 °C for 3 h. The resulting mixture was extracted with ethyl acetate (3 x 50 mL), and the organic layers were combined, washed with brine (3 x 10 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 6-bromo-3-(3,6-dihydro-2H-pyran-4-yl)-1H-indole, which was used directly in the next step without further purification. ESI-MS m / z = 278.0 [M+H] + .

[0330] The following intermediates were synthesized according to the procedure described for the preparation of intermediate L, using the appropriate building blocks and modifying the reaction conditions (such as reagents, reagent ratios, temperature, and reaction time) as needed. [Table 7]

[0331] M: 6-bromo-2-(2-(methoxymethyl)phenyl)-1H-indole [ka] Step A A solution of (2-(methoxymethyl)phenyl)boronic acid (1.66 g, 10.0 mmol, 1.0 equiv.), tert-butyl 6-bromo-2-iodo-1H-indole-1-carboxylate (4.2 g, 10.0 mmol, 1.0 equiv.), Pd(dppf)Cl₂·CHCl₂ (408 mg, 0.5 mmol, 0.05 equiv.), and KCO₃ (4.14 g, 30 mmol, 3.0 equiv.) in dioxane (20 mL) and water (4 mL) was stirred at 80 °C for 5 h. After concentration, the residue was purified by silica gel chromatography (petroleum ether) to give tert-butyl 6-bromo-2-(2-(methoxymethyl)phenyl)-1H-indole-1-carboxylate (2.95 g, 71% yield). ESI-MS m / z: 438.0 [M+Na] + .

[0332] Step B To a stirred solution of tert-butyl 6-bromo-2-(2-(methoxymethyl)phenyl)-1H-indole-1-carboxylate (2.95 g, 7.1 mmol, 1.0 equiv) in dichloromethane (10 mL) at 0° C., TFA (10 mL) was added dropwise. The resulting mixture was stirred at 15° C. for 1.5 h and then concentrated under reduced pressure. The resulting mixture was diluted with water (100 mL). The mixture was basified with saturated Na2CO3 to pH 8. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, washed with brine (200 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (petroleum ether / ethyl acetate (10:1)) packed with silica gel to give 6-bromo-2-(2-(methoxymethyl)phenyl)-1H-indole (1.25 g, 55% yield) as a white solid. ESI-MS m / z: 316.0 [M+H] + .

[0333] N: 6-bromo-3-cyclopropyl-1H-indole [ka] Step A A solution containing 5-bromo-2-iodoaniline (5.0 g, 16.8 mmol, 1.0 equiv.), Na2CO3 (4.5 g, 42.5 mmol, 2.5 equiv.), Pd(PPh3)2Cl2 (1.3 g, 2.0 mmol, 0.1 equiv.), and (cyclopropylethynyl)trimethylsilane (3.9 g, 28.3 mmol, 1.7 equiv.) was stirred at 80 °C for 15 h. The resulting mixture was diluted with ethyl acetate and washed with brine (3 x 40 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography using petroleum ether / ethyl acetate (20:1) to afford 3.6 g (70% yield) of 6-bromo-3-cyclopropyl-2-(trimethylsilyl)-1H-indole as a yellow oil. 1 H NMR (300 MHz, DMSO-d6) δ 10.66 (s, 1H), 7.58 - 7.38 (m, 2H), 7.05 (dd, J = 8.5, 1.8 Hz, 1H), 1.88 (tt, J = 8.4, 5.2 Hz, 1H), 0.98 - 0.84 (m, 2H), 0.72 - 0.59 (m, 2H), 0.39 (s, 9H).

[0334] Step B To a solution of 6-bromo-3-cyclopropyl-2-(trimethylsilyl)-1H-indole (1.8 g, 5.9 mmol, 1 equiv.) in THF (18 mL) was added TBAF / THF (1 M). The resulting solution was stirred at 70 °C for 1 h. After concentration, the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate 1:1) to afford 1.30 g (94% yield) of 6-bromo-3-cyclopropyl-1H-indole as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.89 (s, 1H), 7.71 - 7.31 (m, 2H), 7.21 - 6.96 (m, 2H), 1.90 (ddd, J = 13.4, 8.5, 5.0 Hz, 1H), 0.95 - 0.73 (m, 2H), 0.58 (h, J = 3.7 Hz, 2H).

[0335] O: 6-bromo-3-cyclobutyl-1H-indole [ka] To a stirred solution of 6-bromo-1H-indole (4.0 g, 20.40 mmol, 1 equiv.) in toluene (20 mL), cyclobutanone (1.5 g, 21.40 mmol, 1.05 equiv.) was added in small portions. This solution was then added over 30 min to a stirred solution of 2,2,2-trichloroacetic acid (5.0 g, 30.60 mmol, 1.50 equiv.) and EtSiH (7.1 g, 61.06 mmol, 2.99 equiv.) in toluene (20 mL) at 70 °C. The resulting mixture was stirred for an additional 16 h at 70 °C, at which point the mixture was concentrated under reduced pressure. The residue was basified with 10% aqueous NaCO to approximately pH 8. The mixture was then extracted with ethyl acetate (3 x 200 mL). The organic layers were combined, washed with water (100 mL) and saturated NaCl (100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with petroleum ether / dichloromethane (20:1)) to give 6-bromo-3-cyclobutyl-1H-indole (1.9 g, 32% yield) as a pale yellow solid. ESI-MS m / z = 250.3 [M+H].

[0336] P: 2-bromo-5-methoxy-9H-carbazole [ka] Step A A solution of (2-methoxyphenyl)boronic acid (1.0 g, 6.58 mmol, 1.0 equiv), 4-bromo-1-iodo-2-nitrobenzene (2.59 g, 7.90 mmol, 1.2 equiv), Pd(PPh3)2Cl2 (100 mg, 0.142 mmol, 0.02 equiv), and K2CO3 (4.55 g, 32.9 mmol, 5.00 equiv) in dioxane (10 mL) and water (2 mL) was stirred at 60 °C for 15 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with petroleum ether / ethyl acetate (3:1)) to give 4-bromo-2'-methoxy-2-nitro-1,1'-biphenyl (1.3 g, 64% yield) as a yellow solid.

[0337] Step B A solution containing 4-bromo-2'-methoxy-2-nitro-1,1'-biphenyl (1.2 g, 3.89 mmol, 1.0 equiv.), PPh3 (3.58 g, 13.63 mmol, 3.5 equiv.), and 1,2-dichlorobenzene (10 mL) was prepared. The reaction mixture was irradiated in a microwave oven at 180 °C for 12 h. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate, 100:1 → 10:1) to give 2-bromo-5-methoxy-9H-carbazole (890 mg, 83% yield) as a yellow solid. ESI-MS m / z = 276.1 [M+H] + .

[0338] The following intermediates were synthesized according to the procedure described for the preparation of intermediate P, using the appropriate building blocks and modifying the reaction conditions (such as reagents, reagent ratios, temperature, and reaction time) as needed. [Table 8]

[0339] Q: 6-bromo-3-(pyridin-2-ylmethyl)-1H-indole [ka] Step A To a stirred solution of 6-bromo-1H-indole (1.0 g, 5.10 mmol, 1.0 equiv) and pyridine-2-carbaldehyde (546 mg, 5.10 mmol, 1.0 equiv) in MeOH (10 mL) at 0 °C was added NaOH (224 mg, 5.61 mmol, 1.1 equiv) in small portions. The resulting mixture was stirred at 0 °C for 1 h and at room temperature for an additional 5 h. The resulting mixture was concentrated under reduced pressure, and the mixture was diluted with water (30 mL). The aqueous layer was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude 6-bromo-1H-indol-3-yl)(pyridin-2-yl)methanol (1.5 g) was used in the next step without further purification.

[0340] Step B A solution of crude (6-bromo-1H-indol-3-yl)(pyridin-2-yl)methanol (1.5 g, 4.948 mmol, 1.0 equiv) in dichloromethane (20 mL) was treated with TFA (6.2 g, 54.4 mmol, 11 equiv) followed by EtSiH (633 mg, 5.44 mmol, 1.10 equiv). The resulting solution was stirred at room temperature for 2 h. The mixture was then concentrated under reduced pressure, and 40 mL of water was added. The resulting solution was extracted with ethyl acetate (3 x 40 mL) and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel chromatography (eluting with ethyl acetate / petroleum ether (1:4)) to give 6-bromo-3-[(pyridin-2-yl)methyl]-1H-indole (1.1 g, 77% yield over two steps). ESI-MS m / z = 287.0 [M+H]+.

[0341] The following intermediates were synthesized according to the procedure described for the preparation of intermediate Q, using the appropriate building blocks and modifying the reaction conditions (such as reagents, reagent ratios, temperature, and reaction time) as needed. [Table 9]

[0342] R: 6-bromo-3-((tetrahydrofuran-3-yl)methyl)-1H-indole [ka] Step A To a solution of oxolane-3-carboxylic acid (4.39 g, 37.807 mmol, 1.21 equiv) in dichloromethane (45 mL) at 0 °C, oxalyl chloride (9.5 g, 74.847 mmol, 2.39 equiv) and N,N-dimethylformamide (0.150 mL) were added dropwise. The resulting mixture was stirred under argon at 0 °C to 25 °C for 2 h and then concentrated under reduced pressure. To a stirred solution of 6-bromo-1H-indole (6.14 g, 31.3 mmol, 1.0 equiv) in dichloromethane (70 mL) at 0 °C, tetrachlorostannane (37.3 mL) was added dropwise. The resulting mixture was stirred at 0 °C for 10 min, and then tetrahydrofuran-3-carbonyl chloride and nitromethane (3.37 mL) were added dropwise at 0 °C. The resulting mixture was stirred at 0°C to 25°C for 15 hours. The reaction was quenched by adding ice water. The precipitated solid was collected by filtration and washed with ethyl acetate (10 mL x 3). The filtrate was extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with brine (100 mL x 1), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with petroleum ether / ethyl acetate (10:1 → 2:1)) to give 6-bromo-3-(oxolane-3-carbonyl)-1H-indole (6.13 g, 52% yield) as a brown solid. ESI-MS m / z = 294.0 [M+H] + .

[0343] Step B To a stirred solution of 6-bromo-3-(oxolane-3-carbonyl)-1H-indole (6.0 g, 20.398 mmol, 1.0 equiv.), 1N BH in THF (60 mL) was added dropwise. The mixture was stirred at room temperature for 2 hours. The mixture was quenched with MeOH (20 mL) at 0 °C. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with brine (100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with petroleum ether / ethyl acetate (20:1 to 6:1)) to give 6-bromo-3-[(oxolan-3-yl)methyl]-1H-indole (2.7 g, 44% yield) as a brown oil. ESI-MS m / z = 282.0 [M+H] + .

[0344] S: 3-(6-bromo-1H-indol-3-yl)propanenitrile [ka] Step A A solution of 6-bromo-1H-indole-3-carbaldehyde (5.0 g, 22.3 mmol, 1 equiv.) in THF (50 mL) at 0 °C was treated with NaH (60%, 535 mg, 22.3 mmol, 1.0 equiv.) and maintained at that temperature for 30 min. Diethyl (cyanomethyl)phosphonate (7.91 g, 44.632 mmol, 2.0 equiv.) was added dropwise, and the reaction mixture was stirred at room temperature overnight. Water was added, and the organic solution was removed under reduced pressure. The resulting aqueous layer was extracted with ethyl acetate (3 x 250 mL). The organic layers were combined, washed with water (3 x 250 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with petroleum ether / ethyl acetate (1:1)) to give (E)-3-(6-bromo-1H-indol-3-yl)acrylonitrile (2.5 g, 45% yield) as a yellow solid. ESI-MS m / z = 245.0 [M−H] - .

[0345] Step B To a solution of (E)-3-(6-bromo-1H-indol-3-yl)acrylonitrile (2.5 g, 10.1 mmol, 1.0 equiv) in THF (15 mL) and EtOH (15 mL) was added Pd / C (10%, 500 mg, 4.7 mmol, 0.46 equiv). The reaction was stirred under a hydrogen atmosphere for 48 h. The mixture was filtered, and the filter cake was washed with EtOH (30 mL x 3). The filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography (45-50% water / MeCN in the presence of 0.1% FA) to give 3-(6-bromo-1H-indol-3-yl)propanenitrile (1.1 g, 44% yield) as a dark yellow oil. ESI-MS m / z = 247.0 [MH] - .

[0346] T: 6-bromo-2-(pyridin-3-ylmethyl)-1H-indole [ka] Step A 6-Bromo-1-(phenylsulfonyl)-1H-indole (10.0 g, 29.8 mmol, 1.0 equiv) in THF (300 mL) at −78° C. was treated with LDA (2 M in THF, 22.4 mL, 44.8 mmol, 1.5 equiv). The mixture was stirred at −78° C. for 0.5 h, after which pyridine-3-carbaldehyde (3.8 g, 35.8 mmol, 1.2 equiv) was added. The reaction mixture was stirred at −78° C. for 3 h, after which water (50 mL) was added. After the addition of additional water (1 L), the mixture was extracted with ethyl acetate (3×500 mL). The organic solutions were combined, washed with brine (500 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate=1:2) to give (6-bromo-1-(phenylsulfonyl)-1H-indol-2-yl)(pyridin-3-yl)methanol (10.8 g, 81% yield) as a yellow solid. ESI-MS m / z: 443.0 [M+H] + .1 H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 1.9 Hz, 1H), 8.50 (dd, J = 4.8, 1.6 Hz, 1H), 8.15 - 8.08 (m, 1H), 7.90 - 7.80 (m, 2H), 7.73 - 7.65 (m, 2H), 7.63 - 7.52 (m, 3H), 7.43 (dd, J = 8.3, 1.7 Hz, 1H), 7.36 (dd, J = 7.8, 4.8 Hz, 1H), 6.75 (s, 1H), 6.42 (q, J = 5.5 Hz, 2H).

[0347] Step B To a solution of (6-bromo-1-(phenylsulfonyl)-1H-indol-2-yl)(pyridin-3-yl)methanol (10.2 g, 23.0 mmol, 1.0 equiv) in TFA (50 mL) was added EtSiH (50 mL). After stirring at 80 °C for 10 h, the reaction was concentrated to dryness to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3:1) to give 6-bromo-1-(phenylsulfonyl)-1H-indole (9.3 g, 95% yield) as a yellow solid. ESI-MS m / z = 427.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 1.8 Hz, 1H), 8.71 (dd, J = 5.3, 1.3 Hz, 1H), 8.17 - 8.13 (m, 1H), 8.13 - 8.09 (m, 1H), 7.92 - 7.85 (m, 2H), 7.73 (ddd, J = 10.3, 5.0, 3.1 Hz, 2H), 7.65 - 7.56 (m, 2H), 7.49 (d, J = 8.3 Hz, 1H), 7.43 (dd, J = 8.3, 1.7 Hz, 1H), 6.52 (d, J = 0.6 Hz, 1H), 4.55 (s, 2H).

[0348] Step C To a solution of 6-bromo-1-(phenylsulfonyl)-1H-indole (9.0 g, 21.1 mmol, 1.0 equiv) in MeOH (300 mL) and water (90 mL) was added KOH (23.6 g, 42.2 mmol, 2.0 equiv). After stirring at 90 °C for 16 h, the reaction was concentrated to dryness to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1:1) to give 6-bromo-2-(pyridin-3-ylmethyl)-1H-indole (4.98 g, 82% yield) as a yellow solid. ESI-MS m / z = 287.0 [M+H] + .

[0349] U: 2-(6-bromo-1-(3-hydroxy-2,2-dimethylpropyl)-1H-indazol-3-yl)-2-methylpropanenitrile [ka]

[0350] To a stirred solution of 6-bromo-1H-indazole-3-carbaldehyde (2.24 g, 9.95 mmol, 1.0 equiv) in formamide (50 mL) and MeOH (50 mL) was added NaBH (1883 mg, 49.77 mmol, 5.0 equiv) in portions. The resulting mixture was stirred at room temperature for 2 h, and then KCN (3.241 g, 49.7 mmol, 5.00 equiv) was added in portions. The resulting mixture was stirred at 60 °C for 16 h and then concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, washed with brine (3 x 100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with petroleum ether / ethyl acetate) to give 2-(6-bromo-1H-indazol-3-yl)acetonitrile (900 mg, 38% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 13.25 (s, 1H), 7.91 - 7.68 (m, 2H), 7.32 (dd, J = 8.7, 1.5 Hz, 1H), 4.40 (s, 2H).

[0351] Step B To a stirred solution / mixture of 2-(6-bromo-1H-indazol-3-yl)acetonitrile (1.1 g, 4.660 mmol, 1.0 equiv), TEA (0.71 g, 6.989 mmol, 1.5 equiv), and DMAP (57 mg, 0.466 mmol, 0.1 equiv) in dichloromethane (20 mL) was added BocO (1.12 g, 5.13 mmol, 1.10 equiv) in small portions at 0 °C. The resulting mixture was stirred at room temperature for 3 h and then extracted with dichloromethane (3 x 30 mL). The organic layers were combined, washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / ethyl acetate (5:1)) to give tert-butyl 6-bromo-3-(cyanomethyl)-1H-indazole-1-carboxylate (1.3 g, 83% yield) as a yellow solid. 1 H NMR (300 MHz, CDCl3) δ = 8.43 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.54 (dd, J = 8.6, 1.6 Hz, 1H), 4.11 (s, 2H), 1.75 (s, 9H).

[0352] Step C To a stirred solution of tert-butyl 6-bromo-3-(cyanomethyl)-1H-indazole-1-carboxylate (2.4 g, 7.139 mmol, 1 equiv) in THF (50 mL) was added LiHMDS (21 mL) dropwise at −78°C under an argon atmosphere. The resulting mixture was stirred at −78°C for 1 h, and then MeI (3.04 g, 21.418 mmol, 3.00 equiv) was added dropwise over 30 min at −78°C. The resulting mixture was stirred at room temperature for an additional 16 h. The reaction was quenched with saturated aqueous NH4Cl at 0°C. The aqueous layer was extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, washed with brine (3 x 100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (aqueous MeCN concentration 0% to 100% in the presence of 0.1% FA) to give tert-butyl 6-bromo-3-(2-cyanopropan-2-yl)-1H-indazole-1-carboxylate (800 mg, crude product) as a yellow solid.

[0353] Step D To a stirred solution of tert-butyl 6-bromo-3-(2-cyanopropan-2-yl)-1H-indazole-1-carboxylate (800 mg, 2.2 mmol, 1 equiv.) in dichloromethane (12 mL) was added TFA (6 mL) in small portions at 0°C. The resulting mixture was stirred at 0°C for 2 hours and then concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (0% to 69% MeCN in water gradient in the presence of 0.1% FA) to give 2-(6-bromo-1H-indazol-3-yl)-2-methylpropanenitrile (500 mg, 86% yield) as a white solid. ESI-MS m / z = 264.4 [M+H] +

[0354] V: (2-(bromomethyl)butoxy)(tert-butyl)diphenylsilane [ka] A solution of 2-(((tert-butyldiphenylsilyl)oxy)methyl)butan-1-ol (2.7 g, 7.9 mmol, 1 equiv.) in dichloromethane (30 mL) was treated with PPh3 (3.1 g, 12 mmol, 1.5 equiv.). After cooling to 0 °C, CBr4 (3.9 g, 12 mmol, 1.5 equiv.) was added. The resulting solution was stirred at room temperature for 1 h and then concentrated. The residue was purified by silica gel chromatography with petroleum ether to give (2-(bromomethyl)butoxy)(tert-butyl)diphenylsilane (2.7 g, 85% yield) as a pale yellow oil. 1 H-NMR (300 MHz, DMSO-d6) δ 7.68 - 7.58 (m, 4H), 7.54 - 7.38 (m, 6H), 3.66 (dqd, J = 16.5, 10.0, 5.4 Hz, 4H), 1.78 (septet, J = 6.0 Hz, 1H), 1.36 (dq, J = 14.1, 7.2 Hz, 2H), 1.01 (s, 9H), 0.84 (td, J = 7.6, 7.1, 1.8 Hz, 5H).

[0355] W: 3-((tert-butyldiphenylsilyl)oxy)-2-fluoropropyl methanesulfonate [ka] Step A A solution of methyl 2-fluoro-3-hydroxypropanoate (5.0 g, 41 mmol, 1.0 equiv.) in dichloromethane (100 mL) was treated with imidazole (5.576 g, 82 mmol, 2.0 equiv.) and TBDPS-Cl (12.33 g, 45 mmol, 1.1 equiv.) at 0 °C. The solution was stirred at room temperature for 2 h, and then ice water (100 mL) was added. The solution was extracted with dichloromethane (2 x 100 mL), and the organic layers were combined and washed with brine (2 x 100 mL). The mixture was dried over anhydrous sodium sulfate. Purification by silica gel chromatography (eluting with ethyl acetate / petroleum ether (1:20 → 1:5)) afforded methyl 3-(tert-butyldiphenylsilyloxy)-2-fluoropropanoate (16 g) as a white solid.

[0356] Step B A solution of methyl 3-(tert-butyldiphenylsilyloxy)-2-fluoropropanoate (8 g, 22.2 mmol, 1.0 equiv.) in THF (100 mL) at 0 °C was treated with LiBH (1.95 g, 88.8 mmol, 4.0 equiv.). After stirring the solution at room temperature for 15 h, the reaction was quenched with ice-water (100 mL). After extraction with ethyl acetate (3 x 100 mL), the organic layers were combined. The solution was dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography (eluting with ethyl acetate / petroleum ether (1:10 → 1:3)) to give 3-((tert-butyldiphenylsilyl)oxy)-2-fluoropropan-1-ol (7.0 g, 95% yield) as a colorless oil. 1 H-NMR (300 MHz, DMSO-d6) δ7.74-7.59 (m, 4H), 7.54-7.35 (m, 6H), 4.94 (t, J = 5.6 Hz, 1H), 4.74- 4.59 (m, 1H), 4.56-4.43 (m, 2H), 3.62 (m, 5.3 Hz, 2H), 1.01 (s, 9H).

[0357] Step C A solution of 3-((tert-butyldiphenylsilyl)oxy)-2-fluoropropan-1-ol (2 g, 6.024 mmol, 1 equiv.) in dichloromethane (20 mL) at 0 °C was treated with EtN (1.22 g, 12.048 mmol, 2.0 equiv.), DMAP (73 mg, 0.602 mmol, 0.05 equiv.), and methanesulfonyl chloride (0.89 g, 7.831 mmol, 1.3 equiv.). After stirring the solution at room temperature for 3 h, the crude product was purified by silica gel chromatography (eluting with ethyl acetate / petroleum ether (1:10 → 1:3)) to give 3-((tert-butyldiphenylsilyl)oxy)-2-fluoropropyl methanesulfonate (2.6 g, crude) as a yellow oil. ESI-MS m / z = 433.2 [M+Na] + .

[0358] X: 3-bromo-2-(cyclopropylmethyl)propoxy)(tert-butyl)diphenylsilane [ka] Step A To a stirred solution of 1,3-diethyl 2-(cyclopropylmethyl)propanedioate (2.2 g, 10.268 mmol, 1 equiv.) in THF (40 mL) was added LiBH4 (1.36 g, 62.43 mmol, 6.08 equiv.) in portions at 0 °C. The resulting mixture was stirred at 50 °C for 14 h and then diluted with water (200 mL). After extraction with ethyl acetate (3 x 100 mL), the organic layers were combined, washed with brine (20 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product, 2-(cyclopropylmethyl)propane-1,3-diol (1.3 g, crude), was used directly in the next step without further purification. ESI-MS m / z = 131.2 [M+H] + .

[0359] Step B To a stirred solution of 2-(cyclopropylmethyl)propane-1,3-diol (1.3 g, 9.99 mmol, 1 equiv) in THF (30 mL) was added NaH (480 mg, 12 mmol, 1.2 equiv, 60% dispersion in mineral oil) in small portions at 0 °C. The mixture was stirred at 0 °C for 1 h, and then TBDPSCl (2.87 g, 10.442 mmol, 1.05 equiv) was added dropwise over 15 min. The resulting mixture was stirred at 0 °C for an additional 1 h and then concentrated under reduced pressure. The residue was diluted with water (200 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, washed with brine (50 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with petroleum ether / EA (5:1)) to give 3-[(tert-butyldiphenylsilyl)oxy]-2-(cyclopropylmethyl)propan-1-ol (3.4 g, 65% yield) as a pale yellow oil. ESI-MS m / z = 369.2 [M+H] + .

[0360] Step C To a stirred solution of 3-[(tert-butyldiphenylsilyl)oxy]-2-(cyclopropylmethyl)propan-1-ol (3.4 g, 9.22 mmol, 1 equiv.) in dichloromethane (40 mL) was added PPh3 (9.7 g, 37.0 mmol, 4.0 equiv.) and NBS (2.5 g, 14.1 mmol, 1.5 equiv.) in small portions at 0 °C. The resulting mixture was stirred at room temperature for 14 h and then concentrated under reduced pressure. The resulting mixture was filtered, and the filter cake was washed with petroleum ether (3 x 100 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluting with 100% petroleum ether) to give [3-bromo-2-(cyclopropylmethyl)propoxy](tert-butyl)diphenylsilane (2.3 g, 55% yield) as a colorless oil. ESI-MS m / z = 431.1 [M+H] + .

[0361] Y: (3-bromo-2-(cyclopropylmethyl)propoxy)(tert-butyl)diphenylsilane [ka] To a stirred solution of oxalyl chloride (580 mg, 4.570 mmol, 1.5 equiv) in dichloromethane (10.0 mL) was added DMSO (714 mg, 9.1 mmol, 3.0 equiv) dropwise at −78° C. The resulting mixture was stirred at −78° C. for 30 minutes under a nitrogen atmosphere. To this mixture was added (2S)-3-[(tert-butyldiphenylsilyl)oxy]-2-methylpropan-1-ol (1.00 g, 3.044 mmol, 1.0 equiv) dropwise over 10 minutes at −78° C. The resulting mixture was stirred at −78° C. for an additional 30 minutes. To this mixture was added TEA (1.23 g, 12.155 mmol, 3.99 equiv) dropwise over 10 minutes at −78° C. The resulting mixture was stirred at −78° C. for an additional 30 minutes and then warmed to room temperature. The mixture was diluted with water (100 mL). The resulting mixture was extracted with dichloromethane (3 x 50 mL). The organic layers were combined, washed with brine (50 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with petroleum ether / ethyl acetate (5:1)) to give (2R)-3-[(tert-butyldiphenylsilyl)oxy]-2-methylpropanal (930 mg, 84% yield) as a colorless oil. 1 H-NMR (300 MHz, DMSO-d6) δ 9.69 (d, J = 1.3 Hz, 1H), 7.64 - 7.57 (m, 4H), 7.49 - 7.41 (m, 6H), 4.02 - 3.78 (m, 2H), 2.63 (qddd, J = 7.0, 5.8, 4.6, 1.4 Hz, 1H), 1.04 (d, J = 7.0 Hz, 3H), 0.98 (s, 9H).

[0362] Z: 6-bromo-1-((1-(hydroxymethyl)cyclopropyl)methyl)-1H-indole-3-carbonitrile [ka] Step A A solution of 6-bromo-1H-indole-3-carboxamide (1.2 g, 5.0 mmol, 1.0 equiv.), KCO (1.38 g, 10.0 mmol, 2.0 equiv.), KI (0.83 g, 5.0 mmol, 1.0 equiv.), and ((1-(bromomethyl)cyclopropyl)methoxy)(tert-butyl)diphenylsilane (2.2 g, 5.5 mmol, 1.1 equiv.) in DMSO (15 mL) was stirred at 150 °C overnight. The reaction mixture was cooled to 15 °C, and ice water (100 mL) was added. The resulting solution was extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (dichloromethane 100% → dichloromethane / MeOH = 20:1) to give 6-bromo-1-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl)-1H-indole-3-carbonitrile (2.18 g, 80% yield) as a clear oil.

[0363] Step B To a solution of 6-bromo-1-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl)-1H-indole-3-carbonitrile (2.18 g, 4.0 mmol, 1.0 equiv) in THF (20 mL) was added TBAF (8.0 mL, 1 M in THF) dropwise at 0° C. The mixture was stirred at 0° C. for 2 hours. The mixture was poured into water and extracted with ethyl acetate (200 mL). The organic phase was washed with brine (3×50 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude residue. The crude residue was purified by silica gel chromatography (petroleum ether → petroleum ether / ethyl acetate=3:1) to give 6-bromo-1-((1-(hydroxymethyl)cyclopropyl)methyl)-1H-indole-3-carbonitrile (1.05 g, 86% yield) as a white solid. ESI-MS m / z = 307.0 [M+H] + .

[0364] The following compounds were synthesized according to the procedure described for the preparation of intermediate Z, using the appropriate building blocks and modifying the reaction conditions (such as reagents, reagent ratios, temperature, and reaction time) as needed. [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5] [Table 10-6] [Table 10-7]

[0365] AA: 4-(3-hydroxypropoxy)-2-iodobenzo[b]thiophene-7-carbonitrile [ka] Step A To a stirred solution of 1-benzothiophen-4-ol (2.0 g, 13.32 mmol, 1.0 equiv) in acetonitrile (20 mL) at 0 °C, N-bromosuccinimide (2.5 g, 14.05 mmol, 1.05 equiv) was added in small portions. The resulting mixture was stirred at room temperature for 16 h. The residue was purified by silica gel chromatography (ethyl acetate / petroleum ether (1:4)) to give 7-bromo-1-benzothiophen-4-ol (2.0 g, 59% yield) as a pale yellow solid. 1H-NMR (300 MHz, CDCl3) δ 7.58 (d, J = 5.5 Hz, 1H), 7.46 (d, J = 5.5 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 6.68 (d, J = 8.2 Hz, 1H).

[0366] Step B A solution of 7-bromo-1-benzothiophen-4-ol (2.0 g, 8.73 mmol, 1 equiv.), 3-bromopropyl acetate (1.89 g, 10.44 mmol, 1.2 equiv.), and CsCO (4.29 g, 13.17 mmol, 1.51 equiv.) in DMF (20 mL) was stirred at room temperature for 16 h. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 x 150 mL). The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (1:4)) to give 3-[(7-bromo-1-benzothiophen-4-yl)oxy]propyl acetate (2.5 g, 78% yield) as a pale yellow liquid. 1 H-NMR (300 MHz, CDCl3)) δ 7.60 (d, J = 5.4 Hz, 1H), 7.46 - 7.36 (m, 2H), 6.68 (d, J = 8.3 Hz, 1H), 4.34 (t, J = 6.3 Hz, 2H), 4.21 (t, J = 6.1 Hz, 2H), 2.24 (h, J = 6.6 Hz, 2H), 2.08 (s, 3H).

[0367] Step C A solution containing 3-[(7-bromo-1-benzothiophen-4-yl)oxy]propyl acetate (2.5 g, 7.59 mmol, 1.0 equiv.), N,N-dimethylformamide (25 mL), Zn(CN) (1.55 g, 15.07 mmol, 1.98 equiv.), and Pd(PPh) (1.76 g, 1.52 mmol, 0.2 equiv.) was stirred at 130 °C for 16 h. The resulting mixture was diluted with water (250 mL) and extracted with ethyl acetate (3 x 150 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether 1:4) to give 3-[(7-cyano-1-benzothiophen-4-yl)oxy]propyl acetate (1.6 g, 69% yield) as a yellow solid. ESI-MS m / z = 276.1 [M+H] + .

[0368] Step D To a stirred solution of 3-[(7-cyano-1-benzothiophen-4-yl)oxy]propyl acetate (1.6 g, 5.81 mmol, 1 equiv.) in THF (16 mL) was added LiOH (698 mg, 29.2 mmol, 5.0 equiv.) in portions at 0° C. The resulting mixture was warmed to room temperature and stirred at room temperature for 16 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×70 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 4-(3-hydroxypropoxy)-1-benzothiophene-7-carbonitrile (1.5 grams, 99% yield) as a purple solid. 1 H-NMR (300 MHz, methanol-d4) δ 7.76 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 5.5 Hz, 1H), 7.58 (d, J = 5.5 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 4.36 (t, J = 6.2 Hz, 2H), 3.83 (t, J = 6.2 Hz, 2H), 2.13 (p, J = 6.2 Hz, 2H).

[0369] Step E To a stirred solution of 4-(3-hydroxypropoxy)-1-benzothiophene-7-carbonitrile (1.5 g, 6.43 mmol, 1 equivalent) in tetrahydrofuran (15 mL) at 0° C. was added NaH (60% dispersion in mineral oil, 387 mg, 9.68 mmol, 1.50 equivalents) in portions. The resulting mixture was stirred at 0° C. for 30 minutes, after which TBSCl (1.16 grams, 7.70 mmol, 1.20 equivalents) was added in portions. The resulting mixture was stirred at room temperature for an additional 4 hours. The mixture was then neutralized to pH 7.0 with saturated aqueous ammonium chloride. The resulting mixture was extracted with ethyl acetate, and the organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate / petroleum ether (1:4)) to give 4-[3-[(tert-butyldimethylsilyl)oxy]propoxy]-1-benzothiophene-7-carbonitrile (2.1 g, 75% yield) as a pale yellow liquid. 1 H-NMR (300 MHz, CDCl3) δ 7.68 (d, J = 8.2 Hz, 1H), 7.56 (d, J = 5.4 Hz, 1H), 7.48 (d, J = 5.5 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 4.31 (t, J = 6.2 Hz, 2H), 3.88 (t, J = 5.9 Hz, 2H), 2.12 (p, J = 6.1 Hz, 2H), 0.91 (s, 9H), 0.06 (s, 6H).

[0370] Step F To a stirred solution of 4-[3-[(tert-butyldimethylsilyl)oxy]propoxy]-1-benzothiophene-7-carbonitrile (800 mg, 2.30 mmol, 1 equiv.) in THF was added dropwise lithium diisopropylamine in THF (1 M, 3.4 mL, 3.4 mmol, 1.50 equiv.) at −60°C. The resulting mixture was stirred at −30°C for 1 hour, and then N-iodosuccinimide (778 mg, 3.46 mmol, 1.50 equiv.) was added portionwise at −60°C. The resulting mixture was stirred at room temperature for an additional 16 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride (200 mL). The resulting mixture was extracted with ethyl acetate (3×100 mL). The organic layers were combined, washed with water (1×100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (1:1)) to give 4-[3-[(tert-butyldimethylsilyl)oxy]propoxy]-2-iodo-1-benzothiophene-7-carbonitrile (800 mg, 62% yield) as a yellow solid. 1 H-NMR (300 MHz, CDCl3) δ 7.75 (d, J = 1.6 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 4.29 (t, J = 6.3 Hz, 2H), 3.86 (t, J = 5.9 Hz, 2H), 2.11 (q, J = 7.4, 6.8 Hz, 2H), 0.91 (d, J = 1.8 Hz, 9H), 0.07 (s, J = 1.7 Hz, 6H).

[0371] Step G To a stirred solution of 4-[3-[(tert-butyldimethylsilyl)oxy]propoxy]-2-iodo-1-benzothiophene-7-carbonitrile (800 mg, 1.69 mmol, 1 equiv.) in THF (10 mL) at 0 °C, TBAF (1.0 M in THF, 2 mL) was added dropwise. The reaction was monitored by LC-MS, and upon completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / petroleum ether 1:1) to give 4-(3-hydroxypropoxy)-2-iodo-1-benzothiophene-7-carbonitrile (500 mg, 74.14% yield) as a yellow solid. 1 H-NMR (300 MHz, CDCl3) δ 7.73 (s, 1H), 7.56 (t, J = 8.1 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 4.33 (t, J = 6.3 Hz, 2H), 4.02 - 3.84 (m, 2H), 2.17 (p, J = 6.2 Hz, 2H).

[0372] AB: 3-(6-bromo-2-methyl-1H-benzo[d]imidazol-1-yl)-2,2-dimethylpropan-1-ol [ka] Step A To a stirred solution of 4-bromo-2-fluoro-1-nitrobenzene (1.0 g, 45.4 mmol, 1.0 equiv) in DMSO (5.0 mL) at 0 °C, KCO (1.25 g, 90.8 mmol, 2.0 equiv) was added, followed by 3-amino-2,2-dimethylpropan-1-ol (0.70 g, 68.1 mmol, 1.5 equiv). The mixture was stirred at 25 °C for 2 h. The solution was diluted with ethyl acetate (50 mL) and water (50 mL). The layers were separated, and the organic layer was washed with water (2 x 30 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure to give 3-((5-bromo-2-nitrophenyl)amino)-2,2-dimethylpropan-1-ol (1.3 g, 95% yield) as a yellow solid. ESI-MS m / z = 303.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.59 (t, J = 4.7 Hz, 1H), 7.98 (d, J = 9.1 Hz, 1H), 7.31 (s, 1H), 6.80 (d, J = 9.1 Hz, 1H), 5.02 (t, J = 4.9 Hz, 1H), 3.28 (d, J = 4.9 Hz, 2H), 3.21 (d, J = 5.2 Hz, 2H), 0.93 (s, 6H).

[0373] Step B To a stirred suspension of 3-((5-bromo-2-nitrophenyl)amino)-2,2-dimethylpropan-1-ol (1.3 g, 4.3 mmol, 1.0 equiv.) and iron powder (1.2 g, 21.5 mmol, 5.0 equiv.) in ethanol (10 mL) and water (10 mL) was added NHCl (690 mg, 12.9 mmol, 3.0 equiv.). After stirring at 70 °C for 1 h, the mixture was filtered. The filtrate was concentrated under reduced pressure to give crude 3-((2-amino-5-bromophenyl)amino)-2,2-dimethylpropan-1-ol (1.2 grams) as a brown oil. ESI-MS m / z = 273.1 [M+H] + .

[0374] Step C A solution containing 3-((2-amino-5-bromophenyl)amino)-2,2-dimethylpropan-1-ol (6.0 g, 22.0 mmol, 1.2 equiv.), 1,1,1-trimethoxyethane (20 mL), and concentrated hydrochloric acid (3.0 mL) was stirred at 25 °C for 16 h. After concentration, the residue was purified by silica gel chromatography (petroleum / ethyl acetate = 3 / 1 → 1 / 1) to give 3-(6-bromo-2-methyl-1H-benzo[d]imidazol-1-yl)-2,2-dimethylpropan-1-ol (4.1 g, 63% yield) as an off-white solid. ESI-MS m / z = 297.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 7.89 (d, J = 1.7 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.25 (dd, J = 8.5, 1.8 Hz, 1H), 5.01 (t, J = 5.0 Hz, 1H), 4.04 (s, 2H), 3.15 (d, J = 5.0 Hz, 2H), 2.54 (s, 3H), 0.86 (s, 6H).

[0375] The following intermediates were synthesized according to the procedure described for the preparation of intermediate AB, using the appropriate building blocks and modifying the reaction conditions (such as reagents, reagent ratios, temperature, and reaction time) as needed. [Table 11]

[0376] AC: 3-(6-bromo-2-(methoxymethyl)-1H-benzo[d]imidazol-1-yl)-2,2-dimethylpropan-1-ol [ka] Step A To a solution of 3-((2-amino-5-bromophenyl)amino)-2,2-dimethylpropan-1-ol (10.0 g, 37 mmol, 1.0 equiv.), imidazole (12.6 g, 185 mmol, 5.0 equiv.), and DMAP (22.0 g, 183 mmol, 5.0 equiv.) in dichloromethane (250 mL) was added TIPSCl (35.0 g, 183 mmol, 5.0 equiv.). After stirring the mixture for 48 h, the solution was poured into water (500 mL) and extracted with ethyl acetate (3 x 300 mL). The organic layers were combined, washed with water (2 x 300 mL), brine (300 mL), dried over sodium sulfate, and purified by silica gel chromatography (cyclohexane / ethyl acetate: 1:3 → 2:1) to give 5-bromo-N,N-dimethylpropan-1-ol. 1 -(2,2-dimethyl-3-((triisopropylsilyl)oxy)propyl)benzene-1,2-diamine (2.5 g, 37% yield) was obtained as a black oil. ESI-MS m / z = 429.2 [M+H] + .

[0377] Step B To a stirred solution of 5-bromo-N1-(2,2-dimethyl-3-((triisopropylsilyl)oxy)propyl)benzene-1,2-diamine (10.0 g, 9.3 mmol, 1.0 equiv) and 2-methoxyacetic acid (922 mg, 10.2 mmol, 1.1 equiv) in DMF (50 mL) was added DIPEA (6.0 g, 46.5 mmol, 5.0 equiv), followed by HATU (5.3 g, 13.9 mmol, 1.5 equiv). The resulting solution was stirred for 1 h, after which the solution was diluted with ethyl acetate (20 mL) and water (20 mL). The layers were separated and the organic layer was washed with water (3 x 20 mL), brine (10 mL), dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to give N-(4-bromo-2-((2,2-dimethyl-3-((triisopropylsilyl)oxy)propyl)amino)phenyl)-2-methoxyacetamide (12.0 g) as an oil. The crude product was used in the next step without further purification. ESI-MS m / z = 501.3 [M+H] + .

[0378] Step C A solution of N-(4-bromo-2-((2,2-dimethyl-3-((triisopropylsilyl)oxy)propyl)amino)-phenyl)-2-methoxyacetamide (10.5 g, 20.9 mmol, 1.0 equiv) in AcOH (110 mL) was stirred at 75° C. for 16 h. After concentration, the crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate (3:1)) to give 6-bromo-1-(2,2-dimethyl-3-((triisopropylsilyl)oxy)propyl)-2-(methoxymethyl)-1H-benzo[d]imidazole (3.4 g, 57% yield) as a brown oil. ESI-MS m / z = 483.2 [M+H] + .

[0379] Step D A solution of 6-bromo-1-(2,2-dimethyl-3-((triisopropylsilyl)oxy)propyl)-2-(methoxymethyl)-1H-benzo[d]imidazole (3.4 g, 7.0 mmol, 1.0 equiv) in HCl / MeOH (10 M, 18 mL) was stirred for 1 h. After concentration, the crude product was washed with ether (20 mL) and filtered to give 3-(6-bromo-2-(methoxymethyl)-1H-benzo[d]imidazol-1-yl)-2,2-dimethylpropan-1-ol as a brown solid (1.5 g, 65% yield). ESI-MS m / z = 327.1 [M+H] + . 1 H NMR(400 MHz, DMSO-d6) δ 7.99 (d, J = 1.7 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.32 (dd, J = 8.5, 1.8 Hz, 1H), 5.05 (t, J = 5.0 Hz, 1H), 4.72 (s, 2H), 4.16 (s, 2H), 3.31 (s, 3H), 3.14 (d, J = 5.0 Hz, 2H), 0.86 (s, 6H).

[0380] The following intermediates were synthesized according to the procedure described for Intermediate AC, using the appropriate building blocks and modifying the reaction conditions (such as reagent ratios, temperatures, coupling conditions, and reaction times) as needed. [Table 12]

[0381] AD: 3-(6-bromo-2-methyl-1H-benzo[d]imidazol-1-yl)butan-1-ol [ka] A solution containing 3-((2-amino-5-bromophenyl)amino)propan-1-ol (3.0 g, 12.3 mmol, 1.0 equiv.) and 3-methoxybenzaldehyde (1.7 g, 12.3 mmol, 1.0 equiv.) in DMSO (15 mL) was stirred at 40° C. for 16 h. Water (10 mL) was added, and the solution was extracted with ethyl acetate (3×20 mL). The organic layers were combined and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate (3 / 1→1 / 1)) to give the product, 3-(6-bromo-2-(3-methoxyphenyl)-1H-benzo[d]imidazol-1-yl)propan-1-ol (2.5 g, 57% yield) as a colorless oil. ESI-MS m / z = 361.0 [M+H] + .

[0382] The following intermediates were synthesized according to the procedure described for the synthesis of intermediate AD, using the appropriate building blocks and modifying the reaction conditions (such as reagent ratios, temperatures, coupling conditions, and reaction times) as needed. [Table 13]

[0383] AE: (S)-2-(4-(2-chloroacetyl)-2-oxopiperazin-1-yl)-3-methylbutanoic acid [ka] Step A A solution of 5-bromo-2-nitroaniline (1 g, 4.61 mmol, 1 equiv.) in DMF (12 mL) at 0 °C was treated with NaH (60%, 222 mg, 9.25 mmol, 2.01 equiv.). After 30 min, di-tert-butyl dicarbonate (1.2 g, 5.53 mmol, 1.2 equiv.) was added. The resulting solution was stirred at 0 °C for 2 h, after which water was added. The solution was extracted with ethyl acetate (3 x 250 mL), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography using ethyl acetate / petroleum ether (1:2) to give tert-butyl N-(5-bromo-2-nitrophenyl)carbamate (1.4 g, 96% yield) as a yellow solid. ESI-MS m / z = 316.9 [M+H] + .

[0384] Step B A solution containing tert-butyl N-(5-bromo-2-nitrophenyl)carbamate (600 mg, 1.89 mmol, 1 equiv.), (2R)-3-bromo-2-methylpropyl acetate (443 mg, 2.27 mmol, 1.2 equiv.), MeCN (10 mL), KI (31 mg, 0.19 mmol, 0.1 equiv.), and CsCO (1232.8 mg, 3.78 mmol, 2.0 equiv.) was stirred at 65 °C for 15 h. The solids were removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography using ethyl acetate / petroleum ether (1:5) to afford (2S)-3-[(5-bromo-2-nitrophenyl)[(tert-butoxy)carbonyl]amino]-2-methylpropyl acetate (580 mg, 64%) as a yellow oil.

[0385] Step C A solution containing (2S)-3-[(5-bromo-2-nitrophenyl)[(tert-butoxy)carbonyl]amino]-2-methylpropyl acetate (580 mg, 1.34 mmol, 1 equiv.), dichloromethane (6 mL), and TFA (3 mL) was stirred at 0° C. for 1 h. The resulting mixture was concentrated to give (2S)-3-[(5-bromo-2-nitrophenyl)amino]-2-methylpropyl acetate (600 mg) as a red oil. ESI-MS m / z = 289.1 [M+H] + .

[0386] Step D A solution containing (2S)-3-[(5-bromo-2-nitrophenyl)amino]-2-methylpropyl acetate (600 mg, 1.81 mmol, 1 equiv.), CHCOOH (3 mL), HO (3 mL, 166.53 mmol, 91.91 equiv.), and zinc (592.3 mg, 9.06 mmol, 5 equiv.) was stirred at 0 °C for 1 h. After warming to room temperature and stirring at 110 °C for an additional 2 h, the solution was neutralized to approximately pH 7 with aqueous NaCO. The resulting solution was extracted with ethyl acetate (3 x 80 mL), washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to silica gel column chromatography using ethyl acetate / petroleum ether (1:2) to give (2S)-3-(6-bromo-2-methyl-1H-1,3-benzodiazol-1-yl)-2-methylpropan-1-ol (260 mg, 51% yield) as a black oil. ESI-MS m / z = 283.1 [M+H] + .

[0387] AF: (R)-3-(6-bromo-2-methyl-1H-benzo[d]imidazol-1-yl)-2-methylpropyl acetate [ka] Step A To a stirred solution of tert-butyl (5-bromo-2-nitrophenyl)carbamate (630 mg, 1.99 mmol, 1.0 equiv.), CsCO (1.3 g, 3.99 mmol, 1.0 equiv.), and KI (67.4 mg, 0.41 mmol, 0.18 equiv.) in MeCN (10 mL) was added (S)-3-bromo-2-methylpropyl acetate (440 mg, 2.26 mmol, 1.2 equiv.) at room temperature. The resulting mixture was stirred at 65 °C for 3 h and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with petroleum ether / ethyl acetate (3:1)) to give (R)-3-((5-bromo-2-nitrophenyl)amino)-2-methylpropyl acetate (400 mg, 54% yield) as a pale yellow oil. ESI-MS m / z = 331.0 [M+H] + .

[0388] Step B To a stirred solution of (R)-3-((5-bromo-2-nitrophenyl)amino)-2-methylpropyl acetate (400 mg, 1.21 mmol, 1 equiv.) in acetic acid (5 mL) and water (5 mL) was added zinc (380 mg, 5.81 mmol, 4.81 equiv.) at room temperature. The resulting mixture was stirred at 110° C. for 2 hours and then diluted with water (100 mL). The mixture was neutralized to pH 7 with saturated aqueous sodium bicarbonate. The resulting solution was extracted with ethyl acetate (2×100 mL). The organic layers were combined, washed with brine (2×100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with petroleum ether / ethyl acetate (1:1)) to give (R)-3-(6-bromo-2-methyl-1H-benzo[d]imidazol-1-yl)-2-methylpropyl acetate (280 mg, 64% yield) as an off-white solid. ESI-MS m / z = 325.1 [M+H] + .

[0389] AG: 3-(6-bromo-2-methyl-1H-benzo[d]imidazol-1-yl)butan-1-ol [ka] Step A A solution of 5-bromo-1,3-difluoro-2-nitrobenzene (5.0 g, 21 mmol, 1.0 equiv.), 3-aminopropan-1-ol (1.6 g, 21 mmol, 2 equiv.), and K2CO3 (8.7 g, 63 mmol, 3.0 equiv.) in DMF (70 mL) was stirred at room temperature for 3 h. The resulting solution was diluted with 100 mL of HO. The solution was extracted with ethyl acetate (3 x 100 mL). The organic solution was washed with brine (3 x 100 mL). The mixture was dried over anhydrous sodium sulfate, and the residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (3:2) to give 5.5 g (89% yield) of 3-((5-bromo-3-fluoro-2-nitrophenyl)amino)propan-1-ol as a yellow solid. ESI-MS m / z = 293.0 [M+H] + .

[0390] Step B 3-[(5-Bromo-3-fluoro-2-nitrophenyl)amino]propan-1-ol (2.5 g, 8.56 mmol, 1.0 equiv.) and tetraethylammonium cyanide (1.6 g, 10.3 mmol, 1.2 equiv.) were stirred in MeCN (30 mL) at 55° C. for 20 min. The resulting mixture was concentrated, and the residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1:1) to give 2.6 g of 5-bromo-3-((3-hydroxypropyl)amino)-2-nitrobenzonitrile as a yellow solid. ESI-MS m / z = 300.0 [M+H] + .

[0391] Step C A solution of 5-bromo-3-[(3-hydroxypropyl)amino]-2-nitrobenzonitrile (900 mg, 3 mmol, 1.0 equiv) and zinc (960 mg, 15 mmol, 5.0 equiv) in AcOH (9 mL) and HO (9 mL) was stirred at room temperature for 1 h. The solution was basified with aqueous NaHCO to pH 8. The resulting solution was extracted with ethyl acetate (3 x 20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 720 mg (89% yield) of 2-amino-5-bromo-3-((3-hydroxypropyl)amino)benzonitrile as a brown oil. This oil was used without further purification. ESI-MS m / z = 270.0 [M+H] + .

[0392] Step D A solution of 2-amino-5-bromo-3-[(3-hydroxypropyl)amino]benzonitrile (600 mg, 2.23 mmol, 1.0 equiv) in formic acid (2 mL) and aqueous HCl (9 mL) was stirred at 110 °C for 2 h. The solution was basified wi...

Claims

1. Formula I: 【Chemical 1】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: the first ring in Q is bonded to X and the second ring in Q is bonded to Z; Q is, 【Chemistry 2】 is selected from the group consisting of During the ceremony: V １ , V ２ , V ３ , and V ４ are each independently C, CH, or N; R Ｑ１ But -S(O) ２ -R Ｑ１１ , —C(O)—R Ｑ１１ , -S(O) ２ -N(R Ｑ１１ ) R Ｑ１２ , -C(O)-N(R Ｑ１１ ) R Ｑ１２ , C １ -C １０ Alkyl, C ３ -C １０ cycloalkyl, 4- to 14-membered heterocyclyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; or R Ｑ１ taken together with the nitrogen atom to which it is attached and adjacent ring atoms form an optionally substituted 4- to 8-membered ring, which ring is optionally further fused to a 5- or 6-membered ring; R Ｑ１１ and R Ｑ１２ are each independently, C １ -C １０ Alkyl, C ３ -C １０ cycloalkyl, 4- to 14-membered heterocyclyl, aryl, or heteroaryl; R Ｑ１１ and R Ｑ１２ are each optionally replaced, or R Ｑ１１ and R Ｑ１２ taken together with the nitrogen atom to which they are both attached form an optionally substituted 4- to 8-membered ring; R Ｑ１１ and R Ｑ１２ taken together is optionally fused to another 5- or 6-membered ring; or Q is, 【Chemistry 3】 is selected from the group consisting of During the ceremony: V １ , V ２ , V ３ , and V ４ are each independently C, CH, N, C(F), C(CH ３ ), C(OH), C(OCH ３ ), or C(CN), V ５ , V ６ , and V ７ are each independently C(R １７ａ ) (R １７ｂ ) or C(═O), and R １７ａ and R １７ｂ are hydrogen, halo, and -C, respectively. １ -C ３ Alkyl, —C １ -C ３ Haloalkyl, —O—C １ -C ３ Alkyl, —O—C １ -C ３ haloalkyl; V ５ , V ６ , and V ７ at most two of are C(=O), R ＮＱ１ is hydrogen, optionally substituted —S(O) ２ -R Ｑ１１ , —C(O)—R Ｑ１１ , -S(O) ２ -N(R Ｑ１１ ) R Ｑ１２ , -C(O)-N(R Ｑ１１ ) R Ｑ１２ , C １ -C １０ Alkyl, C ３ -C １０ cycloalkyl, 4- to 14-membered heterocyclyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; Each R Ｑ２ are independently hydrogen, CN, optionally substituted —S(O) ２ -R Ｑ１１ , —C(O)—R Ｑ１１ , -S(O) ２ -N(R Ｑ１１ ) R Ｑ１２ , -C(O)-N(R Ｑ１１ ) R Ｑ１２ , C １ -C １０ Alkyl, C ３ -C １０ cycloalkyl, 4- to 14-membered heterocyclyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; or R ＮＱ１ and one R Ｑ２ taken together with the atoms to which they are attached form an optionally substituted 4- to 8-membered ring; R ＮＱ１ and one R Ｑ２ taken together is optionally further fused to a 5- or 6-membered ring; Each R Ｑ３ are independently hydrogen, CN, optionally substituted —S(O) ２ -R Ｑ１１ , —C(O)—R Ｑ１１ , -S(O) ２ -N(R Ｑ１１ ) R Ｑ１２ , -C(O)-N(R Ｑ１１ ) R Ｑ１２ , C １ -C １０ Alkyl, C ３ -C １０ cycloalkyl, 4- to 14-membered heterocyclyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; or Two Rs bonded to the same atom Ｑ３ together to form =CH, =O, =S, or =NR Ｖ４ Forming, or Two Rs bonded to the same atom Ｑ３ taken together with the atoms to which they are attached form an optionally substituted 4- to 8-membered ring, and each R Ｑ３ taken together is optionally further fused to a 5- or 6-membered ring, or R ＮＱ１ and one R Ｑ３ taken together with the atoms to which they are attached form an optionally substituted 4- to 8-membered ring; R ＮＱ１ and R Ｑ３ taken together is optionally further fused to a 5- or 6-membered ring; R Ｑ１１ and R Ｑ１２ are each independently, C １ -C １０ Alkyl, C ３ -C １０ cycloalkyl, 4- to 14-membered heterocyclyl, aryl, or heteroaryl; R Ｑ１１ and R Ｑ１２ are each optionally replaced, or R Ｑ１１ and R Ｑ１２ taken together with the atoms to which they are attached form an optionally substituted 4- to 8-membered ring; R Ｑ１１ and R Ｑ１２ taken together is optionally further fused to another 5- or 6-membered ring; " ＊＊ " represents the moiety where Q is attached to the Z ring; or Q is, 【Chemistry 4】 is selected from the group consisting of During the ceremony: V １ , V ２ , and V ３ are each independently CH, N, C(F), C(CH ３ ), C(OH), C(OCH ３ ), or C(CN), R ＮＱ１ represents hydrogen, optionally substituted —S(O) ２ -R Ｑ１１ , —C(O)—R Ｑ１１ , -S(O) ２ -N(R Ｑ１１ ) R Ｑ１２ , -C(O)-N(R Ｑ１１ ) R Ｑ１２ , C １ -C １０ Alkyl, C ３ -C １０ cycloalkyl, 4- to 14-membered heterocyclyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; Each R Ｑ２ are independently hydrogen, CN, optionally substituted —S(O) ２ -R Ｑ１１ , —C(O)—R Ｑ１１ , -S(O) ２ -N(R Ｑ１１ ) R Ｑ１２ , -C(O)-N(R Ｑ１１ ) R Ｑ１２ , C １ -C １０ Alkyl, C ３ -C １０ cycloalkyl, 4- to 14-membered heterocyclyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; or R ＮＱ１ and one R Ｑ２ taken together with the atoms to which they are attached form an optionally substituted 4- to 8-membered ring; R ＮＱ１ and one R Ｑ２ is optionally further fused to a 5- or 6-membered ring; Each R Ｑ３ are independently hydrogen, CN, optionally substituted —S(O) ２ -R Ｑ１１ , —C(O)—R Ｑ１１ , -S(O) ２ -N(R Ｑ１１ ) R Ｑ１２ , -C(O)-N(R Ｑ１１ ) R Ｑ１２ , C １ -C １０ Alkyl, C ３ -C １０ cycloalkyl, 4- to 14-membered heterocyclyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; or Two Rs bonded to the same atom Ｑ３ together form =CH, =O, =S, or =NR Ｖ４ Forming, or Two Rs bonded to the same atom Ｑ３ taken together with the atoms to which they are attached form an optionally substituted 4- to 8-membered ring, and each R Ｑ３ is optionally further fused to a 5- or 6-membered ring; or R ＮＱ１ and one R Ｑ３ taken together with the atoms to which they are attached form an optionally substituted 4- to 8-membered ring; R ＮＱ１ and R Ｑ３ is optionally further fused to a 5- or 6-membered ring; R Ｑ１１ and R Ｑ１２ are each independently １ -C １０ Alkyl, C ３ -C １０ cycloalkyl, 4- to 14-membered heterocyclyl, aryl, or heteroaryl; R Ｑ１１ and R Ｑ１２ are each optionally replaced by, or R Ｑ１１ and R Ｑ１２ taken together with the atoms to which they are attached form an optionally substituted 4- to 8-membered ring; R Ｑ１１ and R Ｑ１２ is optionally further fused to another 5- or 6-membered ring; " ＊＊ " represents the moiety where Q is attached to the Z ring; or Q is, 【Chemistry 5】 is selected from the group consisting of During the ceremony: "1" indicates the position where Q is bonded to X, X is a bond; fluoro, —CN, —C １ -C ３ Alkyl, and —O—C １ -C ３ a straight-chain C optionally substituted with 1 to 3 substituents independently selected from alkyl; １ -C ３ Alkylene; —O—; —S(O) ０－２ -; ＊ -CH ２ -O-; ＊ -CH ２ -S(O) ０－２ -; ＊ -O-CH ２ -;or ＊ -CH ２ -S(O) ０－２ - and " ＊ ", X is -C(R ４ ) (R ５ )- represents the moiety bonded to Y is —O—, —NH—, or —N(C １ -C ３ alkyl)-, the Z ring is phenyl or a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; R １ is optionally substituted C １ -C ６ Alkyl, -(CH ２ ) ０－１ - (optionally substituted C ３ -C ６ cycloalkyl), -(CH ２ ) ０－１ -(optionally substituted aryl), or optionally substituted heterocyclyl; R ２ but, 【Chemistry 6】 and Ring A is a 4- to 8-membered cycloalkyl or a 4- to 8-membered heterocyclyl; W is -N(R １２ )-, -O-, or -C(R １２ａ ) (R １２ｂ ) - and Each R Ａ each independently represents fluoro; chloro; —CN; —OH; —NH ２ CN, OH, NH ２ , or -O-C １ -C ３ -C optionally substituted with alkyl １ -C ３ Alkyl; —O—C １ -C ３ Alkyl; or —NH—C １ -C ３ is alkyl, R ９ If present, -N(C ０ -C ５ Alkylene-H)-, -N(C(O)-(C ０ -C ５ alkylene-H)-, -C(C ０ -C ３ alkylene-H)(C ０ -C ５ alkylene-H)-, or -C(C ０ -C ３ alkylene-H)(C(O)-C ０ -C ５ alkylene-H)-, and R ９ each alkylene moiety is optionally substituted with one or more substituents, each substituent being halo, —CN, —OH, —C １ -C ３ Alkyl, and —O—C １ -C ３ independently selected from alkyl, R １０ is optionally substituted by one or more substituents, if present; １ -C ４ alkylene, each substituent being halo, —CN, —OH, —C １ -C ３ Alkyl, and —O—C １ -C ３ independently selected from alkyl, R １１ But -N(C ０ -C ５ Alkylene-H)-, -N(C(O)-(C ０ -C ５ alkylene-H)-, -C(C ０ -C ３ alkylene-H)(C ０ -C ５ alkylene-H)-, -C(C ０ -C ３ alkylene-H)(C(O)-C ０ -C ５ alkylene-H)-, or nitrogen-containing saturated heterocyclyl, and R １１ each alkylene moiety is optionally substituted with one or more substituents, each substituent being halo, —CN, —OH, —C １ -C ３ Alkyl, and —O—C １ -C ３ independently selected from alkyl, R １２ is hydrogen or -C １ -C ３ is alkyl, or R １２ But one R Ａ taken together with the atoms to which they are respectively attached and any intervening atoms, form an optionally substituted 5- to 8-membered heterocyclyl fused or spirofused to ring A, or R １２ But, R １０ Any methylene unit or R １１ taken together with any methylene units therein, the atoms to which they are respectively attached, and any intervening atoms, form an optionally substituted 5- to 8-membered heterocyclyl; R １２ａ and R １２ｂ are each independently hydrogen or —C １ -C ３ alkyl or R １２ａ and R １２ｂ together with the carbon atoms to which they are attached form a 3- to 6-membered cycloalkyl ring, R １３ is O, S, N-CN, or N-O-C １ -C ３ is alkyl, WH, 【Chemistry 7】 and Each R １４ are independently hydrogen; —CN; or —OH, —O—C １ -C ３ Alkyl, —NH ２ , —NH(C １ -C ３ alkyl), -N(C １ -C ３ alkyl) ２ or an optionally substituted 4- to 7-membered saturated heterocyclyl; １ -C ３ is alkyl, R １５ But -OH, -O-C １ -C ３ Alkyl, —NH ２ , —NH(C １ -C ３ alkyl), -N(C １ -C ３ alkyl) ２ or an optionally substituted 4- to 7-membered saturated heterocyclyl １ -C ３ is alkyl, R １６ is hydrogen; or —OH, —O—C １ -C ３ Alkyl, —NH ２ , —NH(C １ -C ３ alkyl), -N(C １ -C ３ alkyl) ２ or an optionally substituted 4- to 7-membered saturated heterocyclyl １ -C ３ is alkyl, or R １４ But, R ９ Or R １１ taken together with the atom to which they are attached and any intervening atoms, form an optionally substituted 5- to 8-membered ring system; or R １６ But, R ９ Or R １１ taken together with the atom to which they are attached and any intervening atoms, form an optionally substituted 5- to 8-membered ring system; R ３ But hydrogen, halogen, C １ -C ３ Alkyl, or C １ -C ３ is a hydroxyalkyl, R ４ is hydrogen, halogen, or optionally substituted C １ -C ３ is alkyl, R ５ is hydrogen, halogen, —OH, optionally substituted C １ -C ３ Alkyl, -(CH ２ ) ０－１ -aryl, -(CH ２ ) ０－１ -cycloalkyl, or -(CH ２ ) ０－１ -heterocyclyl, or R ４ and R ５ But by coming together, =CH ２ , optionally substituted C ３ -C ６ forming a cycloalkyl or a 3- to 7-membered saturated heterocyclyl, or R ５ is a ring atom in Q, R ４ together with the carbon atom to which is attached and X, form a 4- to 9-membered saturated or unsaturated heterocyclyl fused to Q; R ６ is hydrogen or -CH ３ and Each R ７ But independently, Halo, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Hydroxyalkyl, —OH, —O—C １ -C ３ Alkyl, —O—C １ -C ３ Haloalkyl, —NR ｎ１ R ｎ２ , -NR ｎ１ OR ｎ２ , -ONR ｎ１ R ｎ２ , or -NR ｎ１ NR ｎ２ R ｎ３ and R ｎ１ But H, C １ -C ３ Alkyl, C １ -C ３ Heteroalkyl, C １ -C ３ Haloalkyl, —C １ -C ３ hydroxyalkyl, or C １ -C ３ aminoalkyl, and R ｎ１ One of the methylene units of 【Chemistry 8】 is optionally replaced by R ｎ２ But H, C １ -C ３ Alkyl, C １ -C ３ Heteroalkyl, C １ -C ３ Haloalkyl, C １ -C ３ hydroxyalkyl, or C １ -C ３ aminoalkyl, and R ｎ２ One of the methylene units of 【Chemistry 9】 is optionally replaced by R ｎ３ But H, C １ -C ３ Alkyl, C １ -C ３ Heteroalkyl, C １ -C ３ Haloalkyl, C １ -C ３ hydroxyalkyl, or C １ -C ３ aminoalkyl, and R ｎ３ One of the methylene units of 【Chemistry 10】 is optionally replaced by Each R ８ But independently, Halo, C １ -C ３ Alkyl, or C １ -C ３ is haloalkyl, n is 0, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, or 3; The compound, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein r is 0, 1, 2, 3, or 4.

2. The compound has the formula (Ia): 【Chemistry 11】 and having the structure During the ceremony: X is a bond, —O—, or —CH ２ -, -CH(CH ３ ) -, ＊ -CH ２ —O—, or —CH ２ -CH ２ - and " ＊ ", X is C(R ４ ) (R ５ ) and represents the portion that is bonded to Y is —O— or —NH—; R １ But, -C １ -C ４ Alkyl, -(CH ２ ) ０－１ -(C ３ -C ６ cycloalkyl), or —C ４ -C ６ is cycloalkyl, R ２ but, 【Chemistry 12】 and Ring A is a 4- to 8-membered cycloalkyl or a 4- to 8-membered saturated heterocyclyl; Each R Ａ each independently represents fluoro; chloro; —CN; —OH; —NH ２ CN, OH, NH ２ , or -O-C １ -C ３ -C optionally substituted with alkyl １ -C ３ Alkyl; —O—C １ -C ３ Alkyl; or —NH—C １ -C ３ is alkyl, n is 0, 1, 2, 3, 4, 5, or 6; R ９ If present, -N(C ０ -C ５ Alkylene-H)-, -N(C(O)-(C ０ -C ５ alkylene-H)-, -C(C ０ -C ３ alkylene-H)(C ０ -C ５ alkylene-H)-, or -C(C ０ -C ３ alkylene-H)(C(O)-C ０ -C ５ alkylene-H)-, and R ９ Each alkylene moiety is halo, —CN, —OH, —C １ -C ３ Alkyl, and —O—C １ -C ３ optionally substituted by one or more substituents independently selected from alkyl; R １０ When present, halo, —CN, —OH, —C １ -C ３ Alkyl, and —O—C １ -C ３ C optionally substituted with one or more substituents independently selected from alkyl １ -C ４ is alkylene, R １１ But -N(C ０ -C ５ Alkylene-H)-, -N(C(O)-(C ０ -C ５ alkylene-H)-, -C(C ０ -C ３ alkylene-H)(C ０ -C ５ alkylene-H)-, or -C(C ０ -C ３ alkylene-H)(C(O)-C ０ -C ５ alkylene-H)-, and R １１ Each alkylene moiety is halo, —CN, —OH, —C １ -C ３ Alkyl, and —O—C １ -C ３ optionally substituted by one or more substituents independently selected from alkyl; R １２ is hydrogen or -C １ -C ３ is alkyl, or R １２ But one R Ａ taken together with the atoms to which they are respectively attached and any intervening atoms, form an optionally substituted 5- to 8-membered heterocyclyl fused to ring A, or R １２ But, R １０ Any methylene unit or R １１ taken together with any methylene units therein, the atoms to which they are respectively attached, and any intervening atoms, form an optionally substituted 5- to 8-membered heterocyclyl; WH, 【Chemistry 13】 and Each R １４ are independently hydrogen, —CN, —C １ -C ３ Alkyl, -C １ -C ３ Hydroxyalkyl, —O—C １ -C ３ is alkyl, R １５ But, -C １ -C ３ Alkyl, -C １ -C ３ hydroxyalkyl, or —C １ -C ３ Alkylene -O-C １ -C ３ is alkyl, R １６ is hydrogen, -C １ -C ３ Alkyl, -C １ -C ３ hydroxyalkyl, or —C １ -C ３ Alkylene -O-C １ -C ３ is alkyl, or R １４ But, R ９ Or R １１ taken together with the atom to which they are attached and any intervening atoms, form an optionally substituted 5- to 8-membered ring system; or R １６ But, R ９ Or R １１ taken together with the atom to which they are attached and any intervening atoms, form an optionally substituted 5- to 8-membered ring system; R ４ is hydrogen, halo, or C １ -C ３ is alkyl, R ５ is hydrogen, halo, -OH, C １ -C ３ Alkyl, C １ -C ３ Hydroxyalkyl, C １ -C ３ Alkylene -O-C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, -(CH ２ ) ０－１ -C ３ -C ６ Cycloalkyl, C １ -C ３ cyanoalkyl, or -(CH ２ ) ０－１ -aryl(benzyl), or R ４ and R ５ But by coming together, =CH ２ Or C ３ -C ６ forming a cycloalkyl, or R ５ together with the ring atoms of Q, the carbon atom to which it is attached, and X form a 5- to 7-membered saturated heterocyclyl; R ７ But -OH, -NH ２ , or C １ -C ３ 10. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, which is haloalkyl.

3. The compound has the formula (Ib): 【Chemistry 14】 or The compound has formula (Ic): 【Chemistry 15】 3. The compound of claim 1 or 2, having the structure: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

4. Q is, 【Chemistry 16】 is selected from the group consisting of During the ceremony: V １ , V ２ , and V ３ are each independently CH, N, C(F), C(CH ３ ), C(OH), C(OCH ３ ), or C(CN), R ＮＱ１ represents hydrogen, optionally substituted —S(O) ２ -R Ｑ１１ , —C(O)—R Ｑ１１ , -S(O) ２ -N(R Ｑ１１ ) R Ｑ１２ , -C(O)-N(R Ｑ１１ ) R Ｑ１２ , C １ -C １０ Alkyl, C ３ -C １０ cycloalkyl, 4- to 14-membered heterocyclyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; Each R Ｑ２ are independently hydrogen, CN, optionally substituted —S(O) ２ -R Ｑ１１ , —C(O)—R Ｑ１１ , -S(O) ２ -N(R Ｑ１１ ) R Ｑ１２ , -C(O)-N(R Ｑ１１ ) R Ｑ１２ , C １ -C １０ Alkyl, C ３ -C １０ cycloalkyl, 4- to 14-membered heterocyclyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; or R ＮＱ１ and one R Ｑ２ taken together with the atoms to which they are attached form an optionally substituted 4- to 8-membered ring; R ＮＱ１ and one R Ｑ２ is optionally further fused to a 5- or 6-membered ring; Each R Ｑ３ are independently hydrogen, CN, optionally substituted —S(O) ２ -R Ｑ１１ , —C(O)—R Ｑ１１ , -S(O) ２ -N(R Ｑ１１ ) R Ｑ１２ , -C(O)-N(R Ｑ１１ ) R Ｑ１２ , C １ -C １０ Alkyl, C ３ -C １０ cycloalkyl, 4- to 14-membered heterocyclyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; or Two Rs bonded to the same atom Ｑ３ together form =CH, =O, =S, or =NR Ｖ４ Forming, or Two Rs bonded to the same atom Ｑ３ taken together with the atoms to which they are attached form an optionally substituted 4- to 8-membered ring, and each R Ｑ３ taken together is optionally further fused to a 5- or 6-membered ring, or R ＮＱ１ and one R Ｑ３ taken together with the atoms to which they are attached form an optionally substituted 4- to 8-membered ring; R ＮＱ１ and R Ｑ３ is optionally further fused to a 5- or 6-membered ring; R Ｑ１１ and R Ｑ１２ are each independently １ -C １０ Alkyl, C ３ -C １０ cycloalkyl, 4- to 14-membered heterocyclyl, aryl, or heteroaryl; R Ｑ１１ and R Ｑ１２ are each optionally replaced by, or R Ｑ１１ and R Ｑ１２ taken together with the atoms to which they are attached form an optionally substituted 4- to 8-membered ring; R Ｑ１１ and R Ｑ１２ is optionally further fused to another 5- or 6-membered ring; " ＊＊ " represents the moiety where Q is attached to the Z ring, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

5. The compound of claim 1, wherein the compound has formula (Id): 【Chemistry 17】 or The compound has the formula (Ij): 【Chemistry 18】 5. The compound of claim 4, having the structure: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

6. The compound has the formula (IL): 【Chemistry 19】 and R １８ is Br or Cl, or The compound has the formula (Im): 【Chemistry 20】 and each R １４ is H, During the ceremony: V １ , V ２ , and V ３ are each independently CH, N, C(F), C(CH ３ ), C(OH), C(OCH ３ ), or C(CN), R ＮＱ１ represents hydrogen, optionally substituted —S(O) ２ -R Ｑ１１ , —C(O)—R Ｑ１１ , -S(O) ２ -N(R Ｑ１１ ) R Ｑ１２ , -C(O)-N(R Ｑ１１ ) R Ｑ１２ , C １ -C １０ Alkyl, C ３ -C １０ cycloalkyl, 4- to 14-membered heterocyclyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; Each R Ｑ２ are independently hydrogen, CN, optionally substituted —S(O) ２ -R Ｑ１１ , —C(O)—R Ｑ１１ , -S(O) ２ -N(R Ｑ１１ ) R Ｑ１２ , -C(O)-N(R Ｑ１１ ) R Ｑ１２ , C １ -C １０ Alkyl, C ３ -C １０ cycloalkyl, 4- to 14-membered heterocyclyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; or R ＮＱ１ and one R Ｑ２ taken together with the atoms to which they are attached form an optionally substituted 4- to 8-membered ring; R ＮＱ１ and one R Ｑ２ is optionally further fused with a 5- to 6-membered ring, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

7. Q is, 【Chemical Formula 21】 is selected from the group consisting of During the ceremony: "1" indicates the position where Q is bonded to X, 4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein Q is optionally further substituted.

8. Q is, 【Chemical 22】 is selected from the group consisting of During the ceremony: "1" indicates the position where Q is bonded to X, R is -CH ２ CH ３ , -CH ２ CH ２ -OCH ３ , -CH ２ CHF ２ , -CH ２ -CN, -C （ CH ３ ) ２ -CN, -C(CH ３ ) ２ -CH ２ CN, -CH ２ CH ２ -CN, cyclohexyl, cyclobutyl, cyclopropyl, pyridin-4-yl, tetrahydropyran-4-yl, tetrahydropyran-4-ylmethyl, oxetan-3-ylmethyl, 2-cyano-5-methoxyphenyl, 2-cyano-5-methoxymethylphenyl, 2-cyano-6-(methoxymethyl)phenyl, 2-cyano-6-bromophenyl, 2-methoxyethan-1-yl, 2-cyanopropan-2-yl, 2-tetrahydropyran-4-ylethan-1-yl, 3-cyanopentan-3-yl, or 2-cyano-4-methoxybutan-2-yl, or R is, 【Chemical 23】 and R ２３ is hydrogen or fluoro; R ２４ is hydrogen, chloro, -CN, -CH ３ , -CH ２ CH ３ , -CHF ２ , -CF ３ , -CH ２ -CN, -CH(CN)-CH ３ , --C(CH ３ ) ２ , -C(CH ２ CH ３ ) ２ , -CH ２ , -CH ２ , -C(CH ３ )=N-O-CH(CH ３ ) ２ , -C(CH ３ )=N-O-CH ３ , -C(O)-N(CH ３ ) ２ , -C(O)-NH-CH ３ , -OCH ３ , -CH ２ , -O-CH ３ , -C≡CH, -C≡C-CH ３ , -S(O) ２ CH ３ , 1-(cyclopentyl)-1-cyanoethan-1-yl, 1-(tetrahydropyran-4-yl)-1-cyanoethan-1-yl, 1-(tetrahydrofuran-3-yl)-1-cyanoethan-1-yl, 1,3-dimethoxy-2-cyanopropan-2-yl, 1,4-dimethylpyrazol-5-yl, 1-cyanocyclobutyl, 1-cyanocyclopropyl, 1-cyanocyclopentyl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 1-methylpyrazol-3-yl, 1-methyl 4-aminopyrazolylcyanomethyl, 1-methylpiperidin-4-yl, 1-methylpyrazol-5-yl, 1-oxoindolin-5-yl, 1-oxoisoindolin-4-yl, 1-oxoisoindolin-6-yl, 2-(2-methoxyethan-1-yl)phenyl, 2-(methoxymethyl)phenyl, 2-(tetrahydropyran-4-yloxy)phenyl, 2,2-difluoro-benzo[d][1,3]dioxol-4-yl, 2,3-dicyanopropan-2-yl, 2-chlorophenoxy 2-cyano-3-(tetrahydropyran-4-yl)propan-2-yl, 2-cyano-3-chlorophenyl, 2-cyano-3-fluorophenyl, 2-cyano-3-methoxyphenyl, 2-cyano-4-fluorophenyl, 2-cyano-4-chlorophenyl, 2-cyano-5-chlorophenyl, 2-cyano-5-fluorophenyl, 2-cyano-5-methoxyphenyl, 2-cyano-6-chlorophenyl, 2-cyano-6-fluorophenyl, 2-cyano-6-(tetrahydropyran-4-yl)propan-2-yl oxy)phenyl, 2-cyanomethylphenyl, 2-cyanophenyl, 2-cyanopropan-2-yl, 2-cyclopentylphenyl, 2-difluoromethoxyphenyl, 2-fluorophenyl, 2-methoxy-6-cyanophenyl, 2-methoxyphenyl, 2-methoxycarbonylphenyl, 2-nitrophenyl, 2-oxopyrrolidin-1-yl, 2-phenoxyphenyl, 3-(1,1-dioxothiomorpholin-4-ylmethyl)phenyl, 3-(2-methoxyethan-1-yl)phenyl, 3,5-difluoro-4-(pyrrolidin-1-ylcarbonyl)phenyl, 3-cyano-2-methylpropan-2-yl, 3-cyanomethylphenyl, 3-cyanopentan-3-yl, 3-cyanophenyl, 3-hydroxy-2-methylbutan-2-yl, 3-hydroxy-3-methyl-but-1-yn-1-yl, 3-methoxy-2-methylbutan-2-yl, 3-methoxymethyl-5-methylisoxazol-4-yl, 3-methoxyphenyl, 3-methoxycarbonylphenyl, 3-oxo-2-methylbutan-2-yl, 4-cyanophenyl, 4-cyanotetrahydropyran-4-yl, 4-methoxyphenyl, benzo[d][1,3]dioxole -4-yl, benzo[d]oxazol-7-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-7-yl, cyclobutyl, cyclopropyl, cyclopropylcyanomethyl, N-methoxycyclopropanecarbimidoyl, phenyl, pyridin-2-ylmethyl, pyridin-3-yl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, tetrahydrofuran-3-ylmethyl, tetrahydrofuran-3-ylcyanomethyl, tetrahydropyran-4-yl, or tetrahydropyran-4-ylcyanomethyl, R ２７ is hydrogen, -CH ３ , -CHF ２ , -CH ２ CH ３ , -CH ２ -O-CH ３ , C.H. ２ CN, -CN, -CH ２ -O-CH ２ -CN, -C(O)-N(CH ３ ) ２ , -C(O)-NH-CH ３ , -CH ２ -O-CH ２ -C≡CH, 2-methoxyphenyl, 3-methoxyphenyl, 2,2-difluorobenzo[d][1,3]dioxol-4-yl, 2-cyanophenyl, 3-cyanophenyl, phenyl, 2-benzyl methyl ether, 2-(2-methoxyethyl)benzene, 2-(2-difluoromethoxyethyl)benzene, 2-(2-dimethylmethoxyethyl)benzene, pyridin-3-yl, pyridin-2-yl, pyridin-3-ylmethyl, or tetrahydropyridin-4-yl; or R ２４ and R ２７ together to form 4-cyanobenzene-1,2-diyl, 3-cyanobenzene-1,2-diyl, 5-methyl-5-cyanotetrahydropyran-3,4-diyl, 3-cyanocyclohexane-1,2-diyl, 3-methoxybenzene-1,2-diyl, benzene-1,2-diyl, 3-oxocyclohexyl-1,2-diyl, 3-cyanocyclopentane-1,2-diyl, or pyridine-3,4-diyl; R ２８ is hydrogen, -CH ３ , or -CH ２ -O-CH ３ and R ２９ is hydrogen, acetyl, CN, -CH ２ -CN, -CH ２ -CH ２ -CN, -CH ２ -O-CH ３ , -CH=CH-CN, -CH ２ -O-C(O)-N(CH ３ ) ２ , morpholin-4-ylmethyl, pyrazol-1-ylmethyl, pyridin-3-yl, pyridin-3-ylethynyl, pyridin-2-yloxymethyl, or 2-cyanopropan-2-yl; or R ２８ and R ２９ taken together form 2,3-dihydrobenzofuran-3,3-diyl, 2,3-dihydrofuro[2,3-b]pyridine-3,3-diyl, tetrahydropyran-3,3-diyl, 6,7-dihydro-5H-cyclopenta[c]pyridin-6-yl, tetrahydropyran-4,4-diyl, or 4-methoxycyclohexane, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

9. R １ But -CH ３ , -CH ２ CH ３ , -(CH ２ ) ２ CH ３ , -CH(CH ３ ) ２ , -CH(CH ３ ) CH ２ CH ３ , cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxybenzyl, or tetrahydropyran-4-yl, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

10. R ９ is absent and ring A is a nitrogen-containing saturated heterocyclyl, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

11. R ２ Among them, 【Chemistry 24】 The part represented by 【Chemistry 25】 and R ２ Each ring system in ２ CN, OH, NH ２ , or —O—C １ -C ３ -C optionally substituted with alkyl １ -C ３ Alkyl; —O—C １ -C ３ Alkyl; and —NH—C １ -C ３ 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, optionally substituted with up to four substituents independently selected from: alkyl;

12. R ２ In the above, the portion represented by WH is —C(O)—C≡C—CH ３ , -C(O)-CH=CH ２ , -S(O) ２ -CH=CH ２ , —C(O)—CH ２ Cl, -C(O)-CH(CH ３ )Cl, or —C(O)—CH(Cl)—CH ２ -O-CH ３ and R ２ Among them, -R １１ The moiety represented by -WH is R １１ is one R １４ When combined with 【Chemical 26】 12. The compound of any one of claims 1 to 11, wherein: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

13. R ２ 1-(2-chloro-3-methoxypropanoyl)azetidin-3-yl-N-methylcarboxamide, 1-(2-chloroacetyl)azetidin-3-ylcarboxamide, 1-(2-chloroacetyl)azetidin-3-yl-N-ethylcarboxamide, 1-(2-chloroacetyl)azetidin-3-yl-N-methylcarboxamide, 1-(2-chloroacetyl)piperidin-3-yl-N-methylcarboxamide, 1-(2-chloroacetyl)piperidin-4-yl-N-methylcarboxamide, 1-(2-chloroacetyl)pyrrolidine-3- yl-N-methylcarboxamide, 1-(2-chloropropanoyl)-piperidin-4-yl-N-methylcarboxamide, 1-(2-chloropropanoyl)-3-fluoroazetidin-3-yl-N-methylcarboxamide, 1-(2-chloropropanoyl)azetidin-3-yl-N-methylcarboxamide, 1-(2-chloropropanoyl)pyrrolidin-3-yl-N-methylcarboxamide, 1-(2-chloropropanoyl)pyrrolidin-3-yl-N-methylcarboxamide, 1-(but-2-ynoyl)-4-fluoropiperidin-4-ylcarbonylmethylamino, 1-(but-2-ynoyl)azetidin-2-yl-N- Methylcarboxamide, 1-(but-2-ynoyl)azetidin-3-yl-N-methylcarboxamide, 1-(but-2-ynoyl)-piperidin-3-ylcarbonylmethylamino, 1-(but-2-ynoyl)-piperidin-4-ylcarbonylmethylamino, 1-(but-2-ynoyl)pyrrolidin-2-ylcarbonyl-N-methylamino, 1-(but-2-ynoyl)pyrrolidin-3-ylcarbonyl-N-methylamino, 1-acryloyl-2-oxo-imidazolidin-3-yl, 1-acryloyl-3-fluoroazetidin-3-yl 1-acryloyl-N-methylcarboxamide, 1-acryloyl-3-fluoropyrrolidin-3-yl-N-methylcarboxamide, 1-acryloyl-4-fluoropiperidin-4-ylcarbonylmethylamino, 1-acryloylazetidin-2-yl-N-methylcarboxamide, 1-acryloylazetidin-3-yl-N-methylcarboxamide, 1-acryloyl-piperidin-3-ylcarbonylmethylamino, 1-acryloyl-piperidin-4-ylcarbonylmethylamino, 1-acryloylpyrrolidin-2-yl-N-methylcarboxamide,1-Acryloylpyrrolidin-3-yl-N-methylcarboxamide, 1-oxo-7-(2-chloroacetyl)-2,7-diazaspiro[4.3]octan-2-yl, 1-oxo-7-(2-chloroacetyl)-2,7-diazaspiro[4.4]nonan-2-yl, 1-oxo-2-(2-chloroacetyl)-2,7-diazaspiro[4.5]decan-7-yl, 1-oxo-7-(2-chloroacetyl)-2,7-diazaspiro[4.5]decan-2-yl, 1-oxo-7-(2-chloropropanoyl)-2,7-diazaspiro[4.3]octan-2-yl ]octan-2-yl, 1-oxo-7-(but-2-ynoyl)-2,7-diazaspiro[4.4]nonan-2-yl, 1-oxo-7-acryloyl-2,7-diazaspiro[4.3]octan-2-yl, 1-oxo-7-acryloyl-2,7-diazaspiro[4.4]nonan-2-yl, 1-oxo-7-acryloyl-2,7-diazaspiro[4.5]decan-2-yl, 1-oxo-8-(2-chloroacetyl)-2,8-diazaspiro[4.5]decan-2-yl, 1-oxo-8-(but-2-ynoyl)-2,8-diazas Pyrro[4.5]decan-2-yl, 1-oxo-8-acryloyl-2,8-diazaspiro[4.5]decan-2-yl, 1-vinylsulfonyl-2-oxoimidazolidin-3-yl, 1-vinylsulfonylazetidin-3-yl-N-methylcarboxamide, 2-(1-acryloylpiperidin-4-yl)-N-methylacetamide, 2-(but-2-ynoyl)-5-oxo-2,6-diazaspiro[3.4]octan-6-yl, 2,5-dioxo-3,4-dimethyl-2,5-dihydropyrrol-1-yl-N-methylacetamide , 2-acryloyl-2-azabicyclo[2.1.1]hexan-4-yl-N-methylcarboxamide, 2-chloroacetamidomethyl-N-methylcarboxamide, 2-oxo-2,5-dihydro-1H-pyrrol-1-yl-N-methylacetamide, 2-oxo-3-(2-chloroacetamido)pyrrolidin-1-yl, 2-oxo-3-(N-methyl-2-chloroacetamido)pyrrolidin-1-yl, 2-oxo-3-(N-methylacrylamide)pyrrolidin-1-yl, 2-oxo-3-acrylamidopyrrolidin-1-yl,2-oxo-4-(2-chloroacetyl)piperazin-1-yl, 2-oxo-4-acryloylpiperazin-1-yl, 2-oxo-4-vinylsulfonylpiperazin-1-yl, 2-oxocyclopent-3-en-1-yl-N-methylacetamide, 3-(4-(dimethylamino)but-2-enamido)phenyl-N-methylcarboxamide, 4-(but-2-ynoyl)-piperazin-1-yl-N-methylcarboxamide 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, selected from the group consisting of 4-acryloylpiperazin-1-yl-N-methylcarboxamide, 6-oxo-2-(2-chloroacetyl)-2,7-diazaspiro[4.5]decan-7-yl, and 6-oxo-2-acryloyl-2,7-diazaspiro[4.5]decan-7-yl.

14. R ４ is hydrogen, fluoro, or —CH ３ and R ５ is hydrogen, fluoro, chloro, -OH, -CH ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , -CH ２ OH, -CH ２ OCH ３ , -CH ２ F, -CHF ２ , C.H. ２ CN, -CH ２ -cyclopropyl, cyclopropyl, pyridyl, phenyl, or -CH ２ -phenyl, and R ５ Any phenyl moiety in １ -C ３ optionally substituted with up to four substituents independently selected from alkyl; R ４ and R ５ But by coming together, =CH ２ or forms cyclopropyl or cyclobutyl or cyclopentyl or cyclohexyl, or R ５ is taken together with the carbon atom to which it is attached, the ring atom of Q, and X to form an oxazepane, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

15. R ７ But -OH, -NH ２ , or -CHF ２ 15. The compound of any one of claims 1 to 14, wherein:

16. The following compounds: 【Chemistry 27-1】 【Chemistry 27-2】 【Chemistry 27-3】 【Chemistry 27-4】 【Chemistry 27-5】 【Chemistry 27-6】 【Chemistry 27-7】 【Chemistry 27-8】 【Chemistry 27-9】 【Chemistry 27-10】 【Chemistry 27-11】 【Chemistry 27-12】 【Chemistry 27-13】 【Chemistry 27-14】 【Chemistry 27-15】 【Chemistry 27-16】 【Hua 27-17】 【Chemistry 27-18】 【Chemistry 27-19】 【Chemistry 27-20】 【Chemistry 27-21】 【Chemistry 27-22】 【Chemistry 27-23】 【Chemistry 27-24】 【Chemistry 27-25】 【Chemistry 27-26】 【Hua 27-27】 【Chemistry 27-28】 【Chemistry 27-29】 【27-30】 【Chemistry 27-31】 【Chemistry 27-32】 【Chemistry 27-33】 【Chemistry 27-34】 【Chemistry 27-35】 【Chemistry 27-36】 【Hua 27-37】 【Chemistry 27-38】 【Chemistry 27-39】 【Chemistry 27-40】 【Chemistry 27-41】 【Chemistry 27-42】 【Chemistry 27-43】 【Chemistry 27-44】 【Chemistry 27-45】 【Chemistry 27-46】 【Hua 27-47】 【27-48】 【Chemistry 27-49】 【Chemistry 27-50】 【Hua 27-51】 【Hua 27-52】 【Hua 27-53】 【Hua 27-54】 【Hua 27-55】 【Hua 27-56】 【Hua 27-57】 【Hua 27-58】 【Hua 27-59】 【Chemistry 27-60】 【Hua 27-61】 【Hua 27-62】 【Hua 27-63】 【Hua 27-64】 【Hua 27-65】 【Hua 27-66】 【Hua 27-67】 【27-68】 【Hua 27-69】 【Hua 27-70】 【Hua 27-71】 【Hua 27-72】 【Hua 27-73】 【Hua 27-74】 【Hua 27-75】 【Hua 27-76】 【Hua 27-77】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

17. 17. A pharmaceutical composition comprising a compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

18. A complex comprising a presenter protein, a RAS protein, and the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof.

19. 17. A method for producing a complex, said method comprising contacting a presenter protein and a KRAS G12C protein with a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, under conditions suitable to allow complex formation.

20. 17. A pharmaceutical composition for the treatment of cancer, comprising a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

21. 17. A pharmaceutical composition for a method of inhibiting KRAS G12C protein in a cell, comprising a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

22. 17. A pharmaceutical composition for the treatment of a KRAS G12C protein-associated disorder, comprising a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

23. 17. A pharmaceutical composition for a method of inhibiting RAF-RAS binding in a cell, comprising a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

24. 23. The pharmaceutical composition of claim 20 or 22, wherein an additional therapeutic agent is administered to a subject in need of said treatment.

25. 24. The pharmaceutical composition of claim 21 or 23, wherein the method further comprises administering an additional therapeutic agent.

26. 26. The pharmaceutical composition of claim 24 or 25, wherein the additional therapeutic agent is a HER2 inhibitor, an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, an SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, or a combination thereof.

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