Checkpoint kinase 1 (CHK1) inhibitors and uses thereof

Abstract

Provided herein are compounds and methods for the treatment of cancer, comprising administering to a subject in need of treatment a therapeutically effective amount of a Chk1 inhibitor as disclosed herein.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 193,990, filed May 27, 2021, the entirety of which is incorporated herein by reference.

[0002] Described herein are compounds for inhibiting checkpoint kinase 1 (CHK1), methods for making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds. [Background technology]

[0003] Checkpoint kinases (Chks) are protein kinases involved in the control of the cell cycle. Two checkpoint kinase subtypes, Chk1 and Chk2, have been identified. Chk1 is a central component of the genome surveillance pathway and a key regulator of the cell cycle and cell survival. Chk1 is required for the initiation of the DNA damage checkpoint and has recently been shown to play a role in normal (unperturbed) cell cycle. Chk1 affects various phases of the cell cycle, including S phase, G2 / M transition, and M phase. In addition to mediating cell cycle checkpoints, Chk1 also contributes to DNA repair processes, gene transcription, embryonic development, the cellular response to HIV infection, and somatic cell viability.

[0004] Chk1 is essential for maintaining genome integrity. Chk1 monitors DNA replication during an unperturbed cell cycle and responds to genotoxic stress when present. Chk1 can recognize DNA strand instability during replication and halt DNA replication to allow time for DNA repair mechanisms to repair the genome. Recently, Chk1 has been shown to mediate DNA repair mechanisms and does so by activating various repair factors. Furthermore, Chk1 is associated with three specific aspects of S phase, including regulating anaphase origin firing, controlling the elongation process, and maintaining DNA replication fork stability.

[0005] In response to DNA damage, Chk1 is a key signaling agent for G2 / M checkpoint activation. Activation of Chk1 holds cells in the G2 phase until they are ready to enter mitosis. This delay allows time for DNA to be repaired or for cell death to occur if DNA damage is irreversible. Chk1 must be inactivated for cells to move from the G2 phase into mitosis, and Chk1 expression levels are mediated by regulatory proteins.

[0006] Chk1 has a regulatory role in the spindle checkpoint. However, this relationship is less clear compared to checkpoints in other cell cycle phases. During this phase, Chk1-activating elements of single-stranded DNA (ssDNA) cannot be generated, suggesting an alternative form of activation. Studies on Chk1-deficient chicken lymphoma cells have shown increased levels of genomic instability and failure to arrest during the spindle checkpoint phase in mitosis. Furthermore, haploinsufficient mammary epithelial cells showed misaligned chromosomes and abnormal segregation. These studies suggest that Chk1 depletion may cause spindle checkpoint defects and lead to mitotic abnormalities.

[0007] DNA damage induces activation of Chk1, which promotes the initiation of the DNA damage response (DDR) and cell cycle checkpoints. The DNA damage response is a network of signaling pathways that leads to checkpoint activation, DNA repair, and apoptosis, inhibiting the progression of damaged cells through the cell cycle.

[0008] Chk1 is regulated by ATR through phosphorylation, forming the ATR-Chk1 pathway. This pathway recognizes ssDNA, which can be the result of UV-induced damage, replication stress, and interstrand crosslinks. In many cases, ssDNA can be the result of aberrant replication during S phase due to uncoupling of the replicative enzymes helicase and DNA polymerase. These ssDNA structures attract ATR, ultimately activating the checkpoint pathway.

[0009] However, activation of Chk1 does not depend solely on ATR. Intermediate proteins involved in DNA replication are often required. Regulatory proteins such as replication protein A, Claspin, Tim / Tipin, Rad17, and TopBP1 may be involved to promote Chk1 activation. Additional protein interactions are involved to induce maximal phosphorylation of Chk1. Chk1 activation can further be ATR-independent through interactions with other protein kinases such as PKB / AKT, MAPKAPK, and p90 / RSK.

[0010] Chk1 interacts with many downstream effectors to induce cell cycle arrest. In response to DNA damage, Chk1 primarily phosphorylates Cdc25, which leads to its proteasomal degradation. The degradation has an inhibitory effect on the formation of cyclin-dependent kinase complexes, which are key drivers of the cell cycle. By targeting Cdc25, cell cycle arrest can occur at multiple time points, including the G1 / S transition, S phase, and G2 / M transition. In addition, Chk1 can indirectly target Cdc25 by phosphorylating Nek11.

[0011] Chk1 has been shown to mediate DNA repair mechanisms and does so by activating repair factors such as proliferating cell nuclear antigen (PCNA), FANCE, Rad51, and TLK. Chk1 promotes replication fork stabilization during DNA replication and repair, but more studies are needed to define the underlying interactions.

[0012] There is a need for Chk1 inhibitors, potent inhibitors of cell cycle checkpoints that can effectively act as potentiators of DNA damaging agents to address the need for safe and effective treatments of cancer. Summary of the Invention

[0013] Described herein are Chk1 inhibitors useful in the treatment of cancer.

[0014] Disclosed herein is a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof,

[0015] [ka] During the ceremony, Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 1 are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NHS(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same atom 1 come together to form oxo, n is 0 to 4; R 2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R 3 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R 4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 5 are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SRa , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NHS(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same atom 5 come together to form oxo, m is 0 to 4; L is -O- or -NR 6 - and R 6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Ring C is cycloalkyl; R 7 are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NRc R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NHS(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same atom 7 come together to form oxo, p is 0 to 8; R aare each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo each alkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; R bare each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloa each alkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; R c and R dare each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, each of the alkyl, aryl, and heteroaryl is independently optionally substituted with one or more of oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; Or, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl.

[0016] Also disclosed herein is a compound of formula (Ia), or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof,

[0017] [ka] During the ceremony, X 1 is N or CR 5a and X 2 is N or CR 5b and X 3 is N or CR 5c and X 4 is N or CR 5d and R 5a , R 5b , R 5c , and R 5d are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NHS(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0018] Also disclosed herein are pharmaceutical compositions comprising a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a pharma- ceutically acceptable excipient.

[0019] Also disclosed herein is a method of treating cancer in a subject, the method comprising administering to the subject a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein.

[0020] Also disclosed herein is a method of inhibiting CHK1 in a subject, the method comprising administering to the subject a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein.

[0021] INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned herein are hereby incorporated by reference for the specific purposes identified herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] definition As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "an agent" includes a plurality of such agents, a reference to "a cell" includes a reference to one or more cells (or cells), and equivalents known to those of skill in the art, and so forth. When ranges relating to physical properties, such as molecular weight, or chemical properties, such as chemical formulas, are used herein, all combinations and subcombinations of the ranges, and specific embodiments within the ranges, are intended to be encompassed. The term "about," when referring to a number or range of numbers, means that the referenced number or range of numbers is an approximation within experimental variation (or within statistical experimental error), and thus the number or range of numbers may vary, in some cases, by 1% to 15% of the stated number or range of numbers. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other specific embodiments, for example, any compositions of matter, compositions, methods, or processes described herein "consist of" or "consist essentially of" the described features.

[0023] As used in this specification and the appended claims, unless specified to the contrary, the following terms have the meanings specified below.

[0024] "Oxo" refers to =O.

[0025] "Alkyl" refers to an optionally substituted straight chain or optionally substituted branched chain saturated hydrocarbon monoradical having 1 to about 10 carbon atoms, or 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, etc. Wherever a numerical range appears herein, such as "C1-C6 alkyl," it means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but this definition also encompasses occurrences of the term "alkyl" when no numerical range is specified. In some embodiments, alkyl is any of the C1-C6 alkyl groups. 10Alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, or C1 alkyl. Unless otherwise specified herein, alkyl groups are optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, alkyl is optionally substituted with halogen. In some embodiments, alkyl is optionally substituted with -COOH, -COOMe, -CONH2, -CONHMe, or -CONMe2.

[0026] "Alkenyl" refers to an optionally substituted straight chain or an optionally substituted branched chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The group may be in either the cis or trans configuration about the double bond and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and the like. Whenever a numerical range such as "C2-C6 alkenyl" appears herein, it means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the definition also encompasses occurrences of the term "alkenyl" when no numerical range is explicitly stated. In some embodiments, alkenyl is any of the C2-C6 alkenyls. 10alkenyl, C2-C9 alkenyl, C2-C8 alkenyl, C2-C7 alkenyl, C2-C6 alkenyl, C2-C5 alkenyl, C2-C4 alkenyl, C2-C3 alkenyl, or C2 alkenyl. Unless otherwise specified herein, an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, an alkenyl is optionally substituted with halogen. In some embodiments, the alkenyl is optionally substituted with -COOH, -COOMe, -CONH2, -CONHMe, or -CONMe2.

[0027] "Alkynyl" refers to an optionally substituted straight chain or an optionally substituted branched chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever appearing herein, a numerical range such as "C2-C6 alkynyl" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition includes C2-C6 alkynyl. 10It also encompasses alkynyl that is alkynyl, C2-C9 alkynyl, C2-C8 alkynyl, C2-C7 alkynyl, C2-C6 alkynyl, C2-C5 alkynyl, C2-C4 alkynyl, C2-C3 alkynyl, or C2 alkynyl. Unless otherwise specified herein, alkynyl groups are optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with halogen. In some embodiments, the alkynyl is optionally substituted with -COOH, -COOMe, -CONH2, -CONHMe, or -CONMe2.

[0028] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specified in the specification, an alkylene group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, an alkylene is optionally substituted with halogen. In some embodiments, an alkylene is optionally substituted with -COOH, -COOMe, -CONH2, -CONHMe, or -CONMe2.

[0029] "Alkoxy" refers to a radical of the formula -Oalkyl, where alkyl is as defined. Unless otherwise specified in the specification, an alkoxy group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, an alkoxy is optionally substituted with halogen. In some embodiments, an alkoxy is optionally substituted with -COOH, -COOMe, -CONH2, -CONHMe, or -CONMe2.

[0030] "Aminoalkyl" refers to an alkyl radical, as defined above, substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0031] "Aryl" refers to a radical derived from a hydrocarbon ring system containing hydrogen, 6 to 30 carbon atoms, and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl. Aryl radicals include, but are not limited to, aryl radicals derived from anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene hydrocarbon ring systems. In some embodiments, the aryl is phenyl. Unless otherwise specified herein, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, an aryl is optionally substituted with halogen. In some embodiments, an aryl is optionally substituted with -COOH, -COOMe, -CONH2, -CONHMe, or -CONMe2.

[0032] "Cycloalkyl" refers to a partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or heteroaryl ring, the cycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3 to 15 carbon atoms (C3-C4). 15 Cycloalkyl), 3 to 10 carbon atoms (C3-C 10cycloalkyl), cycloalkyl having 3 to 8 carbon atoms (C3-C8 cycloalkyl), 3 to 6 carbon atoms (C3-C6 cycloalkyl), 3 to 5 carbon atoms (C3-C5 cycloalkyl), or 3 to 4 carbon atoms (C3-C4 cycloalkyl). In some embodiments, the cycloalkyl is a 3-membered to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5-membered to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 3-membered to 10-membered monocyclic or bicyclic cycloalkyl. In some embodiments, the cycloalkyl is a 3-membered to 8-membered monocyclic or bicyclic cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specified herein, cycloalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.In some embodiments, the cycloalkyl is optionally substituted with -COOH, -COOMe, -CONH2, -CONHMe, or -CONMe2.

[0033] "Deuteroalkyl" refers to an alkyl radical, as defined above, substituted by one or more deuterium atoms. In some embodiments, the alkyl is substituted with one deuterium atom. In some embodiments, the alkyl is substituted with one, two, or three deuterium atoms. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuterium atoms. Deuteroalkyls include, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.

[0034] "Haloalkyl" refers to an alkyl radical, as defined above, substituted by one or more halogens. In some embodiments, the alkyl is substituted with 1, 2, or 3 halogen atoms. In some embodiments, the alkyl is substituted with 1, 2, 3, 4, 5, or 6 halogens. Haloalkyl includes, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. In some embodiments, the haloalkyl is trifluoromethyl.

[0035] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro. In some embodiments, the halogen is chloro. In some embodiments, the halogen is bromo. In some embodiments, the halogen is iodo.

[0036] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In some embodiments, the heteroalkyl is a C1-C6 heteroalkyl containing 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, where the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CHOCH3, -CHCH2OCH3, -CHCH2OCH2CH2OCH3, or -CH(CH3)OCH3. Unless otherwise specified in this specification, the heteroalkyl is optionally substituted, e.g., with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroalkyl is optionally substituted with halogen. In some embodiments, heteroalkyl is optionally substituted with -COOH, -COOMe, -CONH2, -CONHMe, or -CONMe2.

[0037] "Hydroxyalkyl" refers to an alkyl radical, as defined above, substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0038] "Heterocycloalkyl" refers to a 3-24 membered partially or fully saturated, not fully aromatic ring radical containing 2-23 carbon atoms and 1-8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl contains 1 or 2 heteroatoms selected from the group consisting of nitrogen and oxygen. Unless otherwise specified herein, a heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or heteroaryl ring, the heterocycloalkyl is joined by a non-aromatic ring atom) or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized and the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having 2-15 carbon atoms (C2-C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C30, C31, C32, C33, C34, C35, C35, C46, ​​C47, C48, C49, C51, C52, C53, C54, C55, C56, C67, C68, C69, C70, C71, C72, C73, C74, C75, C75, C76, C77, C78, ​​C79, C81, C82, C83, C84, C85, C86, C87, C88, C89, C91, C92, C93, C94, C95, C96, C97, 15 Heterocycloalkyl, 2 to 10 carbon atoms (C2-C 10Heterocycloalkyl includes heterocycloalkyls having 2 to 8 carbon atoms (C2-C8 heterocycloalkyl), 2 to 6 carbon atoms (C2-C6 heterocycloalkyl), 2 to 5 carbon atoms (C2-C5 heterocycloalkyl), or 2 to 4 carbon atoms (C2-C4 heterocycloalkyl). In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, and 4-piperidonyl. , pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term "heterocycloalkyl" also includes all cyclic forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. When referring to the number of carbon atoms in a heterocycloalkyl, it is noted that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise in the specification, heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.In some embodiments, heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heterocycloalkyl is optionally substituted with halogen. In some embodiments, heterocycloalkyl is optionally substituted with -COOH, -COOMe, -CONH2, -CONHMe, or -CONMe2.

[0039] "Heteroaryl" refers to a radical of a 5-14 membered ring system containing a hydrogen atom, 1-13 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring containing at least one heteroatom. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded by an aromatic ring atom) or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized and the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5-10 membered heteroaryl. In some embodiments, the heteroaryl is a 5-6 membered heteroaryl. In some embodiments, the heteroaryl is a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl is a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen.Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, Includes isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified herein, heteroaryl is optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroaryl is optionally substituted with halogen.In some embodiments, the heteroaryl is optionally substituted with -COOH, -COOMe, -CONH2, -CONHMe, or -CONMe2.

[0040] The term "one or more" when referring to any substituent means that the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.

[0041] The terms "treat", "treated", "treatment", or "treating" as used herein refer to therapeutic treatment, the purpose of which is to prevent or delay (lessen) an undesirable physiological disease, disorder, or condition, or to obtain a beneficial or desired clinical outcome. For purposes described herein, beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms, reduction in the extent of the disease, disorder, or disease, stabilization (i.e., not worsening) of the disease, disorder, or disease state, delay in onset or slowing of progression of the disease, disorder, or disease, improvement of the disease, disorder, or disease state, and remission (whether partial or total), or enhancement or amelioration of the disease, disorder, or disease, whether detectable or undetectable. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment further includes extending survival time as compared to the expected survival time in the absence of treatment. The terms "treat", "treated", "treatment", or "treating", as well as the words derived therefrom, as used herein, do not necessarily mean 100% or complete treatment. Rather, there are various degrees of treatment that those skilled in the art will recognize as potentially beneficial or therapeutic. In this regard, the disclosed methods can provide any level of treatment of a mammalian disorder in any amount. For example, a disorder, including its symptoms or condition, can be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%.

[0042] The term "effective amount" or "therapeutically effective amount", as used herein, refers to a sufficient amount of a compound disclosed herein being administered that relieves to some extent one or more of the symptoms of the disease or condition being treated, e.g., cancer or inflammatory disease. In some embodiments, the result is a reduction and / or amelioration of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound as disclosed herein that is required to clinically significantly reduce a disease symptom. In some embodiments, the appropriate "effective" amount in a particular case is determined using techniques such as a dose escalation study.

[0043] The term "ecDNA signature" as used herein generally refers to one or more features common to tumors or tumor cells that are ecDNA+. In some cases, the ecDNA signature is selected from the group consisting of gene amplification, p53 loss-of-function mutations, lack of microsatellite instability (MSI-H), low levels of PD-L1 expression, low levels of tumor inflammation signature (TIS), low levels of tumor mutation burden (TMB), increased frequency of allelic substitutions, insertions, or deletions (indels), and any combination thereof. In some cases, the ecDNA signature includes detection or identification of ecDNA using imaging techniques. In some cases, the ecDNA signature does not include any imaging or direct detection of ecDNA.

[0044] compound Described herein are Chk1 inhibitors useful for the treatment of cancer.

[0045] Disclosed herein is a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof,

[0046] [ka] During the ceremony, Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 1 are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NHS(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same atom 1 come together to form oxo, n is 0 to 4; R 2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R 3 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -NRc R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R 4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 5 are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NHS(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same atom 5 come together to form oxo, m is 0 to 4; L is -O- or -NR 6 - and R 6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Ring C is cycloalkyl; R 7 are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NHS(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same atom 7 come together to form oxo, p is 0 to 8; R a are each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo each alkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; R bare each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloa each alkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; R c and R dare each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, each of the alkyl, aryl, and heteroaryl is independently optionally substituted with one or more of oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; Or, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl.

[0047] Also disclosed herein is a compound of formula (I'), or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof,

[0048] [ka] During the ceremony, Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 1 are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NHS(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same atom 1 come together to form oxo, n is 0 to 4; R 2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R 3 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a, -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R 4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 5 are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NHS(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same atom 5 come together to form oxo, m is 0 to 4; L is -O- or -NR 6 - and R 6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Ring C is cycloalkyl; R 7 are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NHS(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same atom 7 come together to form oxo, p is 0 to 4; R a are each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo each alkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; R bare each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloa each alkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; R c and R dare each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, each of the alkyl, aryl, and heteroaryl is independently optionally substituted with one or more of oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; Or, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl.

[0049] In some embodiments of the compounds of formula (I) or (I'), ring B is cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I) or (I'), ring B is aryl or heteroaryl. In some embodiments of the compounds of formula (I) or (I'), ring B is aryl. In some embodiments of the compounds of formula (I) or (I'), ring B is heteroaryl. In some embodiments of the compounds of formula (I) or (I'), ring B is 5- or 6-membered heteroaryl. In some embodiments of the compounds of formula (I) or (I'), ring B is 6-membered heteroaryl. In some embodiments of the compounds of formula (I) or (I'), ring B is phenyl. In some embodiments of the compounds of formula (I) or (I'), ring B is pyridyl.

[0050] In some embodiments of the compounds of Formula (I) or (I′), R 5 are each independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compound of formula (I) or (I'), R 5 are each independently halogen, -OR a , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of formula (I) or (I'), R 5 are each independently a halogen. In some embodiments of the compounds of Formula (I) or (I'), R 5 are each independently -OR a In some embodiments of the compounds of formula (I) or (I'), R 5are each independently C alkyl. In some embodiments of the compounds of formula (I) or (I'), R 5 are each independently C1-C6 haloalkyl.

[0051] In some embodiments of the compound of formula (I) or (I'), m is 0 to 2. In some embodiments of the compound of formula (I) or (I'), m is 0 or 1. In some embodiments of the compound of formula (I) or (I'), m is 1 or 2. In some embodiments of the compound of formula (I) or (I'), m is 0. In some embodiments of the compound of formula (I) or (I'), m is 1. In some embodiments of the compound of formula (I) or (I'), m is 2. In some embodiments of the compound of formula (I) or (I'), m is 3.

[0052] In some embodiments of the compound of Formula (I), the compound, or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is a compound of Formula (Ia):

[0053] [ka] During the ceremony, X 1 is N or CR 5a and X 2 is N or CR 5b and X 3 is N or CR 5c and X 4 is N or CR 5d and R 5a , R 5b , R 5c , and R 5d are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR cR d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NHS(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0054] In some embodiments of the compound of Formula (I'), the compound, or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is a compound of Formula (Ia'):

[0055] [ka] During the ceremony, X 1 is N or CR 5a and X 2 is N or CR 5b and X 3 is N or CR 5c and X 4 is N or CR 5d and R 5a , R 5b , R 5c , and R5d are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NHS(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0056] In some embodiments of the compounds of formula (Ia) or (Ia′), X 1 is N. In some embodiments of the compounds of formula (Ia) or (Ia'), X 1 is CR 5a It is.

[0057] In some embodiments of the compounds of Formula (Ia) or (Ia′), R 5a are hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NRc R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compound of formula (Ia) or (Ia'), R 5a is hydrogen, halogen, -OR a , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of formula (Ia) or (Ia'), R 5a is hydrogen. In some embodiments of the compounds of formula (Ia) or (Ia'), R 5a is halogen. In some embodiments of the compounds of formula (Ia) or (Ia'), R 5a -OR a In some embodiments of the compounds of formula (Ia) or (Ia'), R 5a is C1-C6 alkyl. In some embodiments of the compounds of formula (Ia) or (Ia'), R 5a is C1-C6 haloalkyl.

[0058] In some embodiments of the compounds of formula (Ia) or (Ia′), X 2 is N. In some embodiments of the compounds of formula (Ia) or (Ia'), X 2 is CR 5b It is.

[0059] In some embodiments of the compounds of Formula (Ia) or (Ia′), R 5b are hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compound of formula (Ia) or (Ia'), R 5b is hydrogen, halogen, -OR a , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of formula (Ia) or (Ia'), R 5b is hydrogen. In some embodiments of the compounds of formula (Ia) or (Ia'), R 5b is halogen. In some embodiments of the compounds of formula (Ia) or (Ia'), R 5b -OR a In some embodiments of the compounds of formula (Ia) or (Ia'), R 5b is C1-C6 alkyl. In some embodiments of the compounds of formula (Ia) or (Ia'), R 5b is C1-C6 haloalkyl.

[0060] In some embodiments of the compounds of formula (Ia) or (Ia′), X 3 is N. In some embodiments of the compounds of formula (Ia) or (Ia'), X 3 is CR 5c It is.

[0061] In some embodiments of the compounds of Formula (Ia) or (Ia′), R 5c are hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compound of formula (Ia) or (Ia'), R 5c is hydrogen, halogen, -OR a , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of formula (Ia) or (Ia'), R 5c is hydrogen. In some embodiments of the compounds of formula (Ia) or (Ia'), R 5c is halogen. In some embodiments of the compounds of formula (Ia) or (Ia'), R 5c -OR a In some embodiments of the compounds of formula (Ia) or (Ia'), R 5c is C1-C6 alkyl. In some embodiments of the compounds of formula (Ia) or (Ia'), R 5c is C1-C6 haloalkyl.

[0062] In some embodiments of the compounds of formula (Ia) or (Ia′), X 4 is N. In some embodiments of the compounds of formula (Ia) or (Ia'), X 4 is CR 5d It is.

[0063] In some embodiments of the compounds of Formula (Ia) or (Ia′), R 5d are hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compound of formula (Ia) or (Ia'), R 5d is hydrogen, halogen, -OR a , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of formula (Ia) or (Ia'), R 5d is hydrogen. In some embodiments of the compounds of formula (Ia) or (Ia'), R 5d is halogen. In some embodiments of the compounds of formula (Ia) or (Ia'), R 5d -OR a In some embodiments of the compounds of formula (Ia) or (Ia'), R 5d is C1-C6 alkyl. In some embodiments of the compounds of formula (Ia) or (Ia'), R 5d is C1-C6 haloalkyl.

[0064] In some embodiments of the compounds of formula (I), (I'), (Ia), or (Ia'), ring A is cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I), (I'), (Ia), or (Ia'), ring A is aryl or heteroaryl. In some embodiments of the compounds of formula (I), (I'), (Ia), or (Ia'), ring A is heteroaryl. In some embodiments of the compounds of formula (I), (I'), (Ia), or (Ia'), ring A is 5- or 6-membered heteroaryl.

[0065] In some embodiments of the compounds of formula (I), (I'), (Ia), or (Ia'), ring A is a 6-membered heteroaryl. In some embodiments of the compounds of formula (I), (I'), (Ia), or (Ia'), ring A is pyridinyl, pyrimidinyl, or pyrazinyl. In some embodiments of the compounds of formula (I), (I'), (Ia), or (Ia'), ring A is pyrazinyl.

[0066] In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), R 1 are each independently deuterium, halogen, -CN, -OH, -OR a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compound of Formula (I), (I'), (Ia), or (Ia'), R 1 are each independently deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), R 1 are each independently -CN.

[0067] In some embodiments of the compound of formula (I), (I'), (Ia), or (Ia'), n is 0 or 1. In some embodiments of the compound of formula (I), (I'), (Ia), or (Ia'), n is 0 to 2. In some embodiments of the compound of formula (I), (I'), (Ia), or (Ia'), n is 1 or 2. In some embodiments of the compound of formula (I), (I'), (Ia), or (Ia'), n is 1. In some embodiments of the compound of formula (I), (I'), (Ia), or (Ia'), n is 0. In some embodiments of the compound of formula (I), (I'), (Ia), or (Ia'), n is 2.

[0068] In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), R 2 is hydrogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), R 2 is hydrogen.

[0069] In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), R 3 is hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), R 3 is hydrogen.

[0070] In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), R 4 is hydrogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), R 4 is hydrogen.

[0071] In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), L is -O-. In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), L is -NR6 -It is.

[0072] In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), R 6 is hydrogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), R 6 is hydrogen.

[0073] In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), R 6 is a monocyclic cycloalkyl or a bicyclic cycloalkyl. In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), R 6 is a monocyclic cycloalkyl.

[0074] In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), R 6 is a bicyclic cycloalkyl.

[0075] In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), R 6 is cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), R 6 In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), R 6 is cyclopentyl. In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), R 6 is cyclohexyl. In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), R 6 is cycloheptyl.

[0076] In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), R 7are each independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; or two R 7 In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), R 7 are each independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; or two R 7 In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), R 7 are each independently -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), R 7 are each independently -NR c R d It is.

[0077] In some embodiments of the compounds of formula (I), (I'), (Ia), or (Ia'), p is 0 to 7. In some embodiments of the compounds of formula (I), (I'), (Ia), or (Ia'), p is 0 to 6. In some embodiments of the compounds of formula (I), (I'), (Ia), or (Ia'), p is 0 to 5. In some embodiments of the compounds of formula (I), (I'), (Ia), or (Ia'), p is 0 to 4. In some embodiments of the compounds of formula (I), (I'), (Ia), or (Ia'), p is 0 to 3. In some embodiments of the compounds of formula (I), (I'), (Ia), or (Ia'), p is 1 to 3. In some embodiments of the compounds of formula (I), (I'), (Ia), or (Ia'), p is 0 to 2. In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), p is 0 or 1. In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), p is 1 or 2. In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), p is 1. In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), p is 2. In some embodiments of the compounds of Formula (I), (I'), (Ia), or (Ia'), p is 0.

[0078] In some embodiments of the compounds disclosed herein, R aare each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of the compounds disclosed herein, R a Each is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, R a Each is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of the compounds disclosed herein, R a Each is independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R a are each independently C1-C6 alkyl.

[0079] In some embodiments of the compounds disclosed herein, R bare each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH, -S(=O)CH, -S(=O)CH, -S(=O)NH, -S(=O)NHCH, -S(=O)N(CH), -NH, -NHCH, -N(CH), -C(=O)CH, -C(=O)OH, -C(=O)OCH, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, or C-C aminoalkyl. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, R b Each is independently C1-C6 alkyl. In some embodiments of the compounds disclosed herein, R a are hydrogen.

[0080] In some embodiments of the compounds disclosed herein, R c and R dare each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH, -S(=O)CH, -S(=O)CH, -S(=O)NH, -S(=O)NHCH, -S(=O)N(CH), -NH, -NHCH, -N(CH), -C(=O)CH, -C(=O)OH, -C(=O)OCH, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, or C-C aminoalkyl. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, R c and R d Each is independently C1-C6 alkyl. In some embodiments of the compounds disclosed herein, R c and R d are hydrogen.

[0081] In some embodiments of the compounds disclosed herein, R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of the compounds disclosed herein, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl.

[0082] In some embodiments of the compounds disclosed herein, R c and R d taken together form a heterocycloalkyl, which is independently substituted with one, two, three, or four substituents as defined herein. In some embodiments of the compounds disclosed herein, R c and R d taken together form a heterocycloalkyl, which is independently substituted with one, two, or three substituents as defined herein. In some embodiments of the compounds disclosed herein, R c and R dtaken together form a heterocycloalkyl, which is independently substituted with one or two substituents as defined herein. In some embodiments of the compounds disclosed herein, R c and R d taken together form a heterocycloalkyl, which is independently substituted with one substituent as defined herein. In some embodiments of the compounds disclosed herein, R c and R d taken together form a heterocycloalkyl, which is independently substituted with two substituents as defined herein. In some embodiments of the compounds disclosed herein, R c and R d taken together form a heterocycloalkyl, which is independently substituted with three substituents as defined herein.

[0083] In some embodiments of the compounds disclosed herein, the compound is selected from the compounds of Table 1, Table 2, or Table 3.

[0084] [Table 1-1]

[0085] [Table 1-2]

[0086] [Table 1-3]

[0087] [Table 1-4]

[0088] [Table 1-5]

[0089]

Table 1-6

[0090]

Table 1-7

[0091]

Table 1-8

[0092]

Table 1-9

[0093]

Table 1-10

[0094]

Table 1-11

[0095]

Table 1-12

[0096]

Table 1-13

[0097]

Table 1-14

[0098]

Table 1-15

[0099]

Table 1-16

[0100]

Table 1-17

[0101]

Table 1-18

[0102]

Table 1-19

[0103]

Table 1-20

[0104]

Table 1-21

[0105]

Table 1-22

[0106]

Table 1-23

[0107]

Table 1-24

[0108]

Table 1-25

[0109] [Table 1-26]

[0110] [Table 2]

[0111] [Table 3]

[0112] Further forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers and their corresponding mixtures. In some circumstances, the compounds described herein have one or more chiral centers, each of which exists in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, as well as their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers derived from a single preparation step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, separable complexes are preferred. In some embodiments, diastereomers have distinct physical properties (e.g., melting points, boiling points, solubility, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, diastereomers are separated by chiral chromatography, or preferably, separation / resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomers are recovered with the resolving agent.

[0113] labeled compound In some embodiments, the compounds described herein are present in isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating disease by administering isotopically labeled compounds such as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those listed herein except for the fact that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that can be incorporated into the compounds described herein, or their solvates, tautomers, or stereoisomers, respectively, include: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Included among the isotopes are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as Cl. Compounds described herein, and pharma- ceutically acceptable salts, solvates, or stereoisomers thereof, that contain the aforementioned isotopes and / or other isotopes of other atoms, are within the scope of the present disclosure. Certain isotopically labeled compounds, e.g., 3 H and 14 Isotopically labeled compounds, into which a radioactive isotope such as C is incorporated, are useful in drug and / or substrate tissue distribution assays. Tritium-labeled, i.e., 3 H, and carbon-14, i.e. 14 The C isotope is particularly preferred because it is easy to prepare and detect. In addition, deuterium, i.e. 2Substitution with heavy isotopes such as H offers certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. In some embodiments, an isotopically-labeled compound, or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is prepared by any suitable method.

[0114] In some embodiments, the compounds described herein are labeled by other means, including but not limited to, a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

[0115] Pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as their pharma- ceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharma- ceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharma- ceutically acceptable salts as pharmaceutical compositions.

[0116] In some embodiments, the compounds described herein have acidic or basic groups and thus react with any of a number of inorganic or organic bases, as well as inorganic and organic acids, to form pharma- ceutically acceptable salts. In some embodiments, these salts are prepared during the final isolation and purification of the compounds disclosed herein, or in situ by separately reacting the purified compounds in free form with the appropriate acid or base and isolating the salt thus formed.

[0117] Examples of pharma- ceutically acceptable salts include salts prepared by reaction of a mineral, organic acid, or inorganic base with the compounds described herein, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, or the like. acid salt, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate Metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate, and xylenesulfonate.

[0118] Additionally, the compounds described herein can be prepared as pharma- ceutically acceptable salts formed by reacting the free base form of the compound with a pharma- ceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like, and organic acids including, but not limited to, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) These include benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0119] In some embodiments, the compounds described herein that contain free acid groups are reacted with a suitable base, such as hydroxide, carbonate, bicarbonate, or sulfate, of a pharma- ceutically acceptable metal cation, with ammonia, or with a pharma-ceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, as well as aluminum salts. Illustrative examples of bases are sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C1-4 alkyl)4, and the like. Representative salts include the alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, as well as aluminum salts of tetrazole, and the like.

[0120] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It is noted that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.

[0121] solvate In some embodiments, the compounds described herein exist as solvates.The present disclosure provides a method for treating disease by administering such solvates.The present disclosure further provides a method for treating disease by administering such solvates as pharmaceutical compositions.

[0122] Solvates contain stoichiometric or non-stoichiometric amounts of solvent, such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. The solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. Generally, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0123] Tautomers In some circumstances, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that can be interconverted by migration of a hydrogen atom, accompanied by switching of a single bond and an adjacent double bond. In bond structures that allow tautomerization, chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0124] Preparation of compounds The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in the art, beginning with commercially available chemicals and / or compounds described in the chemical literature. "Commercially Available Chemicals" refers to Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI; includes Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chem Service Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CT), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hannover, Germany), Spectrum Quality Products, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0125] Suitable references and articles detailing the synthesis of reactants useful in the preparation of the compounds described herein or referencing articles describing the preparation include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S.R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions", 2nd Ed., W.A. Benjamin, Inc. Menlo Park, Calif. 1972; T.L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley Interscience, New York, 1992. Additional suitable references and articles detailing the synthesis or referring to articles describing the preparation of reactants useful for the preparation of the compounds described herein include, for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3 527-29074-5; Hoffman, RV “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC“Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons,ISBN:0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, TWG “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, JC, “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; 8 volumes of “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X; 55 volumes of “Organic Reactions” (1942-2000) John Wiley & Sons, and 73 volumes of “Chemistry of Functional Groups” John Wiley & Sons.

[0126] Specific and similar reactants are optionally identified through indexes of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, available in most public and university libraries and through online databases. Chemical products that are known but not sold in catalogs are optionally prepared by custom chemical synthesis houses, and many of the standard drug supply companies (e.g., those listed above) offer custom synthesis services. For the preparation and selection of pharmaceutical salts of the compounds described herein, see PH Stahl & CG Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0127] Pharmaceutical Compositions In certain embodiments, the compounds as described herein are administered as pure chemicals. In some embodiments, the compounds as described herein are combined with a pharma- ceutically suitable or acceptable carrier (also referred to herein as pharma- ceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) that is selected based on the selected route of administration and standard pharmaceutical practice, for example, as described in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0128] Accordingly, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a pharma- ceutically acceptable excipient.

[0129] In certain embodiments, the compounds provided herein are substantially pure, in that they contain less than about 5%, or less than about 1%, or less than about 0.1%, of other small organic molecules, e.g., unreacted intermediates or synthetic by-products produced during one or more of the steps of a synthetic method.

[0130] The pharmaceutical composition is administered in a manner appropriate for the disease to be treated (or prevented). The appropriate dose and the appropriate duration and frequency of administration are determined by factors such as the patient's disease, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition in an amount sufficient to provide a therapeutic and / or prophylactic benefit (e.g., improved clinical outcome), such as an increased overall response rate, an increased duration of response, more frequent complete or partial remissions, or a longer disease-free and / or overall survival, or a reduced severity of symptoms. Optimal doses are generally determined using experimental models and / or clinical trials. Optimal doses vary depending on the patient's body type, weight, or blood volume.

[0131] In some embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, pulmonary, intradermal, intrathecal, epidural, or intranasal administration. Parenteral applications include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection. In some embodiments, the pharmaceutical composition is formulated as a tablet, pill, capsule, liquid, inhalant, nasal spray solution, suppository, suspension, gel, colloid, dispersion, suspension, solution, emulsion, ointment, lotion, eye drop, or nasal drop. In some embodiments, the pharmaceutical composition is formulated as a tablet.

[0132] The appropriate dose and administration regimen is determined by conventional distance measuring techniques known to those skilled in the art. Generally, treatment is initiated with a small dosage that is less than the optimal dose of the compounds described herein. The dosage is then increased by small increments until the optimal effect under such circumstances is achieved. In some embodiments, the method includes administration of about 0.1 μg to about 50 mg of at least one compound described herein per kg of subject body weight. For a 70 kg patient, a dosage of about 10 μg to about 200 mg of the compounds disclosed herein will generally be used, depending on the physiological response of the subject.

[0133] By way of example only, doses of the compounds described herein for the methods of treating the diseases described herein are from about 0.001 to about 1 mg per kg of subject body weight per day, e.g., about 0.001 mg, about 0.002 mg, about 0.005 mg, about 0.010 mg, 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.050 mg, about 0.075 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, or about 1 mg per kg of body weight per day. In some embodiments, the dose of a compound described herein for the above methods is about 1 to about 1000 mg per kg of body weight of the subject being treated per day, e.g., about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg per day.

[0134] Treatment Disclosed herein is a method for treating cancer in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. Disclosed herein is a method for treating Chk1-associated cancer in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharma-ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0135] In some embodiments, cancer includes malignant tumors whose size can be reduced, whose growth or spread can be halted, or whose symptoms can be ameliorated or alleviated and / or completely cured by deleting, suppressing, and / or inhibiting the function of Chk1. Malignant tumors of interest include, but are not limited to, head and neck cancer, gastrointestinal cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder cancer, bile duct cancer, etc.), pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.)), lung cancer (non-small cell lung cancer, small cell lung cancer, squamous cell lung cancer, mesothelioma, etc.), breast cancer, genital cancer (ovarian cancer, uterine cancer, cervical cancer, endometrial cancer, etc.), urinary tract cancer (kidney cancer, bladder cancer, prostate cancer, testicular cancer, etc.), hematopoietic tumors (leukemia, malignant lymphoma, multiple myeloma, etc.), bone and soft tissue tumors (e.g., soft tissue sarcoma and osteosarcoma), skin cancer, brain tumors (e.g., glioblastoma), and the like.

[0136] In some embodiments, the term cancer is used according to its ordinary and plain meaning in light of this disclosure to refer to all types of cancers, neoplasms, or malignant tumors found in mammals, including leukemias, lymphomas, melanomas, neuroendocrine tumors, carcinomas, and sarcomas. Exemplary cancers that may be treated with the compounds disclosed herein, or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, pharmaceutical compositions include acute myeloid leukemia, adrenal cortical carcinoma, adrenal gland cancer, bladder cancer, bone cancer, brain cancer, breast cancer (e.g., ductal carcinoma, lobular carcinoma, primary, metastatic), breast cancer, cancer of the endocrine system, cancer of hepatic stellate cells, cancer of pancreatic stellate cells, cervical cancer, colon cancer, colorectal cancer, ductal carcinoma, endometrial cancer, esophageal cancer, gastric cancer, cancer of the genitourinary tract, glioblastoma, glioma, head and neck cancer, hepatocellular carcinoma, Hodgkin's disease, kidney cancer, leukemia (e.g., lymphoblastic leukemia, chronic lymphocytic leukemia, hairy cell leukemia), liver cancer (e.g., hepatocellular carcinoma), lobular carcinoma, lung cancer (e.g., non-small cell lung cancer, squamous cell lung cancer, adenocarcinoma, large cell lung cancer, small cell lung cancer, carcinoid, sarcoma), lymph node cancer, lymphoma (e.g., mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, marginal zone lymphoma, Burkitt's lymphoma, non-Hodgkin's lymphoma), malignant carcinoid, malignant hypercalcemia, malignant pancreatic insulinoma, medullary thyroid carcinoma, medulloblastoma, melanoma, mesothelioma, multiple myeloma, myocarcinoma, neoplasms of the endocrine or exocrine pancreas, neuroblastoma, ovarian cancer, Paget's disease of the nipple, pancreatic cancer, papillary thyroid carcinoma, phyllodes tumor, premalignant skin lesions, primary thrombocythemia, prostate cancer (e.g., castration-resistant prostate cancer), rhabdomyosarcoma, salivary gland cancer, sarcoma, soft tissue sarcoma, squamous cell carcinoma (e.g., head, neck, or esophagus), gastric cancer, testicular cancer, thyroid cancer, bladder cancer, or uterine cancer. In embodiments, the cancer is selected from bladder cancer, breast cancer, colon cancer, esophageal cancer, glioblastoma, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, salivary gland cancer, soft tissue sarcoma, squamous cell lung cancer, gastric cancer, and uterine cancer.

[0137] ecDNA mediates an important and clinically distinct mechanism of resistance to targeted therapy. There is an immediate therapeutic opportunity for the utility of one or more Chk1 inhibitors described herein, either as a single agent or in combination with other therapies. In some embodiments, one or more Chk1 inhibitors described herein can be used to treat ecDNA+ cancers, ecDNA+ tumors, or ecDNA+ tumor cells. One or more Chk1 inhibitors described herein can be used to treat tumors with one or more amplified cancer genes (e.g., FGFR, EGFR, MET, KRAS, MDM2 amplified), etc., and in some cases, the one or more amplified cancer genes include non-mutated cancer genes, and in some cases, the amplified cancer genes include mutated cancer genes. One or more Chk1 inhibitors described herein can be used to treat tumors that have no approved targeted therapy or lack highly effective therapies. One or more Chk1 inhibitors described herein can be used to treat tumors that have developed resistance to another therapy, such as resistance to a targeted agent. In some cases, tumors (or tumor cells) treated with one or more targeted agents develop resistance to the targeted agents, e.g., targeted agents directed at cancer genes or targeted agents that directly inhibit activating mutant forms of particular cancer proteins (e.g., KRAS, BRAF, EGFR), or as a result of local amplification, such as ecDNA-based amplification, of the target gene itself, and one or more Chk1 inhibitors described herein can be used to treat such tumors or tumor cells.

[0138] Provided herein is a method in which inhibition of Chk1 by one or more Chk1 inhibitors described herein shows synthetic lethality with a cancer targeting agent. In some embodiments, synthetic lethality occurs with one or more Chk1 inhibitors described herein in combination with a cancer targeting agent. In some cases, a tumor background is identified as highly sensitive to Chk1 inhibitors, allowing a sufficient therapeutic index to allow effective tolerance dose. In some embodiments, synthetic lethality occurs with one or more Chk1 inhibitors described herein in combination with a cancer targeting agent, where the tumor or tumor cells are ecDNA+. In some cases, Chk1 inhibition results in a reduction in ecDNA copy number. In some cases, Chk1 inhibition results in enhanced cytotoxicity in ecDNA+ cells. In some cases, enhanced cytotoxicity occurs from the combination of Chk1 inhibition and inhibition of a cancer target, such as an oncogene.

[0139] In some embodiments of the method herein, the tumor or tumor cell treated is ecDNA+. In some cases, such tumor or tumor cell is determined to have ecDNA signature. In some cases, if the tumor or tumor cell has one or more features associated with ecDNA+ tumor or tumor cell, the tumor or tumor cell is determined to have ecDNA signature. For example, in some cases, the ecDNA signature is selected from the group consisting of gene amplification, p53 loss-of-function mutation, lack of microsatellite instability (MSI-H), low level of PD-L1 expression, low level of tumor inflammation signature (TIS), low level of tumor mutation burden (TMB), increased frequency of allelic substitution, insertion, or deletion (indel), and any combination thereof.

[0140] Combination therapy In certain instances, the compounds described herein, or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, are administered in combination with a second therapeutic agent or cancer targeting agent.

[0141] In some embodiments of the method herein, the method further comprises administering a cancer targeting agent that targets the activity of the protein product of the target gene.In some cases, the cancer targeting agent and Chk1 inhibitor treatment disclosed herein reduce the amplification or expression of the target gene in tumor or tumor cell.In some cases, the cancer targeting agent is administered before the Chk1 inhibitor.In some cases, the cancer targeting agent is administered simultaneously with the Chk1 inhibitor.

[0142] In some embodiments of the method herein, tumor or tumor cell has ecDNA signature.In some cases, tumor or tumor cell expresses ecDNA signature after administration of cancer targeting therapeutic agent.In some cases, tumor or tumor cell expresses ecDNA signature before treatment.In some cases, the method prevents the increase of ecDNA in tumor or tumor cell.

[0143] In some embodiments, the second therapeutic or cancer targeting agent comprises antimetabolites, platinum drugs, plant alkaloid drugs, and molecular targeted drugs.

[0144] In some embodiments, the second therapeutic or cancer targeted agent comprises a DNA damaging agent.

[0145] In some embodiments, the second therapeutic agent comprises radiation therapy.

[0146] In some embodiments, antimetabolites include 5-fluorouracil, 5-fluoro-2'-deoxyuridine, tegafur, tegafur-uracil, tegafur-gimeracil-oteracil, pemetrexed, trifluridine, trifluridine-tipiracil hydrochloride, fludarabine (or the active metabolite fludarabine nucleoside), cytarabine, gemcitabine, capecitabine, nelarabine, clofarabine, and DNA methylation inhibitors such as decitabine, guadecitabine, azacitidine.

[0147] In some embodiments, the platinum agents include cisplatin, oxaliplatin, carboplatin, and nedaplatin.

[0148] In some embodiments, plant alkaloid drugs include microtubule inhibitors such as paclitaxel, docetaxel, vinblastine, vincristine, vindesine, vinorelbine, and eribulin, and topoisomerase inhibitors such as irinotecan (or the active metabolite SN-38), topotecan, and etoposide.

[0149] In some embodiments, the molecular targeted drug is an ATR (ataxia telangiectasia and Rad3 related protein) inhibitor, an AXL inhibitor, a BRAF inhibitor, a CDK4 / 6 inhibitor, another Chk1 (checkpoint kinase 1) inhibitor, a CSF1R (colony stimulating factor 1 receptor) inhibitor, an EGFR (epidermal growth factor receptor) inhibitor, an FGFR (fibroblast growth factor receptor) inhibitor, an FLT3 (fms-related tyrosine kinase 3) inhibitor, an HER2 inhibitor, an HSP (heat shock protein) 90 inhibitor, agents, KIT inhibitors, KRAS inhibitors, KRAS inhibitors, MDM2 (mouse double minute 2) inhibitors, MDM4 (mouse double minute 4) inhibitors, MET inhibitors, MYC inhibitors, PARP (poly ADP-ribose polymerase) inhibitors, PDGFR (platelet derived growth factor receptor) inhibitors, RET inhibitors, RNR (ribonucleotide reductase) inhibitors, TIE2 (intima endothelial cell kinase 2) inhibitors, TRK inhibitors, VEGFR (vascular endothelial growth factor receptor) inhibitors, and Wee1 inhibitors.

[0150] In some embodiments, ATR inhibitors include ART-0380, ATRN-119, ATRN-212, AZ-20, AZZ-6738, BAY-1895344, beruzosertib (M-6620), BKT-300, IMP-9064, M-1774, M-4344 (VX-803), M-6620, nLs-BG-129, NU-6027, RP-3500, SC-0245, VE-822, and VX-970. In some embodiments, AXL inhibitors include cabozantinib and gilteritinib.

[0151] In some embodiments, the BRAF inhibitors include ASN-003, AZ-304, AZ-628, DP-2874, EBI-907, EBI-945, GDC-0879, LYN204, NMS-P285, NMS-P730, PF-04880594, TL-241, UAI-201, and UB-941. In some embodiments, the BRAF inhibitors include ABM-1310, agerafenib (RXDX-105), ARQ-736, BAL-3833, belbalafenib, BGB-3245, BI-882370, DAY101, lifirafenib, LUT-014, PF-07284890, PLX-8394, RX-208, VS-6766, and XL-281. In some embodiments, BRAF inhibitors include dabrafenib, encorafenib, and vemurafenib.

[0152] In some embodiments, CDK4 / 6 inhibitors include AG-122275, AM-5992, AU2-94, IIIM-985, IIIM-290, GW-491619, HEC-80797, MM-D37K, MS-140, NP-102, QHRD-110, R-547, RGB-286199, RGT-419B, ribiciclib, RO-0505124, THR-53, THR-79, TQB-3303, TY-302, VS2-370, XH-30002, and WXWH-0240. In some embodiments, CDK4 / 6 inhibitors include auceliciclib, AT-7519, BEBT-209, BPI-1178, BPI-16350, CS-3002, fascaplysin, FCN-437, FN-1501, GLR-2007, HS-10342, relociclib, milciclib maleate, NUV-422, ON-123300, PF-06842874, PF-06873600, PF-07220060, SHR-6390, TQB-3616, TY-302, voruciclib, and XZP-3287. In some embodiments, CDK4 / 6 inhibitors include abemaciclib, palbociclib, ribociclib, and trilaciclib.

[0153] In some embodiments, other Chk1 inhibitors include AZD-7762, BEBT-260, GDC-0575, LY-2880070, PF-477736, prexasertib, ravusertib (LY-2603618), RG-7602, SCH-900776, SRA737, and XCCS-605B.

[0154] In some embodiments, CSF1R inhibitors include ARRY-382, BLZ-945, and sunitinib.

[0155] In some embodiments, the EGFR inhibitor is a small molecule inhibitor, such as APL-1898, BDTX-1535, BLU-701, BPI-361175, CH-7233163, DS-2087, E-10C, FWD-1509, IN-A008, JS-111, JS-113, LL-191, LYN205, neptinib, NT-004, ORIC-114, PRB-001, SIM-200, TGRX-360, WJ-13404, yinlitinib maleate maleate), and ZSP-0391, as well as anti-EGFR antibodies such as 705, 707, ABX-900, CMAB-017, GB-263, KN-023, SSGJ-612, and SHR-A1307.In some embodiments, the EGFR inhibitor is a small molecule inhibitor, such as abivertinib, alfutinib mesylate, agerafenib (RXDX-105), ASK-120067, BBT-176, BDTX-189, BEBT-109, befotertinib mesylate (befortinib mesylate), beitatinib, BPI-7711, BPI-D0316, BLU-945, CK-101, docitinib, DFP-17729, DZD-9008, epertinib, epitinib (HMPL-813), ES-072, FCN-411, FHND-9041, fulmonertinib, GMA-204, Hemay-022, JRF-103, KP-673, larotinib, lazertinib, maihuatinib, marizomib, mobocertinib, naptinib tosylate, nazartinib, NRC-2694-A, OBX1-012, olafeltinib, olmutinib, oritinib, pyrotinib, Poziotinib, SPH-1188, tarloxotinib, teliatinib (HMPL-309), TAS-6417, TPC-064, TQB-3804, TY-9591, WSD-0922, XZP-5809, YK-029A, YZJ-0318, and zolifertinib, as well as anti-EGFR antibodies, such as 602, C- 005, CDP1, depatuxizumab, E01001, GC-1118A, GR-1401, HLX-07, HS-627, I-010, imgatuzumab, JMT-101, JZB-28, KN-026, MP-0274, QL-1203, SCT-200, cercultamab, SYN-004, and TAD-011. In some embodiments, EGFR inhibitors include small molecule inhibitors such as afatinib, amivantamab, aumolertinib (almonertinib), dacomitinib, erlotinib, gefitinib, icotinib, lapatinib, osimertinib, and pyrotinib, as well as anti-EGFR antibodies such as cetuximab, necitumumab, nimotuzumab, and panitumumab.

[0156] In some embodiments, FGFR inhibitors include small molecule inhibitors such as ABSK-012, ABSK-061, AST-56100, BIO-1262, BGS-2219, EVT-601, FPI-1966, JAB-6000, KIN-3248, SAR-439115, SC-0011, and WXSH-0011, as well as anti-FGFR antibodies such as M-6123, OM-RCA-001. In some embodiments, the FGFR inhibitor is 3D-185, ABSK-011, ABSK-091, aldafermin, allofanib, AZD-4547, BFKB-8488A, BPI-17509, BPI-43487, CPL-304-110, derazantinib, E-7090, EVER-4010001, FGF-401, fisogatinib, futibatinib, ganglionib, FGFR inhibitors include small molecule inhibitors such as latinib, H3B-6527, HH-185, HMPL-453, HS-236, ICP-105, ICP-192, infigratinib, MAX-40279, RLY-4008, rogaratinib, SAR-442501, SY-4798, TT-00434, and zoligratinib (FF-284), and anti-FGFR antibodies such as bemarituzumab. In some embodiments, FGFR inhibitors include small molecule inhibitors such as erdafitinib and pemigatinib.

[0157] In some embodiments, FLT3 inhibitors include cabozantinib, gilteritinib, midostaurin, sorafenib, and sunitinib.

[0158] In some embodiments, HER2 inhibitors include small molecule inhibitors such as LL-191, NT-004, SPH-3261, and VRN-10, and anti-HER2 antibodies such as 704, 706, AbGn-110, ACE-1702, ALL-C-2137, ANT-043, AT-501, ATV:HER2, BSI-001, GB-251, Herceptarg, HK-001, IGEM-H, KL-A166, KM-254, KM-257, LIN-001, LIN-002, MI-180021, SHR-A1811, SSGJ-612, VB7-756, ZV-0201. In some embodiments, the HER2 inhibitor is a small molecule inhibitor such as AR-788, BDTX-189, DZD-1516, epertinib, JRF-103, larotinib, maihuatinib, mobocertinib, NRC-2694-A, pyrotinib, poziotinib, tarloxotinib, TAS-0728, and ZN-A-1041, as well as AC-101, ARX-788, B00-2, BAT-1006, BAY-2701439, BCD and anti-HER2 antibodies such as -147, DAC-001, dicitamab vedotin, DP-303c, E01001, GP-2, GQ-1001, HLX-22, KN-026, LCB-14, MB-103, MBS-301, MRG-002, MRT-201, MP-0273, PF-06804103, QL-1209, TAA-013, WLB-301, zanidatamab, zenocutuzumab, and ZW-49. In some embodiments, HER2 inhibitors include small molecule inhibitors such as afatinib, dacomitinib, lapatinib, neratinib, pyrotinib, and tucatinib, as well as anti-HER2 antibodies such as margetuximab, pertuzumab, and trastuzumab.

[0159] In some embodiments, HSP90 inhibitors include ganetespib, luminespib, and onarespib.

[0160] In some embodiments, KIT inhibitors include lenvatinib, midostaurin, pazopanib, sorafenib, and sunitinib.

[0161] In some embodiments, KRAS includes small molecule inhibitors such as ABREV01, ARS-1620, APG-1842, ATG-012, BBP-454, BEPT-607, BI-2852, BI-1823911, BPI-421286, BTX-2541, COTI-219, IMM-1811900, JAB-21000, JAB-22000, JAB-23000, JAB-BX300, JP-002, KR-12, LYN202, MRTX-1133, RAS-F, RMC-6236, RMC-6291, SDGR5, STX-301, and YL-15293, as well as anti-KRAS antibodies such as SBT-100, SBT-102, and SBT-300. In some embodiments, KRAS comprises a small molecule inhibitor such as adagrasib, ARS-3248, D-1553, GDC-6036, JDQ-443, LY3537982, sotalasib (AMG510), and BI 1701963.

[0162] In some embodiments, MDM2 inhibitors include AD-021.32, CYC700, DS-5272, MI-1061, MI-219, MI-43, MD-224, MK-8242, NU-8231, OM-301, PXN-527, Rigel-3, RO-2468, RO-5353, RO-5963, and SIL-43. In some embodiments, MDM2 inhibitors include ALRN-6924, APG-115, ASTX-295, ATSP-7041, BI-907828, CGM-097, idasanutlin, KRT-232 (AMG-232), MI-77301 (SAR405838, SAR299155), NVP-CGM097, RAIN-32 (milademetan), RG7112 (RO5045337), RG7388 (RG7775), cerdemethane (JNJ-26854165), siremadrine, and UBX-0101.

[0163] In some embodiments, MDM4 inhibitors include 17AAG, 489-PXN, CTX1, FL-118, inulanolide A, K-178, and SAH-p53-8. In some embodiments, MDM4 inhibitors include APG-115, ALRN-6924, ATSP-7041, and BI-907828.

[0164] In some embodiments, a MET small molecule inhibitor, such as ABP-1130, BPI-1831, BPI-2021, BYON-3521, CG-203306, CX-1003, Debio-1144, EMD-94283, EMT-100, EMT-101, HE-003, LMV-12, LS-177, NX-125, OMO-2, PF-4254644, PRX- MET, PTX-2173, QBH-196, RP-1400, SAB-Y14, SAR-125844, SGX-126, SYD-3521, WXSH-0011, X-379, and XL-265, and anti-MET antibodies, such as ABX-900, GB-263, FS-101, LY-3164530, LY-3343544, PMC-002, and SAIT-301. In some embodiments, a MET small molecule inhibitor, such as ABN-401, ABT-700, AMG-208, AMG-337, ARGX-111, BAY-85-3474, BMS-817378, bozitinib, BPI-9016M, grumetinib, golvatibinib tartrate, GST-HG161, HQP-8361, I-020, JNJ-38877605, canitinib, merestinib, MK-2461, MK-8033, OMO-1, pamfetinib, S-49076, In some embodiments, MET small molecule inhibitors such as amivantamab, capatinib, crizotinib, and tepotinib.

[0165] In some embodiments, PARP inhibitors include niraparib, olaparib, rucaparib, talazoparib, veliparib.

[0166] In some embodiments, the PDGFR inhibitor is a PDGFRα and / or PDGFRβ inhibitor, including lenvatinib, midostaurin, pazopanib, sorafenib, and sunitinib.

[0167] In some embodiments, RET inhibitors include sunitinib, cabozantinib, sorafenib, lenvatinib, and vandetanib.

[0168] In some embodiments, RNR inhibitors include 5-chloro-2-(n-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide, cladribine, clofarabine, COH29 (N-[4-(3,4-dihydroxyphenyl)-5-phenyl-1,3-thiazol-2-yl]-3,4-dihydroxybenzamide), fluarabine, gemcitabine, hydroxyurea, motexafin gadolinium, osalmid, TAS1553, tezacitabine, and triapine.

[0169] In some embodiments, the TIE2 inhibitor comprises cabozantinib.

[0170] In some embodiments, TRK inhibitors include cabozantinib and entrectinib.

[0171] In some embodiments, the VEGFR inhibitor is an inhibitor of at least one of VEGFR1, VEGFR2, and VEGFR3, including small molecule inhibitors such as sunitinib, cabozantinib, midostaurin, sorafenib, vandetanib, pazopanib, lenvatinib, and axitinib, and anti-VEGFR antibodies such as ramucirumab.

[0172] In some embodiments, Wee1 inhibitors include adavosertib, AZD1775 (MK1775), Bos-I, bosutinib, DC-859 / A, Debio 0123, IMP7068, NUV-569, PD407824, PD0166285, PD0166285, PD0407824, SC-0191, SDR-7778, SDR-7995, WEE1-IN-3, and ZN-c3.

[0173] In some embodiments, the benefit experienced by the patient is increased by administering one of the compounds described herein in conjunction with a second therapeutic agent (including a therapeutic regimen) that also has a therapeutic effect.

[0174] In a specific embodiment, a compound described herein, or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is co-administered with a second therapeutic agent, where the compound described herein, or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the second therapeutic agent modulate different aspects of the disease, disorder, or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.

[0175] In all cases, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient will be simply the addition of the two therapeutic agents or the patient will experience a synergistic benefit.

[0176] In certain embodiments, various therapeutically effective dosages of the compounds disclosed herein are utilized in the formulation of pharmaceutical compositions and / or treatment regimens when the compounds disclosed herein are administered in combination with a second therapeutic agent. The therapeutically effective dosages of drugs and other agents used in combination therapy regimens are optionally determined by means similar to those specified above for the active ingredients themselves. In addition, the prevention / treatment methods described herein include the use of metronomic dosing, i.e., providing more frequent, lower doses to minimize toxic side effects. In some embodiments, combination therapy regimens include treatment regimens in which administration of the compounds described herein, or pharma- ceutically acceptable salts, solvates, tautomers, or stereoisomers thereof, is initiated before, during, or after treatment with a second agent described herein, and continues until any time during or after the end of treatment with the second agent. It further includes treatments in which the compound described herein, or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the second agent used in combination are administered simultaneously or at different times, and / or at decreasing or increasing intervals during the treatment period. Combination therapy also includes periodic treatments that are started and stopped at different times to aid in the clinical management of the patient.

[0177] It will be understood that the dosage regimen to treat, prevent, or ameliorate the condition for which relief is sought will be modified to suit a variety of factors (e.g., the disease, disorder, or condition from which the subject suffers, the age, weight, sex, diet, and medical condition of the subject). Thus, in some instances, the dosage regimen utilized will vary and, in some embodiments, will deviate from the dosage regimens set forth herein.

[0178] With respect to the combination therapies described herein, the dosage of the co-administered compound will vary depending on the type of co-drug used, the particular drug used, the disease or condition being treated, etc. In further embodiments, when co-administered with a second therapeutic agent, the compounds provided herein are administered simultaneously or sequentially with the second therapeutic agent.

[0179] In combination therapy, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order, or even simultaneously. When administration is simultaneous, the multiple therapeutic agents can be provided in a single, unified form, or in multiple forms (e.g., as a single pill, or two separate pills, a single infusion, or two separate infusions), by way of example only.

[0180] The compounds described herein, or pharma- ceutically acceptable salts, solvates, tautomers, or stereoisomers thereof, as well as combination therapies, are administered before, during, or after the onset of a disease or condition, and the timing of administering a composition containing the compound varies. Thus, in one embodiment, the compounds described herein are used as prophylactics and are administered continuously to subjects prone to a disease or condition to prevent the onset of a disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of symptoms. In certain embodiments, the compounds described herein are administered as soon as practicable after the onset of a disease or condition is detected or suspected, and for the period of time required to treat the condition. In some embodiments, the period of time required for treatment varies, and the treatment period is tailored to the particular needs of each subject. For example, in certain embodiments, the compounds described herein or formulations containing the compounds are administered for at least 2 weeks, about 1 month to about 5 years.

[0181] In some embodiments, the compound disclosed herein, or its pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer, is administered in combination with an adjuvant.In one embodiment, the therapeutic effect of one of the compounds described herein is enhanced by the administration of an adjuvant (i.e., the adjuvant has minimal therapeutic benefit by itself, but when combined with another therapeutic agent, enhances the overall therapeutic benefit to the patient). EXAMPLES

[0182] All final compounds were purified by either high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC) and proton ( 1 All chemicals were purchased from commercial suppliers and used as received unless otherwise indicated. 1 H NMR (H NMR) spectra were recorded on a Bruker AVANCE 400 MHz spectrometer. Chemical shifts are expressed in δ ppm and calibrated to the residual solvent peak (CDCl3, 7.26 ppm, DMSO-d6, 2.54 ppm). Coupling constants (J), when given, are reported in Hertz. Multiplicities are reported using the following abbreviations: s = singlet, d = doublet, dd = doublet of doublets, t = triplet, q = quartet, m = multiplet (range of multiplet given), br = broad signal, and dt = doublet of triplet. Carbon Nuclear Magnetic Resonance ( 13 C NMR spectra were recorded at 100 MHz on a Bruker AVANCE HD spectrometer. Chemical shifts are reported in δ ppm and calibrated to the solvent peak: carbon (CDCl3, 77.23 ppm).

[0183] All final compounds were purified by reversed-phase HPLC or SFC. Purity of test compounds was determined by HPLC on a Shimazu LC-2010A HT instrument. HPLC conditions were as follows: XBRIDGE C18 column, 3.5 μm, 2.1 mm×50 mm, water (+0.05% TFA):acetonitrile (+0.05% TFA), acetonitrile 0-60% (over 7 min), acetonitrile 60%-100% (over 1 min), flow rate 0.8 mL / min, UV detection (λ=214, 254 nm). Mass spectra were obtained using LCMS with electrospray ionization (ESI)-LCMS on an Agilent 6125 instrument. LCMS conditions were as follows: Waters Cortecs C18+ column, 2.7 μm, 2.1 mm×30 mm, column temperature 45° C., mobile phase, acetonitrile (+0.05% formic acid):water (+0.05% formic acid), gradient, 5% acetonitrile to 95% acetonitrile in 1.0 min, hold 1.0 min, total 2.5 min, flow rate 1.8 mL / min, UV detection (λ=214, 254 nm). Chiral purity of test compounds was determined using a Thar SFC prep 80 instrument.

[0184] Preparation P1-1: 5-((5-(2-hydroxy-6-methoxyphenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile

[0185] [ka]

[0186] Step 1: 1-(2-methoxy-6-((4-methoxybenzyl)oxy)phenyl)ethan-1-one (2) To a mixture of 1-(2-hydroxy-6-methoxyphenyl)ethan-1-one (10 g, 60.2 mmol) and potassium carbonate (16.64 g, 120.4 mmol) in anhydrous N,N-dimethylformamide (70 mL) at 0° C., 4-methoxybenzichloride (10.37 g, 66.2 mmol) was added dropwise over 10 min. The reaction mixture was heated to 35° C. for 18 h. The reaction mixture was poured into ice water (350 mL) and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with water (3×200 mL) and brine (300 mL), dried over sodium sulfate, filtered and evaporated. The crude product was purified by gradient silica gel column chromatography to give the title compound (15 g, 87% yield) as a white solid. LCMS: Rt=1.291 min, ESMS m / z=308.9 [M+Na] + .

[0187] Step 2: 1-(2-methoxy-6-((4-methoxybenzyl)oxy)phenyl)-3,3-bis(methylthio)prop-2-en-1-one (3) To a mixture of lithium tert-butoxide (8.71 g, 108.8 mmol) in anhydrous dimethyl sulfoxide (160 mL) was added 1-(2-methoxy-6-((4-methoxybenzyl)oxy)phenyl)ethan-1-one (14.5 g, 50.6 mmol) under nitrogen and the reaction mixture was stirred at room temperature for 30 min. To the reaction mixture was added carbon disulfide (4.82 g, 63.3 mmol) slowly over 10 min while maintaining the internal temperature below 30° C. The reaction mixture was stirred at room temperature for 1 h. To the reaction mixture was added iodomethane (15.8 g, 111.3 mmol) slowly while maintaining the internal temperature below 30° C. The resulting mixture was stirred at room temperature for 5 h. The reaction mixture was poured into ice water (600 mL) and the mixture was extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with water (3x300mL) and brine (300mL), dried over sodium sulfate, filtered and evaporated. The crude product was purified by gradient silica gel column chromatography to give the title compound (18g, 91% yield) as a yellow solid. LCMS: Rt=1.365min, ESMS m / z=412.6[M+Na] + .

[0188] Step 3: 5-((3-(2-methoxy-6-((4-methoxybenzyl)oxy)phenyl)-1-(methylthio)-3-oxoprop-1-en-1-yl)amino)pyrazine-2-carbonitrile (4) To a mixture of sodium hydride (60% dispersion in mineral oil, 1.54 g, 38.5 mmol) in anhydrous tetrahydrofuran (200 mL) was added 5-aminopyrazine-2-carbonitrile (3.69 g, 30.7 mmol) in four portions over 5 minutes at 0° C. under nitrogen. The reaction mixture was stirred for 45 minutes while allowing the mixture to warm to 5° C. To the reaction mixture was added 1-(2-methoxy-6-((4-methoxybenzyl)oxy)phenyl)-3,3-bis(methylthio)prop-2-en-1-one (10 g, 25.6 mmol) in several portions. The resulting slurry was stirred for 5 minutes at 5° C. The reaction mixture was stirred at 66° C. for 8 hours. The reaction was quenched with ice water (300 mL) and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered and evaporated to give the title compound (12 g, crude), which was used without further purification. LCMS: Rt=1.386 min, ESMS m / z=462.7 [M+H] + .

[0189] Step 4: 5-((5-(2-methoxy-6-((4-methoxybenzyl)oxy)phenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile (5) To a mixture of crude 5-((3-(2-methoxy-6-((4-methoxybenzyl)oxy)phenyl)-1-(methylthio)-3-oxoprop-1-en-1-yl)amino)pyrazine-2-carbonitrile (12 g) and acetic acid (4.67 g, 77.6 mmol) in ethanol (150 mL) was added hydrazine hydrate (2.59 g, 51.8 mmol), resulting in a slight exotherm. The resulting yellow slurry was slowly heated to 70° C. and the reaction mixture was stirred at 70° C. under nitrogen for 6 h. The thick slurry was allowed to cool slowly to below 30° C. The precipitate was collected and the solid was washed with cold ethanol (200 mL). The product was dried under vacuum at 40° C. to give the title compound (8 g, 73% yield for two steps) as a yellow solid. LCMS: Rt=1.313 min, ESMS m / z=428.7 [M+H] + .

[0190] Step 5: 5-((5-(2-hydroxy-6-methoxyphenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile (P1-1) A solution of 5-((5-(2-methoxy-6-((4-methoxybenzyl)oxy)phenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile (8 g, 18.7 mmol) and hydrogen chloride (4 M in 1,4-dioxane, 80 mL, 320 mmol) was heated to 65° C. for 5 h. The brown slurry was cooled to room temperature. The precipitate was collected and the solid was washed with ethyl acetate (150 mL) to give the title compound as the dihydrochloride salt (7 g, 18.4 mmol). The product (7 g) was suspended in tetrahydrofuran (100 mL). To the mixture was added triethylamine (4.65 g, 46 mmol) and the resulting slurry was stirred at room temperature for 2 h. The mixture was filtered and the filtrate was evaporated. The residue was suspended in diethyl ether (20 mL) and the mixture was stirred at room temperature for 30 min. The precipitate was collected to give the title compound (5 g, 87% yield) as a yellow solid. LCMS: Rt=1.160 min, ESMS m / z=308.8 [M+H] + . 1 H NMR (400MHz,DMSO-d6) δ ppm 10.83(s,1H),8.65(s,1H),8.56(s,1H),7.15(t,J=8.4Hz,1H),6.86(s,1H),6.61(d,J=8.4Hz,1H),6.58(d,J=8.4Hz,1H),3.79(s,3H).

[0191] The following compounds were prepared by the same general method.

[0192] [Table 4]

[0193] Preparation P2-1: 1-(2-((4-methoxybenzyl)oxy)-6-(2,2,2-trifluoroethoxy)phenyl)ethan-1-one

[0194] [ka]

[0195] Step 1: 1-(2-hydroxy-6-((4-methoxybenzyl)oxy)phenyl)ethan-1-one (2) To a mixture of 1-(2,6-dihydroxyphenyl)ethan-1-one (10 g, 65.7 mmol) and 4-methoxybenzyl alcohol (9.08 g, 65.7 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (8.16 mL, 72.3 mmol) at room temperature. The reaction mixture was heated to 30° C. for 18 h. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography to give the title compound (11 g, 52% yield) as a yellow solid. LCMS: Rt=1.398 min, ESMS m / z=294.8. [M+Na] + .

[0196] Step 2: 1-(2-((4-methoxybenzyl)oxy)-6-(2,2,2-trifluoroethoxy)phenyl)ethan-1-one (P2-1) To a mixture of 1-(2-hydroxy-6-((4-methoxybenzyl)oxy)phenyl)ethan-1-one (28 g, 102.8 mmol) and 1,1,1-trifluoro-2-iodoethane (30.21 g, 143.9 mmol) in N,N-dimethylformamide (100 mL) was added potassium carbonate (25.57 g, 185 mmol) at room temperature. The reaction mixture was heated to 100° C. for 18 h. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography to give the title compound (12.57 g, 33% yield) as a white solid. LCMS: Rt=1.393 min, ESMS m / z=376.7 [M+H] + .

[0197] The following compounds were prepared by the same general method.

[0198] [Table 5]

[0199] Preparation P3-1: 1-(4-fluoro-2-methoxy-6-((4-methoxybenzyl)oxy)phenyl)ethan-1-one

[0200] [ka]

[0201] Step 1: 1-(4-fluoro-2,6-dimethoxyphenyl)ethan-1-one (2)

[0202] To a solution of aluminum trichloride (17.15 g, 127.9 mmol) in toluene (80 mL) was added 1-fluoro-3,5-dimethoxybenzene (20 g, 128 mmol) at 0° C. The reaction mixture was stirred for 2 h at 0° C. To the reaction mixture was added acetyl chloride (9.06 mL, 128.2 mmol) at 0° C. and the reaction mixture was stirred for 30 min at 0° C. The reaction mixture was evaporated and the residue was purified by gradient silica gel column chromatography to give the title compound (9.6 g, 38% yield) as a yellow solid. LCMS: Rt=1.090 min, ESMS m / z=199.1 [M+H] + .

[0203] Step 2: 1-(4-fluoro-2-hydroxy-6-methoxyphenyl)ethan-1-one (3) To a mixture of 1-(4-fluoro-2,6-dimethoxyphenyl)ethan-1-one (3.1 g, 15.6 mmol) in dichloromethane (30 mL) was added boron tribromide (2.25 mL, 23.4 mmol) at -20°C and the reaction mixture was stirred for 1 h. The reaction mixture was evaporated and the residue was purified by gradient silica gel column chromatography to give the title compound (2.6 g, 90% yield) as a yellow oil. LCMS: Rt = 1.305 min, ESMS m / z = 184.9 [M + H] + .

[0204] Step 3: 1-(4-fluoro-2-methoxy-6-((4-methoxybenzyl)oxy)phenyl)ethan-1-one (P3-1) To a mixture of 1-(4-fluoro-2-hydroxy-6-methoxyphenyl)ethan-1-one (2.6 g, 14.1 mmol) and 4-methoxybenzyl chloride (2.25 mL, 16.9 mmol) in anhydrous N,N-dimethylformamide (20 mL) at 0° C. was added potassium carbonate (2.33 g, 16.9 mmol). The reaction mixture was warmed to room temperature and stirred for 18 h. The reaction was quenched with water (20 mL) and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by gradient silica gel column chromatography to give the title compound (3.8 g, 65% yield) as a colorless oil. LCMS: Rt=1.237 min, ESMS m / z=327.1 [M+Na] + .

[0205] The following compounds were prepared by the same general method.

[0206] [Table 6]

[0207] Preparation P4-1: 1-(3-((4-methoxybenzyl)oxy)-6-methylpyridin-2-yl)ethan-1-one

[0208] [ka]

[0209] Step 1: 2-Bromo-3-((4-methoxybenzyl)oxy)-6-methylpyridine (2) To a solution of 2-bromo-6-methylpyridin-3-ol (15 g, 79.8 mmol) and potassium carbonate (27.6 g, 199.5 mmol) in N,N-dimethylformamide (100 mL) was added 4-methoxybenzyl chloride (13 mL, 95.8 mmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (300 mL) and evaporated. The residue was purified by gradient silica gel column chromatography to give the title compound (22 g, 81% yield) as an off-white solid. LCMS: Rt=1.135 min, ESMS m / z=308.0 [M+H] + .

[0210] Step 2: 2-(1-ethoxyvinyl)-3-((4-methoxybenzyl)oxy)-6-methylpyridine (3) To a solution of 2-bromo-3-((4-methoxybenzyl)oxy)-6-methylpyridine (6.6 g, 21.4 mmol) and tributyl(1-ethoxyethenyl)stannane (15.46 g, 42.8 mmol) in toluene (50 mL) was added tetrakis(triphenylphosphine)palladium(0) (7.42 g, 6.42 mmol) and the reaction mixture was stirred at 100° C. for 16 h under nitrogen. The reaction mixture was evaporated and the residue was purified by gradient silica gel column chromatography to give the title compound (6.0 g, 84% yield) as a colorless oil. LCMS: Rt=1.144 min, ESMS m / z=300.0 [M+H] + .

[0211] Step 3: 1-(3-((4-methoxybenzyl)oxy)-6-methylpyridin-2-yl)ethan-1-one (P4-1) To a solution of 2-(1-ethoxyvinyl)-3-((4-methoxybenzyl)oxy)-6-methylpyridine (6.0 g, 20 mmol) in acetonitrile (20 mL) was added 1N hydrochloric acid (50 mL, 50 mmol) and the reaction mixture was stirred at room temperature for 2 h. The mixture was neutralized (pH 7) by the addition of solid sodium bicarbonate. The mixture was evaporated and the residue was purified by gradient silica gel column chromatography to give the title compound (2.0 g, 33% yield) as an off-white solid. LCMS: Rt=1.332 min, ESMS m / z=272.0 [M+H] + .

[0212] Preparation P5-1: 5-((5-(2-fluoro-6-hydroxyphenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile

[0213] [ka]

[0214] Step 1: 3-(dimethylamino)-1-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)prop-2-en-1-one (2) A mixture of 1-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)ethan-1-one (5 g, 18.24 mmol) and N,N-dimethylformamide dimethyl acetal (9.69 mL, 73.0 mmol) in anhydrous N,N-dimethylformamide (40 mL) was heated to 80° C. for 3 h. The reaction mixture was evaporated to give the crude title compound (6.5 g) as a yellow oil which was used without further purification. LCMS: Rt=1.205 min, ESMS m / z=329.8 [M+H] + .

[0215] Step 2: 5-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)isoxazole (3) A mixture of crude 3-(dimethylamino)-1-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)prop-2-en-1-one (5.85 g, 17.78 mmol) and hydroxylamine hydrochloride (1.35 g, 19.6 mmol) in absolute ethanol (60 mL) was stirred at 40° C. for 3 h under nitrogen. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was taken up in ethyl acetate (20 mL). Petroleum ether (30 mL) was added to the solution. The precipitate was collected and the solid was dried under vacuum at 40° C. to give the title compound (4.5 g, 82% yield for two steps) as a yellow solid. LCMS: Rt=1.258 min, ESMS m / z=300.1 [M+H] + .

[0216] Step 3: 3-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-3-oxopropanenitrile (4) A mixture of 5-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)isoxazole (1 g, 3.34 mmol) and potassium hydroxide (156 mg, 5.02 mmol) in absolute ethanol (10 mL) was stirred at 50° C. for 1 h under nitrogen. The reaction mixture was evaporated and the residue was taken up in water (20 mL). The mixture was acidified to pH 5 by addition of saturated citric acid solution. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give the crude title compound (900 mg) as a yellow solid that was used without further purification. LCMS: Rt=1.180 min, ESMS m / z=322.1 [M+Na] + .

[0217] Step 4: 5-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-1H-pyrazol-3-amine (5) A mixture of crude 3-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-3-oxopropanenitrile (900 mg), hydrazine hydrate (1.22 mL, 18.06 mmol), and acetic acid (688 μL, 12.04 mmol) in absolute ethanol (10 mL) was slowly heated to 80° C., and the reaction mixture was stirred at 80° C. under nitrogen for 18 h. The reaction mixture was evaporated and the crude product was purified by gradient silica gel column chromatography to give the title compound (900 mg, 86% yield for two steps) as a yellow solid. LCMS: Rt=1.017 min. ESMS m / z=314.1 [M+H] + .

[0218] Step 5: 5-((5-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile (6) To a mixture of 5-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-1H-pyrazol-3-amine (1 g, 3.19 mmol) and 5-chloropyrazine-2-carbonitrile (533 mg, 3.83 mmol) in dimethylsulfoxide (10 mL) was added 4-ethylmorpholine (1.21 mL, 9.57 mmol) and the reaction mixture was stirred at 80° C. for 3 h. The reaction mixture was cooled to room temperature and diluted with water (20 mL). The mixture was extracted with ethyl acetate (3×20 mL) and the combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by gradient silica gel column chromatography to give the title compound (600 mg, 45% yield) as a yellow solid. LCMS: Rt=1.196 min, ESMS m / z=417.1 [M+H] + .

[0219] Step 6: 5-((5-(2-fluoro-6-hydroxyphenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile (P5-1) A solution of 5-((5-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile (560 mg, 1.89 mmol) and hydrogen chloride (4 M in 1,4-dioxane, 5 mL, 20 mmol) was heated to 40° C. for 1 h. The reaction mixture was cooled to room temperature and the precipitate was collected. The filter cake was washed with ethyl acetate (30 mL) to give the crude dihydrochloride salt (400 mg). The crude solid was suspended in tetrahydrofuran (10 mL). To the mixture was added triethylamine (336 μL, 2.42 mmol) and the slurry was stirred at room temperature for 2 h. The mixture was filtered and evaporated. The residue was suspended in diethyl ether (10 mL) and the mixture was stirred at room temperature for 30 min. The precipitate was collected and dried to give the title compound (210 mg, 53% yield) as a yellow solid. LCMS:Rt=1.101 min, ESMS m / z=297.2[M+H] + .

[0220] The following compounds were prepared by the same general method.

[0221] [Table 7-1]

[0222] [Table 7-2]

[0223] Preparation P6-1: tert-butyl ((1S,3R)-3-((2-acetyl-6-cyclopropylpyridin-3-yl)oxy)cyclopentyl)carbamate

[0224] [ka]

[0225] Step 1: Methyl 6-bromo-3-hydroxypicolinate (2) To a solution of methyl 3-hydroxypyridine-2-carboxylate (3 g, 19.6 mmol) in water (30 mL) was added bromine (1.20 mL, 23.5 mmol) dropwise at −15° C. under nitrogen. The reaction mixture was stirred at room temperature for 4 h. The reaction was quenched with saturated aqueous sodium thiosulfate (20 mL) and the mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography to give the title compound (2.6 g, 59% yield) as a yellow solid. LCMS: Rt=1.165 min, ESMS m / z=232.0 [M+H] + .

[0226] Step 2: Methyl 6-bromo-3-(((1R,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)oxy)picolinate (3) To a solution of methyl 6-bromo-3-hydroxypicolinate (1.5 g, 6.5 mmol), tert-butyl ((1S,3S)-3-hydroxycyclopentyl)carbamate (1.57 g, 7.8 mmol), and triphenylphosphine (3.41 g, 13 mmol) in anhydrous dichloromethane (15 mL) at 0° C. under nitrogen was added diisopropyl azodicarboxylate (2.56 mL, 13 mmol). The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and evaporated. The residue was purified by gradient silica gel column chromatography to give the title compound (2.6 g, 52% yield) as a yellow solid. LCMS: Rt=1.344 min, ESMS m / z=436.9 [M+Na] + .

[0227] Step 3: 6-Bromo-3-(((1R,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)oxy)picolinic acid (4) To a solution of methyl 6-bromo-3-{[(1S,3S)-3-{[(tert-butoxy)carbonyl]amino}cyclopentyl]oxy}pyridine-2-carboxylate (2.6 g, 6.3 mmol) in methanol (15 mL) was added aqueous sodium hydroxide (5.4 M, 2.3 mL, 12.6 mmol) dropwise at 0° C. under nitrogen. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was evaporated. The residue was diluted with water (20 mL) and the mixture was neutralized (pH 7) by addition of 1N hydrochloric acid. The mixture was extracted with ethyl acetate (3×20 mL) and the combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography to give the title compound (1.9 g, 68% yield) as a colorless oil. LCMS: Rt=1.229 min, ESMS m / z=423.1 [M+Na] + .

[0228] Step 4: Pyridin-2-yl 6-bromo-3-(((1R,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)oxy)picolinate (5) A mixture of 6-bromo-3-(((1R,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)oxy)picolinic acid (1.9 g, 4.7 mmol), picolinic anhydride (1.53 g, 7.1 mmol), and 4-(dimethylamino)pyridine (57 mg, 0.47 mmol) in dichloromethane (20 mL) was stirred at room temperature under nitrogen for 2 h. The mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated. The residue was purified by gradient silica gel column chromatography to give the title compound (1.6 g, 71% yield) as a colorless oil. LCMS: Rt=1.335 min, ESMS m / z=478.1 [M+H] + .

[0229] Step 5: tert-Butyl ((1S,3R)-3-((2-acetyl-6-bromopyridin-3-yl)oxy)cyclopentyl)(methyl)carbamate (6) To a solution of pyridin-2-yl 6-bromo-3-(((1R,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)oxy)picolinate (1.6 g, 3.3 mmol) in tetrahydrofuran (15 mL) is added a solution of methylmagnesium bromide (3 M in diethyl ether, 1.2 mL, 3.6 mmol) dropwise under nitrogen at 0° C. The reaction mixture was stirred for 1 h at 0° C. The reaction was quenched with saturated aqueous ammonium chloride solution (30 mL) and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by gradient silica gel column chromatography to give the title compound (170 mg, 14% yield) as a yellow oil. LCMS: Rt=1.374 min, ESMS m / z=421.1 [M+Na] + .

[0230] Step 6: tert-Butyl ((1S,3R)-3-((2-acetyl-6-cyclopropylpyridin-3-yl)oxy)cyclopentyl)carbamate (P6-1) A mixture of tert-butyl ((1S,3R)-3-((2-acetyl-6-bromopyridin-3-yl)oxy)cyclopentyl)carbamate (170 mg, 0.425 mmol), cyclopropylboronic acid (73 mg, 0.85 mmol), tetrakis(triphenylphosphine)palladium(0) (98 mg, 0.085 mmol), and cesium carbonate (277 mg, 0.85 mmol) in a mixture of 1,4-dioxane and water (5:1, 6 mL) was stirred at 90° C. for 18 h under nitrogen. The reaction mixture was evaporated and the residue was purified by gradient silica gel column chromatography to give the title compound (25 mg, 16% yield) as a yellow oil. LCMS: Rt=1.448 min, ESMS m / z=361.1 [M+H] + .

[0231] Preparation P7-1: tert-butyl ((1S,3R)-3-(2-acetyl-4-chloro-3-methoxyphenoxy)cyclopentyl)carbamate

[0232] [ka]

[0233] To a mixture of 1-(3-chloro-6-hydroxy-2-methoxyphenyl)ethan-1-one (2.0 g, 9.97 mmol), tert-butyl ((1S,3S)-3-hydroxycyclopentyl)carbamate (2.4 g, 11.96 mmol), and triphenylphosphine (5.2 g, 19.93 mmol) in anhydrous tetrahydrofuran (20 mL) was added diisopropyl azodicarboxylate (3.89 mL, 19.93 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with water (50 mL) and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated. The crude product was purified by gradient silica gel column chromatography to give the title compound (2.6 g, 68% yield) as a yellow oil. LCMS: Rt=1.415 min, ESMS m / z=406.1[M+Na] + .

[0234] The following compounds were prepared by the same general method.

[0235] [Table 8]

[0236] Preparation P8-1: tert-butyl ((1S,3R)-3-(2-acetyl-3-methoxy-4-methylphenoxy)cyclopentyl)carbamate

[0237] [ka]

[0238] A mixture of tert-butyl ((1S,3R)-3-(2-acetyl-4-chloro-3-methoxyphenoxy)cyclopentyl)carbamate (1.0 g, 2.6 mmol), trimethylboroxine (490 mg, 3.9 mmol), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride (PEPPSI-IPr, 180 mg, 0.26 mmol), and potassium carbonate (1.08 g, 7.8 mmol) in 1,4-dioxane (10 mL) was heated to 100° C. under nitrogen for 18 h. The mixture was evaporated and the residue was purified by gradient silica gel column chromatography to give the title compound (800 mg, 85% yield) as a white solid. LCMS: Rt=1.403 min, ESMS m / z=386.0 [M+Na] + .

[0239] The following compounds were prepared by the same general method.

[0240] [Table 9]

[0241] Preparation P9-1: 1-(2-fluoro-6-hydroxy-4-methylphenyl)ethan-1-one

[0242] [ka]

[0243] Step 1: 1-(2-fluoro-6-methoxy-4-methylphenyl)ethan-1-one (2) To a solution of 1-(2,6-difluoro-4-methylphenyl)ethan-1-one (690 mg, 4.05 mmol) in methanol (10 mL) was added sodium methoxide (5.4 M in methanol, 1.12 mL, 6.07 mmol) at room temperature. The reaction mixture was heated to 70° C. for 2 h. The reaction mixture was evaporated. The crude product was taken up in water (30 mL) and the mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by gradient silica gel column chromatography to give the title compound (410 mg, 50% yield) as a white solid. LCMS: Rt=1.246 min, ESMS m / z=183.1 [M+1] + .

[0244] Step 2: 1-(2-fluoro-6-hydroxy-4-methylphenyl)ethan-1-one To a mixture of 1-(2-fluoro-6-methoxy-4-methylphenyl)ethan-1-one (410 mg, 1.7 mmol) in dichloromethane (10 mL) was added aluminum trichloride (453 mg, 3.4 mmol) at 0° C. and the reaction mixture was stirred at room temperature under nitrogen for 2 h. The reaction was quenched with water (50 mL) and the mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by gradient silica gel column chromatography to give the title compound (220 mg, 69% yield) as a colorless oil. LCMS: Rt=1.336 min, ESMS no mass.

[0245] Preparation P10-1: 3-Fluoro-2-(isoxazol-5-yl)-5-methylphenol

[0246] [ka]

[0247] Step 1: 3-(Dimethylamino)-1-(2-fluoro-6-hydroxy-4-methylphenyl)prop-2-en-1-one (2) A mixture of 1-(2-fluoro-6-hydroxy-4-methylphenyl)ethan-1-one (220 mg, 1.31 mmol) and N,N-dimethylformamide dimethyl acetal (522 μL, 3.9 mmol) in anhydrous N,N-dimethylformamide (5 mL) was heated to 80° C. for 18 h. The reaction mixture was evaporated to give the crude title compound (240 mg) as a yellow oil which was used without further purification. LCMS: Rt=1.266 min, ESMS m / z=224.2 [M+H] + .

[0248] Step 2: 3-Fluoro-2-(isoxazol-5-yl)-5-methylphenol (P10-1) A mixture of crude 3-(dimethylamino)-1-(2-fluoro-6-hydroxy-4-methoxyphenyl)prop-2-en-1-one (240 mg) and hydroxylamine hydrochloride (112 mg, 1.61 mmol) in absolute ethanol (5 mL) was stirred at 50° C. for 1 h under nitrogen. The reaction mixture was evaporated and the residue was taken up in water (30 mL). The mixture was extracted with ethyl acetate (3×20 mL) and the combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by gradient silica gel column chromatography to give the title compound (180 mg, 71% yield for two steps) as a yellow solid. LCMS: Rt=1.168 min, ESMS m / z=194.1 [M+H] + .

[0249] The following compounds were prepared by the same general method.

[0250] [Table 10]

[0251] Preparation P11-1: (1s,3s)-3-((tert-butoxycarbonyl)(methyl)amino)cyclobutyl methanesulfonate

[0252] [ka]

[0253] To a solution of tert-butyl ((1s,3s)-3-hydroxycyclobutyl)(methyl)carbamate (300 mg, 1.48 mmol) and triethylamine (620 μL, 4.45 mmol) in dichloromethane (10 mL) was added methanesulfonyl chloride (190 μL, 2.22 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 18 h. The reaction mixture was evaporated to give the crude title compound (450 mg) as a white solid which was used without further purification. LCMS: Rt=1.222 min, ESMS m / z=302.1 [M+Na] + .

[0254] The following compounds were prepared by the same general method.

[0255] [Table 11]

[0256] Preparation P12-1: tert-Butyl 3-((tert-butoxycarbonyl)(5-cyanopyrazin-2-yl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate

[0257] [ka]

[0258] Step 1: 5-((5-bromo-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile (2) A mixture of 5-chloropyrazine-2-carbonitrile (10 g, 71.7 mmol), 5-bromo-1H-pyrazol-3-amine (12.19 g, 75.25 mmol), and cesium carbonate (70.0 g, 215 mmol) in dimethylsulfoxide (250 mL) was stirred at 80° C. for 18 h. The reaction mixture was poured into ice water (1 L) and the mixture was stirred for 30 min. The precipitate was collected, the filter cake was washed with water (1 L), and dried to give the title compound (18 g, 95% yield) as a light brown solid. LCMS: Rt=1.080 min, ESMS m / z=264.9 [M+H] + .

[0259] Step 2: tert-Butyl 5-bromo-3-((tert-butoxycarbonyl)(5-cyanopyrazin-2-yl)amino)-1H-pyrazole-1-carboxylate (3) A mixture of 5-((5-bromo-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile (18 g, 67.9 mmol) and di-tert-butyl dicarbonate (76 g, 348 mmol) was heated to 80° C. for 18 h. The mixture was evaporated under vacuum and the crude product was purified by gradient silica gel column chromatography to give the title compound (28 g, 89% yield) as a white solid. LCMS: Rt=1.440 min, ESMS m / z=486.9 [M+Na] + .

[0260] Step 3: tert-Butyl 3-((tert-butoxycarbonyl)(5-cyanopyrazin-2-yl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (P12-1) A mixture of tert-butyl 5-bromo-3-((tert-butoxycarbonyl)(5-cyanopyrazin-2-yl)amino)-1H-pyrazole-1-carboxylate (3.0 g, 6.46 mmol), bis(pinacolato)diboron (2.3 g, 9.06 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (948 mg, 1.30 mmol), and potassium acetate (1.27 g, 12.94 mmol) in 1,4-dioxane (100 mL) was stirred at 90° C. for 2.5 h under nitrogen. The mixture was cooled to room temperature and diluted with dichloromethane (100 mL). The mixture was filtered and the solid was washed with dichloromethane (2×100 mL). The filtrate was evaporated and the residue was taken up in dichloromethane (20 mL). The crude product was purified by gradient silica gel column chromatography to give the title compound (2.2 g, 66% yield) as a yellow oil. LCMS: Rt=1.261 min, ESMS m / z=331.1 [M+H-Boc-pinacol] + .

[0261] Preparation P13-1: 2-Bromo-5-fluoro-6-methylpyridin-3-ol

[0262] [ka]

[0263] To a solution of 5-fluoro-6-methylpyridin-3-ol (100 mg, 0.79 mmol) in pyridine (3 mL) was added bromine (44 μL, 0.87 mmol) dropwise at 0° C. under nitrogen. The reaction mixture was stirred at 30° C. for 18 h. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography to give the title compound (200 mg, 97% yield) as a pale orange oil. LCMS: Rt=1.087 min, ESMS m / z=206.0 [M+H] + .

[0264] Preparation P14-1: tert-butyl ((1S,3R)-3-(3-fluoro-2-iodo-4-methylphenoxy)cyclopentyl)carbamate

[0265] [ka]

[0266] To a mixture of 3-fluoro-2-iodo-4-methylphenol (300 mg, 1.19 mmol), tert-butyl ((1S,3S)-3-hydroxycyclopentyl)carbamate (288 mg, 1.43 mmol), and triphenylphosphine (624 mg, 2.38 mmol) in anhydrous tetrahydrofuran (5 mL) was added diisopropyl azodicarboxylate (469 μL, 2.38 mmol) at 0° C. under nitrogen. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and evaporated. The residue was purified by gradient silica gel column chromatography to give the title compound (350 mg, 61% yield) as a yellow solid. LCMS: Rt=1.530 min, ESMS m / z=458.0 [M+Na] + .

[0267] The following compounds were prepared by the same general method.

[0268] [Table 12-1]

[0269] [Table 12-2]

[0270] [Table 12-3]

[0271] [Table 12-4]

[0272] [Table 12-5]

[0273] Preparation P15-1: N-((1S,2S)-2-(2-bromo-3-fluorophenoxy)cyclobutyl)-2-methylpropane-2-sulfinamide, and Preparation P15-2: N-((1S,2R)-2-(2-bromo-3-fluorophenoxy)cyclobutyl)-2-methylpropane-2-sulfinamide

[0274] [ka]

[0275] Step 1: 2-(2-bromo-3-fluorophenoxy)cyclobutan-1-one (2) A mixture of 2-bromo-3-fluorophenol) (3 g, 16 mmol), 2-bromocyclobutan-1-one (7.07 g, 80 mmol), and potassium carbonate (5.45 g, 40 mmol) in N,N-dimethylformamide (30 mL) was stirred at 50° C. for 12 h. The reaction mixture was filtered and evaporated. The residue was purified by gradient silica gel column chromatography to give the title compound (1.65 g, 42% yield) as a white solid. LCMS: Rt=1.303 min, ESMS m / z=258.9 [M+H] + .

[0276] Step 2: N-((1S,2S)-2-(2-bromo-3-fluorophenoxy)cyclobutyl)-2-methylpropane-2-sulfinamide and N-((1S,2R)-2-(2-bromo-3-fluorophenoxy)cyclobutyl)-2-methylpropane-2-sulfinamide (P15-1 and P15-2) A solution of 2-(2-bromo-3-fluorophenoxy)cyclobutan-1-one (200 mg, 0.772 mmol), (S)-2-methylpropane-2-sulfinamide (103 mg, 0.849 mmol), and titanium(IV) ethoxide (302 μL, 1.16 mmol) in tetrahydrofuran (6 mL) was stirred at room temperature under nitrogen for 3 h. Sodium borohydride (58 mg, 1.54 mmol) was added to the reaction mixture at 0° C. The reaction mixture was heated to 40° C. for 2 h. The reaction was quenched by the addition of methanol (5 mL) and water (50 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated. The residue was purified by preparative HPLC to give N-((1S,2S)-2-(2-bromo-3-fluorophenoxy)cyclobutyl)-2-methylpropane-2-sulfinamide (30 mg, 12% yield) as a white solid and N-((1S,2R)-2-(2-bromo-3-fluorophenoxy)cyclobutyl)-2-methylpropane-2-sulfinamide (30 mg, 12% yield) as a white solid.

[0277] The isomers were assigned arbitrarily.

[0278] Isomer 1 LCMS: Rt=1.332 min, ESMS m / z=364.0[M+H] + .

[0279] Isomer 2LCMS: Rt=1.366 min, ESMS m / z=364.0[M+H] + .

[0280] The following compounds were prepared by the same general method.

[0281] [Table 13-1]

[0282] [Table 13-2]

[0283] Preparation P16-1: tert-butyl ((1S,3R)-3-((2-bromo-6-isopropylpyridin-3-yl)oxy)cyclopentyl)carbamate, and P16-2: tert-butyl ((1S,3R)-3-((2-bromo-6-propylpyridin-3-yl)oxy)cyclopentyl)carbamate

[0284] [ka]

[0285] Step 1: tert-Butyl ((1S,3R)-3-((2-bromo-6-iodopyridin-3-yl)oxy)cyclopentyl)carbamate (2) To a solution of 2-bromo-6-iodopyridin-3-ol (2.0 g, 6.67 mmol), tert-butyl ((1S,3S)-3-hydroxycyclopentyl)carbamate (1.6 g, 8.00 mmol), and triphenylphosphine (2.5 g, 9.34 mmol) in dichloromethane (20 mL) was added diisopropyl azodicarboxylate (1.95 mL, 10.0 mmol) at 0° C. under nitrogen. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was poured into water (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and evaporated. The crude product was purified by gradient silica gel column chromatography to give the title compound (2.4 g, 74% yield) as a yellow oil. LCMS: Rt=1.446 min, ESMS m / z=504.8[M+Na] + .

[0286] Step 2: tert-butyl ((1S,3R)-3-((2-bromo-6-(prop-1-en-2-yl)pyridin-3-yl)oxy)cyclopentyl)carbamate and tert-butyl ((1S,3R)-3-((2-bromo-6-(prop-1-en-1-yl)pyridin-3-yl)oxy)cyclopentyl)carbamate (3a and 3b) To a solution of tert-butyl ((1S,3R)-3-((2-bromo-6-iodopyridin-3-yl)oxy)cyclopentyl)carbamate (1.0 g, 2.07 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (400 mg, 2.48 mmol), and sodium carbonate (700 mg, 6.21 mmol) in a mixture of 1,4-dioxane and water (5:1, 12 mL), tetrakis(triphenylphosphine)palladium(0) (500 mg, 0.41 mmol) was added and the reaction mixture was stirred at 70° C. under nitrogen for 18 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and evaporated. The residue was purified by gradient silica gel column chromatography to give a mixture of the title compounds (400 mg, 49% yield) as a colorless oil, which was used without further purification. LCMS: Rt=1.488 min, ESMS m / z=397.0 [M+H] + .

[0287] Step 3: tert-butyl ((1S,3R)-3-((2-bromo-6-isopropylpyridin-3-yl)oxy)cyclopentyl)carbamate and tert-butyl ((1S,3R)-3-((2-bromo-6-propylpyridin-3-yl)oxy)cyclopentyl)carbamate (P16-1 and P16-2) To a mixture of tert-butyl ((1S,3R)-3-((2-bromo-6-(prop-1-en-2-yl)pyridin-3-yl)oxy)cyclopentyl)carbamate and tert-butyl ((1S,3R)-3-((2-bromo-6-(prop-1-en-1-yl)pyridin-3-yl)oxy)cyclopentyl)carbamate (200 mg, 0.51 mmol) in methanol (5 mL) was added tris(triphenylphosphine)rhodium(I) chloride (93 mg, 0.10 mmol) and the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 18 hours. The mixture was filtered and evaporated. The residue was purified by preparative thin layer chromatography to give a mixture of the title compounds (120 mg, 60% yield) as a colorless oil, which was used without further purification. LCMS:Rt=1.477min, ESMS m / z=398.9[M+H] + .

[0288] Preparation P17-1: tert-butyl ((1S,3R)-3-((2-bromo-6-(difluoromethyl)pyridin-3-yl)oxy)cyclopentyl)carbamate

[0289] [ka]

[0290] Step 1: Methyl 6-bromo-5-hydroxypicolinate (2) To a solution of methyl 6-bromo-5-methoxypicolinate (600 mg, 2.45 mmol) in anhydrous dichloromethane (10 mL) was added aluminum trichloride (326 mg, 2.45 mmol) at 0° C. The reaction mixture was heated to 40° C. under nitrogen for 50 h. The reaction mixture was poured into water (60 mL) and extracted with dichloromethane (3×40 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography to give the title compound (300 mg, 53% yield) as a white solid. LCMS: Rt=1.008 min, ESMS m / z=232.0 [M+H] +.

[0291] Step 2: Methyl 6-bromo-5-(((1R,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)oxy)picolinate (3) A solution of methyl 6-bromo-5-hydroxypicolinate (300 mg, 1.30 mmol), tert-butyl ((1S,3S)-3-hydroxycyclopentyl)carbamate (314 mg, 1.56 mmol), triphenylphosphine (511 mg, 1.95 mmol), and diisopropyl azodicarboxylate (384 μL, 1.95 mmol) in anhydrous dichloromethane (20 mL) was stirred at room temperature under nitrogen for 18 h. The reaction mixture was poured into water (60 mL) and extracted with dichloromethane (3×40 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered, and evaporated. The residue was purified by gradient silica gel column chromatography to give the title compound (420 mg, 78% yield) as a white solid. LCMS: Rt=1.306 min, ESMS m / z=437.1 [M+Na] + .

[0292] Step 3: tert-Butyl ((1S,3R)-3-((2-bromo-6-(hydroxymethyl)pyridin-3-yl)oxy)cyclopentyl)carbamate (4) A mixture of methyl 6-bromo-5-(((1R,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)oxy)picolinate (420 mg, 1.01 mmol), sodium borohydride (39 mg, 1.01 mmol), and calcium chloride (112 mg, 1.01 mmol) in absolute ethanol (20 mL) was heated to reflux under nitrogen for 1 h. The reaction mixture was poured into water (60 mL) and the mixture was extracted with dichloromethane (3×40 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered, and evaporated. The crude product was purified by gradient silica gel column chromatography to give the title compound (310 mg, 79% yield) as a white solid. LCMS: Rt=1.229 min, ESMS m / z=387.1 [M+H] + .

[0293] Step 4: tert-Butyl ((1S,3R)-3-((2-bromo-6-formylpyridin-3-yl)oxy)cyclopentyl)carbamate (5) A solution of tert-butyl ((1S,3R)-3-((2-bromo-6-(hydroxymethyl)pyridin-3-yl)oxy)cyclopentyl)carbamate (310 mg, 0.80 mmol) and Dess-Martin periodinane (339 mg, 0.80 mmol) in anhydrous dichloromethane (10 mL) was stirred at room temperature under nitrogen for 1 h. The reaction mixture was poured into water (60 mL) and extracted with dichloromethane (3x40 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography to give the title compound (220 mg, 57% yield) as a white solid. LCMS: Rt=1.340 min, 407.1 [M+Na] + .

[0294] Step 5: tert-Butyl ((1S,3R)-3-((2-bromo-6-(difluoromethyl)pyridin-3-yl)oxy)cyclopentyl)carbamate (P17-1) To a solution of tert-butyl ((1S,3R)-3-((2-bromo-6-formylpyridin-3-yl)oxy)cyclopentyl)carbamate (220 mg, 0.57 mmol) in anhydrous dichloromethane (10 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (BAST, 378 mg, 1.71 mmol) at 0° C. The reaction mixture was heated to 40° C. under nitrogen for 1 h. The reaction mixture was poured into water (60 mL) and extracted with dichloromethane (3×40 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography to give the title compound (150 mg, 65% yield) as a yellow solid. LCMS: Rt=1.331 min, ESMS m / z=407.1 [M+H] + .

[0295] Preparation P18-1: tert-butyl ((1S,3R)-3-(2-bromo-3-(methoxy-d3)phenoxy)cyclopentyl)carbamate

[0296] [ka]

[0297] Step 1: tert-Butyl ((1S,3R)-3-(2-bromo-3-hydroxyphenoxy)cyclopentyl)carbamate (2) To a solution of 2-bromobenzene-1,3-diol (220 mg, 1.17 mmol), tert-butyl ((1S,3S)-3-hydroxycyclopentyl)carbamate (235 mg, 1.17 mmol), and triphenylphosphine (613 mg, 2.34 mmol) in tetrahydrofuran (5 mL) at 0° C. was added diisopropyl azodicarboxylate (460 μL, 2.34 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction was quenched with water (20 mL) and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated. The crude product was purified by gradient silica gel column chromatography to give the title compound (180 mg, 41% yield) as a yellow solid. LCMS: Rt=1.307 min, ESMS m / z=393.9 [M+Na] + .

[0298] Step 2: tert-Butyl ((1S,3R)-3-(2-bromo-3-(methoxy-d3)phenoxy)cyclopentyl)carbamate (P18-1) To a mixture of tert-butyl ((1S,3R)-3-(2-bromo-3-hydroxyphenoxy)cyclopentyl)carbamate (126 mg, 0.34 mmol) and potassium carbonate (70 mg, 0.51 mmol) in acetonitrile (5 mL) was added iodomethane-d3 (106 μL, 1.70 mmol) dropwise. The reaction mixture was stirred at room temperature for 18 h. The reaction was quenched with water (50 mL) and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by gradient silica gel column chromatography to give the title compound (100 mg, 75% yield) as a yellow solid. LCMS: Rt=1.419 min, ESMS m / z=411.1 [M+Na] + .

[0299] Preparation P19-1: tert-butyl (2-((2-bromo-3-methoxyphenoxy)methyl)cyclopropyl)carbamate

[0300] [ka]

[0301] Step 1: Ethyl 2-(hydroxymethyl)cyclopropane-1-carboxylate (2) To a mixture of ethyl 2-formylcyclopropane-1-carboxylate (5 g, 35 mmol) in absolute ethanol (50 mL) was added sodium borohydride (3.99 g, 105 mmol) at 0° C. and the reaction mixture was stirred at room temperature under nitrogen for 2 h. The mixture was cooled to 0° C. and the reaction was quenched with 1N hydrochloric acid (10 mL). The mixture was poured into water (50 mL) and extracted with dichloromethane (3×60 mL). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography to give the title compound (5 g, 80% yield) as a white oil. LCMS: Rt=0.947 min, ESMS m / z=145.1 [M+H] + .

[0302] Step 2: Ethyl 2-(((methylsulfonyl)oxy)methyl)cyclopropane-1-carboxylate (3) To a mixture of ethyl 2-(hydroxymethyl)cyclopropane-1-carboxylate (5 g, 34.7 mmol) and methanesulfonic anhydride (6.65 g, 38.2 mmol) in dichloromethane (35 mL) was added triethylamine (7.74 mL, 41.6 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 18 h. The mixture was poured into water (20 mL) and extracted with dichloromethane (3x20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography to give the title compound (4 g, 42% yield) as a white oil. LCMS: Rt=1.109 min, ESMS m / z=223.1 [M+H] + .

[0303] Step 3: Ethyl 2-((2-bromo-3-methoxyphenoxy)methyl)cyclopropane-1-carboxylate (4) To a mixture of ethyl 2-(((methylsulfonyl)oxy)methyl)cyclopropane-1-carboxylate (4 g, 18 mmol) and 2-bromo-3-methoxyphenol (4.75 g, 23.4 mmol) in N,N-dimethylformamide (15 mL) was added cesium carbonate (8.21 g, 25.2 mmol) and the reaction mixture was heated to 65° C. under nitrogen for 18 h. The reaction mixture was poured into water (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated. The crude product was purified by gradient silica gel column chromatography to give the title compound (2.6 g, 39% yield) as a colorless oil. LCMS: Rt=1.374 min, ESMS m / z=329.0 [M+H] + .

[0304] Step 4: 2-((2-bromo-3-methoxyphenoxy)methyl)cyclopropane-1-carboxylic acid (5) To a solution of ethyl 2-((2-bromo-3-methoxyphenoxy)methyl)cyclopropane-1-carboxylate (2.6 g, 7.92 mmol) in methanol (10 mL) was added sodium hydroxide (4 M aqueous solution, 5 mL, 20 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 18 h. The reaction mixture was poured into water (20 mL) and extracted with dichloromethane (3x10 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered and evaporated. The crude product was purified by gradient silica gel column chromatography to give the title compound (2 g, 77% yield) as a white oil. LCMS: Rt=1.199 min, ESMS m / z=301.0 [M+H] + .

[0305] Step 5: tert-Butyl (2-((2-bromo-3-methoxyphenoxy)methyl)cyclopropyl)carbamate (P19-1) To a solution of 2-((2-bromo-3-methoxyphenoxy)methyl)cyclopropane-1-carboxylic acid (400 mg, 1.33 mmol) in dichloromethane (10 mL) was added oxalyl chloride (337 μL, 3.99 mmol) and N,N-dimethylformamide (2 drops) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The mixture was evaporated and the residue was dissolved in N,N-dimethylformamide (6 mL). To the solution was added sodium azide (259 mg, 3.99 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated. The residue was taken up in a mixture of toluene and tertbutanol (5:1, 6 mL) and the reaction mixture was heated to 110 °C for 18 h. The mixture was poured into water (20 mL) and extracted with dichloromethane (3x20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated. The crude product was purified by gradient silica gel column chromatography to give the title compound (260 mg, 55% yield) as a colorless oil. LCMS: Rt=1.383 min, ESMS m / z=393.9 [M+Na] + .

[0306] Preparation P20-1: 5-((5-(3-fluoro-2-hydroxy-6-methoxyphenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile

[0307] [ka]

[0308] Step 1: 2-Bromo-4-fluoro-1-methoxy-3-((4-methoxybenzyl)oxy)benzene (2) To a mixture of 2-bromo-6-fluoro-3-methoxyphenol (420 mg, 1.9 mmol) and potassium carbonate (525 mg, 3.8 mmol) in N,N-dimethylformamide (10 mL) was added 4-methoxybenzyl chloride (335 μL, 2.47 mmol) dropwise over 2 min at 0° C. The reaction mixture was stirred at room temperature for 6 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography to give the title compound (230 mg, 36% yield) as a white solid. LCMS: Rt=1.312 min, ESMS m / z=363.0 [M+Na] + .

[0309] Step 2: tert-Butyl 3-((tert-butoxycarbonyl)(5-cyanopyrazin-2-yl)amino)-5-(3-fluoro-6-methoxy-2-((4-methoxybenzyl)oxy)phenyl)-1H-pyrazole-1-carboxylate (3) 2-Bromo-4-fluoro-1-methoxy-3-((4-methoxybenzyl)oxy)benzene (220 mg, 0.64 mmol), tert-butyl 3-((tert-butoxycarbonyl)(5-cyanopyrazin-2-yl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (532 mg, 1.29 mmol), 2-dicyclohexylphosphino-2',4' To a solution of ,6'-triisopropylbiphenyl (XPhos, 46 mg, 0.097 mmol) and tripotassium phosphate (274 mg, 1.29 mmol) was added tris(dibenzylideneacetone)dipalladium(0) (88 mg, 0.097 mmol) and the reaction mixture was stirred at 90° C. for 3 h under nitrogen. The mixture was poured into water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography to give the title compound (220 mg, 56% yield) as a yellow solid. LCMS: Rt=1.527 min, ESMS m / z=669.1 [M+Na] + .

[0310] Step 3: 5-((5-(3-fluoro-2-hydroxy-6-methoxyphenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile (P20-1) A mixture of tert-butyl 3-((tert-butoxycarbonyl)(5-cyanopyrazin-2-yl)amino)-5-(3-fluoro-6-methoxy-2-((4-methoxybenzyl)oxy)phenyl)-1H-pyrazole-1-carboxylate (220 mg, 0.40 mmol) and hydrogen chloride (4M in 1,4-dioxane, 2.5 mL, 10 mmol) was stirred at room temperature for 1 h. The reaction mixture was evaporated and the crude product was purified by gradient silica gel column chromatography to give the title compound (60 mg, 43% yield) as a yellow solid. LCMS: Rt=1.201 min, ESMS m / z=327.0 [M+H] + .

[0311] Example 1-1: 5-((5-(2-(((1r,4r)-4-aminocyclohexyl)oxy)-6-methoxyphenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile

[0312] [ka]

[0313] Step 1: tert-butyl ((1r,4r)-4-(2-(3-((5-cyanopyrazin-2-yl)amino)-1H-pyrazol-5-yl)-3-methoxyphenoxy)cyclohexyl)carbamate (1) To a solution of 5-((5-(2-hydroxy-6-methoxyphenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile (200 mg, 0.649 mmol), cis-4-(tert-butoxycarbonylamino)cyclohexanol (279 mg, 1.30 mmol), and triphenylphosphine (511 mg, 1.95 mmol) in tetrahydrofuran (5 mL) at 0° C. under nitrogen was added a solution of diisopropyl azadicarboxylate (394 mg, 1.95 mmol) in tetrahydrofuran (1 mL) dropwise. The reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water (20 mL) and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated. The crude product was purified by gradient silica gel column chromatography to give the title compound as a yellow solid (120 mg, 36% yield). LCMS:Rt=1.233min, ESMS m / z=506.2[M+H] + .

[0314] Step 2: 5-((5-(2-(((1r,4r)-4-aminocyclohexyl)oxy)-6-methoxyphenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile formate To a solution of tert-butyl ((1r,4r)-4-(2-(3-((5-cyanopyrazin-2-yl)amino)-1H-pyrazol-5-yl)-3-methoxyphenoxy)cyclohexyl)carbamate (120 mg, 0.23 mmol) in dichloromethane (2 mL) was added hydrogen chloride (4 M in 1,4-dioxane, 2 mL, 8 mmol) and the reaction mixture was stirred for 1 h at room temperature. The mixture was evaporated and the residue was purified by preparative HPLC to give the title compound (30 mg, 31% yield) as a white solid. LCMS: Rt=3.952 min, ESMS m / z=406.2 [M+H] + . 1 H NMR (400MHz,CD3OD) δ ppm 8.53(s,1H),8.50(d,J=1.2Hz,1H),8.47(s,1H),7.34(t,J=8.4Hz,1H),6.96(s,1H),6.82(d,J=8Hz,1H),6.79(d,J=8. 4Hz,1H),4.40-4.34(m,1H),3.90(s,3H),3.21-3.15(m,1H),2.26-2.22(m,2H),2.14-2.06(m,2H),1.67-1.49(m,4H).

[0315] The following compounds were prepared by the same general method.

[0316] [Table 14-1]

[0317] [Table 14-2]

[0318] Example 2: 5-((5-(2-(((1S,3R)-3-aminocyclopentyl)oxy)phenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile

[0319] [ka]

[0320] Step 1: tert-butyl ((1R,3S)-3-(2-(3-((5-cyanopyrazin-2-yl)amino)-1H-pyrazol-5-yl)phenoxy)cyclopentyl)carbamate (2) A mixture of crude (1R,3R)-3-((tert-butoxycarbonyl)amino)cyclopentyl methanesulfonate (300 mg, 1.07 mmol), 5-((5-(2-hydroxyphenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile (269 mg, 0.96 mmol), and cesium carbonate (697 mg, 2.14 mmol) in anhydrous tetrahydrofuran (10 mL) was stirred at 70° C. for 18 h under nitrogen. The reaction was quenched with water (20 mL) and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by gradient silica gel column chromatography to give the title compound (150 mg, 34% yield) as a colorless oil. LCMS (method 1): Rt=1.449 min, ESMS m / z=461.7[M+H] + .

[0321] Step 2: 5-((5-(2-(((1S,3R)-3-aminocyclopentyl)oxy)phenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile formate To a mixture of tert-butyl ((1R,3S)-3-(2-(3-((5-cyanopyrazin-2-yl)amino)-1H-pyrazol-5-yl)phenoxy)cyclopentyl)carbamate (150 mg, 0.32 mmol) in ethyl acetate (5 mL) was added hydrogen chloride (4 M in 1,4-dioxane, 5 mL, 20 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was evaporated and the residue was purified by preparative HPLC to give the title compound (24 mg, 20% yield) as a white solid. LCMS (Method 1): Rt=0.917 min, ESMS m / z=362.2 [M+H] + . 1H NMR (400MHz,DMSO-d6) δ ppm 8.66(d,J=1.2Hz,1H),8.49(br s,1H),8.33(s,1H),7.68(dd,J=7.6, 1.6Hz,1H),7.35-7.29(m,1H),7.13(d,J=8.4Hz,1H),7.05-6.09(m,2H),5.06-4.94(m,1H),3 .63-3.52(m,1H),2.31-2.25(m,1H),2.02-1.93(m,3H),1.84-1.76(m,1H),1.73-1.64(m,1H).

[0322] The following compounds were prepared by the same general method.

[0323] [Table 15]

[0324] Example 3-1: 5-((5-(2,3-difluoro-6-(((1R,3R)-3-(methylamino)cyclopentyl)oxy)phenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile

[0325] [ka]

[0326] Step 1: tert-Butyl 3-((tert-butoxycarbonyl)(5-cyanopyrazin-2-yl)amino)-5-(6-(((1R,3R)-3-((tert-butoxycarbonyl)(methyl)amino)cyclopentyl)oxy)-2,3-difluorophenyl)-1H-pyrazole-1-carboxylate (2) To a solution of tert-butyl ((1R,3R)-3-(2-bromo-3,4-difluorophenoxy)cyclopentyl)(methyl)carbamate (150 mg, 0.37 mmol), tert-butyl 3-((tert-butoxycarbonyl)(5-cyanopyrazin-2-yl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (P12-1, 227 mg, 0.44 mmol), sodium carbonate (117 mg, 1.11 mmol) in a mixture of 1,4-dioxane and water (5:1, 6 mL), tetrakis(triphenylphosphine)palladium(0) (85 mg, 0.07 mmol) was added and the reaction mixture was stirred at 90 °C under nitrogen for 2.5 h. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography to give the title compound (80 mg, 30% yield) as a white solid. LCMS (Method 1): Rt=1.379 min, ESMS m / z=512.1 [M+H-2Boc] + .

[0327] Step 2: 5-((5-(2,3-difluoro-6-(((1R,3R)-3-(methylamino)cyclopentyl)oxy)phenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile formate To a solution of tert-butyl 3-((tert-butoxycarbonyl)(5-cyanopyrazin-2-yl)amino)-5-(6-(((1R,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)oxy)-2,3-difluorophenyl)-1H-pyrazole-1-carboxylate) (80 mg, 0.11 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.5 mL, 6.53 mmol) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated. Saturated aqueous sodium carbonate solution (3 mL) was added to the residue to achieve pH 8. Formic acid (5 mL) was added to the mixture until a clear solution resulted. The mixture was purified by preparative HPLC to give the title compound (6.9 mg, 15% yield) as a white solid. LCMS (method 1): Rt=1.087 min, ESMS m / z=412.0[M+H] + . 1 H NMR(400MHz,DMSO-d6) δ ppm 12.70(s,1H),10.93(s,1H),8.68(s,1H),8.50(s,1H),8.35(s,1H),7.52-7.40(m,1H),7.06-6.85(m,2H),5.02-4.95(m,1H),3 .41-3.32(m,1H),2.38(s,3H),2.20-2.07(m,2H),2.05-1.98(m,1H),1.95-1.86(m,1H),1.82-1.72(m,1H),1.67-1.56(m,1H).

[0328] The following compounds were prepared by the same general method.

[0329] [Table 16]

[0330] Example 4-1: 5-((5-(6-(((1R,3S)-3-aminocyclopentyl)oxy)-2-methoxy-3-methylphenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile

[0331] [ka]

[0332] Step 1: tert-Butyl ((1S,3R)-3-(2-(3-(dimethylamino)acryloyl)-3-methoxy-4-methylphenoxy)cyclopentyl)carbamate (2) A mixture of tert-butyl ((1S,3R)-3-(2-acetyl-3-methoxy-4-methylphenoxy)cyclopentyl)carbamate (650 mg, 1.79 mmol) and N,N-dimethylformamide dimethyl acetal (920 μL, 7.15 mmol) in anhydrous N,N-dimethylformamide (5 mL) was heated to 120° C. for 18 h. The mixture was evaporated to give the crude title compound (900 mg) as a yellow oil, which was used in the next step without further purification. LCMS (Method 1): Rt=1.273 min, ESMS m / z=419.1 [M+H] + .

[0333] Step 2: tert-Butyl ((1S,3R)-3-(2-(isoxazol-5-yl)-3-methoxy-4-methylphenoxy)cyclopentyl)carbamate (3) A mixture of tert-butyl ((1S,3R)-3-(2-3-(dimethylamino)acryloyl)-3-methoxy-4-methylphenoxy)cyclopentylcarbamate (900 mg, 2.15 mmol) and hydroxylamine hydrochloride (224 mg, 3.22 mmol) in absolute ethanol (10 mL) was stirred at 50° C. under nitrogen for 2 h. The reaction mixture was evaporated and the residue was taken up in water (30 mL). The mixture was extracted with ethyl acetate (3×20 mL) and the combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by gradient silica gel column chromatography to give the title compound (600 mg, 82% yield for two steps) as a white solid. LCMS (Method 1): Rt=1.404 min, ESMS m / z=411.0 [M+Na] + .

[0334] Step 3: tert-Butyl ((1S,3R)-3-(2-(2-cyanoacetyl)-3-methoxy-4-methylphenoxy)cyclopentyl)carbamate (4) A mixture of tert-butyl ((1S,3R)-3-(2-(isoxazol-5-yl)-3-methoxy-4-methylphenoxy)cyclopentyl)carbamate (350 mg, 0.91 mmol) and potassium hydroxide (77 mg, 1.36 mmol) in absolute ethanol (10 mL) was stirred at 50° C. under nitrogen for 18 h. The reaction mixture was evaporated. The residue was taken up in water (20 mL) and the mixture was neutralized (pH 7) by addition of saturated citric acid solution. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound (300 mg, 86% yield) as a white solid, which was used without further purification. LCMS (Method 1): Rt=1.356 min, ESMS m / z=411.0 [M+Na] + .

[0335] Step 4: tert-Butyl ((1S,3R)-3-(2-(3-amino-1H-pyrazol-5-yl)-3-methoxy-4-methylphenoxy)cyclopentyl)carbamate (5) A mixture of tert-butyl ((1S,3R)-3-(2-(2-cyanoacetyl)-3-methoxy-4-methylphenoxy)cyclopentyl)carbamate (300 mg, 0.77 mmol), hydrazine hydrate (75 μL, 1.54 mmol), and acetic acid (132 μL, 2.31 mmol) in absolute ethanol (10 mL) was slowly heated to 90° C. under nitrogen. The reaction mixture was stirred at 90° C. for 18 h. The reaction mixture was cooled to room temperature and evaporated. The crude product was purified by gradient silica gel column chromatography to give the title compound (300 mg, 97% yield) as a white solid. LCMS (Method 1): Rt=1.166 min, ESMS m / z=403.3 [M+H] + .

[0336] Step 5: tert-butyl ((1S,3R)-3-(2-(3-((5-cyanopyrazin-2-yl)amino)-1H-pyrazol-5-yl)-3-methoxy-4-methylphenoxy)cyclopentyl)carbamate (6) A mixture of tert-butyl ((1S,3R)-3-(2-(3-amino-1H-pyrazol-5-yl)-3-methoxy-4-methylphenoxy)cyclopentyl)carbamate (300 mg, 0.74 mmol), 5-chloropyrazine-2-carbonitrile (114 mg, 0.82 mmol), and 4-ethylmorpholine (285 μL, 2.23 mmol) in anhydrous dimethylsulfoxide (5 mL) was stirred at 80° C. for 3 h under nitrogen. The reaction mixture was cooled to room temperature and diluted with water (20 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated. The crude product was purified by gradient silica gel column chromatography to give the title compound (300 mg, 80% yield) as a yellow solid. LCMS (method 1): Rt=1.355 min, ESMS m / z=506.2[M+H] + .

[0337] Step 6: 5-((5-(6-(((1R,3S)-3-aminocyclopentyl)oxy)-2-methoxy-3-methylphenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile formate To a mixture of tert-butyl ((1S,3R)-3-(2-(3-((5-cyanopyrazin-2-yl)amino)-1H-pyrazol-5-yl)-3-methoxy-4-methylphenoxy)cyclopentyl)carbamate (100 mg, 0.19 mmol) in ethyl acetate (5 mL) at 0° C. was added hydrogen chloride (4 M in 1,4-dioxane, 5 mL, 20 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated and the residue was purified by preparative HPLC to give the title compound (60 mg, 75% yield) as a yellow solid. LCMS (Method 1): Rt=1.060 min, ESMS m / z=406.1 [M+H] + . 1H NMR (400MHz,DMSO-d6) δ ppm 8.65(d,J=1.2Hz,1H),8.52(br s,1H),8.38(s,1H),7.18(d,J=8.8Hz,1H),6.86(s,1H),6.78(d,J=8.8Hz,1H),4.84-4.78(m,1H),3. 53-3.45(m,1H),3.42(s,3H),2.39-2.32(m,1H),2.21(s,3H),1.96-1.87(m,3H),1.75-1.70(m,2H).

[0338] The following compounds were prepared by the same general method.

[0339] [Table 17]

[0340] Example 5-1: 5-((5-(2-(((1R,3R)-3-aminocyclopentyl)oxy)-6-fluoro-4-methylphenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile

[0341] [ka]

[0342] Step 1: tert-butyl ((1R,3R)-3-(3-fluoro-2-(isoxazol-5-yl)-5-methylphenoxy)cyclopentyl)carbamate (2) To a solution of 3-fluoro-2-(isoxazol-5-yl)-5-methylphenol (400 mg, 2.07 mmol), tert-butyl ((1R,3S)-3-hydroxycyclopentyl)carbamate (833 mg, 4.14 mmol), and triphenylphosphine (1.63 g, 6.21 mmol) in anhydrous tetrahydrofuran (10 mL) was added diisopropyl azodicarboxylate (1.22 mL, 6.21 mmol) under nitrogen at 0° C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and evaporated. The residue was purified by gradient silica gel column chromatography to give the title compound (700 mg, 90% yield) as a white solid. LCMS (method 1): Rt=1.411 min, ESMS m / z=399.0[M+Na] + .

[0343] Step 2: tert-Butyl ((1R,3R)-3-(2-(2-cyanoacetyl)-3-fluoro-5-methylphenoxy)cyclopentyl)carbamate (3) A mixture of tert-butyl ((1R,3R)-3-(3-fluoro-2-(isoxazol-5-yl)-5-methylphenoxy)cyclopentyl)carbamate (700 mg, 1.86 mmol) and potassium hydroxide (150 mg, 3.72 mmol) in absolute ethanol (15 mL) was stirred at 50° C. under nitrogen for 2 h. The reaction mixture was evaporated and the residue was taken up in water (20 mL). The mixture was neutralized (pH 7) by addition of saturated citric acid solution. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give the title compound (600 mg, 86% yield) as a white solid. LCMS (Method 1): Rt=1.305 min, ESMS m / z=398.9 [M+Na] + .

[0344] Step 3: tert-butyl ((1R,3R)-3-(2-(3-amino-1H-pyrazol-5-yl)-3-fluoro-5-methylphenoxy)cyclopentyl)carbamate (4) A mixture of tert-butyl ((1R,3R)-3-(2-(2-cyanoacetyl)-3-fluoro-5-methylphenoxy)cyclopentyl)carbamate (900 mg, 2.39 mmol), hydrazine hydrate (697 μL, 14.34 mmol), and acetic acid (547 μL, 9.56 mmol) in absolute ethanol (10 mL) was slowly heated to 50° C. and the reaction mixture was heated under nitrogen for 3 h. The reaction mixture was cooled to room temperature and evaporated. The residue was purified by gradient silica gel column chromatography to give the title compound (700 mg, 75% yield) as a white solid. LCMS (Method 1): Rt=1.189 min, ESMS m / z=391.2 [M+H] + .

[0345] Step 4: tert-butyl ((1R,3R)-3-(2-(3-((5-cyanopyrazin-2-yl)amino)-1H-pyrazol-5-yl)-3-fluoro-5-methylphenoxy)cyclopentyl)carbamate (5) A mixture of tert-butyl N-[(1R,3R)-3-[2-(5-amino-2H-pyrazol-3-yl)-3-fluoro-5-methylphenoxy]cyclopentyl]-N-methylcarbamate (200 mg, 0.51 mmol), 5-chloropyrazine-2-carbonitrile (107 mg, 0.77 mmol), and 4-ethylmorpholine (208 μL, 1.63 mmol) in anhydrous dimethylsulfoxide (7 mL) was stirred at 80° C. for 3 h under nitrogen. The reaction mixture was cooled to room temperature and diluted with water (20 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated. The residue was purified by gradient silica gel column chromatography to give the title compound (150 mg, 53% yield) as a yellow solid. LCMS (method 1): Rt=1.362 min, ESMS m / z=494.3[M+H] + .

[0346] Step 5: 5-((5-(2-(((1R,3R)-3-aminocyclopentyl)oxy)-6-fluoro-4-methylphenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile formate To a solution of tert-butyl ((1R,3R)-3-(2-(3-((5-cyanopyrazin-2-yl)amino)-1H-pyrazol-5-yl)-3-fluoro-5-methylphenoxy)cyclopentyl)carbamate (100 mg, 0.21 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3 mL) and the reaction mixture was stirred for 30 min at room temperature. The solvent reaction mixture was evaporated. Saturated aqueous sodium carbonate (3 mL) was added to the residue to achieve pH 8. Formic acid (5 mL) was added to the mixture until a clear solution resulted. The solution was purified by preparative HPLC to give the title compound (44 mg, 54% yield) as a yellow solid. LCMS (Method 1): Rt=1.095 min, ESMS m / z=394.2 [M+H] + . 1 H NMR (400MHz,DMSO-d6) δ ppm 12.48(s,1H),8.68(d,J=1.6Hz,1H),8.51(s,1H),8.41(s,1H),6.87-6.75(m,3H),5.06-5.01(m,1H),3.68-3.60(m ,1H),2.35(s,3H),2.22-2.12(m,2H),2.12-2.03(m,1H),1.99-1.88(m,1H),1.83-1.74(m,1H),1.66-1.55(m,1H).

[0347] The following compounds were prepared by the same general method.

[0348] [Table 18]

[0349] Example A: Kinase HTRF Biochemical Assay Chk1 enzyme activity was measured using HTRF KinEASE assay (Cisbio, Catalog No. 62ST1PEC). Full-length human Chk1 protein (GenBank accession no. NP_001265.1) was obtained from Carna Biosciences, Inc. (Kobe, Japan, Catalog No. 02-117). Enzyme reactions were performed in assay buffer containing Chk1 enzyme (0.012 ng / μL), MgCl2 (5 mM), and DTT (1 mM) (final concentrations). To determine compound dose response, DMSO stock solutions were serially diluted in a 10-point concentration series in duplicate. Compound solutions (50 nL) were added to a 384-well assay plate (Greiner, Catalog No. 784075). To each well containing compound solution, assay buffer solution (5 μL) was added. Plates were centrifuged at 1000 rpm for 1 min and then incubated at room temperature for 10 min. The reaction was initiated by the addition of substrate buffer (5 μL / well) containing STK substrate 1-biotin (120 nM) and ATP (1 mM) (final concentrations). The assay plate was centrifuged at 1000 rpm for 1 min and then incubated at room temperature for 60 min. The reaction was stopped by the addition of detection buffer (Cisbio, 10 μL) containing STK antibody-cryptate (0.25 nM) and streptavidin-XL665 (7.5 nM) (final concentrations). The plate was centrifuged at 1000 rpm for 1 min and then incubated at 25 °C for 2 h. HTRF signals were read in HTRF mode on an EnVision multimode plate reader (CisBio). The data were fitted to dose-response curves using XLfit (IDBS, Surrey, UK) or Prism (GraphPad Software, La Jolla, CA, USA) to determine the IC of each compound tested. 50 The value was calculated.

[0350] Example B: AlphaLisa Cell Assay Compound activity in cells was measured using AlphaLISA® SureFire® Ultra™ p-CHK1 (Ser345) assay (Perkin Elmer, Cat. No. ALSU-PCHK1-A10K). HT29 cells were cultured in McCoy's 5A medium with 10% FBS and 1% penicillin-streptomycin and seeded in 96-well plates (Corning, Cat. No. 3599). Compounds were serially diluted in DMSO over a 10-point dose range in 3-fold dilutions and compound solutions were added to each well containing cells. Plates were centrifuged at 1000 rpm for 30 seconds. Plates were incubated at 37°C for 16 hours. Supernatants were removed by tapping the plates against a paper towel. Wells were washed once with PBS solution. Freshly prepared lysis buffer was added to each well and the plates were agitated at 400 rpm on a plate shaker for 30 minutes. The 96-well cell plate was centrifuged at 1500 rpm for 1 min. From each well, 10 μL of lysate was transferred to a 384-well Optiplate™ (Perkin Elmer, Cat. No. 6007290). To each well, Acceptor Mix (5 μL) was added, the plate was sealed and wrapped in foil. The plate was agitated on a plate shaker for 2 min and then incubated at room temperature for 1 h. To each well, Donor Mix (5 μL) was added, the plate was sealed and wrapped in foil. The plate was agitated on a plate shaker for 2 min and then incubated at room temperature for 1 h. AlphaLisa signals were read on an EnVision multimode plate reader (Perkin Elmer). The data were fitted to dose-response curves using XLfit (IDBS, Surrey, UK) or Prism (GraphPad Software, La Jolla, CA, USA) to determine the IC of each compound tested. 50 The value was calculated.

[0351] Data for Examples A and B can be found in Table 4.

[0352] [Table 19-1]

[0353] [Table 19-2]

[0354] [Table 19-3]

[0355] Example C: Pharmaceutical Compositions Example C1: Parenteral Composition To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100mg of the water-soluble salt of the compound described herein is dissolved in DMSO, and then mixed with 10mL of 0.9% sterile saline.The mixture is incorporated into a dosage unit form suitable for administration by injection.

[0356] Example C2: Oral Composition To prepare a pharmaceutical composition for oral delivery, 100 mg of the compound described herein is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit suitable for oral administration, such as a hard gelatin capsule.

[0357] Example C3: Sublingual (hard lozenge) composition To prepare a pharmaceutical composition for buccal delivery, such as a hard lozenge, 100 mg of a compound described herein mixed with 420 mg of powdered sugar is combined with 1.6 mL of light corn syrup, 2.4 mL of distilled water, and 0.42 mL of mint extract. The mixture is gently mixed and poured into a mold to form a lozenge suitable for buccal administration.

[0358] The examples and embodiments described herein are for illustrative purposes only and, depending on the embodiment, various modifications or variations are intended to be within the scope of the disclosure and the appended claims.

Claims

1. A compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein 【Chemical 1】 in the formula,[[]] ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R １ is each independently deuterium, halogen, -CN, -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NHS(=O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ deuterated alkyl, C １ -C ６ hydroxyalkyl, C １ -C ６ aminoalkyl, C １ -C ６ heteroalkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and Alternatively, two Rs on the same atom combine to form an oxo group, １ and n is 0 to 4; R ２ is hydrogen, C １ -C ６ -alkyl, C １ -C ６ -haloalkyl, C １ -C ６ -deuterated alkyl, C １ -C ６ -hydroxyalkyl, C １ -C ６ -aminoalkyl, C １ -C ６ -heteroalkyl, cycloalkyl, or heterocycloalkyl, and R ３ is hydrogen, deuterium, halogen, -CN, -NO ２ , -OH, -OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ deuterated alkyl, C １ -C ６ hydroxyalkyl, C １ -C ６ aminoalkyl, C １ -C ６ heteroalkyl, cycloalkyl, or heterocycloalkyl, and R ４ is hydrogen, C １ -C ６ -alkyl, C １ -C ６ -haloalkyl, C １ -C ６ -deuterated alkyl, C １ -C ６ -hydroxyalkyl, C １ -C ６ -aminoalkyl, C １ -C ６ -heteroalkyl, cycloalkyl, or heterocycloalkyl, and X1 is N or CR5a; X2 is N or CR5b; X3 is N or CR5c; X4 is N or CR5d; R5a, R5b, R5c, and R5d are each independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NHS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; L is -O-; ring C is cycloalkyl; R ７ is each independently deuterium, halogen, -CN, -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NHS(=O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ deuterated alkyl, C １ -C ６ hydroxyalkyl, C １ -C ６ aminoalkyl, C １ -C ６ heteroalkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and Alternatively, two Rs on the same atom combine to form an oxo group, ７ and p is 0 to 8. R ａ is each independently, C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ deuterated alkyl, C １ -C ６ hydroxyalkyl, C １ -C ６ aminoalkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ alkyl(cycloalkyl), C １ -C ６ alkyl(heterocycloalkyl), C １ -C ６ alkyl(aryl), or C １ -C ６ alkyl(heteroaryl), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently one or more oxo, halogen, -CN, -OH, -OCH ３ , -S(=O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ NH ２ , -S(=O) ２ NHCH ３ , -S(=O) ２ N(CH ３ ) ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -C(=O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ Deuterated alkyl, C １ -C ６ Hydroxyalkyl, or C １ -C ６ Optionally substituted with aminoalkyl, R ｂ is each independently hydrogen, C １ -C ６ -alkyl, C １ -C ６ -haloalkyl, C １ -C ６ -deuterated alkyl, C １ -C ６ -hydroxyalkyl, C １ -C ６ -aminoalkyl, C ２ -C ６ -alkenyl, C ２ -C ６ -alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ -alkyl(cycloalkyl), C １ -C ６ -alkyl(heterocycloalkyl), C １ -C ６ -alkyl(aryl), or C １ -C ６ -alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently one or more oxo, halogen, -CN, -OH, -OCH ３ , -S(=O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ NH ２ , -S(=O) ２ NHCH ３ , -S(=O) ２ N(CH ３ ) ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -C(=O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , C １ -C ６ -alkyl, C １ -C ６ -haloalkyl, C １ -C ６ Deuterated alkyl, C １ -C ６ Hydroxyalkyl, or C １ -C ６ Optionally substituted with aminoalkyl, and, R ｃ and R ｄ are each independently hydrogen, C １ -C ６ -alkyl, C １ -C ６ -haloalkyl, C １ -C ６ -deuterated alkyl, C １ -C ６ -hydroxyalkyl, C １ -C ６ -aminoalkyl, C ２ -C ６ -alkenyl, C ２ -C ６ -alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ -alkyl(cycloalkyl), C １ -C ６ -alkyl(heterocycloalkyl), C １ -C ６ -alkyl(aryl), or C １ -C ６ -alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently one or more oxo, halogen, -CN, -OH, -OCH ３ , -S(=O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ NH ２ , -S(=O) ２ NHCH ３ , -S(=O) ２ N(CH ３ ) ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -C(=O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , C １ -C ６ -alkyl, C １ -C ６ -haloalkyl, C １ -C ６ deuterated alkyl, C １ -C ６ hydroxyalkyl, or C １ -C ６ optionally substituted with aminoalkyl, Alternatively, R ｃ and R ｄ are combined with the atoms to which they are attached to form, together with said atoms, one or more oxo, halogen, -CN, -OH, -OCH ３ , -S(=O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ NH ２ , -S(=O) ２ NHCH ３ , -S(=O) ２ N(CH ３ ) ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -C(=O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ deuterated alkyl, C １ -C ６ hydroxyalkyl, or C １ -C ６ heterocycloalkyl optionally substituted with aminoalkyl, a compound, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein X1 is CR5a and R5a is hydrogen, halogen, -ORa, C1-C6 alkyl, or C1-C6 haloalkyl.

3. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein X2 is CR5b and R5b is hydrogen, halogen, -ORa, C1-C6 alkyl, or C1-C6 haloalkyl.

4. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein X3 is N. **Claim 5** The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein X3 is CR5c and R5c is hydrogen, halogen, -ORa, C1-C6 alkyl, or C1-C6 haloalkyl. **Claim 6** The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein X4 is N. **Claim 7** The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein X4 is CR5d and R5d is hydrogen, halogen, -ORa, C1-C6 alkyl, or C1-C6 haloalkyl. **Claim 8** The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein ring A is pyrazinyl. **Claim 9** The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein n is 1 and R1 is -CN. **Claim 10** R2 is hydrogen, R3 is hydrogen, R4 is hydrogen. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. **Claim 11** The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein ring C is cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. **Claim 12** The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein p is 1 and R7 is -NRcRd. **Claim 13** A compound selected from the group consisting of, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, a compound selected from, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】 【Table 1-15】 【Table 1-16】 【Table 1-17】 【Table 1-18】 【Table 1-19】 【Table 1-20】 【Table 1-21】 【Table 1-22】 【Table 1-23】 **Claim 14** A pharmaceutical composition comprising the compound according to claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient. Use of the compound according to claim 1 in the manufacture of a medicament for the treatment of a cancer of interest, wherein the treatment comprises administering to the subject the compound, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

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