Fused polycyclic compounds and their use as PARP1 inhibitors

Abstract

Provided herein are certain fused polycyclic compounds having a polycyclic linker, such as compounds of Formula (I), as PARP1 inhibitors, pharmaceutical compositions comprising these compounds, and methods of using these compounds or pharmaceutical compositions in the treatment of diseases or conditions. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to International Patent Application No. PCT / CN2022 / 130788 filed on November 9, 2022 and International Patent Application No. PCT / CN2023 / 076158 filed on February 15, 2023, the entire contents of each of these international patent applications are incorporated herein by reference. Technical Field

[0003] Provided herein are certain fused polycyclic compounds having polycyclic linkers that are PARP1 inhibitors, pharmaceutical compositions comprising these compounds, and methods of using these compounds or pharmaceutical compositions to treat diseases or conditions. Background Art

[0004] Poly(ADP-ribose) polymerase (PARP) catalyzes poly(ADP-ribosylation) using nicotinamide adenine dinucleotide (NAD) as a substrate. DNA damage-induced parylation is primarily mediated by PARP1 (also known as ARTD1), which is primarily activated by DNA single-strand and double-strand breaks and accounts for >90% of DNA damage-induced parylation (Nucleic Acids Research 44, 10386-10405).

[0005] AutoPARylation through the catalytic activity of PARP releases PARP from DNA, allowing the acquisition of additional repair proteins and resolving the problem of DNA breaks and stalled replication forks (Sci. Transl. Med. 8 (362) (2016) 362ps17.). Inhibition of PARP family enzymes has been explored as a strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Currently clinically used PARP inhibitors (PARPi) inhibit PARylation by competitively binding to the NAD+ binding sites of PARP1 and PARP2, which has improved clinical benefits for BRCA mutant tumors. In addition to catalytic inhibition, "PARP capture" is another important mechanism involving PARPi. PARPi is reported to be more cytotoxic than PARP depletion because they are able to trap PARP enzymes on damaged DNA, which interferes with DNA replication (Cancer Res. 2012; 72: 5588-5599).

[0006] BRCA1 and BRCA2 play important roles in DNA replication and double-strand break (DSB) repair. Both factors promote homologous recombination repair (HR), a DNA repair pathway active during the S / G2 phase of the cell cycle that also provides a way to restart stalled replication forks. Several studies have shown that BRCA-deficient cells (and more broadly, cells with HR deficiency (HRD)) appear to be highly sensitive to PARP inhibition (Nat Rev Cancer 2004; 4: 814-9).

[0007] Hematological toxicity is a common adverse event involving PARPi therapy. PARP2 has been shown to be required for the survival of hematopoietic stem / progenitor cells (HSPCs) under steady-state conditions and in response to stress (Blood. 2013 Jul 4; 122(1): 44-54.). It is believed that PARP inhibitors with improved selectivity for PARP1 may have improved efficacy and reduced toxicity compared to other clinical PARP1 / 2 inhibitors. It is believed that selective and potent inhibition of PARP1 will lead to the capture of PARP1 on DNA, thereby causing DNA double-strand breaks (DSBs) by the collapse of the replication fork in S phase. It is also believed that PARP1-DNA capture is an effective mechanism for selectively killing tumor cells with HRD.

[0008] Therefore, there is an unmet medical need for effective and safe PARP inhibitors, especially those that are selective for PARP1. Summary of the Invention

[0009] In one embodiment, provided herein are fused polycyclic compounds having a polycyclic linker as PARP1 inhibitors.

[0010] In one embodiment, provided herein is a compound of formula (I):

[0011]

[0012] or a stereoisomer thereof, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein X 1 、X 2 、X 3 、X 4 、R a5 , Ring A, Y 1 、Y 2 and R are as defined herein or elsewhere.

[0013] Also provided herein are pharmaceutical compositions comprising a compound provided herein and a pharmaceutically acceptable excipient.

[0014] Also provided herein are methods of inhibiting a PARP1 protein comprising contacting the PARP1 protein with a compound provided herein or a pharmaceutical composition provided herein.

[0015] Also provided herein are methods of treating a PARP1-mediated disease or cancer, comprising administering to a subject suffering from the disease or cancer a therapeutically effective amount of a compound provided herein or a pharmaceutical composition provided herein. DETAILED DESCRIPTION

[0016] definition

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. Where multiple definitions exist for a term in this article, those in this section shall prevail unless otherwise stated.

[0018] As used herein and in the specification and claims that follow, the indefinite articles "a" and "an" and the definite article "the" include plural as well as singular referents, unless the context clearly dictates otherwise.

[0019] As used herein, the terms "comprising" and "including" can be used interchangeably. The terms "comprising" and "including" should be interpreted as specifying the presence of the features or components mentioned, but not excluding the presence or addition of one or more features or components or groups thereof. In addition, the terms "comprising" and "including" are intended to include examples encompassed by the term "consisting of." Therefore, the term "consisting of" can be used in place of the terms "comprising" and "including" to provide more specific embodiments.

[0020] As used herein, the term "or" should be interpreted as an inclusive "or," meaning any one or any combination. Thus, "A, B, or C" means any of the following: "A; B; C; A and B; A and C; B and C; A, B, and C." An exception to this definition occurs only when a combination of elements, functions, steps, or actions are inherently mutually exclusive to some extent.

[0021] As used herein, the phrase "and / or" as used herein in phrases such as "A and / or B" is intended to include both A and B; A or B; A (alone); and B (alone). Similarly, the phrase "and / or" as used herein in phrases such as "A, B and / or C" is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0022] It should be noted that if there is a discrepancy between a depicted structure and the name of that structure, the depicted structure will be given greater weight.

[0023] As used herein, and unless otherwise indicated, the term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which is saturated. In one embodiment, an alkyl group has, for example, one to twenty-four carbon atoms (C1-C 24 alkyl), four to twenty carbon atoms (4-C 20 alkyl), six to sixteen carbon atoms (6-C 16 alkyl), six to nine carbon atoms (6-C9 alkyl), one to fifteen carbon atoms (1-C 15 alkyl), one to twelve carbon atoms (1-C 12 The alkyl group is an alkyl radical (e.g., C-C alkyl), one to eight carbon atoms (1-C alkyl), or one to six carbon atoms (C -C alkyl), and is connected to the rest of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, and the like. Unless otherwise indicated, alkyl groups are optionally substituted.

[0024] As used herein, and unless otherwise indicated, the term "alkenyl" refers to a straight or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, containing one or more carbon-carbon double bonds. As understood by those of ordinary skill in the art, the term "alkenyl" also includes radicals with "cis" and "trans" configurations (or alternatively, "E" and "Z" configurations). In one embodiment, an alkenyl group has, for example, two to twenty-four carbon atoms (C2-C 24 alkenyl), four to twenty carbon atoms (4-C 20 alkenyl), six to sixteen carbon atoms (6-C 16 alkenyl), six to nine carbon atoms (6-C9 alkenyl), two to fifteen carbon atoms (2-C 15 alkenyl), two to twelve carbon atoms (2-C 12 The term "alkenyl" refers to a group consisting of two to eight carbon atoms (2-C alkenyl), two to eight carbon atoms (2-C alkenyl), or two to six carbon atoms (C2-C6 alkenyl) connected to the rest of the molecule by a single bond. Examples of alkenyl groups include, but are not limited to, vinyl, prop-1-enyl, but-1-enyl, pent-1-enyl, pent-1,4-dienyl, and the like. Unless otherwise indicated, alkenyl groups are optionally substituted.

[0025] As used herein, and unless otherwise indicated, the term "alkynyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon triple bonds. In one embodiment, an alkynyl group has, for example, two to twenty-four carbon atoms (C2-C 24 Alkynyl), four to twenty carbon atoms (4-C 20 Alkynyl), six to sixteen carbon atoms (6-C 16 Alkynyl), six to nine carbon atoms (6-C9 alkynyl), two to fifteen carbon atoms (2-C 15 Alkynyl), two to twelve carbon atoms (2-C 12 Alkynyl groups are optionally substituted unless otherwise indicated.

[0026] As used herein, and unless otherwise indicated, the term "cycloalkyl" refers to a non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, and which is saturated. Cycloalkyl groups may include fused, bridged, or spirocyclic ring systems. In one embodiment, a cycloalkyl group has, for example, 3 to 15 ring carbon atoms (C3-C 15 cycloalkyl), 3 to 10 ring carbon atoms (C3-C 10 The cycloalkyl radicals are preferably C-C cycloalkyl radicals or C-C cycloalkyl radicals. The cycloalkyl radicals are connected to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl radicals include, but are not limited to, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise indicated, cycloalkyl radicals are optionally substituted.

[0027] As used herein, and unless otherwise indicated, the term "cycloalkenyl" refers to a non-aromatic monocyclic or polycyclic hydrocarbon radical consisting only of carbon and hydrogen atoms, and containing one or more carbon-carbon double bonds. Cycloalkenyl groups may include fused, bridged, or spirocyclic ring systems. In one embodiment, a cycloalkenyl group has, for example, 3 to 15 ring carbon atoms (C3-C 15 cycloalkenyl), 3 to 10 ring carbon atoms (C3-C 10The term "cycloalkenyl" refers to a non-aromatic monocyclic or polycyclic hydrocarbon radical consisting of only carbon and hydrogen atoms, and includes one or more carbon-carbon triple bonds.

[0028] As used herein, and unless otherwise indicated, the term "heteroalkyl" refers to an alkyl radical having one or more backbone chain atoms selected from atoms other than carbon (e.g., oxygen, nitrogen, sulfur, and phosphorus, or a combination thereof). A numerical range can be given to refer to the total chain length. For example, -CH2OCH2CH3 radical is referred to as "C4" heteroalkyl. Connection to the parent molecular structure can be through heteroatoms or carbon in the heteroalkyl chain. One or more heteroatoms in the heteroalkyl radical can be optionally oxidized. One or more nitrogen atoms (if present) can also be optionally quaternized. Unless otherwise indicated, a heteroalkyl group is optionally substituted.

[0029] As used herein, and unless otherwise indicated, the term "aryl" refers to a monocyclic aromatic group and / or a polycyclic aromatic group containing at least one aromatic hydrocarbon ring. In certain embodiments, an aryl group has 6 to 18 ring carbon atoms (C6-C 18 aryl), 6 to 14 ring carbon atoms (C6-C 14 aryl) or 6 to 10 ring carbon atoms (C6-C 10 Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthracenyl, phenanthrenyl, pyrenyl, biphenyl, and terphenyl. The term "aryl" also refers to bicyclic, tricyclic, or other polycyclic hydrocarbon rings, wherein at least one of the rings is aromatic and the other rings may be saturated, partially unsaturated, or aromatic, such as dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl. Unless otherwise indicated, aryl groups are optionally substituted.

[0030] As used herein, and unless otherwise indicated, the term "heteroaryl" refers to a monocyclic aromatic group and / or a polycyclic aromatic group containing at least one aromatic ring, wherein at least one aromatic ring contains one or more (e.g., one, one or two, one to three or one to four) heteroatoms independently selected from O, S and N. Heteroaryl can be connected to the main structure at any heteroatom or carbon atom. In certain embodiments, heteroaryl has 5 to 20, 5 to 15 or 5 to 10 ring atoms. The term "heteroaryl" also refers to a bicyclic, tricyclic or other polycyclic ring, wherein at least one of these rings is aromatic, and the other rings can be saturated, partially unsaturated or aromatic, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S and N. Examples of monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl. Examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolyl, tetrahydroisoquinolyl, isoquinolyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, isobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, purinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, dihydroisoindolyl, and tetrahydroquinolyl. Examples of tricyclic heteroaryl groups include, but are not limited to, carbazolyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, and xanthenyl.Unless otherwise specified, heteroaryl groups are optionally substituted.

[0031] As used herein, and unless otherwise indicated, the term "heterocyclyl" refers to a monocyclic and / or polycyclic non-aromatic group containing one or more (e.g., one, one or two, one to three, or one to four) heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. The heterocyclyl group may be attached to the main structure at any heteroatom or carbon atom. The heterocyclyl group may be a monocyclic, bicyclic, tricyclic, tetracyclic, or other polycyclic ring system, wherein the polycyclic ring system may be a fused, bridged, or spirocyclic ring system. The heterocyclyl polycyclic ring system may contain one or more heteroatoms in one or more rings. The heterocyclyl group may be saturated or partially unsaturated. A saturated heterocyclyl group may be referred to as a "heterocycloalkyl." If the heterocyclyl group contains at least one double bond, a partially unsaturated heterocyclyl group may be referred to as a "heterocycloalkenyl," or if the heterocyclyl group contains at least one triple bond, a partially unsaturated heterocyclyl group may be referred to as a "heterocycloalkynyl." In one embodiment, heterocyclic radical has, for example, 3 to 18 ring atoms (3 to 18 membered heterocyclic radicals), 4 to 18 ring atoms (4 to 18 membered heterocyclic radicals), 5 to 18 ring atoms (5 to 18 membered heterocyclic radicals), 4 to 8 ring atoms (4 to 8 membered heterocyclic radicals) or 5 to 8 ring atoms (5 to 8 membered heterocyclic radicals). Examples of heterocyclic radical groups include, but are not limited to, imidazolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, isoxazolidinyl, isothiazolidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl and piperidinyl. Unless otherwise indicated, heterocyclic radical groups are optionally substituted.

[0032] Whenever it appears herein, a numerical range such as "3 to 18" refers to each integer in the given range; for example, a heterocyclyl group having "3 to 18 ring atoms" means that the heterocyclyl group can consist of 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms, etc. (up to and including 18 ring atoms). Similarly, a C1-C6 alkyl group means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms.

[0033] As used herein, and unless otherwise indicated, a "cycloalkylalkyl" group is a radical of the formula: -alkyl-cycloalkyl, wherein alkyl and cycloalkyl are as defined above. Substituted cycloalkylalkyl groups may be substituted on the alkyl, cycloalkyl, or both the alkyl and cycloalkyl portions of the group. Representative cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cyclopentylpropyl, cyclohexylpropyl, and the like.

[0034] As used herein, and unless otherwise indicated, an "aralkyl" group is a radical of the formula: -alkyl-aryl, wherein the alkyl and aryl groups are as defined above. A substituted aralkyl group may be substituted on the alkyl, aryl, or both the alkyl and aryl portions of the group. Representative aralkyl groups include, but are not limited to, benzyl and phenethyl groups, and aralkyl groups in which an aryl group is fused to a cycloalkyl group such as indan-4-ylethyl.

[0035] As used herein, and unless otherwise indicated, other similar compound terms reflect the above description of "cycloalkylalkyl" and "aralkyl." For example, a "heterocyclylalkyl" group is a radical of the formula: -alkyl-heterocyclyl, in which alkyl and heterocyclyl are as defined above. A "heteroarylalkyl" group is a radical of the formula: -alkyl-heteroaryl, in which alkyl and heteroaryl are as defined above. A "heterocycloalkylalkyl" group is a radical of the formula: -alkyl-heterocycloalkyl, in which alkyl and heterocycloalkyl are as defined above.

[0036] As used herein, and unless otherwise indicated, the terms "halogen," "halide," or "halo" refer to fluorine, chlorine, bromine, and / or iodine. As used herein, and unless otherwise indicated, the terms "haloalkyl," "haloalkenyl," "haloalkynyl," and "haloalkoxy" refer to alkyl, alkenyl, alkynyl, and alkoxy structures substituted with one or more halo groups or combinations thereof.

[0037] As used herein, and unless otherwise indicated, the term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. As used herein, and unless otherwise indicated, the term "aryloxy" refers to -O-(aryl), wherein aryl is as defined above.

[0038] As used herein, and unless otherwise indicated, the term "alkylsulfonyl" refers to a -SO2-alkyl group, wherein alkyl is as defined above.

[0039] As used herein, and unless otherwise indicated, the terms "carboxyl" and "carboxy" refer to -COOH.

[0040] As used herein, and unless otherwise indicated, the term "alkoxycarbonyl" refers to -C(=O)O-(alkyl), wherein alkyl is as defined above. As used herein, and unless otherwise indicated, the term "arylalkoxy" refers to -O-(alkyl)-(aryl), wherein alkyl and aryl are as defined above. As used herein, and unless otherwise indicated, the term "cycloalkyloxy" refers to -O-(cycloalkyl), wherein cycloalkyl is as defined above. As used herein, and unless otherwise indicated, the term "cycloalkylalkoxy" refers to -O-(alkyl)-(cycloalkyl), wherein cycloalkyl and alkyl are as defined above.

[0041] As used herein, and unless otherwise indicated, the term "acyl" refers to a -C(O)-R a , where R a R can be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is as defined above. a It may be unsubstituted or substituted with one or more substituents.

[0042] As used herein, and unless otherwise indicated, the term "acyloxy" refers to -OC(O)-R a , where R a R can be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is as defined above. a It may be unsubstituted or substituted with one or more substituents.

[0043] As used herein, and unless otherwise indicated, the term "amino" refers to a -N(R # )(R # ), where each R # independently can be, but are not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is as defined above. # )(R # ) group has two R # When , they can be combined with nitrogen atoms to form a ring. In one embodiment, the ring is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring. In one embodiment, one or more ring atoms are heteroatoms independently selected from O, S, or N. The term "amino" also includes N-oxides (-N + (R # )(R # )O - ). In certain embodiments, each R # Or by -N(R# )(R # ) may independently be unsubstituted or substituted with one or more substituents.

[0044] As used herein, and unless otherwise indicated, the term "amide" or "amido" refers to a -C(O)N(R # )2 or -NR # C(O)R # , where each R # independently can be, but are not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is as defined above. # )2 group has two R other than hydrogen # In one embodiment, the ring is a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered ring. In one embodiment, one or more ring atoms are heteroatoms independently selected from O, S, or N. In certain embodiments, each R # Or by -N(R # )(R # ) may independently be unsubstituted or substituted with one or more substituents.

[0045] As used herein, and unless otherwise indicated, the term "aminoalkyl" refers to -(alkyl)-(amino), wherein alkyl and amino are as defined above. As used herein, and unless otherwise indicated, the term "aminoalkoxy" refers to -O-(alkyl)-(amino), wherein alkyl and amino are as defined above.

[0046] As used herein, and unless otherwise indicated, the term "alkylamino" refers to -NH(alkyl) or -N(alkyl)(alkyl), where alkyl is as defined above. Examples of such alkylamino groups include, but are not limited to, -NHCH3, -NHCH2CH3, -NH(CH2)2CH3, -NH(CH2)3CH3, -NH(CH2)4CH3, -NH(CH2)5CH3, -N(CH3)2, -N(CH2CH3)2, -N((CH2)2CH3)2, -N(CH3)(CH2CH3), and the like.

[0047] As used herein, and unless otherwise indicated, the term "arylamino" refers to -NH(aryl) or -N(aryl)(aryl), where aryl is as defined above. As used herein, and unless otherwise indicated, similar compound terms such as "arylalkylamino" and "cycloalkylamino" reflect the above description of "alkylamino" and "arylamino".

[0048] As used herein, and unless otherwise indicated, the term "sulfanyl," "sulfide," or "thio" refers to a -SR a , where R a can be, but is not limited to, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is as defined above. In certain embodiments, R a It may be unsubstituted or substituted with one or more substituents.

[0049] As used herein, and unless otherwise indicated, the term "sulfoxide" refers to -S(O)-R a , where R a can be, but is not limited to, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is as defined above. In certain embodiments, R a It may be unsubstituted or substituted with one or more substituents.

[0050] As used herein, and unless otherwise indicated, the term "sulfonyl" or "sulfone" refers to -S(O)2-R a , where R a can be, but is not limited to, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is as defined above. In certain embodiments, R a It may be unsubstituted or substituted with one or more substituents.

[0051] As used herein, and unless otherwise indicated, the term "sulfonylamino" or "sulfonamide" refers to -S(=O)2-N(R # )2 or -N(R # )-S(=O)2-R # , where each R # independently can be, but are not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is as defined above. # )2 group has two R other than hydrogen # In one embodiment, the ring is a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered ring. In one embodiment, one or more ring atoms are heteroatoms independently selected from O, S, or N. In certain embodiments, each R # Or by -N(R # )(R # ) may independently be unsubstituted or substituted with one or more substituents.

[0052] "Azide" refers to the -N3 radical.

[0053] "Cyano" refers to the -CN free radical.

[0054] "Nitro" refers to the -NO2 free radical.

[0055] "Oxa" refers to the -O- radical.

[0056] "Oxo" refers to the =0 radical.

[0057] As used herein, and unless otherwise indicated, the term "optional" or "optionally" (e.g., optionally substituted) means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" means that an alkyl radical may or may not be substituted, and that the description includes both substituted alkyl radicals and unsubstituted alkyl radicals.

[0058] When groups described herein are referred to as "substituted," they may be substituted with any appropriate substituent(s). Illustrative examples of substituents include, but are not limited to, those found in the exemplary compounds and embodiments provided herein, as well as halogen (chlorine, iodine, bromine, or fluorine); alkyl; alkenyl; alkynyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxyl; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; amido; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; carbamate; oxime; hydroxylamine; alkoxyamine; aryloxyamine, arylalkyloxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxo (=O); B(OH)2, O(alkyl); )aminocarbonyl; cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or heterocyclyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothienyl, or benzofuranyl); aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclylalkoxy.

[0059] As used herein, and unless otherwise indicated, the term "isomer" refers to different compounds with the same molecular formula. "Stereoisomers" are isomers that differ only in the spatial arrangement of atoms. "Atropisomers" are stereoisomers produced by hindered rotation of a single bond. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A mixture of a pair of enantiomers in any ratio can be referred to as a "racemic" mixture. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry can be specified according to the Cahn-Ingold-Prelog R-S system. When a compound is an enantiomer, the stereochemistry on each chiral carbon can be specified by R or S. Resolved compounds with unknown absolute configuration can be specified as (+) or (-) based on the direction in which they rotate plane polarized light (right-handed or left-handed) at the wavelength of the sodium D line. However, the signs of the optical rotation, (+) and (-), have nothing to do with the absolute configuration R and S of the molecule. Certain compounds described herein contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)-, according to the absolute stereochemistry at each asymmetric atom. The chemical entities, pharmaceutical compositions, and methods of the present invention are intended to include all such possible isomers, including racemic mixtures, optically substantially pure forms, and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared, for example, using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0060] "Stereoisomers" may also include E and Z isomers or mixtures thereof, as well as cis and trans isomers or mixtures thereof. In certain embodiments, the compounds described herein are isolated as E or Z isomers. In other embodiments, the compounds described herein are mixtures of E and Z isomers.

[0061] "Tautomers" refer to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment in which the compound is located and can differ depending on, for example, whether the compound is a solid or in an organic or aqueous solution. For example, in aqueous solution, pyrazole can exhibit the following isomeric forms, which are referred to as tautomers of each other:

[0062]

[0063] As used herein, and unless otherwise indicated, the term "pharmaceutically acceptable salt" includes both acid addition salts and base addition salts.

[0064] Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, hexanoic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptanoic acid, gluconic acid, thiaminic ... Gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc.

[0065] Examples of pharmaceutically acceptable base addition salts include, but are not limited to, salts prepared by addition of inorganic or organic bases to free acid compounds. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. In one embodiment, the inorganic salt is an ammonium, sodium, potassium, calcium, and magnesium salt. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amine salts, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. In one embodiment, the organic base is isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0066] As used herein, and unless otherwise indicated, the term "subject" refers to an animal, including but not limited to primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms "subject" and "patient" are used interchangeably herein with respect to, for example, mammalian subjects (such as human subjects). In one embodiment, the subject is a mammal. In one embodiment, the subject is a human.

[0067] As used herein, and unless otherwise indicated, the terms "treat," "treating," and "treatment" refer to eradicating or ameliorating a disease or condition, or one or more symptoms associated with a disease or condition. Typically, treatment occurs after the onset of the disease or condition. In certain embodiments, the term refers to minimizing the spread or worsening of a disease or condition caused by administering one or more prophylactic or therapeutic agents to a subject suffering from such disease or condition.

[0068] As used herein, and unless otherwise indicated, the terms "prevent," "preventing," and "prevention" refer to preventing the onset, recurrence, or spread of a disease or condition, or one or more symptoms thereof. Typically, prevention occurs before the onset of a disease or condition.

[0069] As used herein, and unless otherwise indicated, the terms "manage," "managing," and "management" refer to preventing or slowing the progression, spread, or worsening of a disease or condition, or one or more symptoms thereof. Sometimes, the beneficial effects that a subject obtains from a prophylactic or therapeutic agent do not result in a cure of the disease or condition.

[0070] As used herein, and unless otherwise indicated, the term "therapeutically effective amount" is intended to include an amount of a compound that, when administered, is sufficient to prevent the development of, or alleviate to some extent, one or more symptoms of, the disorder, disease, or condition being treated. The term "therapeutically effective amount" also refers to an amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or clinician.

[0071] As used herein, and unless otherwise indicated, the term "IC 50 ” refers to the amount, concentration or dose of a compound required to inhibit 50% of a maximal response in an assay measuring such response.

[0072] As used herein, and unless otherwise indicated, the terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refer to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for use in contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th ed., Rowe et al., eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd ed., Ash and Ash, eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson, ed., CRC Press LLC: Boca Raton, FL, 2004.

[0073] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. Examples of isotopes that can be incorporated into the compounds provided herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, for example, 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 For example, provided herein are compounds having the structures of the present invention except that hydrogen is replaced or enriched with deuterium or tritium at one or more atoms in the molecule, or carbon is replaced or enriched with 13C or 14 In one embodiment, provided herein are isotopically labeled compounds having one or more hydrogen atoms substituted or enriched with deuterium. In one embodiment, provided herein are isotopically labeled compounds having one or more hydrogen atoms substituted or enriched with tritium. In one embodiment, provided herein are isotopically labeled compounds having one or more hydrogen atoms substituted or enriched with tritium. 13 In one embodiment, provided herein are compounds having one or more carbon atoms replaced or enriched with C. 14 C-substituted or enriched carbon atom isotope-labeled compounds.

[0074] As used herein, and unless otherwise indicated, the term "about" or "approximately" means the acceptable error for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0075] Compound

[0076] In one embodiment, provided herein are fused polycyclic compounds with polycyclic linkers as PARP1 inhibitors. In one embodiment, provided herein are bicyclic or tricyclic compounds with octahydropyrrolo[3,4-c]pyrrole (in a specific embodiment, a specific stereoisomer of octahydropyrrolo[3,4-c]pyrrole) linkers as PARP1 inhibitors.

[0077] In one embodiment, provided herein is a compound of formula (I):

[0078]

[0079] or a stereoisomer thereof, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:

[0080] Is a single bond or a double bond;

[0081] X 1 It's CR a1 、C(R a1 )2 or NR a1 ;

[0082] X 2 It's CR a2 、C(R a2 )2、N、NRa2 or O;

[0083] Each R a1 are independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or C1-C6 alkoxy;

[0084] Each R a2 are independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or C1-C6 alkoxy;

[0085] or R a1 and R a2 Together with the atoms to which they are attached, they form a 3- to 6-membered ring B;

[0086] X 3 It's CR a3 or N; R a3 is hydrogen, C1-C6 alkyl or halogen;

[0087] X 4 It's CR a4 or N; R a4 is hydrogen, C1-C6 alkyl or halogen;

[0088] R a5 is hydrogen, C1-C6 alkyl or halogen;

[0089] Ring A is a fused, bridged or spiro heterocyclic group;

[0090] Y 1 It's CR 2 or N;

[0091] Y 2 It's CR 2 or N;

[0092] Each R 2 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C8 cycloalkyl;

[0093] R is halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)-R 3 、-C(=O)-OR 3 、-C(=O)-NHR 3 、-S(O)2-R 3 、-NH-C(=O)-R 3 or nitro;

[0094] R 3 is hydrogen, C1-C6 alkyl, (C1-C6 alkoxy)-(C1-C6 alkyl), C3-C8 cycloalkyl, or a 4- to 10-membered heterocyclyl; and

[0095] wherein the alkyl, cycloalkyl, alkoxy, heterocyclyl, Ring A and Ring B are optionally substituted;

[0096] The condition is that when yes When (i) Ring A is a fused or spiro heterocyclic group; or (ii) R is -C(=O)-NHR 3 .

[0097] In one embodiment, provided herein is a compound of formula (I):

[0098]

[0099] or a stereoisomer thereof, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:

[0100] Is a single bond or a double bond;

[0101] X 1 It's CR a1 、C(R a1 )2 or NR a1 ;

[0102] X 2 It's CR a2 、C(R a2 )2、N、NR a2 or O;

[0103] Each R a1 are independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or C1-C6 alkoxy;

[0104] Each R a2 are independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or C1-C6 alkoxy;

[0105] or R a1 and R a2 Together with the atoms to which they are attached, they form a 3- to 6-membered ring B;

[0106] X 3 It's CR a3 or N; R a3 is hydrogen, C1-C6 alkyl or halogen;

[0107] X 4 It's CR a4 or N; R a4 is hydrogen, C1-C6 alkyl or halogen;

[0108] R a5 is hydrogen, C1-C6 alkyl or halogen;

[0109] Ring A is a fused, bridged or spiro heterocyclic group;

[0110] Y 1 It's CR 2 or N;

[0111] Y 2 It's CR 2 or N;

[0112] Each R 2 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C8 cycloalkyl;

[0113] R is halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)-R 3 、-C(=O)-OR 3 、-C(=O)-NHR 3 、-S(O)2-R 3 、-NH-C(=O)-R 3 or nitro;

[0114] R 3 is hydrogen, C1-C6 alkyl, (C1-C6 alkoxy)-(C1-C6 alkyl) or C3-C8 cycloalkyl; and

[0115] wherein alkyl, cycloalkyl, alkoxy, Ring A and Ring B are optionally substituted;

[0116] The condition is that when yes When (i) Ring A is a fused or spiro heterocyclic group; or (ii) R is -C(=O)-NHR 3 .

[0117] In one embodiment, X 1 It's CR a1 In one embodiment, X 1 In one embodiment, X 1 In one embodiment, X 1 In one embodiment, X 1 is C-(n-propyl) or C-(isopropyl). In one embodiment, X 1 is C-(n-butyl), C-(isobutyl) or C-(tert-butyl). In one embodiment, X 1 In one embodiment, X 1 In one embodiment, X 1In one embodiment, X 1 In one embodiment, X 1 In one embodiment, X 1 In one embodiment, X 1 In one embodiment, X 1 In one embodiment, X 1 In one embodiment, X 1 In one embodiment, X 1 In one embodiment, X 1 In one embodiment, X 1 In one embodiment, X 1 It is C-(C6 alkoxy).

[0118] In one embodiment, X 1 It is C(R a1 ) 2. In one embodiment, X 1 Is C-(C1-C6 alkyl)2. In one embodiment, X 1 Is C-(C3-C8 cycloalkyl)2. In one embodiment, X 1 It is C-(C1-C6 alkoxy)2.

[0119] In one embodiment, X 1 It is NR a1 In one embodiment, X 1 In one embodiment, X 1 In one embodiment, X 1 It is N-(C1-C6 alkoxy).

[0120] In one embodiment, X 1 In one embodiment, X 1 In one embodiment, X 1 In one embodiment, X 1 In one embodiment, X 1 In one embodiment, X 1 In one embodiment, X 1 It is CH-C2H5.

[0121] In one embodiment, X2 It's CR a2 In one embodiment, X 2 In one embodiment, X 2 In one embodiment, X 2 In one embodiment, X 2 is C-(n-propyl) or C-(isopropyl). In one embodiment, X 2 is C-(n-butyl), C-(isobutyl) or C-(tert-butyl). In one embodiment, X 2 In one embodiment, X 2 In one embodiment, X 2 In one embodiment, X 2 In one embodiment, X 2 In one embodiment, X 2 In one embodiment, X 2 In one embodiment, X 2 In one embodiment, X 2 In one embodiment, X 2 In one embodiment, X 2 In one embodiment, X 2 In one embodiment, X 2 In one embodiment, X 2 It is C-(C6 alkoxy).

[0122] In one embodiment, X 2 It is C(R a2 ) 2. In one embodiment, X 2 Is C-(C1-C6 alkyl)2. In one embodiment, X 2 Is C-(C3-C8 cycloalkyl)2. In one embodiment, X 2 It is C-(C1-C6 alkoxy)2.

[0123] In one embodiment, X 2 It is NR a2 In one embodiment, X 2 In one embodiment, X 2In one embodiment, X 2 It is N-(C1-C6 alkoxy).

[0124] In one embodiment, X 2 In one embodiment, X 2 Is N. In one embodiment, X 2 It's O.

[0125] In one embodiment, X 1 It's CR a1 And X 2 In one embodiment, X 1 It's CR a1 And X 2 Is N. In one embodiment, X 1 It is CHR a1 And X 2 It's O.

[0126] In one embodiment, X 1 is C-CH3 and X 2 In one embodiment, X 1 is C-C2H5 and X 2 In one embodiment, X 1 is C-CH3 and X 2 Is N. In one embodiment, X 1 is C-C2H5 and X 2 Is N. In one embodiment, X 1 is CH-CH3 and X 2 Is O. In one embodiment, X 1 is CH-C2H5 and X 2 It's O.

[0127] In one embodiment, Y 1 It's CR 2 In one embodiment, Y 1 In one embodiment, Y 1 In one embodiment, Y 1 In one embodiment, Y 1 In one embodiment, Y 1 In one embodiment, Y 1 It's N.

[0128] In one embodiment, Y 2 It's CR 2In one embodiment, Y 2 In one embodiment, Y 2 In one embodiment, Y 2 In one embodiment, Y 2 In one embodiment, Y 2 In one embodiment, Y 2 It's N.

[0129] In one embodiment, Y 1 It's CR 2 And Y 2 is N. In one embodiment, Y 1 is N and Y 2 It's CR 2 In one embodiment, Y 1 It's CR 2 And Y 2 It's CR 2 In one embodiment, Y 1 is N and Y 2 It's N.

[0130] In one embodiment, Y 1 is CH and Y 2 is N. In one embodiment, Y 1 is CF and Y 2 is N. In one embodiment, Y 1 is N and Y 2 In one embodiment, Y 1 is N and Y 2 It's CF.

[0131] In one embodiment, R is halogen. In one embodiment, R is C1-C6 alkyl. In one embodiment, R is C1-C6 alkoxy. In one embodiment, R is -C(=O)-R 3 In one embodiment, R is -C(=O)-OR 3 In one embodiment, R is -S(O)2-R 3 In one embodiment, R is -NH-C(=O)-R 3 In one embodiment, R is nitro. In one embodiment, R is -CN. In one embodiment, R is -C(=O)-NHR 3 In one embodiment, R is -C(=O)-NHR 3 , and R 3 It is a C3-C8 cycloalkyl group or a 4- to 10-membered heterocyclic group.

[0132] In one embodiment, R is -C(=O)-NH-(C1-C6 alkyl). In one embodiment, R is -C(=O)-NH-(C3-C8 cycloalkyl). In one embodiment, R is -C(=O)-NH-(C3-C6 cycloalkyl). In one embodiment, R is -C(=O)-NH-(4- to 10-membered heterocyclyl). In one embodiment, R is -C(=O)-NH-(4- to 6-membered heterocyclyl). In one embodiment, R is -C(=O)-NH-(4- to 6-membered oxygen-containing heterocyclyl). In one embodiment, R is -C(=O)-(C1-C6 alkyl). In one embodiment, R is -C(=O)-(C3-C8 cycloalkyl). In one embodiment, R is -C(=O)-O-(C1-C6 alkyl). In one embodiment, R is -C(=O)-O-(C3-C8 cycloalkyl). In one embodiment, R is -NH-C(=O)-(C1-C6 alkyl). In one embodiment, R is -NH-C(=O)-(C3-C8 cycloalkyl). In one embodiment, R is -NH-C(=O)-(4- to 10-membered heterocyclyl). In one embodiment, R is -NH-C(=O)-(4- to 6-membered heterocyclyl). In one embodiment, R is -S(O)2-(C1-C6 alkyl). In one embodiment, R is -S(O)2-(C3-C8 cycloalkyl). In one embodiment, R is C(=O)-NH2. In one embodiment, R is C(=O)-NH-CH3. In one embodiment, R is C(=O)-NH-CH2CH2OCH3. In one embodiment, R is C(=O)-NH-cyclopropyl. In one embodiment, R is C(=O)-NH-cyclobutyl.

[0133] In one embodiment, R is selected from the group consisting of:

[0134]

[0135] In one embodiment, provided herein is a compound of formula (IA):

[0136]

[0137] or a stereoisomer thereof, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0138] In one embodiment, It's a double bond.

[0139] In one embodiment, is a double bond and X 1 It's CRa1 In one embodiment, is a double bond and X 1 is CH. In one embodiment, is a double bond and X 1 In one embodiment, is a double bond and X 1 In one embodiment, is a double bond and X 1 It is C-OCH3.

[0140] In one embodiment, is a double bond and X 2 It's CR a2 In one embodiment, is a double bond and X 2 is CH. In one embodiment, is a double bond and X 2 In one embodiment, is a double bond and X 2 In one embodiment, is a double bond and X 2 It's N.

[0141] In one embodiment, is a double bond, X 1 It's CR a1 And X 2 Is N. In one embodiment, is a double bond, X 1 It's CR a1 And X 2 It's CR a2 In one embodiment, is a double bond, X 1 is N and X 2 It's CR a2 .

[0142] In one embodiment, is a double bond, X 1 is C-CH3 and X 2 is CH. In one embodiment, is a double bond, X 1 is C-C2H5 and X 2 is CH. In one embodiment, is a double bond, X 1 is C-CH3 and X 2Is N. In one embodiment, is a double bond, X 1 is C-OCH3 and X 2 It is CH.

[0143] In one embodiment, It is a single bond.

[0144] In one embodiment, is a single bond and X 1 It is C(R a1 ) 2. In one embodiment, is a single bond and X 1 It is CHR a1 In one embodiment, is a single bond and X 1 In one embodiment, is a single bond and X 1 It is CH-CH2CH3.

[0145] In one embodiment, is a single bond and X 1 It is NR a1 .

[0146] In one embodiment, is a single bond and X 2 Is O. In one embodiment, is a single bond and X 2 It is NR a2 .

[0147] In one embodiment, is a single bond, X 1 It is CH(R a1 ) and X 2 Is O. In one embodiment, is a single bond, X 1 It is CH(R a1 ) and X 2 It is NR a2 In one embodiment, is a single bond, X 1 It is N(R a1 ) and X 2 It's CR a2 .

[0148] In one embodiment, is a single bond, X 1 is CH-C2H3 and X 2 Is O. In one embodiment, is a single bond, X 1is CH-CH3 and X 2 It's O.

[0149] In one embodiment, is a single bond, X 1 、X 2 With R a1 and R a2 Together they form a 3- to 6-membered ring B. In one embodiment, is a single bond, X 1 、X 2 With R a1 and R a2 Together they form a 3- to 6-membered heteroaryl group. is a single bond, X 1 、X 2 With R a1 and R a2 Together they form a 3- to 6-membered heterocyclic group. In one embodiment, is a single bond, X 1 、X 2 With R a1 and R a2 Together they form a 5-membered heteroaryl. In one embodiment, is a single bond, X 1 、X 2 With R a1 and R a2 Together they form a 5-membered heterocyclic group.

[0150] In one embodiment, R a1 In one embodiment, R a1 In one embodiment, R a1 is a C3-C8 cycloalkyl group. a1 It is a C1-C6 alkoxy group.

[0151] In one embodiment, R a1 is C1-C4 alkyl. In one embodiment, R a1 is C1-C4 fluoroalkyl. In one embodiment, R a1 is methyl, ethyl, isopropyl, cyclopropyl, 1,1-difluoroethyl, 1-fluoroethyl, trifluoromethyl, difluoromethyl or methoxy. a1 In one embodiment, R a1 In one embodiment, R a1 In one embodiment, R a1 It's a methoxy group.

[0152] In one embodiment, R a2In one embodiment, R a2 In one embodiment, R a2 is a C3-C8 cycloalkyl group. a2 In one embodiment, R a2 In one embodiment, R a2 In one embodiment, R a1 is methyl and R a2 In one embodiment, R a1 is ethyl and R a2 It's hydrogen.

[0153] In one embodiment, R a1 and R a2 Together with the atoms to which they are attached, they form a 3- to 6-membered ring B.

[0154] In one embodiment, the compound is of Formula (IB), (IC) or (ID):

[0155]

[0156] or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof.

[0157] In one embodiment, the compound is of formula (IB-1), (IC-1), or (ID-1):

[0158]

[0159] or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof,

[0160] in:

[0161] m is 0, 1, 2, 3, or 4;

[0162] n is 1, 2, 3, or 4;

[0163] Z is O or C(R 4 )2; and

[0164] Each R 4 are independently hydrogen, C1-C6 alkyl or C1-C6 alkoxy.

[0165] In one embodiment, Ring B is phenyl. In one embodiment, Ring B is a 5- to 6-membered heteroaryl. In one embodiment, Ring B is a 3- to 6-membered cycloalkyl. In one embodiment, Ring B is a 3- to 6-membered heterocyclyl. In one embodiment, Ring B is a 4- to 6-membered heterocyclyl. In one embodiment, Ring B is a 4- to 5-membered heterocyclyl. In one embodiment, Ring B is a 4- to 6-membered oxygen-containing heterocyclyl.

[0166] In one embodiment, Ring B is a 3-membered heterocyclyl. In one embodiment, Ring B is a 4-membered heterocyclyl. In one embodiment, Ring B is a 5-membered heterocyclyl. In one embodiment, Ring B is a 6-membered heterocyclyl. In one embodiment, Ring B is a 4- to 5-membered heterocyclyl containing at least one ring nitrogen atom. In one embodiment, Ring B contains at least one ring oxygen atom. In one embodiment, Ring B contains only one ring oxygen atom. In one embodiment, Ring B is a 5-membered heterocyclyl containing one ring oxygen atom. In one embodiment, Ring B is a 6-membered heterocyclyl containing one ring oxygen atom.

[0167] In one embodiment, Ring B is a 5-membered heteroaryl. In one embodiment, Ring B is a 5-membered heteroaryl containing at least one ring nitrogen atom. In one embodiment, Ring B is a 5-membered heteroaryl containing at least one ring oxygen atom.

[0168] In one embodiment, Ring B is a 4- to 6-membered cycloalkyl. In one embodiment, Ring B is a 4- to 5-membered cycloalkyl. In one embodiment, Ring B is a 4-membered cycloalkyl. In one embodiment, Ring B is a 5-membered cycloalkyl. In one embodiment, Ring B is a 6-membered cycloalkyl.

[0169] In one embodiment, Ring B is a 4- to 6-membered cycloalkenyl. In one embodiment, Ring B is a 4- or 5-membered cycloalkenyl. In one embodiment, Ring B is a 4-membered cycloalkenyl. In one embodiment, Ring B is a 5-membered cycloalkenyl. In one embodiment, Ring B is a 6-membered cycloalkenyl.

[0170] In one embodiment, ring B is a pyrrole ring. In one embodiment, ring B is a pyrrolidine ring. In one embodiment, ring B is an imidazole ring. In one embodiment, ring B is a cyclopentane ring. In one embodiment, ring B is a cyclopentene ring. In one embodiment, ring B is a cyclohexane ring. In one embodiment, ring B is a cyclohexene ring. In one embodiment, ring B is a tetrahydrofuran ring. In one embodiment, ring B is a dihydrofuran ring. In one embodiment, ring B is a tetrahydropyran ring. In one embodiment, ring B is a dihydropyran ring.

[0171] In one embodiment, Ring B is substituted. In one embodiment, Ring B is substituted with one or more halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, or nitro. In one embodiment, Ring B is substituted with fluorine. In one embodiment, Ring B is substituted with chlorine. In one embodiment, Ring B is substituted with bromine. In one embodiment, Ring B is substituted with cyano. In one embodiment, Ring B is substituted with nitro. In one embodiment, Ring B is substituted with methyl. In one embodiment, Ring B is substituted with ethyl. In one embodiment, Ring B is substituted with methoxy. In one embodiment, Ring B is substituted with ethoxy.

[0172] In one embodiment, Ring B is unsubstituted.

[0173] In one embodiment, X 3 It's CR a3 In one embodiment, X 3 In one embodiment, X 3 In one embodiment, X 3 In one embodiment, X 3 It's N.

[0174] In one embodiment, X 4 It's CR a4 In one embodiment, X 4 In one embodiment, X 4 In one embodiment, X 4 In one embodiment, X 4 It's N.

[0175] In one embodiment, X 3 is N and X 4 It's CR a4 In one embodiment, X 3 It's CR a3 And X 4 It's CR a4 In one embodiment, X 3 It's CR a3 And X 4 It's N.

[0176] In one embodiment, X 1 It's CR a1 , X 2 It's CR a2 And X 3 Is N. In one embodiment, X 1 It's CR a1 , X2 is N and X 3 It's CR a3 In one embodiment, X 1 It is CHR a1 , X 2 It is O and X 3 It's CR a3 In one embodiment, X 1 It is CHR a1 , X 2 is N and X 3 It's CR a3 In one embodiment, X 1 It's CR a1 , X 2 It's CR a2 And X 3 It's CR a3 In one embodiment, X 1 It is NR a1 , X 2 It's CR a2 And X 3 Is N. In one embodiment, X 1 It is NR a1 , X 2 It's CR a2 And X 3 It's CR a3 .

[0177] In one embodiment, X 1 It's CR a1 , X 2 It's CR a2 And X 4 Is N. In one embodiment, X 1 It's CR a1 , X 2 is N and X 4 It's CR a4 In one embodiment, X 1 It is CHR a1 , X 2 It is O and X 4 It's CR a4 In one embodiment, X 1 It is CHR a1 , X 2 is N and X 4 It's CR a4 In one embodiment, X 1 It's CR a1 , X 2 It's CR a2 And X 4 It's CRa4 In one embodiment, X 1 It is NR a1 , X 2 It's CR a2 And X 4 Is N. In one embodiment, X 1 It is NR a1 , X 2 It's CR a2 And X 4 It's CR a4 .

[0178] In one embodiment, X 1 It's CR a1 , X 2 It's CR a2 , X 3 is N and X 4 It's CR a4 In one embodiment, X 1 It's CR a1 , X 2 It is N, X 3 It's CR a3 And X 4 It's CR a4 In one embodiment, X 1 It's CR a1 , X 2 It is N, X 3 is N and X 4 It's CR a4 In one embodiment, X 1 It is CHR a1 , X 2 It's O, X 3 is N and X 4 It's CR a4 In one embodiment, X 1 It is CHR a1 , X 2 It's O, X 3 It's CR a3 And X 4 It's CR a4 In one embodiment, X 1 It is CHR a1 、X 2 It is N, X 3 It's CR a3 And X 4 Is N. In one embodiment, X 1 It's CR a1 , X 2 It's CR a2 , X 3 It's CRa3 And X 4 Is N. In one embodiment, X 1 It is NR a1 , X 2 It's CR a2 , X 3 is N and X 4 It's CR a4 In one embodiment, X 1 It is NR a1 , X 2 It's CR a2 , X 3 It's CR a3 And X 4 It's CR a4 .

[0179] In one embodiment, the compound is formula (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), (II-J), (II-K), (II-L), (II-M), (II-N), (II-O), (II-P), (II-Q), (II-R), Compounds of (II-S), (II-T), (II-U), (II-V), (II-W), (II-X), (II-Y), (II-Z), (II-AA), (II-AB), (II-AC), (II-AD), (II-AE), (II-AF), (II-AG), (II-AH), (II-AI) or (II-AJ):

[0180]

[0181]

[0182]

[0183]

[0184] or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof.

[0185] In one embodiment, the compound is of formula (II-V-1), (II-AA-1), (II-AB-1), or (II-AI-1):

[0186]

[0187] or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof,

[0188] in:

[0189] m is 0, 1, 2, 3, or 4;

[0190] n is 1, 2, 3, or 4;

[0191] Z is O or C(R 4 )2; and

[0192] Each R 4 are independently hydrogen, C1-C6 alkyl or C1-C6 alkoxy.

[0193] In one embodiment of Formula (II-D) (or subformulae thereof), Ring A is Where * is toward the connecting ring A and contains X 4 In one embodiment of Formula (II-D) (or its subformula), Ring A is Where * is toward the connecting ring A and contains X 4 The orientation of the methylene groups of the ring.

[0194] In one embodiment, X 1 It's CR a1 , X 2 It's CR a2 And Y 1 It's CR 2 In one embodiment, X 1 It's CR a1 , X 2 is N and Y 1 It's CR 2 In one embodiment, X 1 It is CHR a1 , X 2 is O and Y 1 It's CR 2 In one embodiment, X 1 It is CHR a1 , X 2 is N and Y 1 It's CR 2 In one embodiment, X 1 It's CR a1 , X 2 It's CR a2 And Y 1 It's CR 2 In one embodiment, X 1 It is NR a1 , X 2 It's CR a2 And Y 1 It's CR 2 In one embodiment, X 1It is NR a1 , X 2 It's CR a2 And Y 1 It's CR 2 .

[0195] In one embodiment, X 1 It's CR a1 , X 2 It's CR a2 , Y 1 It's CR 2 And Y 2 Is N. In one embodiment, X 1 It's CR a1 , X 2 It's N, Y 1 It's CR 2 And Y 2 Is N. In one embodiment, X 1 It is CHR a1 , X 2 It's O, Y 1 It's CR 2 And Y 2 Is N. In one embodiment, X 1 It is CHR a1 , X 2 It's N, Y 1 It's CR 2 And Y 2 Is N. In one embodiment, X 1 It's CR a1 , X 2 It's CR a2 , Y 1 It's CR 2 And Y 2 Is N. In one embodiment, X 1 It is NR a1 , X 2 It's CR a2 , Y 1 It's CR 2 And Y 2 Is N. In one embodiment, X 1 It is NR a1 , X 2 It's CR a2 , Y 1 It's CR 2 And Y 2 It's N.

[0196] In one embodiment, X 1 It's CR a1 , X 2 It's CR a2, X 4 It's N, Y 1 It's CR 2 And Y 2 Is N. In one embodiment, X 1 It's CR a1 , X 2 It is N, X 4 It's CR a4 , Y 1 It's CR 2 And Y 2 Is N. In one embodiment, X 1 It is CHR a1 , X 2 It's O, X 4 It's CR a4 , Y 1 It's CR 2 And Y 2 Is N. In one embodiment, X 1 It is CHR a1 , X 2 It is N, X 4 It's CR a4 , Y 1 It's CR 2 And Y 2 Is N. In one embodiment, X 1 It's CR a1 , X 2 It's CR a2 , X 4 It's CR a4 , Y 1 It's CR 2 And Y 2 Is N. In one embodiment, X 1 It is NR a1 , X 2 It's CR a2 , X 4 It's N, Y 1 It's CR 2 And Y 2 Is N. In one embodiment, X 1 It is NR a1 , X 2 It's CR a2 , X 4 It's CR a4 And Y 1 It's CR 2 And Y 2 It's N.

[0197] In one embodiment, X 1 It's CR a1 , X 2It's CR a2 , X 3 It is N, X 4 It's CR a4 , Y 1 It's CR 2 And Y 2 Is N. In one embodiment, X 1 It's CR a1 , X 2 It is N, X 3 It's CR a3 , X 4 It's CR a4 , Y 1 It's CR 2 And Y 2 Is N. In one embodiment, X 1 It's CR a1 , X 2 It is N, X 3 It is N, X 4 It's CR a4 , Y 1 It's CR 2 And Y 2 Is N. In one embodiment, X 1 It is CHR a1 , X 2 It's O, X 3 It is N, X 4 It's CR a4 , Y 1 It's CR 2 And Y 2 Is N. In one embodiment, X 1 It is CHR a1 , X 2 It's O, X 3 It's CR a3 , X 4 It's CR a4 , Y 1 It's CR 2 And Y 2 Is N. In one embodiment, X 1 It is CHR a1 , X 2 It is N, X 3 It's CR a3 , X 4 It's N, Y 1 It's CR 2 And Y 2 Is N. In one embodiment, X 1 It's CR a1 , X 2 It's CR a2 , X 3It's CR a3 , X 4 It's N, Y 1 It's CR 2 And Y 2 Is N. In one embodiment, X 1 It is NR a1 , X 2 It's CR a2 , X 3 It is N, X 4 It's CR a4 , Y 1 It's CR 2 And Y 2 Is N. In one embodiment, X 1 It is NR a1 , X 2 It's CR a2 , X 3 It's CR a3 , X 4 It's CR a4 , Y 1 It's CR 2 And Y 2 It's N.

[0198] In one embodiment, R a5 In one embodiment, R a5 In one embodiment, R a5 In one embodiment, R a5 In one embodiment, R a5 In one embodiment, R a5 In one embodiment, R a5 In one embodiment, R a5 In one embodiment, R a5 In one embodiment, R a5 In one embodiment, R a5 In one embodiment, R a5 It's hydrogen.

[0199] In one embodiment, Ring A is a fused heterocyclyl. In one embodiment, Ring A is a 6- to 12-membered fused heterocyclyl. In one embodiment, Ring A is a 6-membered fused heterocyclyl. In one embodiment, Ring A is a 7-membered fused heterocyclyl. In one embodiment, Ring A is an 8-membered fused heterocyclyl. In one embodiment, Ring A is a 9-membered fused heterocyclyl. In one embodiment, Ring A is a 10-membered fused heterocyclyl. In one embodiment, Ring A is an 11-membered fused heterocyclyl. In one embodiment, Ring A is a 12-membered fused heterocyclyl. In one embodiment, Ring A is a fused bicyclic heterocyclyl.

[0200] In one embodiment, Ring A is a bridged heterocyclyl. In one embodiment, Ring A is a 6- to 12-membered bridged heterocyclyl. In one embodiment, Ring A is a 6-membered bridged heterocyclyl. In one embodiment, Ring A is a 7-membered bridged heterocyclyl. In one embodiment, Ring A is an 8-membered bridged heterocyclyl. In one embodiment, Ring A is a 9-membered bridged heterocyclyl. In one embodiment, Ring A is a 10-membered bridged heterocyclyl. In one embodiment, Ring A is an 11-membered bridged heterocyclyl. In one embodiment, Ring A is a 12-membered bridged heterocyclyl. In one embodiment, Ring A is a bridged bicyclic heterocyclyl.

[0201] In one embodiment, Ring A is a spiroheterocyclyl. In one embodiment, Ring A is a 6- to 12-membered spiroheterocyclyl. In one embodiment, Ring A is a 6-membered spiroheterocyclyl. In one embodiment, Ring A is a 7-membered spiroheterocyclyl. In one embodiment, Ring A is an 8-membered spiroheterocyclyl. In one embodiment, Ring A is a 9-membered spiroheterocyclyl. In one embodiment, Ring A is a 10-membered spiroheterocyclyl. In one embodiment, Ring A is an 11-membered spiroheterocyclyl. In one embodiment, Ring A is a 12-membered spiroheterocyclyl. In one embodiment, Ring A is a spirobicyclic heterocyclyl.

[0202] In one embodiment, Ring A contains at least two heteroatoms. In one embodiment, Ring A contains at least two heteroatoms that are both nitrogen. In one embodiment, Ring A contains only two heteroatoms that are both nitrogen.

[0203] In one embodiment, Ring A is or Where * is toward the connecting ring A and contains X 4 The orientation of the methylene groups of the ring.

[0204] In one embodiment, Ring A is In one embodiment, Ring A is In one embodiment, Ring A is In one embodiment, Ring A is In one embodiment, Ring A is In one embodiment, Ring A is In one embodiment, Ring A is

[0205] In one embodiment, Ring A is octahydropyrrolo[3,4-c]pyrrole. In one embodiment, Ring A is 2,6-diazaspiro[3.3]heptane. In one embodiment, Ring A is 2,5-diazabicyclo[4.1.0]heptane. In one embodiment, Ring A is 2,5-diazabicyclo[2.2.1]heptane. In one embodiment, Ring A is 4,7-diazaspiro[2.5]octane.

[0206] In one embodiment, Ring A is (3ar,6ar)-octahydropyrrolo[3,4-c]pyrrole. In one embodiment, Ring A is (3as,6as)-octahydropyrrolo[3,4-c]pyrrole.

[0207] In one embodiment, X 2 is N, ring A is In one embodiment, X 3 is N and ring A is In one embodiment, X 4 is N and ring A is In one embodiment, X 2 It is N, X 3 is N and ring A is In one embodiment, X 2 It is N, X 4 is N and ring A is In one embodiment, X 2 It's O, X 3 is N and ring A is In one embodiment, X 2 It's O, X 4 is N and ring A is In one embodiment, X 2 is O and ring A is In one embodiment, X 2 It is N, X 3 is N and ring A is In one embodiment, Ring A is and ring B is a heteroaryl group, wherein * is directed toward the group connecting ring A and containing X 4 The orientation of the methylene groups of the ring.

[0208] In one embodiment, Ring A is substituted. In one embodiment, Ring A is substituted with one or more groups selected from the group consisting of halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, and nitro.

[0209] In one embodiment, Ring A is unsubstituted.

[0210] In one embodiment, the compound is of Formula (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (III-I), (III-J), (III-K), (III-L), (III-M), (III-N), (III-O), (III-P), (III-Q), (III-R), (III-S), (III-T), (III-U), (III-V), (III-W), (III-X), (III-Y), (III-Z), (III-AA), (III-AB), (III-AC), (III-AD), (III-AE), (III-AF), (III-AG), (III-AH), (III-AI), or (III-AJ):

[0211]

[0212]

[0213]

[0214]

[0215] or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof.

[0216] In one embodiment of Formula (III-D) (or subformulae thereof), Ring A is Where * is toward the connecting ring A and contains X 4 In one embodiment of Formula (III-D) (or its subformula), Ring A is Where * is toward the connecting ring A and contains X 4 The orientation of the methylene groups of the ring.

[0217] In one embodiment, Ring A is cis

[0218] In one embodiment, Ring A is trans In one embodiment, Ring A is In one embodiment, Ring A is In one embodiment, without being bound by a particular theory, the trans (or stereoisomers, such as ) as ring A, with a cis The compounds exhibit better potency and / or efficacy than the corresponding compounds as Ring A. In one embodiment, without being bound by a particular theory, one of the stereoisomers exhibits better potency and / or efficacy than the other stereoisomer.

[0219] In one embodiment, Ring A is cis In one embodiment, Ring A is trans In one embodiment, Ring A is In one embodiment, Ring A is In one embodiment, Ring A is In one embodiment, Ring A is

[0220] In one embodiment, X 3 is and Ring A is In one embodiment, X 3 is N and ring A is In one embodiment, X 3 is N and ring A is In one embodiment, X 1 It's CR a1 , X 2 It's CR a2 , X 3 It is N, X 4 It's CR a4 and ring A is In one embodiment, X 1 It's CR a1 , X 2 It's CR a2 , X 3 It is N, X 4 It's CR a4 and ring A is In one embodiment, X 1 It's CR a1 , X 2 It's CR a2 , X 3 It is N, X 4 It's CR a4 and ring A is

[0221] In one embodiment, X 2 is N, ring A is In one embodiment, X 3 is N and ring A is In one embodiment, X 4 is N and ring A is In one embodiment, X 2 It is N, X 3 is N and ring A is In one embodiment, X 2 It is N, X 4 is N and ring A is In one embodiment, X 2 It's O, X 3 is N and ring A is In one embodiment, X 2 It's O, X 4 is N and ring A is In one embodiment, X 2 is O and ring A is In one embodiment, X 2 It is N, X 3 is N and ring A is In one embodiment, Ring A is and Ring B is heteroaryl.

[0222] In one embodiment, the compound is of Formula (IV-A1), (IV-B1), (IV-C1), (IV-D1), (IV-E1), (IV-F1), (IV-G1), (IV-H1), (IV-I1), (IV-J1), (IV-K1), (IV-L1), (IV-M1), (IV-N1), (IV-O1), (IV-P1), (IV-Q1), (IV-R1), (IV-S1), (IV-T1), (IV-U1), (IV-V1), (IV-W1), (IV-X1), (IV-Y1), (IV-Z1), (IV-AA1), (IV-AB1), (IV-AC1), (IV-AD1), (IV-AE1), (IV-AF1), (IV-AG1), (IV-AH1), (IV-AI1), or (IV-AJ1):

[0223]

[0224]

[0225]

[0226]

[0227] or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof.

[0228] In one embodiment, the compound is of formula (IV-V1-1), (IV-AA1-1), (IV-AB1-1), or (IV-AI1-1):

[0229]

[0230] or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:

[0231] m is 0, 1, 2, 3, or 4;

[0232] n is 1, 2, 3, or 4;

[0233] Z is O or C(R 4 )2; and

[0234] Each R 4 are independently hydrogen, C1-C6 alkyl or C1-C6 alkoxy.

[0235] In one embodiment, the compound is of Formula (IV-A2), (IV-B2), (IV-C2), (IV-D2), (IV-E2), (IV-F2), (IV-G2), (IV-H2), (IV-i2), (IV-J2), (IV-K2), (IV-L2), (IV-M2), (IV-N2), (IV-O2), (IV-P2), (IV-Q2), (IV-R2), (IV-S2), (IV-T2), (IV-U2), (IV-V2), (IV-W2), (IV-X2), (IV-Y2), (IV-Z2), (IV-AA2), (IV-AB2), (IV-AC2), (IV-AD2), (IV-AE2), (IV-AF2), (IV-AG2), (IV-AH2), (IV-AI2), or (IV-AJ2):

[0236]

[0237]

[0238]

[0239]

[0240] or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof.

[0241] In one embodiment, the compound is of formula (IV-V2-1), (IV-AA2-1), (IV-AB2-1), or (IV-AI2-1):

[0242]

[0243] or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof,

[0244] in:

[0245] m is 0, 1, 2, 3, or 4;

[0246] n is 1, 2, 3, or 4;

[0247] Z is O or C(R 4 )2; and

[0248] Each R 4 are independently hydrogen, C1-C6 alkyl or C1-C6 alkoxy.

[0249] In one embodiment, R 2 It's hydrogen.

[0250] In one embodiment, R 2 In one embodiment, R 2 In one embodiment, R 2 In one embodiment, R 2 It's bromine.

[0251] In one embodiment, R 2 In one embodiment, R 2 is C1-C4 alkyl. In one embodiment, R 2 is C1-C6 haloalkyl. In one embodiment, R 2 is C1-C4 fluoroalkyl. In one embodiment, R 2 In one embodiment, R 2 In one embodiment, R 2 is propyl or isopropyl. In one embodiment, R 2 In one embodiment, R 2 In one embodiment, R 2 In one embodiment, R 2 In one embodiment, R 2 In one embodiment, R 2 It is trifluoromethyl.

[0252] In one embodiment, R 2 In one embodiment, R 2 In one embodiment, R2 It is ethoxy.

[0253] In one embodiment, R 2 is a C3-C8 cycloalkyl group. 2 is a C3-C6 cycloalkyl group. In one embodiment, R 2 In one embodiment, R 2 In one embodiment, R 2 In one embodiment, R 2 is cyclohexyl. In one embodiment, cycloalkyl is optionally substituted.

[0254] In one embodiment, R 2 is hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl or C3-C6 cycloalkyl. 2 is hydrogen, chlorine, fluorine, methyl, difluoromethyl, trifluoromethyl or cyclopropyl.

[0255] In one embodiment, R 3 It's hydrogen.

[0256] In one embodiment, R 3 In one embodiment, R 3 is C1-C4 alkyl. In one embodiment, R 3 In one embodiment, R 3 In one embodiment, R 3 In one embodiment, R 3 In one embodiment, R 3 In one embodiment, R 3 In one embodiment, R 3 is a C3-C8 cycloalkyl group. 3 is a C3-C6 cycloalkyl group. 3 In one embodiment, R 3 In one embodiment, R 3 In one embodiment, R 3 It is cyclohexyl.

[0257] In one embodiment, R 3 is a 4- to 10-membered heterocyclic group. 3 is a 4- to 8-membered heterocyclic group. 3is a 4- to 6-membered heterocyclic group. 3 In one embodiment, R 3 In one embodiment, R 3 In one embodiment, R 3 is a 4- to 8-membered oxygen-containing heterocyclic group. 3 is a 4- to 6-membered oxygen-containing heterocyclic group. 3 is a 4- to 8-membered nitrogen-containing heterocyclic group. 3 In one embodiment, R 3 In one embodiment, R 3 In one embodiment, R 3 In one embodiment, R 3 In one embodiment, R 3 is (R)-tetrahydrofuran-3-yl. In one embodiment, R 3 is (S)-tetrahydrofuran-3-yl. In one embodiment, R 3 It is tetrahydro-2H-pyran-4-yl.

[0258] In one embodiment, R 3 yes In one embodiment, R 3 yes (For example, In one embodiment, R 3 yes (For example, ), and R 4 is a C1-C3 alkoxy group (e.g., methoxy group).

[0259] In one embodiment, when Ring B does not contain an oxygen ring atom (e.g., when Ring B is a carbocyclic ring, e.g., Formula (II-V-1), Formula (II-AI-1), Formula (IV-V1-1), Formula (IV-AI1-1), Formula (IV-V2-1), Formula (IV-AI2-1)), R 3 yes (For example, ).

[0260] In one embodiment, when Ring B contains an oxygen ring atom (e.g., when Ring B is an oxygen-containing heterocyclic group, e.g., Formula (II-AA-1), Formula (II-AB-1), Formula (IV-AA1-1), Formula (IV-AB1-1), Formula (IV-AA2-1), Formula (IV-AB2-1)), R 3 yes (For example, ), and R 4 is C1-C3 alkoxy (e.g., methoxy). In another embodiment, R 4 is hydrogen or C1-C3 alkyl (but not C1-C3 alkoxy).

[0261] In one embodiment, m + n = 1. In one embodiment, m + n = 2. In one embodiment, m + n = 3. In one embodiment, m + n = 4. In one embodiment, m is 0 and n is 1. In one embodiment, m is 0 and n is 2. In one embodiment, m is 0 and n is 3. In one embodiment, m is 0 and n is 4. In one embodiment, m is 1 and n is 1. In one embodiment, m is 1 and n is 2. In one embodiment, m is 1 and n is 3. In one embodiment, m is 2 and n is 2.

[0262] In one embodiment, Z is O. In one embodiment, Z is C(R 4 )2. In one embodiment, Z is CHR 4 In one embodiment, Z is CH2.

[0263] In one embodiment, R 4 In one embodiment, R 4 In one embodiment, R 4 In one embodiment, R 4 In one embodiment, R 4 In one embodiment, R 4 In one embodiment, R 4 In one embodiment, R 4 In one embodiment, R 4 In one embodiment, R 4 In one embodiment, R 4 In one embodiment, R 4 In one embodiment, R 4 It is ethoxy.

[0264] In one embodiment, R 3 is unsubstituted.

[0265] In one embodiment, R 3 is a C1-C6 alkyl group substituted with an alkoxy group. 3 is a C1-C6 alkyl group substituted with a C1-C6 alkoxy group. 3 is (C1-C6 alkoxy)-(C1-C6 alkyl). In one embodiment, R 3 is (C1-C4 alkoxy)-(C1-C4 alkyl). In one embodiment, R 3 is a C1-C6 alkyl group substituted with a methoxy group. 3 is a C1-C6 alkyl group substituted with ethoxy. 3 In one embodiment, R 3 In one embodiment, R 3 In one embodiment, R 3 In one embodiment, R 3 It is a C1-C6 alkyl group substituted by halogen.

[0266] In one embodiment, R 3 is a C3-C8 cycloalkyl group substituted with an alkoxy group. 3 is a C3-C8 cycloalkyl group substituted with a C1-C6 alkoxy group. 3 is (C1-C6 alkoxy)-(C3-C8 cycloalkyl). In one embodiment, R 3 is (C1-C4 alkoxy)-(C3-C6 cycloalkyl). In one embodiment, R 3 is (C1-C6 alkoxy)-(cyclopropyl). In one embodiment, R 3 is (C1-C6 alkoxy)-(cyclobutyl). In one embodiment, R 3 is a C3-C8 cycloalkyl group substituted with methoxy. 3 is a C3-C8 cycloalkyl group substituted with ethoxy. 3 is a C3-C8 cycloalkyl group substituted with halogen. 3 In one embodiment, R 3 is (1S, 3S)-3-methoxycyclobutyl. In one embodiment, R 3It is (1R,3R)-3-methoxycyclobutyl.

[0267] In one embodiment, R 3 is a 4- to 10-membered heterocyclic group substituted with an alkoxy group. 3 is a 4- to 8-membered heterocyclic group substituted with a C1-C6 alkoxy group. 3 It is (C1-C4 alkoxy)-(4-membered to 6-membered heterocyclic group).

[0268] In one embodiment, when R 3 When having a chiral center, it has the S-configuration. In one embodiment, when R 3 When it has a chiral center, it has the R-configuration.

[0269] In one embodiment, when X 1 When the carbon at position 1 is a chiral center, it has the S-configuration. 1 When the carbon at position 1 is a chiral center, it has the R-configuration.

[0270] In one embodiment, the compounds provided herein are single enantiomers. In one embodiment, the compounds provided herein are single diastereomers. In one embodiment, the compounds provided herein are mixtures of enantiomers. In one embodiment, the compounds provided herein are mixtures of diastereomers. In one embodiment, the compounds provided herein are racemic compounds.

[0271] In some embodiments, the compound is a compound in Table 1 or a pharmaceutically acceptable salt thereof.

[0272] Table 1.

[0273]

[0274]

[0275]

[0276]

[0277]

[0278] In one embodiment, without being bound by a particular theory, the compounds provided herein are poly (ADP-ribose) polymerase 1 (PARP1) inhibitors that exhibit strong DNA capture ability. In one embodiment, the compounds provided herein have an IC of less than 100 nM as measured by a DNA capture assay. 50 In one embodiment, IC50 Less than 50 nM. In one embodiment, IC 50 Less than 10nM.

[0279] In one embodiment, without being bound by a particular theory, the compounds provided herein are PARP1 inhibitors that exhibit good tumor penetration and retention (e.g., long residence time in tumor tissue). In one embodiment, without being bound by a particular theory, the compounds can achieve higher concentrations in tumors (e.g., higher tumor / plasma concentration ratios) than in plasma. In one embodiment, without being bound by a particular theory, lower plasma concentrations can result in fewer side effects.

[0280] In one embodiment, the compounds provided herein are poly (ADP-ribose) polymerase 1 (PARP1) inhibitors that reduce the level of PARP1 protein and / or inhibit or reduce at least one biological activity of PARP1 protein. In one embodiment, the expression level of PARP1 protein is reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99%. In one embodiment, the biological activity of PARP1 protein is reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99%.

[0281] In one embodiment, the compounds provided herein are capable of penetrating the blood-brain barrier (BBB). In one embodiment, the ratio of compounds that penetrate the BBB is >0.05, where 1 is complete BBB penetration and 0 is no penetration. In one embodiment, the ratio of compounds that penetrate the BBB is >0.1. In one embodiment, the ratio of compounds that penetrate the BBB is >0.2. In one embodiment, the ratio of compounds that penetrate the BBB is >0.3. In one embodiment, the ratio of compounds that penetrate the BBB is >0.3.

[0282] In one embodiment, the compounds provided herein bind to the PARP1 protein with an affinity ranging from about 1 pM to about 100 μM, about 1 pM to about 1 μM, about 1 pM to about 500 nM, or about 1 pM to about 100 nM. In some embodiments, the compounds provided herein bind to the PARP1 protein with an affinity of about 1 pM to about 100 μM, about 1 nM to about 100 μM, about 1 μM to about 100 μM, about 1 μM to about 50 μM, about 1 μM to about 40 μM, about 1 μM to about 30 μM, about 1 μM to about 20 μM, or about 1 μM to about 10 μM, about 1 μM, about 5 μM, about 10 μM, about 15 μM, about 20 μM, about 25 μM, about 30 μM, about 35 μM, about 40 μM, about 45 μM, about 50 μM, about 60 μM, about 70 μM, about 80 μM, about 90 μM, or about 100 μM. In some embodiments, the compounds provided herein are administered at about 100 nM to about 1 μM, about 100 nM to about 900 nM, about 100 nM to about 800 nM, about 100 nM to about 700 nM, about 100 nM to about 600 nM, about 100 nM to about 500 nM, about 100 nM to about 400 nM, about 100 nM to about 300 nM, about 100 nM to about 200 nM, about 200 nM to about 1 μM, ... The PARPl protein is bound to the PARPl protein with an affinity of 0 nM to about 1 μM, about 400 nM to about 1 μM, about 500 nM to about 1 μM, about 600 nM to about 1 μM, about 700 nM to about 1 μM, about 800 nM to about 1 μM, about 900 nM to about 1 μM, about 100 nM, about 200 nM, about 300 nM, about 400 nM, about 500 nM, about 600 nM, about 700 nM, about 800 nM or about 900 nM. In some embodiments, the compounds provided herein are at about 1 nM to about 100 nM, about 1 nM to about 90 nM, about 1 nM to about 80 nM, about 1 nM to about 70 nM, about 1 nM to about 60 nM, about 1 nM to about 50 nM, about 1 nM to about 40 nM, about 1 nM to about 30 nM, about 1 nM to about 20 nM, about 1 nM to about 10 nM, about 10 nM to about 100 nM, about 20 nM to about 100 nM, about 30 nM to about 100 nM, about 40 nM to about 100 nM, about 5 The protein binds to the PARP1 protein with an affinity of 0 nM to about 100 nM, about 60 nM to about 100 nM, about 70 nM to about 100 nM, about 80 nM to about 100 nM, about 90 nM to about 100 nM, about 1 nM, about 2 nM, about 3 nM, about 4 nM, about 5 nM, about 6 nM, about 7 nM, about 8 nM, about 9 nM, about 10 nM, about 20 nM, about 30 nM, about 40 nM, about 50 nM, about 60 nM, about 70 nM, about 80 nM, about 90 nM or about 100 nM.In some embodiments, the compounds provided herein bind to the PARP1 protein with an affinity of less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. In one embodiment, the compounds provided herein bind to the PARP1 protein with an affinity of less than 1 nM.

[0283] In one embodiment, the compounds provided herein have an IC of about 1 pM to about 100 μM, or about 1 pM to about 1 μM, or about 1 pM to about 500 nM, or about 1 pM to about 100 nM. 50 Inhibit PARP1 activity. In one embodiment, the compounds provided herein have an IC of about 1 pM to about 100 μM, about 1 nM to about 100 μM, about 1 μM to about 100 μM, about 1 μM to about 50 μM, about 1 μM to about 40 μM, about 1 μM to about 30 μM, about 1 μM to about 20 μM, or about 1 μM to about 10 μM, about 1 μM, about 5 μM, about 10 μM, about 15 μM, about 20 μM, about 25 μM, about 30 μM, about 35 μM, about 40 μM, about 45 μM, about 50 μM, about 60 μM, about 70 μM, about 80 μM, about 90 μM, or about 100 μM. 50 In some embodiments, the compounds provided herein are administered at about 100 nM to about 1 uM, about 100 nM to about 900 nM, about 100 nM to about 800 nM, about 100 nM to about 700 nM, about 100 nM to about 600 nM, about 100 nM to about 500 nM, about 100 nM to about 400 nM, about 100 nM to about 300 nM, about 100 nM to about 200 nM, about 200 nM to about 1 An IC of about 100 nM, about 200 nM, about 300 nM, about 400 nM, about 500 nM, about 600 nM, about 700 nM, about 800 nM, about 900 nM, about 1 μM, about 100 nM, about 200 nM, about 300 nM, about 400 nM, about 500 nM, about 600 nM, about 700 nM, about 800 nM, or about 900 nM 50In some embodiments, the compounds provided herein are administered at about 1 nM to about 100 nM, about 1 nM to about 90 nM, about 1 nM to about 80 nM, about 1 nM to about 70 nM, about 1 nM to about 60 nM, about 1 nM to about 50 nM, about 1 nM to about 40 nM, about 1 nM to about 30 nM, about 1 nM to about 20 nM, about 1 nM to about 10 nM, about 10 nM to about 100 nM, about 20 nM to about 100 nM, about 30 nM to about 100 nM, about 40 nM to about 10 An IC of about 0 nM, about 50 nM to about 100 nM, about 60 nM to about 100 nM, about 70 nM to about 100 nM, about 80 nM to about 100 nM, about 90 nM to about 100 nM, about 1 nM, about 2 nM, about 3 nM, about 4 nM, about 5 nM, about 6 nM, about 7 nM, about 8 nM, about 9 nM, about 10 nM, about 20 nM, about 30 nM, about 40 nM, about 50 nM, about 60 nM, about 70 nM, about 80 nM, about 90 nM, or about 100 nM 50 Inhibit PARP1 activity. In one embodiment, the compounds provided herein have an IC of less than 1 μM, less than 500 nM, less than 100 nM, less than 10 nM, or less than 1 nM. 50 Inhibit PARP1 activity. In one embodiment, the compounds provided herein have an IC of less than 1 nM. 50 Inhibits PARP1 activity.

[0284] How to use

[0285] In one embodiment, provided herein is a method of treating a disease or condition by inhibiting PARP1 protein, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein or a pharmaceutical composition provided herein.

[0286] In one embodiment, provided herein is a method of treating cancer, comprising administering to a subject having cancer a therapeutically effective amount of a compound provided herein or a pharmaceutical composition provided herein.

[0287] In one embodiment, the cancer is deficient in a homologous recombination (HR)-dependent DNA double-strand DNA break (DSB) repair pathway.

[0288] In one embodiment, the cancer comprises one or more cancer cells that have a reduced or abrogated ability to repair DNA DSBs by HR relative to normal cells.

[0289] In one embodiment, the cancer is a cancer comprising cancer cells that are heterozygous for mutations in genes encoding components of the HR-dependent DNA DSB repair pathway. Without being bound by a particular theory, a cancer deficient in HR-dependent DNA DSB repair may comprise one or more cancer cells that have a reduced or abrogated ability to repair DNA DSBs via this pathway compared to normal cells.

[0290] In one embodiment, the present invention provides a method for treating cancer lacking homologous recombination (HR) dependent DNA DSB repair activity. Without being bound by a particular theory, the HR dependent DNA DSB repair pathway repairs double-strand breaks (DSBs) in DNA by a homologous mechanism to reform a continuous DNA helix (KK Khanna and SP Jackson, Nat. Genet. 27 (3): 247-254 (2001)). Components of the HR dependent DNA DSB repair pathway include, but are not limited to, ATM (NM_000051), RAD51 (NM_002875), RAD51L1 (NM_002877), RAD51C (NM_002876), RAD51L3 (NM_002878), DMC1 (NM_007068), XRCC2 (NM_005431), XRCC3 (NM_ 005432), RAD52(NM_002879), RAD54L(NM_003579), RAD54B(NM_012415), BRCA1(NM_007 295), BRCA2 (NM_000059), RAD50 (NM_005732), MRE11A (NM_005590) and NBS1 (NM_002485).

[0291] In one embodiment, the cancer cells have a breast cancer type 1 (BRCA1) or breast cancer type 2 (BRCA2) deficient phenotype.

[0292] In one embodiment, the cancer cells lack BRCA1. In one embodiment, the cancer cells lack BRCA2. In one embodiment, the cancer cells lack both BRCA1 and BRCA2.

[0293] In one embodiment, the cancer is a cancer comprising cancer cells that are heterozygous for a mutation in BRCA1 and / or BRCA2.

[0294] In one embodiment, the compounds provided herein are used to treat cancer, wherein the cancer is a BRCA1 mutant cancer. In one embodiment, the compounds provided herein are used to treat cancer, wherein the cancer is a BRCA2 mutant cancer. In one embodiment, the compounds provided herein are used to treat cancer, wherein the cancer is a BRCA1 mutant cancer and a BRCA2 mutant cancer. In one embodiment, the cancer is not a BRCA1 mutant cancer or a BRCA2 mutant cancer. In one embodiment, the cancer is a BRCA1 defective cancer. In one embodiment, the cancer is a BRCA2 defective cancer. In one embodiment, the cancer is a BRCA1 defective cancer and a BRCA2 defective cancer.

[0295] In one embodiment, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, lung cancer, or brain cancer. In one embodiment, the brain cancer is a glioma or glioblastoma. In one embodiment, the brain cancer is a metastatic cancer caused by a tumor elsewhere in the body, such as breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer (such as gastric cancer and colorectal cancer), or lung cancer (such as small cell or non-small cell lung cancer).

[0296] In one embodiment, provided herein is a method of inhibiting PARP1 protein, the method comprising contacting PARP1 protein with an effective amount of a compound provided herein or a pharmaceutical composition provided herein. In one embodiment, the inhibition occurs in a subject suffering from a PARP1-mediated disease or condition.

[0297] In one embodiment, the PARP1 -mediated disease or condition is cancer.

[0298] In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is prostate cancer. In one embodiment, the cancer is a blood cancer. In one embodiment, the cancer is gastrointestinal cancer. In one embodiment, the cancer is lung cancer. In one embodiment, the cancer is brain cancer.

[0299] In some embodiments, such methods comprise (a) identifying a cancer in a subject as a PARP1 inhibitor-sensitive cancer, and then (b) administering to the subject a therapeutically effective amount of a compound provided herein.

[0300] In some embodiments, the compounds provided herein are provided for use as a medicament or for the preparation of a medicament, e.g., a medicament for treating cancer. In some embodiments, compounds provided herein are provided for use in a method for treating cancer.

[0301] In one embodiment, provided are compounds provided herein for use in a method for treating a disease or condition by inhibiting the PARP1 protein.

[0302] Pharmaceutical composition

[0303] Also provided herein are pharmaceutical compositions comprising a compound provided herein and a pharmaceutically acceptable excipient.

[0304] The pharmaceutical compositions provided herein can be administered to mammals, including rodents and humans, by various routes. In one embodiment, administration is intranasal, intravenous, intraperitoneal, intramuscular, intraarticular, intralesional, intratracheal, subcutaneous, or intradermal. In one embodiment, administration is intravenous. In one embodiment, administration is intramuscular.

[0305] In one embodiment, the pharmaceutical compositions provided herein can be orally administered in any orally acceptable dosage form, including capsules, tablets, aqueous suspensions or solutions.

[0306] In one embodiment, the compounds provided herein are administered to mammals in the form of raw chemicals without any other components. In one embodiment, the compounds provided herein are administered to mammals as part of a pharmaceutical composition containing a compound in combination with a suitable pharmaceutically acceptable carrier (see, e.g., Gennaro, Remington: The Science and Practice of Pharmacy with Facts and Comparisons: Drugfacts Plus, 20th Edition (2003); Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition, Lippencott Williams and Wilkins (2004); Kibbe et al., Handbook of Pharmaceutical Excipients, 3rd Edition, Pharmaceutical Press (2000)). Non-limiting examples of pharmaceutically suitable carriers include solids and / or liquids such as water, alcohol, and glycerol. Based on the total weight of the therapeutic composition or therapeutic combination, the amount of the carrier in the therapeutic composition can be in the range of about 5% by weight to about 99% by weight. Pharmaceutically acceptable excipients and diluents include, but are not limited to, buffers, preservatives, binders, fillers, disintegrants, lubricants, wetting agents, antioxidants, flavorings, thickeners, coloring agents, emulsifiers, suspending agents, etc. Non-limiting examples of excipients and diluents also include sucrose, lactose, dextrose, sorbitol, mannitol, erythritol, maltitol, starch, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil.

[0307] In one embodiment, the pharmaceutical compositions provided herein can be prepared as liquid suspensions or solutions using liquids such as oils, water, alcohols, and combinations thereof.

[0308] In one embodiment, provided herein is a pharmaceutical composition that can be prepared as a sterile injection, which can be an aqueous or oily suspension. Suspension can be prepared using suitable dispersants or wetting agents (e.g., polysorbates) according to technology known in the art. Sterile injectable formulations can also be sterile injectable solutions or suspensions in diluents or solvents. In addition, sterile fixed oils are typically used as solvents or suspending media. Pharmaceutically acceptable natural oils or fatty acids can also be used to prepare injectable formulations.

[0309] In one embodiment, the pharmaceutical compositions provided herein may be administered in the form of suppositories for rectal administration.

[0310] In one embodiment, the pharmaceutical compositions provided herein can also be applied topically, particularly when the therapeutic target comprises an area or organ that is easily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Topical application to the lower intestinal tract can be achieved in the form of a rectal suppository formulation or a suitable enema formulation. Topical transdermal patches can also be used. For topical application, the pharmaceutical compositions can be formulated in a suitable ointment, lotion, or cream containing the active ingredient suspended or dissolved in one or more carriers.

[0311] In one embodiment, the pharmaceutical compositions provided herein can also be administered ophthalmically and are formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, or solutions in isotonic, pH-adjusted sterile saline, with or without preservatives such as benzalkonium chloride. In one embodiment, for ophthalmic use, the pharmaceutical compositions can be formulated in an ointment such as petrolatum.

[0312] In one embodiment, the pharmaceutical compositions provided herein can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulations and can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters for enhancing bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0313] In one embodiment, pharmaceutical compositions for in vivo administration can be sterile. In one embodiment, this is achieved by filtration through, for example, sterile filtration membranes.

[0314] In one embodiment, the pharmaceutical compositions provided herein include all compositions in which the compounds provided herein are combined with one or more pharmaceutically acceptable carriers. In one embodiment, the compounds provided herein are present in the composition in an amount effective to achieve their intended therapeutic purpose.

[0315] In one embodiment, the pharmaceutical compositions provided herein can be administered to any patient who may experience the beneficial effects of the compounds provided herein. In one embodiment, the patient is a mammal, e.g., a human or a companion animal. In one embodiment, the patient is a human.

[0316] In one embodiment, there is also provided herein a kit, which includes a compound provided herein (or a composition comprising a compound provided herein), and its packaging is convenient for practicing a method provided herein. In one embodiment, the kit includes a compound provided herein (or a composition comprising a compound provided herein) packaged in containers such as sealed vials, wherein a label is attached to the container or is included in the kit for describing the use of the compound or composition to practice a method provided herein. In one embodiment, the compound or composition are packaged in unit dosage form. In one embodiment, the kit also includes a device suitable for administering the compound or composition according to an intended route of administration. In one embodiment, the kit includes a compound provided herein and instructions for administering the compound to a patient suffering from cancer.

[0317] Example

[0318] Example 1: Preparation method

[0319] In one embodiment, provided herein is a method for preparing a compound provided herein (Method 1), comprising the steps of:

[0320]

[0321] wherein X is a halogen such as Br and Cl.

[0322] Step 1: In the presence of a suitable inorganic base such as sodium hydride in a suitable solvent such as THF at a suitable temperature such as about -78°C to 25°C.

[0323] Step 2: At a suitable temperature (such as 25°C to 80°C) in the presence of a suitable hydrogenation catalyst (such as palladium on carbon) in the presence of hydrogen at a suitable pressure (such as 15 psi to 100 psi) in a suitable solvent (such as EtOAc or EtOH).

[0324] Step 3: At a suitable temperature (such as room temperature to about 120° C.) in the presence of a suitable oxidizing agent (such as DDQ or MnO 2 ) in a suitable solvent (such as THF or dioxane).

[0325] Step 4: In the presence of a suitable reducing agent such as LiAlH4 in a suitable solvent such as THF at a suitable temperature such as 0°C to 25°C.

[0326] Step 5: In the presence of a suitable halogenating agent such as SOCl 2 or HBr in a suitable solvent such as DCM or AcOH at a suitable temperature such as 25° C. to 80° C.

[0327] Step 6: In the presence of a suitable base such as DIEA or TEA in the presence of an additive such as potassium iodide in a suitable solvent such as MeCN at a suitable temperature such as 25 to 80°C.

[0328] In one embodiment, provided herein is a method for preparing a compound provided herein (Method 2), comprising the steps of:

[0329]

[0330] wherein X is a halogen such as Br and Cl.

[0331] Step 1: In the presence of a suitable base such as DIEA or TEA in a suitable solvent such as THF or MeCN at a suitable temperature such as about -78°C to 25°C.

[0332] Step 2: At a suitable temperature (such as 25°C to 80°C) in the presence of a suitable hydrogenation catalyst (such as palladium on carbon) in the presence of hydrogen at a suitable pressure (such as 15 psi to 100 psi) in a suitable solvent (such as EtOAc or EtOH).

[0333] Step 3: At a suitable temperature (such as room temperature to about 120° C.) in the presence of a suitable oxidizing agent (such as DDQ or MnO 2 ) in a suitable solvent (such as THF or dioxane).

[0334] Step 4: In the presence of a suitable reducing agent such as LiAlH4 in a suitable solvent such as THF at a suitable temperature such as 0°C to 25°C.

[0335] Step 5: In the presence of a suitable halogenating agent such as SOCl 2 or HBr in a suitable solvent such as DCM or AcOH at a suitable temperature such as 25° C. to 80° C.

[0336] Step 6: In the presence of a suitable base such as DIEA or TEA in the presence of an additive such as potassium iodide in a suitable solvent such as MeCN at a suitable temperature such as 25 to 80°C.

[0337] In one embodiment, provided herein is a method for preparing a compound provided herein (Method 3), comprising the steps of:

[0338]

[0339] wherein X is a halogen such as Br and Cl.

[0340] Step 1: In the presence of a suitable base such as DIEA or sodium hydride in a suitable solvent such as THF or MeCN at a suitable temperature such as about -78°C to 25°C.

[0341] Step 2: At a suitable temperature (such as 25°C to 80°C) in the presence of a suitable hydrogenation catalyst (such as palladium on carbon) in the presence of hydrogen at a suitable pressure (such as 15 psi to 100 psi) in a suitable solvent (such as EtOAc or EtOH).

[0342] Step 3: At a suitable temperature (such as room temperature to about 120° C.) in the presence of a suitable oxidizing agent (such as DDQ or MnO 2 ) in a suitable solvent (such as THF or dioxane).

[0343] Step 4: In the presence of a suitable reducing agent such as LiAlH4 in a suitable solvent such as THF at a suitable temperature such as 0°C to 25°C.

[0344] Step 5: In the presence of a suitable halogenating agent such as SOCl 2 or HBr in a suitable solvent such as DCM or AcOH at a suitable temperature such as 25° C. to 80° C.

[0345] Step 6: In the presence of a suitable base such as DIEA or TEA in the presence of an additive such as potassium iodide in a suitable solvent such as MeCN at a suitable temperature such as 25 to 80°C.

[0346] In one embodiment, provided herein is a method for preparing a compound provided herein (Method 4), comprising the steps of:

[0347]

[0348] wherein X is a halogen such as Br and Cl; and wherein Alk is a methyl or ethyl group.

[0349] Step 1: In the presence of a suitable base such as DIEA, sodium hydride or 2,6-di-tert-butyl-4-methylpyridine in the presence of a suitable triflation reagent such as trifluoromethanesulfonic anhydride in a suitable solvent such as DCM at a suitable temperature such as -78°C to room temperature.

[0350] Step 2: In the presence of a suitable base such as KOAc in the presence of a suitable palladium such as Pd(dppf)Cl2 in a suitable solvent such as dioxane at a suitable temperature such as room temperature to 120°C.

[0351] Step 3: At a suitable temperature (such as 60°C to 120°C), in the presence of a suitable inorganic base (such as K2CO3 or Cs2CO3), in the presence of a suitable palladium catalyst (such as Pd(dppf)Cl2 or Pd(PPh3)4), in a suitable solvent or mixed solvent (such as dioxane or dioxane / H2O).

[0352] Step 4: At a suitable temperature (such as room temperature to 120° C.), in the presence of a suitable inorganic additive (such as NH 4 Cl), in the presence of a suitable reducing agent (such as Fe), in a suitable solvent mixture (such as THF / MeOH / H 2 O).

[0353] Step 5: In the presence of a suitable reducing agent such as LiAlH4 in a suitable solvent such as THF at a suitable temperature such as 0°C to 25°C.

[0354] Step 6: In the presence of a suitable reducing agent such as SOCl 2 or HBr in a suitable solvent such as DCM or AcOH at a suitable temperature such as 25° C. to 80° C.

[0355] Step 7: In the presence of a suitable base such as DIEA or TEA in the presence of an additive such as potassium iodide in a suitable solvent such as MeCN at a suitable temperature such as 25 to 80°C.

[0356] In one embodiment, provided herein is a method for preparing a compound provided herein (Method 5), comprising the steps of:

[0357]

[0358] wherein Alk is a methyl group or an ethyl group.

[0359] Step 1: In the presence of a suitable base such as DIEA, sodium hydride or 2,6-di-tert-butyl-4-methylpyridine in the presence of a suitable triflation reagent such as trifluoromethanesulfonic anhydride in a suitable solvent such as DCM at a suitable temperature such as -78°C to room temperature.

[0360] Step 2: In the presence of a suitable base such as KOAc in the presence of a suitable palladium such as Pd(dppf)Cl2 in a suitable solvent such as dioxane at a suitable temperature such as room temperature to 120°C.

[0361] Step 3: At a suitable temperature (such as 60°C to 120°C), in the presence of a suitable inorganic base (such as K2CO3), in the presence of a suitable palladium catalyst (such as Pd(dppf)Cl2), in a suitable solvent or mixed solvent (such as dioxane or dioxane / H2O).

[0362] Step 4: At a suitable temperature (such as 60° C. to 120° C.), in the presence of a suitable inorganic base (such as K 2 CO 3 ), in the presence of a suitable palladium catalyst (such as Pd(dppf)Cl 2 ), in a suitable mixed solvent (such as dioxane / H 2 O).

[0363] Step 5: At a suitable temperature (such as room temperature to 60°C), in the presence of a suitable oxidizing reagent combination (such as K2OsO4 / NaIO4), in the presence of a suitable base (such as 2,6-lutidine), in a suitable mixed solvent (such as THF / H2O).

[0364] Step 6: At a suitable temperature (such as room temperature to 60° C.) in the presence of a suitable reducing agent (such as NaBH 3 CN or NaBH(OAc) 3 ) in the presence of a suitable acidic additive (such as AcOH) in a suitable solvent (such as DCM or MeOH).

[0365] Several methods for preparing the compounds provided herein are described in the following examples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification, or alternatively, were synthesized by those skilled in the art using methods known to those skilled in the art.

[0366]

[0367]

[0368] Example 2: Preparation of intermediates

[0369] For intermediates used in the next reaction step as crude products or as partially purified intermediates, in some cases, the molar amount of such intermediates in the next reaction step is not mentioned, or alternatively, the estimated molar amount or theoretical molar amount of such intermediates in the next reaction step is indicated in the following reaction schemes.

[0370] Preparation of intermediate 1

[0371]

[0372] To a solution of ethyl 6-methyl-5-nitronicotinate (10 g, 47.58 mmol) in dioxane (200 mL) was added SeO2 (7.92 g, 71.38 mmol). The mixture was stirred at 110 ° C for 16 hours. The reaction mixture was cooled to room temperature, filtered through a pad of celite, and the celite was washed with ethyl acetate. The combined filtrate was concentrated, and the residue was purified by silica gel chromatography to obtain intermediate 1 (9.3 g, yield: 87%) as a yellow oil.

[0373] Preparation of intermediate 2

[0374]

[0375] To a stirred solution of NaH (6.6 g, 165.10 mmol) in anhydrous THF (100 mL) was added dropwise anhydrous THF (100 mL) containing ethyl 2-(diethoxyphosphoryl)butanoate (41.64 g, 165.10 mmol) at 0 ° C. The resulting mixture was stirred at 0 ° C for 10 min, then warmed to room temperature over 10 min and stirred at 40 ° C for 5 min. The reaction mixture was then cooled to -78 ° C, and a solution of intermediate 1 (15.478 g, 68.79 mmol) in anhydrous THF (150 mL) was slowly added. The mixture was stirred at -78 ° C for 30 min. The mixture was quenched with saturated aqueous ammonium chloride solution in THF (20 mL) and extracted with ethyl acetate (200 × 2 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated, and the obtained residue was purified by silica gel chromatography to give Intermediate 2 (mixture of E / Z isomers = 1:1) as a yellow oil (13.7 g, yield: 62%).

[0376] The following intermediates were synthesized by methods similar to those described above for Intermediate 2.

[0377]

[0378] Preparation of intermediate 3

[0379]

[0380] To a mixture of intermediate 2 (13.7 g, 42.51 mmol) (mixture of E / Z isomers = 1: 1) in EtOH (200 mL) was added 10 wt% Pd / C (7 g), and the mixture was stirred at room temperature overnight under an H2 atmosphere. The mixture was filtered through a celite bed, and the celite bed was washed with ethanol. After concentration, dioxane (100 ml) containing 4M HCl was added to the resulting residue, and the mixture was stirred at room temperature for 1 h. The mixture was diluted with Et2O, and the precipitate was filtered and washed twice with diethyl ether to give intermediate 3 (6.7 g, yield: 63.6%) as a white solid.

[0381] The following intermediates were synthesized by methods similar to those described above for Intermediate 3.

[0382] Preparation

[0383]

[0384] To a solution of intermediate 3 (6.7 g, 26.99 mmol) in 1,4-dioxane (120 mL) was added DDQ (6.738 g, 29.68 mmol). The mixture was stirred at reflux for 3 h. The solvent was removed under reduced pressure, and then a saturated aqueous sodium bicarbonate solution was added to the residue, and the resulting mixture was stirred at rt for 1 h. The precipitate was filtered to obtain intermediate 4 (4 g, yield: 60%) as a gray solid.

[0385] The following intermediates were synthesized by methods similar to those described above for Intermediate 4.

[0386]

[0387]

[0388] Preparation of intermediate 5

[0389]

[0390] At 0 ° C, under nitrogen, LiAlH4 (32.52 mL, 32.52 mmol, 1 M in THF) was added dropwise to a solution of intermediate 4 (4 g, 16.26 mmol) in THF (20 mL) over a period of 45 min. The resulting mixture was stirred at 0 ° C for 1.5 h. The reaction mixture was quenched with 1M HCl (aqueous solution) (15 mL). The reaction mixture was concentrated, and the solid was diluted with water (about 70 mL) and 15 mL of 1M HCl solution to give a yellow suspension. The solid was collected by filtration, washed with water, diethyl ether, and dried to give a crude product as a yellow solid (contaminated with some inorganic salts). The solid was suspended in a mixture of methanol and DCM (2: 1) (100 mL) and heated to reflux for 1 hr. The solid was filtered off. The solid was resuspended in a methanol / DCM mixture, and the procedure was repeated 5 times to extract most of the product from the solid mixture. The combined filtrate was then concentrated to about 40 mL, and the solid was collected by filtration, washed with diethyl ether, and dried under vacuum to give Intermediate 5 (2.67 g, yield: 80.39%) as a yellow solid.

[0391] The following intermediates were synthesized by methods similar to those described above for Intermediate 5.

[0392]

[0393]

[0394] Preparation of intermediate 6

[0395]

[0396] To a suspension of intermediate 6 (204 mg, 1.00 mmol) in DCM (4 mL) was added SOCl (714 mg, 6.00 mmol) and a drop of DMF at 0°C. The resulting mixture was stirred at rt for 6 hours. The mixture was concentrated to give crude intermediate 6 (222 mg, yield: 100%), which was used directly in the next step.

[0397] The following intermediates were synthesized by methods similar to those described above for Intermediate 6.

[0398]

[0399]

[0400] Preparation of intermediate 7

[0401]

[0402] To a solution of 1,3-difluoro-2-nitrobenzene (23.28 mL, 220 mmol) and methyl 2-aminopropanoate (27.22 g, 264 mmol) in DMF (120 mL) was added DIPEA (85.30 g, 660 mmol) dropwise. The mixture was heated to 60 ° C and stirred for 2 hours. The solution was quenched with H2O and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated, and chromatographed on silica gel (PE / EA 20: 1 to 10: 1 to 8: 1) to give intermediate 7 (38.7 g, yield: 72.6%) as a yellow solid.

[0403] The following intermediates were synthesized by methods similar to those described above for Intermediate 7.

[0404]

[0405] Preparation of intermediate 8

[0406]

[0407] To a solution of intermediate 7 (4.4 g, 18.1 mmol) in DMF (50 mL) was added NBS (3.23 g, 18.1 mmol). The mixture was stirred at rt for 18 h under an air atmosphere. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was used in the next step without further purification.

[0408] Preparation of intermediate 9

[0409]

[0410] A mixture of intermediate 8 (9.7 g crude product, 30.2 mmol), Zn (11.8 g, 181 mmol) and NH4Cl (16.2 g, 53.5 mmol) in THF (50 mL) / MeOH (50 mL) / H2O (25 mL) was heated to 80°C and stirred for 3 hr. The mixture was filtered and the filtrate was concentrated to a crude product, which was chromatographed on silica gel (PE / EA 20:1 to 10:1 to 5:1) to give intermediate 9 (7.1 g, yield: 90.7%).

[0411] Preparation of intermediate 10

[0412]

[0413] To a solution of intermediate 9 (620 mg, 2.39 mmol) in DCM (10 mL) was added a solution of DDQ (651 mg, 2.87 mmol) in DCM dropwise. The mixture was stirred at rt for 2 hr and concentrated to give a crude product which was chromatographed on silica gel (PE / EA 10:1 to 7:1 to 5:1) to give intermediate 10 (500 mg, 81.2% yield) as a white solid.

[0414] Preparation of intermediate 11

[0415]

[0416] To a solution of intermediate 10 (1 g, 3.8 mmol) in dioxane (40 mL) was added (tributylstannyl)methanol (1.50 g, 4.6 mmol) and Xphos Pd G2 (0.15 g, 0.195 mmol). The mixture was stirred at 80 ° C for 18 h under N2 atmosphere. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with DCM / MeOH (1 / 0 to 10 / 1) to give intermediate 11 (600 mg, yield: 74%).

[0417] The following intermediates were synthesized by methods analogous to those described above for Intermediate 11.

[0418]

[0419] Preparation of intermediate 12

[0420]

[0421] To a solution of intermediate 11 (200 mg, 0.961 mmol) in AcOH (8 mL) and H2O (4 mL) was added HBr (9.3 g, 115.2 mmol). The mixture was stirred at 80 ° C for 3 hr. The resulting mixture was poured into saturated NaHCO3 (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (eluted with PE / EA (5 / 1 to 1 / 1)) and concentrated under reduced pressure to obtain intermediate 12 (105 mg, yield: 40%).

[0422] The following intermediates were synthesized by methods analogous to those described above for intermediate 12.

[0423]

[0424] Preparation of intermediate 13

[0425]

[0426] To a solution of 6-chloro-5-nitropyridine-3-carboxylic acid methyl ester (1.5 g, 6.92 mmol) in DMF (5 mL) was added 1H-pyrrole-2-carboxylic acid methyl ester (1.04 g, 8.31 mmol) and Cs2CO3 (6.77 g, 20.7 mmol), and the reaction was stirred at 60 ° C for 30 min. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography (eluted with ethyl acetate / petroleum ether (1: 1) to give intermediate 13 (900 mg, yield: 40.4%) as a yellow oil.

[0427] Preparation of intermediate 14

[0428]

[0429] To a solution of intermediate 13 (700 mg, 2.29 mmol) in AcOH (5 mL), H2O (5 mL) and THF (5 mL) was added Zn (1.8 g, 27.5 mmol). The reaction mixture was stirred at 80 ° C for 3 h. The reaction mixture was filtered and washed with DCM / MeOH (1 / 1). The filtrate was concentrated under reduced pressure to give a crude product, which was used in the next step without further purification (500 mg, yield: 89.6%).

[0430] Preparation of intermediate 17

[0431]

[0432] At 0 ℃, under nitrogen, DBU (1.03mL, 6.92mmol) was added to anhydrous tetrahydrofuran (15mL) containing 6-chloro-5-nitropyridine-3-methyl formate (1g, 4.6mmol) and 2-hydroxybutyric acid methyl ester (0.65g, 5.5mmol). The reaction mixture was stirred at 0 ℃ for 30 minutes, then stirred at ambient temperature for one hour. Solid precipitated from the solution. Next, the reaction mixture was diluted with ethyl acetate (15mL), the solid was removed by filtration, and the filtrate was concentrated in the presence of silica to obtain a crude product, which was purified by column chromatography (eluted with 10%-50% ethyl acetate / hexane gradient) to obtain intermediate 17 (1.2g, yield: 87.1%) as a white solid.

[0433] Preparation of intermediate 18

[0434]

[0435] Iron powder (1.12 g, 20.1 mmol) was added to a solution of intermediate 17 (1.2 g, 4.02 mmol) in glacial acetic acid (10 mL). The resulting suspension was heated to 80 ° C for 2 hours. The resulting reaction mixture was then cooled to rt, filtered through diatomaceous earth, and washed with ethyl acetate. The filtrate was washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give intermediate 18 (0.8 g, yield: 84.2%) as a crude product, which was used directly in the next step without further purification.

[0436] The following intermediates were synthesized by methods analogous to those described above for Intermediate 18.

[0437]

[0438] Preparation of intermediate 19

[0439]

[0440] To a solution of intermediate 18 (500 mg, 2.1 mmol) in anhydrous THF (10 mL) was added DIBAL-H (4.2 mL, 1 M in toluene) at 0 ° C. over 1 h. After addition, the reaction mixture was allowed to warm to rt. After TLC analysis indicated completion of the reaction, the reaction was quenched with saturated NH4Cl solution (20 mL) and extracted with EtOAc (100 ml × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (DCM:MeOH = 20:1 to 10:1) to give intermediate 19 (150 mg, yield: 34.1%).

[0441] Preparation of intermediate 21

[0442]

[0443] To a solution of 5-bromo-2-chloro-3-nitropyridine (8 g, 33.69 mmol) in DMF (100 mL) was added (2R)-pyrrolidine-2-carboxylic acid methyl ester hydrochloride (6.14 g, 37.0 mmol) and DIEA (16.7 mL, 101.0 mmol). The resulting reaction mixture was stirred at 80 ° C for 3 h. The reaction was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give intermediate 21 (10 g, yield: 80.9%) as a yellow oil.

[0444] Preparation of intermediate 22

[0445]

[0446] To a solution of intermediate 21 (10.0 g, 27.2 mmol) in MeOH (100 mL) and H2O (20 mL) was added Fe (7.6 g, 136.3 mmol) and NHCl (14.6 g, 272.6 mmol). The resulting reaction mixture was stirred at 85 ° C for 1 h. The reaction was filtered, and the filtrate was diluted with water and extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to obtain intermediate 22 (2 g, yield: 24.6%) as a yellow solid.

[0447] Preparation of intermediate 25

[0448]

[0449] A mixture of methyl 6-chloro-5-nitropyridine-3-carboxylate (2 g, 9.23 mmol), {1-[(tert-butoxy)carbonyl]-1H-pyrrol-2-yl}boronic acid (2.34 g, 11.0 mmol), Pd(dppf)Cl2 (0.68 g, 0.92 mmol) and Na2CO3 (2.94 g, 27.7 mmol) in 1,4-dioxane (60 mL) and H2O (15 mL) was stirred at 100 h under N2 atmosphere for 1 hour. The reaction was diluted with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluted with ethyl acetate / petroleum ether (5: 1)) to give intermediate 25 (1.1 g, yield: 30.8%) as a red oil.

[0450] Preparation of intermediate 26

[0451]

[0452] To a solution of intermediate 25 (1 g, 2.59 mmol) in THF (15 mL) and H2O (15 mL) was added Zn (1.65 g, 25.9 mmol) and NHCl (2.8 g, 51.8 mmol). The reaction was stirred at 80 ° C for 6 hours. The reaction was diluted with EtOAc and brine. The organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluted with methanol / DCM) to give intermediate 26 (300 mg, yield: 45.2%) as a white solid.

[0453] Preparation of intermediate 29

[0454]

[0455] To a solution of tert-butyl 2-bromo-1H-imidazole-1-carboxylate (1.27 g, 5.12 mmol) and [4-(methoxycarbonyl)-2-nitrophenyl]boronic acid (900 mg, 4.0 mmol) in dioxane (20 mL) and water (10 mL) was added Pd(dppf)Cl2 (0.38 g, 0.51 mmol) and Cs2CO3 (3.34 g, 10.2 mmol). The mixture was stirred at 100 ° C for 3 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL×2). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with PE / EA (1 / 0 to 1 / 2)) to give Intermediate 29 (170 mg, yield: 13.6%).

[0456] Preparation of intermediate 32

[0457]

[0458] To a solution of 1,3-difluoro-2-nitrobenzene (5.00 g, 31.4 mmol) in H2SO4 (15 mL) was added NBS (5.60 g, 31.4 mmol). The mixture was stirred at 80 ° C for 18 h. The reaction mixture was poured into ice water (600 mL) and extracted with EtOAc (200 mL). The organic layer was washed with saturated NaHCO3 (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum to obtain a residue, which was purified by silica gel column chromatography to obtain intermediate 32 (6.9 g, yield: 92.6%) as a brown oil.

[0459] Preparation of intermediate 33

[0460]

[0461] To a solution of intermediate 32 (4.75 g, 19.9 mmol) and methyl 2-hydroxypropionate (2.7 g, 25.9 mmol) in DMF (50 mL) was added CsCO (13 g, 39.9 mmol). The mixture was stirred at rt for 18 hr. The reaction was poured into water (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (100 mL × 3). The organic layer was dried over NaSO and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography to obtain intermediate 33 (500 mg, yield: 7.78%) as a brown solid.

[0462] Preparation of intermediate 35

[0463]

[0464] To a solution of intermediate 34 (180 mg, 0.66 mmol) in MeOH (4 mL), THF (2 mL) and H2O (2 mL) was added Zn (259 mg, 3.9 mmol) and NHCl (352 mg, 6.60 mmol). The mixture was stirred at 80 ° C for 3 h. The reaction was filtered and the filtrate was extracted with EtOAc (50 mL × 2). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography to obtain intermediate 35 (50 mg, yield: 35.9%) as a yellow oil.

[0465] Preparation of intermediate 42

[0466]

[0467] A mixture of 5-bromo-2-methyl-3-nitropyridine (1 g, 4.60 mmol) and SeO2 (0.77 g, 6.9 mmol) in dioxane (5 mL) was stirred at 110 ° C for 48 h. The reaction mixture was cooled to room temperature, filtered through a pad of diatomaceous earth, and the diatomaceous earth was washed with ethyl acetate. The combined filtrate was concentrated, and the resulting residue was purified by flash silica gel chromatography (elution gradient of 0% to 70% ethyl acetate / hexane) to obtain intermediate 42 (600 mg, yield: 56.3%) as a brown oil.

[0468] Preparation of intermediate 43

[0469]

[0470] To a solution of intermediate 42 (5.1 g, 22.0 mmol) in THF (45 mL) was added Fe (6.17 g, 110.3 mmol) and AcOH (5 mL). The reaction mixture was stirred at 25 ° C for 1 h, filtered through diatomaceous earth, and washed with EtOAc. The filtrate was diluted with water and extracted with EtOAc. The organic layer was washed with brine and dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography using 0%-5% EtOAc / hexane to give intermediate 43 (4 g, yield: 90.1%) as a yellow solid.

[0471] Preparation of intermediate 44

[0472]

[0473] At -78 ° C, ethyl 2-methoxyacetate (1.763 mL, 14.9 mmol) was added to a solution of Li-HMDS in THF (14.9 mL, 14.9 mmol). After 20 minutes, a solution of intermediate 43 (3 g, 14.9 mmol) in THF (20 mL) was added dropwise from a syringe. The resulting mixture was slowly warmed to room temperature. After 18 hours, the reaction was quenched with 6N HCl (1.1 mL, 6.6 mmol) to obtain a precipitate. The mixture was heated to reflux for 2 hours. The reaction was then concentrated in vacuo, and the residue was ground with dichloromethane and methanol. The solid was removed by filtration, and the filtrate was concentrated in vacuo. The combined filtrates were concentrated and the resulting residue was purified by flash silica gel chromatography (eluent, 100% dichloromethane to 100:10:1 dichloromethane:methanol; triethylamine) to afford Intermediate 44 (2.5 g, 61.34% yield) as a white solid.

[0474] Preparation of intermediate 45

[0475]

[0476] The mixture of intermediate 44 (2.5 g, 9.15 mmol), CDI (4.45 g, 27.4 mmol) in MeCN (30 mL) was degassed and stirred at 50 ° C overnight. The mixture was filtered through diatomaceous earth, and the diatomaceous earth was washed with EtOAc and EtOH. The mixture was diluted with ether, and the solid was filtered out, washed with diethyl ether, and dried under vacuum to obtain intermediate 45 (1.5 g, 64.2% yield) as a white solid.

[0477] Preparation of Intermediate 100

[0478]

[0479] To a solution of 5-bromo-2-chloro-3-nitropyridine (10 g, 42.1 mmol) in DMF (100 mL) was added 2-aminobutyric acid methyl ester hydrochloride (7.76 g, 50.5 mmol) and DIEA (20.8 mL, 126.3 mmol). The mixture was stirred at 80 ° C for 3 hr. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (100 mL × 3). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (eluted with PE / EA (10 / 1)) to obtain intermediate 100 (11.2 g, 84% yield).

[0480] Preparation of Intermediate 101

[0481]

[0482] To a solution of intermediate 100 (3 g, 9.430 mmol) and (tributylstannyl)methanol (3.63 g, 11.3 mmol) in dioxane (60 mL) was added XPhos Pd G2 (24.64 mg, 0.031 mmol). Under an N2 atmosphere, the mixture was stirred at 80 ° C for 18 hr. The reaction was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with PE / EA (10 / 1 to 3 / 1)) to give intermediate 101 (2.3 g, 90% yield).

[0483] Preparation of Intermediate 102

[0484]

[0485] To a solution of intermediate 101 (1.2 g, 4.4 mmol) in MeOH (20 mL) was added Pd / C 10% (0.47 g). Under an H atmosphere, the mixture was stirred at rt for 18 hr. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give intermediate 102 as a crude product, which was used in the next step without further purification.

[0486] Preparation of Intermediate 103

[0487]

[0488] To a solution of intermediate 102 (1.0 g, 4.1 mmol) in DMF (20 mL) was added KCO (1.16 g, 8.3 mmol). The mixture was stirred at 80 ° C for 18 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue, which was triturated in EtOAc (50 mL) and filtered. The filtered precipitate was dried under reduced pressure to give intermediate 103 as a crude product, which was used in the next step without further purification.

[0489] Preparation of Intermediate 104

[0490]

[0491] To the suspension of intermediate 103 (200mg, 0.96mmol) in DCM (8mL) was added SOCl2 (0.070mL, 0.96mmol). The mixture was stirred at rt for 18hr. The reaction was concentrated under reduced pressure to obtain a residue, which was ground and filtered in EtOAc (30mL). The filtrate was dried under reduced pressure to obtain the intermediate 104 (100mg, 46% yield) in crude product, which was used in the next step without further purification.

[0492] Preparation of Intermediate 105

[0493]

[0494] To a solution of intermediate 104 (100 mg, crude) in CHCN (6 mL) was added intermediate 67 (100 mg, 0.33 mmol), DIEA (128.5 mg, 0.99 mmol) and potassium iodide (5.5 mg, 0.03 mmol). The reaction mixture was stirred at 80 ° C for 2 h. It was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with DCM / MeOH (10 / 1)) to give intermediate 105 (43 mg, yield: 28.5%) as a brown solid.

[0495] Preparation of Intermediate 106

[0496]

[0497] To a solution of methyl butyrate (10.9 mL, 95.8 mmol) in THF (50 mL) was added LDA (2N, 49.4 mL, 98.9 mmol) at -75 ° C. After stirring at -78 ° C for 1 hr, 4-amino-6-chloropyridine-3-carboxaldehyde (5 g, 31.935 mmol) was added. The mixture was allowed to warm to rt and stirred overnight. The mixture was quenched by saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give a crude product, which was purified by silica gel column chromatography (DCM: MeOH = 20: 1) to give intermediate 106 (3.7 g, 56.4% yield) as a white solid.

[0498] The following intermediates were synthesized by methods analogous to those described above for intermediate 106.

[0499]

[0500] Preparation of intermediate 107

[0501]

[0502] Pd (dppf) Cl2 (245.4 mg, 0.33 mmol) is added to a stirred mixture of intermediate 106 (700 mg, 3.3 mmol), 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.68 mL, 4.0 mmol) and K2CO3 (1.39 g, 10.0 mmol) in 1,4-dioxane (5 mL) / water (1 mL), and the resulting mixture is stirred overnight at 90 ° C under N2. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered and concentrated to give a crude product. The residue is purified by flash silica gel chromatography (elution gradient is 0% to 20% MeOH / DCM). The product fractions are concentrated to dryness under reduced pressure to give intermediate 107 (600 mg, 89.3% yield) as a yellow solid.

[0503] The following intermediates were synthesized by methods analogous to those described above for intermediate 107.

[0504]

[0505] Intermediate 108 system Preparation

[0506]

[0507] Potassium osmate (VI) (184mg, 0.49mmol) in H The mixture in O (3mL) is added to intermediate 107 (500mg, 2.49mmol), 2,6-lutidine (0.58mL, 4.9mmol) and NaIO4 (2136mg, 9.9mmol) in THF (6mL) solution, and the resulting mixture is stirred overnight at rt. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic layers are merged and concentrated to dryness. The resulting residue is purified by flash silica gel chromatography (elution gradient is 0% to 15% MeOH / DCM). The product fraction is concentrated under reduced pressure to obtain intermediate 108 (250mg, 49.5% yield) in dark yellow foam.

[0508] The following intermediates were synthesized by methods analogous to those described above for intermediate 108.

[0509]

[0510]

[0511] Preparation of intermediate 112

[0512]

[0513] At 0 ° C, NaH (0.68 g, 16.88 mmol) was added to a solution of 2-oxocyclopentane-1-formic acid methyl ester (2 g, 14.07 mmol) in DCM (40 mL). The reaction mixture was stirred for 0.5 hr, and trifluoromethanesulfonic anhydride (4.76 g, 16.88 mmol) was added. The reaction mixture was warmed and stirred at rt for 18 hr. The reaction was quenched with saturated NH4Cl (100 mL) and extracted with DCM (50 mL × 2). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (eluted with PE / EA (10 / 1)) to obtain intermediate 112 (750 mg, yield: 19.44%) as a yellow oil.

[0514] Preparation of intermediate 113

[0515]

[0516] To a solution of intermediate 112 (750 mg, 2.73 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (792.9 mg, 3.12 mmol) in dioxane (10 mL) was added KOAc (510.7 mg, 5.2 mmol) and Pd(dppf)Cl (190.3 mg, 0.26 mmol). The reaction mixture was stirred at 80° C. under N atmosphere for 12 h. After cooling to rt, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL×2). The combined organic layers were dried over NaSO and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography eluted with PE / EA (10 / 1) to give Intermediate 113 (600 mg, yield: 86.64%) as a white solid.

[0517] The following intermediates were synthesized by methods analogous to those described above for intermediate 113.

[0518]

[0519]

[0520] Preparation of intermediate 114

[0521]

[0522] To a solution of intermediate 113 (600 mg, 2.25 mmol) and methyl 6-chloro-5-nitropyridine-3-carboxylate (400 mg, 1.84 mmol) in dioxane (10 mL) and H2O (2 mL) was added Pd(dppf)Cl2 (135.14 mg, 0.185 mmol) and K2CO3 (510.52 mg, 3.694 mmol). The reaction mixture was stirred at 100 ° C for 3 hr under N2 atmosphere. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL×2). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with PE / EA (10 / 1)) to give intermediate 114 (400 mg, yield: 67.62%) as a yellow solid.

[0523] The following intermediates were synthesized by methods analogous to those described above for intermediate 114.

[0524]

[0525]

[0526] Preparation of intermediate 115

[0527]

[0528] To a solution of intermediate 114 (400 mg, 1.24 mmol) in MeOH (6 mL), THF (3 mL) and H o (3 mL) was added NH4Cl (668 mg, 12.4 mmol) and Fe (350 mg, 6.2 mmol). The mixture was stirred at 80 ° C for 2 h. The reaction mixture was poured into water (100 mL) and extracted with DCM / MeOH (10 / 1, 100 mL × 2). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (eluted with DCM / MeOH (3.6% MeOH)) to obtain intermediate 115 (80 mg, yield: 26.23%) as a yellow solid.

[0529] The following intermediates were synthesized by methods analogous to those described above for intermediate 115.

[0530]

[0531] Preparation of intermediate 116

[0532]

[0533] To a solution of intermediate 115 (80 mg, 0.32 mmol) in THF (6 mL) was added LiAlH4 (0.98 mL, 1 N in THF, 0.98 mmol) at 0°C. The mixture was stirred at 0°C for 1 hr. The reaction mixture was quenched with MeoH and concentrated under reduced pressure to afford intermediate 116 (70 mg, 98.83% yield) as a white solid, which was used directly in the next step without further purification.

[0534] The following intermediates were synthesized by methods analogous to those described above for intermediate 116.

[0535]

[0536]

[0537] Preparation of intermediate 117

[0538]

[0539] To a solution of intermediate 116 (65 mg, 0.30 mmol) in DCM (10 mL) was added SOCl (107.2 mg, 0.90 mmol). The mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (eluted with DCM / MeOH (10 / 1)) to give intermediate 117 (70 mg, 99.22% yield) as a white solid.

[0540] The following intermediates were synthesized by methods analogous to those described above for intermediate 117.

[0541]

[0542]

[0543] Preparation of intermediate 118

[0544]

[0545] To a mixture of 5-bromo-2-chloropyridin-4-amine (2.34 g, 11.2 mmol) in dioxane (30 mL) and water (5 mL) was added intermediate 113 (3.0 g, 11.27 mmol), Pd(dppf)Cl2 (826 mg, 1.13 mmol) and K2CO3 (4.67 g, 33.82 mmol). The resulting mixture was stirred at 80 ° C for 5 hr. After cooling to rt, the reaction was diluted with water (20 mL) and extracted with DCM (100 mL×3). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH: DCM = 1: 10) to give intermediate 118 (1.8 g, yield: 72.37%) as a white solid.

[0546] The following intermediates were synthesized by methods analogous to those described above for intermediate 118.

[0547]

[0548] Preparation of Intermediate 121

[0549]

[0550] Under nitrogen atmosphere, to a solution of methyl 4-oxotetrahydrofuran-3-carboxylate (2 g, 13.8 mmol) in DCM (5 mL) was added DIEA (3.59 g, 27.7 mmol) in DCM (30 mL) at -78 ° C., followed by dropwise addition of trifluoromethanesulfonic anhydride (3.5 mL, 20.82 mmol) in DCM (5 mL) at -70 ° C. for 15 min. The reaction mixture was stirred at 0 ° C. for 3 hr and quenched with cold water (30 mL). The mixture was extracted with EtOAc and washed with brine, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1) to give Intermediate 121 (3.2 g, yield: 83.50%) as a yellow oil.

[0551] The following intermediates were synthesized by methods analogous to those described above for intermediate 121.

[0552]

[0553] Preparation of intermediate 122

[0554]

[0555] To a solution of methyl intermediate 121 (1.8 g, 6.52 mmol) in dioxane (20 mL) was added (4-(methoxycarbonyl)-2-nitrophenyl)boronic acid (1.47 g, 6.52 mmol), Pd(PPh3)4 (0.75 g, 0.65 mmol) and Cs2CO3 (4.25 g, 13.04 mmol). The resulting reaction mixture was stirred at 100 ° C. under a nitrogen atmosphere for 3 h. The mixture was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1) to give intermediate 122 (1.6 g, yield: 79.90%) as a white solid.

[0556] Preparation of intermediate 123

[0557]

[0558] To a solution of intermediate 122 (1 g, 3.26 mmol) in EtOH (20 mL) / water (10 mL) was added Fe (0.91 g, 16.28 mmol) and NHCl (0.87 g, 16.28 mmol). The resulting reaction mixture was stirred at 80 ° C for 2 hours under a nitrogen atmosphere. After the mixture was cooled to rt, it was filtered through celite and the filtrate was concentrated to give intermediate 13 (crude, 600 mg, 75.18%) as a yellow solid, which was used directly in the next step without further purification.

[0559] Preparation of intermediate 126

[0560]

[0561] At 0 DEG C, under nitrogen atmosphere, to the stirring solution of 4- oxo oxane -3- methyl formates (2g, 12.65mmol) in DCM (8mL) add 2,6- two - tert-butyl -4- methyl pyridine (2.60mL, 12.65mmol) in DCM (2mL), then at 0 DEG C under nitrogen dropwise add trifluoromethanesulfonic anhydride (2.10mL, 12.65mmol).Gained reaction mixture is stirred at rt for 16 hours.Solid is filtered off by celite pad, and filtrate is evaporated under reduced pressure, obtains the thick intermediate 126 (3g, 10.34mmol) in yellow oil, it is directly used in the next step without further purification.

[0562] The following intermediates were synthesized by methods analogous to those described above for intermediate 126.

[0563]

[0564] Preparation of intermediate 127

[0565]

[0566] To a mixture of [2-amino-4-(methoxycarbonyl)phenyl]boronic acid (2.02 g, 10.34 mmol) and intermediate 126 (3 g, 10.34 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was added PdCl2(dppf) (0.75 g, 1.03 mmol) and K2CO3 (4.29 g, 31.01 mmol). The resulting mixture was stirred at 100 ° C for 5 hours. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with DCM (100 mL×3). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH:DCM=1:10) to give intermediate 127 (1.5 g, yield: 55.97%) as a white solid.

[0567] The following intermediates were synthesized by methods analogous to those described above for intermediate 127.

[0568]

[0569]

[0570] Preparation of intermediate 132

[0571]

[0572] To a solution of methyl 5-amino-6-chloronicotinate (280 mg, 1.50 mmol) and intermediate 131 (482.79 mg, 1.80 mmol) in dioxane / water (4 / 1 ratio, 6 mL) was added KCO (414.78 mg, 3.00 mmol) and Pd(dppf)Cl (109.79 mg, 0.15 mmol). The resulting reaction mixture was stirred at 100 ° C. under N atmosphere for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with DCM / MeOH (25 / 1)) to give intermediate 132 (150 mg, yield: 38.41%) as a brown solid.

[0573] The following intermediates were synthesized by methods analogous to those described above for intermediate 132.

[0574]

[0575] Preparation of intermediate 135

[0576]

[0577] To a solution of 5-bromo-2-chloropyridin-4-amine (1 g, 4.82 mmol) and intermediate 130 (1.55 g, 5.78 mmol) in dioxane and water (4 / 1, 22 mL) was added KCO (1.33 g, 9.64 mmol) and Pd(dppf)Cl (0.35 g, 0.48 mmol). The resulting reaction mixture was stirred at 100 ° C under an N atmosphere for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with DCM / MeOH (25 / 1) to give intermediate 135 (680 mg, 59.61% yield) as a yellow solid.

[0578] Preparation of intermediate 53

[0579]

[0580] A solution of 5-bromopicolinic acid methyl ester (300 mg, 1.39 mmol), hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid (3aRS, 6aRS)-tert-butyl ester (295 mg, 1.39 mmol), Cs2CO3 (893 mg, 2.74 mmol), RuPhosPdG3 (117 mg, 0.14 mmol) in dioxane (20 mL) was stirred at 100 ° C for 3 hours under a nitrogen atmosphere. The solvent was removed, and the residue was diluted with 30 mL of water and extracted with ethyl acetate (20 mL×2). The combined organic layer was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated. The residue was purified by C18 column (acetonitrile: water (0.1% ammonium bicarbonate) = 5% to 60%) to give intermediate 53 (350 mg, yield: 72.56%) as a yellow solid.

[0581] The following intermediates were synthesized by methods analogous to those described above for intermediate 53.

[0582]

[0583] Preparation of intermediate 54

[0584]

[0585] To a solution of intermediate 53 (350 mg, 1.01 mmol) in THF / MeOH (10 mL / 2 mL) was added a solution of lithium hydroxide in water (3 mL, 1.0 mmol). The mixture was stirred at 20 ° C for 3 hours. The mixture was concentrated, diluted with water, acidified to pH = 5 with 1M HCl (aq.), and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated to give intermediate 54 (280 mg, crude) as a yellow oil, which was used directly in the next step.

[0586] The following intermediates were synthesized by methods analogous to those described above for intermediate 54.

[0587]

[0588] Preparation of intermediate 55

[0589]

[0590] At 25 ° C, DIEA (202 mg, 1.56 mmol), HATU (445 mg, 1.17 mmol) and methylamine hydrochloride (79 mg, 1.17 mmol) were added to a solution of intermediate 54 (260 mg, crude product) in N, N-dimethylformamide (5 mL). The resulting mixture was stirred at rt for 5 h. The solvent was removed, and the residue was diluted with 10 mL of water and extracted with ethyl acetate (10 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1) to give intermediate 55 (180 mg, yield: 66.91%) as a yellow solid.

[0591] The following intermediates were synthesized by methods analogous to those described above for intermediate 55.

[0592]

[0593]

[0594]

[0595] Preparation of intermediate 56

[0596]

[0597] The mixture of intermediate 55 (180mg, 0.52mmol) in TFA (1mL) and DCM (5mL) is stirred at rt for 1hr. Remove solvent, residue is diluted with EtOAc, alkalized with 1MNaOH (aqueous solution), and extracted with EtOAc. The organic phase merged is through Na2SO4 dried, filtered and concentrated to obtain intermediate 56 (90mg, crude product) in yellow oil, which is directly used in the next step.

[0598] The following intermediates were synthesized by methods analogous to those described above for intermediate 56.

[0599]

[0600]

[0601]

[0602] Preparation of intermediate 57

[0603]

[0604] At rt, under N2, to a solution of hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid (3aRS, 6aRS)-tert-butyl ester oxalate (3 g, 14.13 mmol), TEA (1.43 g, 14.13 mmol) in DCM (50 mL) was slowly added a solution of 2,5-dioxopyrrolidine-1-carboxylic acid benzyl ester (3.63 g, 15.55 mmol) in DCM (20 mL). The mixture was stirred at 20 ° C for 12 hours. The mixture was diluted with 20 mL of water and extracted with DCM (20 mL×2). The organic layer was washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to give intermediate 57 (4.3 g, yield: 83.4%) as a white solid.

[0605] Preparation of intermediates 58 and 59

[0606]

[0607] Intermediate 57 (4.3 g, 11.79 mmol) was separated by chiral HPLC (separation conditions: column: 1H-3.0 cm; mobile phase: Hex:EtOH=95:5, 25 mL / min; temperature: 40° C.; wavelength: 214 nm). The first fraction was collected as Intermediate 58 (1.7 g, 100% ee, RT=10.72 min) as a white solid, and the second fraction was collected as Intermediate 59 (1.7 g, 97.65% ee, RT=12.43 min) as a white solid.

[0608] Preparation of intermediate 60

[0609]

[0610] To a solution of intermediate 59 (280 mg, 0.81 mmol) in MeOH (10 mL) was added Pd / C 10% (280 mg, 2.63 mmol). The mixture was stirred under an H atmosphere at rt for 18 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give intermediate 60 (crude) as a white solid, which was used in the next step without further purification.

[0611] The following intermediates were synthesized by methods analogous to those described above for intermediate 60.

[0612]

[0613] Preparation of intermediate 62

[0614]

[0615] A solution of 5-bromopicolinate (200 mg, 0.91 mmol), intermediate 60 (193 mg, 0.91 mmol), Cs2CO3 (591 mg, 1.82 mmol) and RuPhos Pd G3 (76 mg, 0.091 mmol) in dioxane (10 mL) was stirred at 100 ° C for 5 hours under a nitrogen atmosphere. The solvent was removed, and the residue was diluted with water (30 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by C18 column (acetonitrile: water (0.1% ammonium bicarbonate) = 5% to 60%) to obtain intermediate 62 (220 mg, yield: 62.8%) as a yellow solid.

[0616] The following intermediates were synthesized by methods analogous to those described above for intermediate 62.

[0617]

[0618] Preparation of intermediate 63

[0619]

[0620] A solution of intermediate 62 (220 mg, 0.63 mmol) in 33% methylamine ethanol solution (2 mL) was stirred at 60° C. for 12 hours. The mixture was concentrated to give intermediate 63 (200 mg, yield: 82.1%) as a yellow oil, which was used in the next step without further purification.

[0621] The following intermediates were synthesized by methods analogous to those described above for intermediate 63.

[0622]

[0623]

[0624] Preparation of intermediate 64

[0625]

[0626] To a solution of intermediate 63 (200 mg, 0.58 mmol) in DCM (5 mL) was added TFA (0.4 mL, 5.77 mmol). The resulting reaction mixture was stirred at rt for 1 h. The solvent was removed, and the residue was diluted with EtOAc, basified with 1 M NaOH (aqueous solution), and extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered and concentrated to give the crude intermediate 64 (120 mg, yield: 84.4%) as a yellow oil, which was used directly in the next step.

[0627] The following intermediates were synthesized by methods analogous to those described above for intermediate 64.

[0628]

[0629] Preparation of intermediate 65

[0630]

[0631] To a solution of intermediate 60 (120 mg, 0.57 mmol) and 5-bromo-6-fluoropyridine-2-carboxylic acid methyl ester (145 mg, 0.62 mmol) in dioxane (10 mL) was added CsCO (368 mg, 1.13 mmol) and RuPhosPdG (12 mg, 0.014 mmol). The mixture was stirred at 80 ° C for 3 h under N2 atmosphere. The reaction was poured into water (50 mL) and extracted with EtOAc (50 mL × 2). The combined organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography to obtain intermediate 65 (80 mg, yield: 38.73%) as a white solid.

[0632] The following intermediates were synthesized by methods analogous to those described above for intermediate 65.

[0633]

[0634] Preparation of intermediate 66

[0635]

[0636] To a solution of intermediate 66 (80 mg, 0.22 mmol) in EtOH (8 mL) was added a solution of methylamine in EtOH (0.009 mL, 0.018 mmol). The resulting reaction mixture was stirred at 60 ° C for 18 h. The reaction was concentrated under reduced pressure to give intermediate 66 (crude) as a white solid, which was used in the next step without further purification.

[0637] The following intermediates were synthesized by methods analogous to those described above for intermediate 66.

[0638]

[0639]

[0640] Preparation of intermediate 67

[0641]

[0642] To a solution of intermediate 66 (79 mg, 0.22 mmol) in DCM was added EtOAc (6 mL, 4 N) containing HCl. The resulting reaction mixture was stirred at rt for 1 h. The reaction was concentrated under reduced pressure to give intermediate 67 (crude), which was used in the next step without further purification.

[0643] The following intermediates were synthesized by methods analogous to those described above for intermediate 67.

[0644]

[0645]

[0646] Preparation of intermediate 99

[0647]

[0648] To a mixture of intermediate 5 (220 mg, 1.08 mmol) in DCM (20 mL) was added MnO (938 mg, 10.80 mmol) at 0° C. The mixture was stirred at 30° C. under a nitrogen atmosphere for 12 hr. The mixture was filtered off and washed with DCM, and the filtrate was concentrated under reduced pressure to give intermediate 99 (180 mg, crude) as a white solid, which was used directly in the next step.

[0649] Preparation of intermediate 182

[0650]

[0651] At -78 ° C, Li-HMDS (52.3 mL, 52.3 mmol) was added to a solution of ethyl 2-diazoacetate (5.96 g, 52.27 mmol) and oxacyclopentane-2-one (3.00 g, 34.85 mmol) in THF (180 mL). The reaction mixture was stirred at rt for 1.5 h under a nitrogen atmosphere. The reaction mixture was poured into saturated NaHCO (200 mL) and extracted with EtOAc. The combined organic layers were washed with brine. The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (eluted with PE / EtOAc (2 / 1)) to obtain intermediate 182 (3.6 g, yield: 40.14%) as a yellow solid.

[0652] Preparation of intermediate 183

[0653]

[0654] To a solution of intermediate 182 (3.6 g, 17.98 mmol) in toluene (360 mL) was added Rh2(OAc)4 (0.08 g, 0.18 mmol). The reaction mixture was stirred at 80 ° C. under a nitrogen atmosphere for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with PE / EtOAc (3 / 1)) to give intermediate 183 (1.23 g, yield: 39.72%) as a yellow oil.

[0655] Preparation of intermediate 184

[0656]

[0657] Under nitrogen atmosphere, at 0 DEG C, to a solution of intermediate 183 (1.23 g, 7.14 mmol) in DCM (35 mL) was added DCM (35 mL) containing 2,6-di-tert-butyl-4-methylpyridine (1.5 mL, 7.14 mmol). Tf2O (2.014 g, 7.14 mmol) was added to the mixture, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with PE / EtOAc (5 / 1) to give intermediate 184 (900 mg, yield: 41.41%) as a yellow oil.

[0658] The following intermediates were synthesized by methods analogous to those described above for intermediate 184.

[0659]

[0660] Preparation of intermediate 185

[0661]

[0662] To a solution of Intermediate 184 (900 mg, 2.96 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (901 mg, 3.55 mmol) in dioxane (15 mL) was added KOAc (580 mg, 5.92 mmol) and Pd(dppf)Cl (216 mg, 0.30 mmol). The reaction mixture was stirred at 80° C. under a nitrogen atmosphere for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with PE / EtOAc (5 / 1)) to give Intermediate 185 (800 mg, 95.85% yield) as a colorless oil.

[0663] The following intermediates were synthesized by methods analogous to those described above for intermediate 185.

[0664]

[0665] Preparation of intermediate 186

[0666]

[0667] To a solution of intermediate 185 (400 mg, 1.42 mmol) and 5-amino-6-chloropyridine-3-carboxylic acid methyl ester (241 mg, 1.29 mmol) in dioxane / water (5 / 1, 6 mL) was added Pd(dppf)Cl2 (94 mg, 0.13 mmol) and K2CO3 (356 mg, 2.58 mmol). The reaction mixture was stirred at 100 ° C for 3 h under a nitrogen atmosphere. The reaction mixture was diluted with water (30 mL). The reaction mixture was extracted with DCM, and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography (MeOH / DCM=0%-10%) to give intermediate 186 (75 mg, yield: 22.36%) as a white solid.

[0668] The following intermediates were synthesized by methods analogous to those described above for intermediate 186.

[0669]

[0670] Preparation of intermediate 194

[0671]

[0672] To a solution of 6-chloro-5-fluoropyridine-2-carboxylic acid (800 mg, 4.56 mmol) in t-BuOH (5 mL) was added (Boc) O (1.988 g, 9.11 mmol) and DMAP (612 mg, 5.01 mmol). The reaction mixture was stirred at 50 ° C for 16 h under N2 atmosphere. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EtOAc (10 / 1)) to give intermediate 194 (300 mg, yield: 28.42%) as a white solid.

[0673] Preparation of intermediate 195

[0674]

[0675] To a solution of (3aS, 6aS)-3a, 6a-dihydro-octahydropyrrolo [3, 4-c] pyrrole-2-carboxylic acid benzyl ester (212 mg, 0.86 mmol) in DMF (5 mL) was added intermediate 194 (200 mg, 0.86 mmol) and DIEA (558 mg, 4.32 mmol). The reaction mixture was stirred at 100 ° C for 16 h under N2 atmosphere. The reaction mixture was poured into water and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EtOAc (1 / 1)) to give intermediate 195 (350 mg, yield: 88.52%) as a white solid.

[0676] Preparation of intermediate 196

[0677]

[0678] At rt, TFA (2 mL, 26.93 mmol) was added to a solution of intermediate 195 (350 mg, 0.76 mmol) in DCM (2 mL). The reaction mixture was stirred at 40 ° C for 4 h. TFA was removed under vacuum, and the residue was diluted with water, and the mixture was adjusted to pH 2 with aqueous hydrochloric acid (1 M). The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give intermediate 196 (300 mg, yield: 97.68%) as a yellow solid.

[0679] Preparation of intermediate 197

[0680]

[0681] To a solution of intermediate 196 (300 mg, 0.75 mmol) in DMF (5 mL) was added oxetanes-3-amine (545 mg, 7.46 mmol), HATU (852 mg, 2.24 mmol) and DIEA (482 mg, 3.73 mmol). The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with water. The mixture was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with PE / EA (1 / 2)) to give intermediate 197 (300 mg, yield: 87.95%) as a yellow solid.

[0682] Preparation of intermediate 198

[0683]

[0684] To a solution of intermediate 197 (300 mg, 0.66 mmol) in EtOH (5 mL) was added PdCl2 (11 mg, 0.066 mmol). Under an H2 atmosphere, the reaction mixture was stirred at rt for 16 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give intermediate 198 (110 mg, yield: 51.90%) as a yellow solid.

[0685] Preparation of intermediate 199

[0686]

[0687] To a solution of methyl 4-bromo-3-nitrobenzoate (2.0 g, 7.69 mmol) in MeOH (20 mL) and H2O (7 mL) was added Fe (2.2 g, 38 mmol) and NHCl (4.1 g, 77 mmol). The reaction mixture was stirred at 80 ° C for 3 h. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give intermediate 199 (1.7 g, yield: 96.1%) as a yellow oil.

[0688] Preparation of Intermediate 200

[0689]

[0690] To a solution of Intermediate 199 (270 mg, 1.17 mmol) and Intermediate 185 (397 mg, 1.41 mmol) in dioxane / water (6 mL, v / v=10:1) was added KCO (324 mg, 2.35 mmol) and Pd(dppf)Cl (86 mg, 0.12 mmol). The reaction mixture was stirred at 80°C under an N atmosphere for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluted with DCM / MeOH (25:1)) to give Intermediate 200 (131 mg, 43.0% yield) as a yellow solid.

[0691] Preparation of intermediate 203

[0692]

[0693] At 0 ° C, Br2 (1.8 mL, 35.47 mmol) was added dropwise to a solution of methyl 3-amino-2-fluorobenzoate (6000 mg, 35.47 mmol) in HOAc (30 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water (30 mL). The reaction mixture was extracted with ethyl acetate, and the combined organic layers were washed with NaOH solution (1 M) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography (EtOAc / PE=0%-10% to ACN / H2O=5%-95%) to give intermediate 203 (550 mg, yield: 6.25%) as a yellow solid.

[0694] Preparation of intermediate 204

[0695]

[0696] To a solution of intermediate 203 (630 mg, 2.54 mmol) and intermediate 113 (676 mg, 2.54 mmol) in dioxane-water (5 / 1, 20 mL) was added Pd (dppf) Cl2 (186 mg, 0.25 mmol) and K2CO3 (1053 mg, 7.62 mmol). The reaction mixture was stirred at 80 ° C for 16 h under a nitrogen atmosphere. The reaction mixture was diluted with water (30 mL). The reaction mixture was extracted with DCM (30 mL × 3), and the combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography (EtOAc / PE = 0%-50%) to give intermediate 204 (300 mg, yield: 45.21%) as a yellow solid.

[0697] Example 3: Preparation of compounds

[0698] Preparation of compound 2

[0699]

[0700] To the mixture of compound intermediate 56 (50mg, 0.24mmol) and intermediate 99 (60mg, 0.24mmol) in DCE (10mL), sodium triacetoxyborohydride (102mg, 0.48mmol) and AcOH (0.01mL) are added. The reaction mixture is stirred overnight at rt. The mixture is concentrated and purified by preparative HPLC (column: Xbridge C18 (5 μm 19*150mm), mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow velocity: 15mL / min, GT: 10min, gradient: 5%-50% (%B)) to obtain compound 2 (28mg, yield: 27.01%) as a white solid.

[0701] The following compounds were synthesized by methods similar to those described above for compound 2.

[0702]

[0703] Preparation of compound 3

[0704]

[0705] To a solution of intermediate 73 (90 mg, 0.299 mmol) in acetonitrile (10 mL) was added intermediate 12 (81.12 mg, 0.299 mmol) and DIEA (0.049 mL, 0.299 mmol). The mixture was stirred at 80 ° C for 2 h under a nitrogen atmosphere. The mixture was concentrated and the residue was dissolved in DMF (1 ml) and purified by preparative HPLC to give compound 3 (20 mg, yield: 14%) as a white solid.

[0706] The following compounds were synthesized by methods similar to those described above for compound 3.

[0707]

[0708]

[0709]

[0710]

[0711] Preparation of compound 9

[0712]

[0713] To a solution of intermediate 76 (109 mg, 0.39 mmol) in MeCN (10 mL) was added intermediate 6 (100 mg, 0.39 mmol), DIEA (1 mL, 6.05 mmol) and potassium iodide (13 mg, 0.077 mmol). The reaction mixture was stirred at 80 ° C for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (Xbridge C18 (5 μm 19*150 mm), mobile phase A: water (0.1% NH4HCO3), mobile phase B: acetonitrile, UV: 214 nm, flow rate: 15 mL / min, temperature: rt, gradient: 10%-40% (% B)) to give compound 9 (28.8 mg, yield: 17.3%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) 11.82 (s, 1H), 8.41 (d, J = 1.6Hz, 1H), 8.29-8.28 (m, 1H), 7.85 (d, J = 2 .4Hz, 1H), 7.79 (d, J=8.8Hz, 1H), 7.74 (s, 1H), 7.62 (s, 1H), 6.93 (dd, J=8.8, 2.8Hz, 1H), 4.0 3-3.94 (m, 2H), 3.53-3.49 (m, 2H), 3.08 (t, J=9.2Hz, 2H), 2.92-2.89 (m, 2H), 2.77 (d, J=4.8 Hz, 3H), 2.66 (t, J=8.8Hz, 2H), 2.57-2.51 (m, 2H), 2.40-2.39 (m, 2H), 1.18 (t, J=7.2Hz, 3H).

[0714] The following compounds were synthesized by methods similar to those described above for compound 9.

[0715]

[0716] Preparation of compound 15

[0717]

[0718] To a solution of intermediate 64 (150 mg, 0.61 mmol), DIEA (393 mg, 3.04 mmol) and potassium iodide (10 mg, 0.061 mmol) in acetonitrile (20 mL) was added intermediate 6 (51 mg, 0.19 mmol). The resulting reaction mixture was stirred at 80 ° C for 2 h. The mixture was concentrated to give the crude compound, which was purified by preparative HPLC (column: RP-PREP-5Xbire C18 (5 μm 19*150 mm), mobile phase A: water (0.1% NH4HCO3), mobile phase B: acetonitrile, UV: 214 nm, flow rate: 15 mL / min, GT: 10 min, temperature: rt, gradient: 10%-55% (% B)) to give compound 15 (130 mg, yield: 49%) as a white solid.

[0719] 1 H NMR (400MHz, DMSO-d6) δ11.83 (s, 1H), 8.40 (d, J=1.6Hz, 1H), 8.30-8.26 (m, 1H), 7.85 (d, J=2 .8Hz, 1H), 7.79 (d, J=8.8Hz, 1H), 7.74 (s, 1H), 7.62 (s, 1H), 6.92 (dd, J=8.8, 2.8Hz, 1H), 4.0 3-3.92 (m, 2H), 3.53-3.49 (m, 2H), 3.08 (t, J=9.6Hz, 2H), 2.92-2.89 (m, 2H), 2.76 (d, J=4.8H z, 2H), 2.66 (t, J=10.0Hz, 2H), 2.59-2.53 (m, 2H), 2.42-2.36 (m, 2H), 1.18 (t, J=7.2Hz, 3H).

[0720] The following compounds were synthesized by methods similar to those described above for compound 15.

[0721]

[0722] Preparation of compound 27

[0723]

[0724] To a solution of intermediate 67 (33 mg, 0.13 mmol) in acetonitrile (6 mL) was added intermediate 6 (33 mg, 0.15 mmol), DIEA (0.062 mL, 0.38 mmol) and potassium iodide (2 mg, 0.013 mmol). The mixture was stirred at 80 ° C for 3 h. The reaction was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (Xbridge C18 (5 μm 19*150 mm), mobile phase A: water (0.1% NH4HCO3), mobile phase B: acetonitrile, UV: 214 nm, flow rate: 15 mL / min, temperature: rt, gradient: 45%-80% (% B)) to give compound 27 (22.6 mg, yield: 38.80%) as a white solid. 1 HNMR (400MHz, DMSO-d6) 11.82 (s, 1H), 8.40 (d, J = 1.6Hz, 1H), 8.18 (d, J = 4.8Hz, 1H ), 7.74-7.72(m, 2H), 7.62(s, 1H), 7.13-7.08(m, 1H), 4.02-3.93(m, 2H), 3.55(d, J=2.8Hz, 2H), 3.25 (d, J=8.8Hz, 2H), 2.90-2.87 (m, 2H), 2.75 (d, J=4.8Hz, 3H), 2. 66-2.62 (m, 2H), 2.57-2.53 (m, 2H), 2.35 (t, J=4.8Hz, 2H), 1.18 (t, J=7.2Hz, 3H).

[0725] The following compounds were synthesized by methods similar to those described above for compound 27.

[0726]

[0727]

[0728] Preparation of compound 28

[0729]

[0730] To a solution of intermediate 72 (80 mg, 0.27 mmol) in MeCN (10 mL) was added intermediate 6 (70 mg, 0.31 mmol), DIEA (0.6 mL, 3.87 mmol) and potassium iodide (10 mg, 0.060 mmol). The mixture was stirred at 80 ° C for 2 h. After cooling to rt, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (Sunfire C18 (5 μm 19 * 150 mm), mobile phase A: water (0.2% HCOOH), mobile phase B: acetonitrile, UV: 214 nm, flow rate: 15 mL / min, temperature: rt, gradient: 5% -25% (% B)) to give compound 28 (10 mg, yield: 8.3%) as a white solid. 1 HNMR (400MHz, DMSO-d6) 11.83 (s, 1H), 8.41 (d, J = 0.8Hz, 1H), 8.26 (s, 0.5H), 8.18 (d , J=4.8Hz, 1H), 7.74-7.73 (m, 2H), 7.62 (s, 1H), 7.13-7.08 (m, 1H), 4.02-3.93 (m, 2H) , 3.55-3.54 (m, 2H), 3.26 (t, J = 8.8Hz, 2H), 2.91-2.87 (m, 2H), 2.75 (d, J = 4.4Hz, 3H) , 2.64 (t, J=9.2Hz, 2H), 2.57-2.51 (m, 2H), 2.36-2.35 (m, 2H), 1.18 (t, J=7.6Hz, 3H).

[0731] Preparation of compound 37

[0732]

[0733] To a solution of intermediate 105 (43 mg, 0.095 mmol) in DCM (16 mL) and MeOH (1.6 mL) was added MnO2 (164.5 mg, 1.89 mmol). Under N2 atmosphere, the reaction mixture was stirred at rt for 16 hours. After filtering through a celite pad, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with DCM / MeOH (10 / 1)) to give compound 37 (11.5 mg, yield: 23.34%) as a yellow solid.

[0734] Preparation of Compound 40

[0735]

[0736] To a solution of intermediate 108 (80 mg, 0.396 mmol) in DCM (8 mL) and MeOH (2 mL) was added intermediate 67 (104.6 mg, 0.40 mmol), NaBHCn (93.2 mg, 1.48 mmol) and 1 drop of AcOH. The resulting reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with DCM / MeOH (10 / 1)) to give a crude product. The crude product was further purified by preparative HPLC (column: Xbridge C18 (5 μm 19*150 mm), mobile phase A: water (0.2% HCOOH), mobile phase B: acetonitrile, UV: 254 nm, flow rate: 15 mL / min, gradient condition: 5% B to 25% B) to give compound 40 (40 mg, yield: 22.44%) as a white solid. 1 HNMR (400MHz, DMSO-d6) 8.71 (s, 1H), 8.18 (d, J=4.4Hz, 1H), 7.79-7.72 (m, 2H), 7.29 (s, 1H), 710 (dd, J=8.4Hz, 10.8Hz, 1H), 4.08-3.98 (m, 2H ), 3.76-3.70 (m, 2H), 3.29-3.25 (m, 2H), 2.97-2.94 (m, 2H), 2.78-2.68 (m, 5H), 2.53-2.50 (m, 2H), 2.39-2.36 (m, 2H), 1.17 (t, J=7.2Hz, 3H).

[0737] The following compounds were synthesized by methods similar to those described above for compound 40.

[0738]

[0739] Preparation of compound 46

[0740]

[0741] To a solution of intermediate 161 (31.1 mg, 0.11 mmol) and intermediate 16 (25 mg, 0.11 mmol) in CH 3 CN (4 mL) was added DIEA (0.053 mL, 0.321 mmol) and KI (17.0 mg, 0.11 mmol). The mixture was stirred at 80 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with DCM / MeOH (10 / 1)) to give a crude compound. The crude product was further purified by preparative HPLC (column: Xbridge C18 (5 μm 19 * 150 mm), mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 254 nm, flow rate: 15 mL / min, gradient condition: 10% B to 60% B) to give compound 46 (11.6 mg, yield: 22.01%) as a white solid. 1 HNMR (400MHz, DMSO-d6) 11.34 (s, 1H), 8.23 ​​(d, J = 5.2Hz, 1H), 8.16 (d, J = 2.4Hz, 1H), 8.12-8.11 ( m, 1H), 7.87 (d, J = 2.8Hz, 1H), 7.79 (d, J = 8.8Hz, 1H), 7.65 (d, J = 1.6Hz, 1H), 7.10-7.09 (m, 1H), 6 .95-6.93(m, 1H), 6.73-6.71(m, 1H), 4.00-3.92(m, 2H), 3.54-3.50(m, 2H), 3.46-3.40(m, 4H), 3 .26 (s, 3H), 3.08 (t, J=9.6Hz, 2H), 2.94-2.90 (m, 2H), 2.67 (t, J=9.6Hz, 2H), 2.43-2.36 (m, 2H).

[0742] The following compounds were synthesized by methods similar to those described above for compound 46.

[0743]

[0744] Preparation of compound 48

[0745]

[0746] To a solution of intermediate 67 (50 mg, 0.19 mmol) in CH 3 CN (8 mL) was added intermediate 117 (44.40 mg, 0.19 mmol), DIEA (0.031 mL, 0.19 mmol) and KI (9.0 mg, 0.02 mmol). The reaction mixture was stirred at 80 ° C for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with DCM / MeOH (10 / 1)) to give a crude product, which was further purified by preparative HPLC (Xbridge C18 5um 19 * 150mm, 10-50% B); mobile phase: B (ACN), mobile phase: A (HO (0.1% NH 4 HCO 3)) to give compound 48 (12.3 mg, 0.026 mmol, 13.62%) as a white solid. 1 H NMR (400MHz, DMSO-d6) 11.66 (s, 1H), 8.41 (d, J=2.0Hz, 1H), 8.20-8.17 (m, 1H), 7.74-7. 72 (m, 1H), 7.65 (d, J=1.6Hz, 1H), 7.13-7.08 (m, 1H), 4.02-3.93 (m, 2H), 3.55 (t, J=5.6H z, 2H), 3.26 (t, J=7.2Hz, 2H), 3.16 (t, J=7.6Hz, 2H), 2.90-2.86 (m, 2H), 2.80 (t, J=7.2H z, 2H), 2.74 (d, J=4.8Hz, 3H), 2.67-2.61 (m, 2H), 2.50-2.32 (m, 2H), 2.15-2.07 (m, 2H).

[0747] The following compounds were synthesized by methods similar to those described above for compound 48.

[0748]

[0749]

[0750] Preparation of compound 52

[0751]

[0752] To a solution of intermediate 168 (60 mg, 0.20 mmol) in MeCN (5 mL) was added intermediate 117 (43.2 mg, 0.20 mmol), DIEA (0.162 mL, 0.979 mmol) and KI (3.3 mg, 0.020 mmol). The resulting reaction mixture was stirred at 80 ° C for 2 hours. The reaction mixture was evaporated under vacuum. The residue was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product, which was purified by preparative HPLC (XBridge C18 (5 μm 19 * 150 mm), mobile phase A: water (0.1% NH4HCO3), mobile phase B: acetonitrile, UV: 254 nm, flow rate: 15 mL / min, gradient: 45% -80% (% B)) to give compound 52 (30 mg, yield: 30.36%) as a white solid. 1 H NMR (400MHz, DMSO-d6) 11.65 (s, 1H), 8.86 (d, J=6.8Hz, 1H), 8.41 (d, J=1.6Hz, 1H), 7.73 (dd, J= 8.4Hz, 1.6Hz, 1H), 7.65 (d, J=1.6Hz, 1H), 7.11 (dd, J=10.8Hz, 8.4Hz, 1H), 5.02-4.93 (m, 1H), 4 .70-4.63(m, 4H), 3.43-3.93(m, 2H), 3.57-3.56(m, 2H), 3.31-3.25(m, 2H), 3.18-3.14(m, 2H), 2.90-2.87(m, 2H), 2.82-2.79(m, 2H), 2.67-2.62(m, 2H), 2.40-2.31(m, 2H), 2.15-2.07(m, 2H).

[0753] The following compounds were synthesized by methods similar to those described above for compound 48.

[0754]

[0755] Preparation of compound 54

[0756]

[0757] To a solution of intermediate 67 (185 mg, 0.70 mmol) in MeOH (5 mL) was added intermediate 120 (150 mg, 0.70 mmol). After the reaction mixture was stirred at rt for 1 hour, NaBH was added CN (132.00 mg, 0.21 mmol) and 1 drop of HOAc were added, and the resulting reaction mixture was stirred overnight at rt. The reaction mixture was concentrated to give residue, which was passed through preparative HPLC (XBridge C18 (5 μm 19*150 mm), mobile phase A: water (0.2% TFA), mobile phase B: acetonitrile, UV: 254 nm, flow velocity: 15 mL / min, gradient: 45%-80% (% B)) to give compound 54 (30 mg, yield: 9.29%) as a white solid. 1 H NMR (400MHz, DMSO-d6) 11.81 (s, 1H), 8.68 (s, 1H), 8.18 (d, J = 5.2Hz, 1H), 7.74 (dd, J = 8.0Hz, 1.6Hz, 1H), 7.34 (s, 1H), 7.11 (dd, J = 10.4Hz, 8.4Hz, 1H), 4 .17-4.08(m, 2H), 3.58-3.56(m, 2H), 3.31-3.27(m, 2H), 3.17-3.13(m, 2H), 3.06-3.02 (m, 2H), 2.82-2.74 (m, 7H), 2.40-2.41 (m, 2H), 2.16-2.08 (m, 2H).

[0758] The following compounds were synthesized by methods similar to those described above for compound 54.

[0759]

[0760]

[0761] Preparation of Compound 60

[0762]

[0763] To a solution of intermediate 125 in CH3CN (10 mL) was added intermediate 67 (112 mg, 0.43 mmol), DIEA (166 mg, 1.29 mmol) and potassium iodide (7 mg, 0.04 mmol). The reaction mixture was stirred at 80 ° C for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (C18 (5 μm 19*150 mm), mobile phase A: water (0.2% HCOOH), mobile phase B: acetonitrile, UV: 214 nm, flow rate: 15 mL / min, temperature: rt, gradient: 10%-25% (% B)) to give compound 60 (16 mg, yield: 8.14%) as a white solid. 1 H NMR (400MHz, DMSO-d6) 11.78 (s, 1H), 8.18-8.14 (m, 1.5H), 7.72 (dd, J=8.4Hz, J=2. 0Hz, 1H), 7.44-7.41 (m, 2H), 7.21-7.18 (m, 1H), 7.13-7.08 (m, 1H), 5.29 (t, J=3.6Hz , 2H), 4.96 (t, J=3.6Hz, 2H), 4.05-3.92 (m, 2H), 3.56-3.53 (m, 2H), 3.28-3.23 (m, 2 H), 2.91-2.88 (m, 2H), 2.74 (d, J=4.8Hz, 3H), 2.68-2.64 (m, 2H), 2.38-2.33 (m, 2H).

[0764] The following compounds were synthesized by methods similar to those described above for compound 60.

[0765]

[0766]

[0767] Preparation of compound 66

[0768]

[0769] To a solution of intermediate 67 (42.34 mg, 0.16 mmol) in MeCN (5 mL) was added DIEA (0.13 mL, 0.80 mmol), potassium iodide (2.6 mg, 0.016 mmol) and intermediate 129 (40 mg, 0.16 mmol). The resulting solution was stirred at 80 ° C for 2 hours. The reaction mixture was evaporated under vacuum. The crude material was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product, which was purified by preparative HPLC (XBridge C18 (5 μm 19*150 mm), mobile phase A: water (0.2% FA), mobile phase B: acetonitrile, UV: 254 nm, flow rate: 15 mL / min, gradient: 45%-80% (% B)) to give compound 66 (30 mg, yield: 37.50%) as a white solid. 1 H NMR (400MHz, DMSO-d6) 11.70 (s, 1H), 8.17 (d, J=5.2Hz, 1H), 8.14 (s, 0.85H), 7.73 (dd, J= 8.0Hz, 2.0Hz, 1H), 7.62 (d, J=8.0Hz, 1H), 7.32 (s, 1H), 7.20 (dd, J=8.4Hz, 0.8Hz, 1H), 7.1 0 (dd, J=10.8Hz, 8.4Hz, 1H), 4.45 (s, 2H), 3.97-3.91 (m, 4H), 3.57-3.53 (m, 2H), 3.29-3.2 4 (m, 2H), 2.91-2.86 (m, 4H), 2.74 (d, J=4.8Hz, 3H), 2.68-2.63 (m, 2H), 2.39-2.30 (m, 2H).

[0770] The following compounds were synthesized by methods similar to those described above for compound 66.

[0771]

[0772] Preparation of compound 69

[0773]

[0774] To a solution of intermediate 129 in MeCN (5 mL) was added intermediate 168 (60 mg, 0.20 mmol), DIEA (0.08 mL, 0.60 mmol) and potassium iodide (3.2 mg, 0.02 mmol). The resulting solution was stirred at 80 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (XBridge C18 (5 μm 19*150 mm), mobile phase A: water (0.2% FA), mobile phase B: acetonitrile, UV: 254 nm, flow rate: 15 mL / min, gradient: 5%-30% (% B)) to give compound 69 (10 mg, yield: 9.9%) as a white solid. 1 H NMR (400MHz, DMSO-d6) 12.70 (s, 1H), 8.86 (d, J = 6.8Hz, 1H), 8.15 (s, 0.71H), 7.74-7.7 2 (m, 1H), 7.62 (d, J = 8.4Hz, 1H), 7.32 (s, 1H), 7.20 (d, J = 8.0Hz, 1H), 7.13-7.08 (m, 1H), 5.00-4.95(m, 1H), 4.70-4.64(m, 4H), 4.45(s, 2H), 4.01-3.91(m, 4H), 3.57-3.48(m, 2 H), 3.27 (t, J=8.8Hz, 2H), 2.91-2.86 (m, 4H), 2.63 (t, J=8.8Hz, 2H), 2.39-2.33 (m, 2H).

[0775] Preparation of compound 71

[0776]

[0777] To a solution of intermediate 134 (50 mg, 0.189 mmol) in CH 3 CN (8 mL) was added intermediate 67 (47.43 mg, 0.189 mmol), DIEA (73.28 mg, 0.57 mmol) and KI (8.98 mg, 0.02 mmol). The resulting reaction mixture was stirred at 80 ° C for 2 hr. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with DCM / MeOH (10 / 1)) to give a crude product, which was further purified by preparative HPLC (Xbridge C18 5um 19 * 150mm 5%-25% B); mobile phase: B (ACN), mobile phase: A (HO (0.2% HCOOH)) to give compound 71 (13.9 mg, 15.3% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) 11.83 (s, 1H), 8.45 (d, J=1.6Hz, 1H), 8.20-8.15 (m, 1.7H), 7.72 (d d, J=8.0Hz, J=1.6Hz, 1H), 7.65 (d, J=1.2Hz, 1H), 7.13-7.08 (m, 1H), 4.47 (s, 2H), 4.05-3. 95 (m, 2H), 3.92 (t, J = 5.6Hz, 2H), 3.59-3.52 (m, 2H), 3.26 (t, J = 8.8Hz, 2H), 3.00-2.94 (m, 2H), 2.91-2.87 (m, 2H), 2.74 (d, J=4.8Hz, 3H), 2.65 (t, J=10.4Hz, 2H), 2.38-2.32 (m, 2H).

[0778] The following compounds were synthesized by methods similar to those described above for compound 71.

[0779]

[0780] Preparation of compound 73

[0781]

[0782] To a solution of intermediate 134 (100 mg, 0.40 mmol) and intermediate 172 (133.4 mg, 0.40 mmol) in CH 3 CN (8 mL) was added DIEA (154.7 mg, 1.20 mmol) and KI (6.4 mg, 0.04 mmol). The resulting reaction mixture was stirred at 80 ° C for 2 hr. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with DCM / MeOH (10 / 1)) to give a crude product. The crude product was further purified by preparative HPLC (column: Sun Fire C185um 19 * 150mm; mobile phase: B (ACN), mobile phase: A (HO (0.2% HCOOH), UV: 254 nm, flow rate: 15 mL / min, gradient: 10% -25% B) to give compound 73 (18.5 mg, yield: 8.40%) as a white solid. 1H NMR (400MHz, DMSO-d6) 11.84 (s, 1H), 8.45 (d, J = 1.6Hz, 1H), 8.33 (d, J = 8.4Hz, 1H), 8. 18(s, 0.47H), 7.73-7.70(m, 1H), 7.65(d, J=1.2Hz, 1H), 7.12-7.08(m, 1H), 4.47(s, 2H ), 4.04-3.91 (m, 5H), 3.59-3.54 (m, 3H), 3.27 (t, J=8.8Hz, 4H), 3.13 (s, 3H), 2.99-2.9 6(m, 2H), 2.97-2.87(m, 2H), 2.67-2.62(m, 2H), 2.39-2.33(m, 2H), 2.05-1.98(m, 2H).

[0783] Preparation of compound 77

[0784]

[0785] To a solution of intermediate 67 (50 mg, 0.19 mmol) in DCM (8 mL) and MeOH (2 mL) was added intermediate 137 (52.26 mg, 0.23 mmol), HOAc (35.3 mg, 0.19 mmol) and NaBH(OAc) (198.64 mg, 0.95 mmol). The resulting reaction mixture was stirred at rt for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with DCM / MeOH (10 / 1)) to give a crude product. The crude product was further purified by preparative HPLC (Xbridge C18 5um 19*150mm 5%-25%B); mobile phase: B (ACN), mobile phase: A (HO (0.2% HCOOH)) to give compound 77 (25.5 mg, yield: 27.96%) as a white solid. 1 H NMR (400MHz, DMSO-d6) 11.93 (s, 1H), 8.79 (s, 1H), 8.19-8.15 (m, 1.88H), 7.75-7.72 (m, 1H), 7.32 (s, 1H), 7.13-7.09 (m, 1H), 4.45 (s, 2H), 4 .10-4.00 (m, 2H), 3.93 (t, J=5.6Hz, 2H), 3.61-3.52 (m, 2H), 3.28 (t, J=8.8Hz, 2H), 3.01-2.91 (m, 4H), 2.75-2.67 (m, 5H), 2.44-2.33 (m, 2H).

[0786] Preparation of compound 81

[0787]

[0788] To a solution of intermediate 188 (55 mg, 0.22 mmol) in MeCN (10 mL) was added intermediate 67 (58 mg, 0.22 mmol), KI (36 mg, 0.22 mmol) and DIEA (28 mg, 0.22 mmol). The reaction mixture was heated to 80 ° C and stirred for 2 h. The reaction mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (SunFire C18 5 μm; 19*150 mm; 10%-25% B); mobile phase: B (ACN), mobile phase: A (HO (0.2% HCOOH)) to give compound 81 (3.9 mg, yield: 3.60%) as a white solid. 1 H NMR (400MHz, DMSO-d6) 11.83 (s, 1H), 8.38 (d, J=1.6Hz, 1H), 8.34 (s, 1.43H), 8.19-8. 16 (m, 1H), 7.74-7.71 (m, 1H), 7.57 (d, J=1.2Hz, 1H), 7.13-7.08 (m, 1H), 4.22 (t, J=4. 0Hz, 2H), 3.99-3.90(m, 2H), 3.60-3.51(m, 2H), 3.26(t, J=8.4Hz, 2H), 2.91-2.86(m, 4H), 2.74 (d, J=4.8Hz, 3H), 2.67-2.60 (m, 2H), 2.38-2.31 (m, 2H), 2.01-1.98 (m, 2H).

[0789] Preparation of Compound 82

[0790]

[0791] To a solution of intermediate 193 (105 mg, 0.42 mmol) and intermediate 67 (93 mg, 0.35 mmol) in MeCN (10 mL) was added DIEA (137 mg, 1.06 mol) and KI (6 mg, 0.04 mmol). The reaction mixture was stirred at 80 ° C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with DCM / MeOH (10 / 1)) to give a crude product, which was further purified by preparative HPLC (column: SunFire C18 5um 19*150mm; mobile phase: B (ACN), mobile phase: A (HO (0.2% HCOOH), UV: 254 nm, flow rate: 15 mL / min, gradient: 5%-35% B) to give compound 82 (9 mg, yield: 5.32%) as a white solid. 1 H NMR (400MHz, DMSO-d6) 11.66 (s, 1H), 8.41 (d, J = 1.6Hz, 1H), 8.17 (d, J = 4.8 Hz, 1H), 7.74-7.72 (m, 1H), 7.60 (s, 1H), 7.11-7.10 (m, 1H), 3.98-3.96 (m, 2H), 3.55-3.54(m, 2H), 3.26-3.21(m, 4H), 2.95(s, 2H), 2.90-2.87(m, 2H) , 2.74 (d, J=4.8Hz, 3H), 2.67-2.61 (m, 2H), 2.37-2.33 (m, 2H), 1.76 (s, 4H).

[0792] The following compounds were synthesized by methods similar to those described above for compound 82.

[0793]

[0794] Preparation of compound 87

[0795]

[0796] To a solution of intermediate 168 (65.3 mg, 0.21 mmol) in MeCN (5 mL) was added DIEA (0.18 mL, 1.07 mmol), KI (3.55 mg, 0.02 mmol) and intermediate 181 (50 mg, 0.21 mmol). The resulting solution was stirred at 80 ° C for 2 hours. The reaction mixture was evaporated under vacuum. The crude material was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product, which was purified by preparative HPLC (XBridge C18 (5 μm 19*150 mm), mobile phase A: water (0.1% NH4HCO3), mobile phase B: acetonitrile, UV: 254 nm, flow rate: 15 mL / min, gradient: 45%-80% (% B)) to give compound 87 (50 mg, yield: 46.43%) as a white solid. 1 H NMR (400MHz, DMSO-d6) 11.50 (s, 1H), 8.86 (d, J = 6.8Hz, 1H), 7.73 (dd, J = 8.0Hz, 1.6Hz, 1H), 7 .47(d, J=8.0Hz, 1H), 7.33(s, 1H), 7.17-7.08(m, 2H), 5.00-4.93(m, 1H), 4.70-4.63(m, 4H), 3.93(dd, J=26.8Hz, 14.0Hz, 2H), 3.57-3.55(m, 2H), 3.31-3.25(m, 2H), 3.09-3.06(m, 2H), 2 .89-2.86 (m, 2H) 2.77-2.74 (m, 2H), 2.66-2.61 (m, 2H), 2.36-2.33 (m, 2H), 2.13-2.06 (m, 2H).

[0797] The following compounds were synthesized by methods similar to those described above for compound 87.

[0798]

[0799] Preparation of Compound 88

[0800]

[0801] To a solution of intermediate 67 (50 mg, 0.19 mmol) and intermediate 202 (40 mg, 0.16 mmol) in MeCN (10 mL) was added DIEA (72 mg, 0.56 mmol) and KI (3.1 mg, 0.019 mmol). The reaction mixture was stirred at 80 ° C for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with DCM / MeOH (10 / 1)) to give a crude product, which was further purified by preparative HPLC (column: SunFire C18 5 μm 19 * 150 mm; mobile phase: B (ACN), mobile phase: A (HO (0.2% HCOOH), UV: 254 nm, flow rate: 15 mL / min, gradient: 5% -35% B) to give compound 88 (38.5 mg, yield: 42.6%) as a white solid. 1 H NMR (400MHz, DMSO-d6) 11.66 (s, 1H), 8.23 ​​(s, 1H), 7.74-7.71 (m, 1H), 7.48 (d , J=8.4Hz, 1H), 7.25 (s, 1H), 7.16-7.08 (m, 2H), 4.15 (t, J=4.8Hz, 2H), 3.95- 3.85(m, 2H), 3.55-3.54(m, 3H), 3.25(t, J=8.8Hz, 2H), 2.88-2.85(m, 2H), 2. 80-2.74 (m, 4H), 2.62 (t, J=10Hz, 2H), 2.37-2.33 (m, 2H), 2.04-2.00 (m, 2H).

[0802] The following compounds were synthesized by methods similar to those described above for compound 82.

[0803]

[0804]

[0805] Example 4: General protocol for LCMS (liquid chromatography / mass spectrometry)

[0806] Use LC pump, diode array (DAD) or UV detector and as specified in the corresponding method post to carry out high performance liquid chromatography (HPLC) measurement.The stream from post is brought to a mass spectrometer (MS) configured with an atmospheric pressure ion source. Tuning parameters (for example, scan range, dwell time etc.) are set so that the ion of the nominal monoisotopic molecular weight (MW) of the compound of interest is within the knowledge of the technician. Carry out data acquisition with suitable software.

[0807] Compounds are described by their experimental retention time (Rt) and ion. If not specified differently in the data table, the reported molecular ion corresponds to [M+H] + (protonated molecules) and / or [MH] - (deprotonated molecule). All results are obtained with experimental uncertainties generally associated with the methods used.

[0808] Method 1: Instrument: Agilent Technologies 1200 Series, G1329A; Column: Xbridge C18, 5μm4.6*50mm; Mobile phase: A: 0.05% TFA; B: CH3CN; Gradient: 95% A for 0.01min, to 40% A within 4.49min, then to 5% A within 0.30min, hold for 1.00min, return to 95% A within 0.20min, hold for 0.50min; Flow rate and column temperature: 1.5mL / min, 40℃; Run time: 6.5min.

[0809] Method 2: Instrument: Agilent Technologies 1200 Series, G1329A; Column: Xbridge C18, 5μm4.6*50mm; Mobile phase: A: 0.05% TFA; B: CH3CN; Gradient: 95% A for 0.01min, to 5% A within 4.49min, hold for 1.30min, return to 95% A within 0.20min, hold for 0.50min; Flow rate and column temperature: 1.5mL / min, 40℃; Run time: 6.5min.

[0810] Method 3: Instrument: SHIMADZU SIL-20A; Column: Xbridge C18, 5μm4.6*50mm; Mobile phase: A: 0.02% NH4OAc; B: CH3CN; Gradient: 95% A for 0.01min, to 40% A within 4.49min, then to 5% A within 0.30min, hold for 1.00min, return to 95% A within 0.20min, hold for 0.50min; Flow rate and column temperature: 1.5mL / min, 40℃; Run time: 6.5min.

[0811] Method 4: Instrument: SHIMADZU SIL-20A; Column: Proshell-EC-C18, 5μm4.6*50mm; Mobile phase: A: 0.05% TFA; B: CH3CN; Gradient: 95% A for 0.01min, to 60% A within 4.49min, then to 5% A within 0.30min, hold for 1.00min, return to 95% A within 0.20min, hold for 0.50min; Flow rate and column temperature: 1.0mL / min, 40℃; Run time: 6.5min.

[0812] Method 5: Instrument: Agilent Technologies 1200 Series, G6130A; Column: Xbridge C18, 3.5 μm 4.6*50 mm; Mobile phase: A: 0.05% TFA; B: CH3CN; Gradient: 95% A for 0.50 min, to 5% A within 3.50 min, hold for 1.50 min, return to 95% A within 0.10 min, hold for 0.40 min; Flow rate and column temperature: 1.5 mL / min, 40°C; Run time: 6.0 min.

[0813] Example 5: Analyzing Data

[0814] Analytical information for the compounds above or in the table below.

[0815]

[0816]

[0817]

[0818] Example 6: PARP1-DNA Enzymatic Capture Assay

[0819] The enzymatic capture assay was designed to measure the dissociation of PARP1 from fluorescein-labeled DNA during enzymatic activity. The assay was performed in a total 10 μL reaction volume, including 10 nM PARP1 and 5 nM DNA probe in binding buffer (50 mM Tris-HCl pH 8.0, 50 mM NaCl, 1 mM MgCl2, 0.1 mM EDTA, and 0.01% IGEPAL), and was initiated by adding NAD+ substrate to a final concentration of 2 mM.

[0820] PARP1 poly ADP ribosylation (PARylation) inhibition assay was performed with compounds dissolved in DMSO at a starting concentration of 5 μM. The dissolved compounds were added to a 384-well microplate and pre-mixed with PARP1 enzyme and DNA probe for 20 minutes of incubation. The enzymatic reaction was initiated by adding NAD+ to the mixture and the enzyme was detected by a microplate reader (VICTOR Each well was read by a fluorescence polarization analyzer (PerkinElmer) to detect the fluorescence polarization signal at 480 nm excitation / 530 nm dual emission.

[0821] All measured ICs 50 Values ​​were calculated using a four-parameter dose-response inhibition model in GraphPad Prism 8.0.2 (La Jolla, California, USA, www.graphpad.com).

[0822] Example 7: PARP2-FL displacement assay

[0823] A potent PARP inhibitor conjugated to a BDY FL fluorophore (PARPi-FL, catalog number 6461, Tocris Bioscience) was used to characterize the activity of PARP2 by measuring the displacement of PARPi-FL binding to PARP2. The test compound was prepared at a concentration of 1 mM-10 mM and a 3-fold serial dilution was prepared in a polypropylene plate (Bio-One small volume microplate, black, catalog number 784076, Greiner) using 100 nL of test compound to be dispensed into a 384-well polypropylene microplate and 10 μL of a reaction solution containing premixed 20 nM PARP2 and 3 nM PARPi-FL was added. After incubation for 4 hours at room temperature, the cells were stained with VICTOR Fluorescence polarization signals were measured using a multimode plate reader (PerkinElmer) under dual emission conditions of 480 / 30 nm excitation and 530 / 30 nm. 50 Values ​​were calculated using a four-parameter dose-response inhibition model in GraphPad Prism 8.0.2 (La Jolla, CA, USA, www.graphpad.com).

[0824] Example 8: Cell proliferation assay

[0825] For PARPi sensitivity, exponentially growing MDA-MB-436 and DLD1BRCA2 - / -Cells were seeded at very low density in 96- or 384-well plates, aiming to not split for at least 7 days (typically 0.3k-1.2k cells / well). Cells were plated on day 1 and treated with DMSO or increasing concentrations of PARP1 inhibitors on day 0. At the end of the experiment, cell viability was estimated using Cell-Titer Glo (Promega).

[0826] The results of Examples 6 to 8 are shown in the following table.

[0827]

[0828]

[0829]

[0830] Example 9: Efficacy Study of Tumor / Plasma Ratio in Mice

[0831] 1×10 7 MDA-MB-436 cells were implanted subcutaneously into the flank of female NOD-SCID mice (6-8 weeks old, weighing approximately 18g-22g). 3 -180mm 3Mice were randomly assigned to treatment groups at 4:00 p.m. on day 29. Compounds were administered to mice continuously for 28 days. On day 29, blood (50 μL) and tumor tissue samples were collected 24 hours after the last dose. The collected blood samples were then centrifuged at 4,600 rpm for 5 minutes at 4°C to obtain plasma. To determine the compound levels in the plasma samples, each plasma sample was prepared using the appropriate dilution factor and compared to an 11-point standard calibration curve (1 ng / mL-5,000 ng / mL) prepared in DMSO and spiked into blank plasma. Acetonitrile (200 μL) was added to 20 μL of plasma sample along with the internal standard, followed by centrifugation at 5,500 rpm for 10 minutes. The supernatant (150 μL) was then diluted in water (150 μL) and analyzed by LC-MS / MS. The tumor tissue samples were weighed and then homogenized with 80% methanol at a ratio of 1:5 or 1:10 (tumor weight (g) to methanol volume (ml)). Acetonitrile (300 μL) was added to 30uL tumor homogenate samples along with the internal standard. The samples were vortexed for 30s and then centrifuged at 5,500rpm for 10min at 4°C. The supernatant (150 μL) was transferred to a 96-well plate, diluted with water (150 μL), and analyzed by LC-MS / MS. If the sample concentration in the initial determination was not within the range of the given standard curve, the appropriate dilution and concentration procedures were used in the repeated tests. The results are shown in the table below. Compared to the reference compound (AZD5305), the compounds described herein exhibited significantly higher tumor / plasma ratios, which indicated better tumor penetration and retention.

[0832]

[0833] The foregoing embodiments are exemplary only, and those skilled in the art will recognize, or will be able to ascertain using no more than routine experimentation, many equivalents to the specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of the present invention and are encompassed by the appended claims.

Claims

1. A compound of formula (I): or a stereoisomer thereof, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein: ---- Is a single bond or a double bond; X 1 It's CR a1 、C(R a1 )2 or NR a1 ; X 2 It's CR a2 、C(R a2 )2、N、NR a2 or O; Each R a1 are independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or C1-C6 alkoxy; Each R a2 are independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or C1-C6 alkoxy; or R a1 and R a2 Together with the atoms to which they are attached, they form a 3- to 6-membered ring B; X 3 It's CR a3 or N; R a3 is hydrogen, C1-C6 alkyl or halogen; X 4 It's CR a4 or N; R a4 is hydrogen, C1-C6 alkyl or halogen; R a5 is hydrogen, C1-C6 alkyl or halogen; Ring A is a fused, bridged or spiro heterocyclic group; Y 1 It's CR 2 or N; Y 2 It's CR 2 or N; Each R 2 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C8 cycloalkyl; R is halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)-R 3 、-C(=O)- OR 3 、-C(=O)-NHR 3 、-S(O)2-R 3 、-NH-C(=O)-R 3 or nitro; R 3 is hydrogen, C1-C6 alkyl, (C1-C6 alkoxy)-(C1-C6 alkyl), C3-C8 cycloalkyl, or a 4- to 10-membered heterocyclyl; and wherein the alkyl, cycloalkyl, alkoxy, heterocyclyl, Ring A and Ring B are optionally substituted; The condition is that when yes When (i) Ring A is a fused or spiro heterocyclic group; or (ii) R is -C(=O)-NHR 3 .

2. The compound according to claim 1, wherein Y 1 It's CR 2 And Y 2 It's N.

3. The compound according to claim 1, wherein Y 1 is N and Y 2 It's CR 2 .

4. The compound according to claim 1, wherein Y 1 It's CR 2 And Y 2 It's CR 2 .

5. The compound according to any one of claims 1 to 4, wherein R is -C(=O)-NHR 3 .

6. The compound according to any one of claims 1 to 4, wherein R is -CN.

7. The compound according to claim 1, which is a compound of formula (IA): or a stereoisomer thereof, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

8. A compound according to any one of claims 1 to 7, wherein It's a double bond.

9. The compound according to claim 8, wherein X 1 It's CR a1 And X 2 It's N.

10. The compound according to any one of claims 1 to 7, wherein It is a single bond.

11. The compound according to claim 10, wherein X 1 It is CH(R a1 ) and X 2 It's O.

12. The compound according to claim 10, wherein X 1 It is CH(R a1 ) and X 2 It is NR a2 .

13. A compound according to any one of claims 1 to 12, wherein R a1 It is a C1-C4 alkyl group or a C1-C4 fluoroalkyl group.

14. The compound according to claim 13, wherein R a1 is methyl, ethyl, isopropyl, cyclopropyl, 1,1-difluoroethyl, 1-fluoroethyl, trifluoromethyl, difluoromethyl or methoxy.

15. The compound according to claim 14, wherein R a1 It is methyl or ethyl.

16. A compound according to any one of claims 1 to 7, wherein R a1 and R a2 Together with the atoms to which they are attached, they form a 3- to 6-membered ring B.

17. The compound according to claim 16, which is a compound of formula (IB), (IC) or (ID): or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof. The compound according to claim 16 , wherein Ring B is a 4- to 6-membered heterocyclic group. The compound according to claim 18 , wherein the heterocyclic group is an oxygen-containing heterocyclic group.

20. The compound according to claim 16, wherein Ring B is a 5-membered heteroaryl. The compound according to claim 16 , wherein Ring B is a 5-membered or 6-membered cycloalkenyl group.

22. The compound according to any one of claims 1 to 21, wherein Ring B is unsubstituted.

23. A compound according to any one of claims 1 to 22, wherein X 3 It's CR a3 .

24. A compound according to any one of claims 1 to 22, wherein X 3 It's N.

25. A compound according to any one of claims 1 to 24, wherein X 4 It's CR a4 .

26. A compound according to any one of claims 1 to 24, wherein X 4 It's N.

27. The compound of claim 1, wherein the compound is a compound of Formula (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), (II-J), (II-K), (II-L), (II-M), (II-N), (II-O), (II-P), (II-Q), (II-R), (II-S), (II-T), (II-U), (II-V), (II-W), (II-X), (II-Y), (II-Z), (II-AA), (II-AB), (II-AC), (II-AD), (II-AE), (II-AF), (II-AG), (II-AH), (II-AI), or (II-AJ): or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof.

28. A compound according to any one of claims 1 to 27, wherein R a5 It's hydrogen.

29. A compound according to any one of claims 1 to 27, wherein R a5 It's fluorine.

30. The compound according to any one of claims 1 to 29, wherein Ring A is a fused bicyclic heterocyclyl.

31. The compound according to any one of claims 1 to 29, wherein Ring A is a spiro bicyclic heterocyclyl.

32. The compound of any one of claims 1 to 29, wherein Ring A is a bridged bicyclic heterocyclyl.

33. The compound according to any one of claims 1 to 32, wherein Ring A contains only two heteroatoms, both of which are nitrogen.

34. The compound according to claim 33, wherein Ring A is Where * is toward the connecting ring A and contains X 4 The orientation of the methylene groups of the ring.

35. The compound according to any one of claims 1 to 34, wherein Ring A is unsubstituted.

36. The compound of claim 1, wherein the compound is a compound of Formula (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (III-I), (III-J), (III-K), (III-L), (III-M), (III-N), (III-O), (III-P), (III-Q), (III-R), (III-S), (III-T), (III-U), (III-V), (III-W), (III-X), (III-Y), (III-Z), (III-AA), (III-AB), (III-AC), (III-AD), (III-AE), (III-AF), (III-AG), (III-AH), (III-AI), or (III-AJ): or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof.

37. The compound according to any one of claims 1 to 36, wherein ring A is cis 38. A compound according to any one of claims 1 to 36, wherein ring A is trans 39. The compound according to claim 38, wherein Ring A is 40. The compound according to claim 38, wherein Ring A is 41. A compound according to claim 1, which is a compound of Formula (IV-A1), (IV-B1), (IV-C1), (IV-D1), (IV-E1), (IV-F1), (IV-G1), (IV-H1), (IV-I1), (IV-J1), (IV-K1), (IV-L1), (IV-M1), (IV-N1), (IV-O1), (IV-P1), (IV-Q1), (IV-R1), (IV-S1), (IV-T1), (IV-U1), (IV-V1), (IV-W1), (IV-X1), (IV-Y1), (IV-Z1), (IV-AA1), (IV-AB1), (IV-AC1), (IV-AD1), (IV-AE1), (IV-AF1), (IV-AG1), (IV-AH1), (IV-AI1), or (IV-AJ1): or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof.

42. A compound according to claim 1, which is a compound of Formula (IV-A2), (IV-B2), (IV-C2), (IV-D2), (IV-E2), (IV-F2), (IV-G2), (IV-H2), (IV-I2), (IV-J2), (IV-K2), (IV-L2), (IV-M2), (IV-N2), (IV-O2), (IV-P2), (IV-Q2), (IV-R2), (IV-S2), (IV-T2), (IV-U2), (IV-V2), (IV-W2), (IV-X2), (IV-Y2), (IV-Z2), (IV-AA2), (IV-AB2), (IV-AC2), (IV-AD2), (IV-AE2), (IV-AF2), (IV-AG2), (IV-AH2), (IV-AI2), or (IV-AJ2): or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof.

43. The compound of claim 42, which is a compound of formula (IV-V2-1), (IV-AA2-1), (IV-AB2-1), or (IV-AI2-1): or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3, or 4; n is 1, 2, 3, or 4; Z is O or C(R 4 )2; and Each R 4 are independently hydrogen, C1-C6 alkyl or C1-C6 alkoxy.

44. The compound of claim 43, wherein Z is O.

45. The compound of claim 43, wherein Z is CHR 4 , and R 4 It is a C1-C3 alkoxy group.

46. ​​A compound according to any one of claims 1 to 45, wherein R 2 It is hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl or C3-C6 cycloalkyl.

47. The compound according to claim 46, wherein R 2 is hydrogen, chlorine, fluorine, methyl, difluoromethyl, trifluoromethyl or cyclopropyl.

48. A compound according to any one of claims 1 to 47, wherein R 3 It is hydrogen, C1-C4 alkyl, (C1-C4 alkoxy)-(C1-C4 alkyl), C3-C6 cycloalkyl or 4- to 8-membered heterocyclic group.

49. The compound according to claim 48, wherein R 3 It is a 4- to 6-membered heterocyclic group.

50. The compound of claim 49, wherein the heterocyclic group is an oxygen-containing heterocyclic group.

51. The compound according to claim 48, wherein R 3 It is methyl, 2-methoxyethyl, cyclopropyl, cyclobutyl, 3-methoxycyclobutyl, oxetan-3-yl, tetrahydrofuran-3-yl or tetrahydro-2H-pyran-4-yl.

52. A compound according to any one of claims 1 to 51, wherein R 3 Substituted by halogen, C1-C6 alkyl or C1-C6 alkoxy.

53. according to the compound described in any one of claim 1 to 52, wherein when X 1 When the carbon at position 2 is a chiral center, it has the S-configuration.

54. A compound of Table 1 or a pharmaceutically acceptable salt thereof.

55. A pharmaceutical composition comprising a compound according to any one of claims 1 to 54 and a pharmaceutically acceptable excipient.

56. A method of treating cancer, comprising administering to a subject suffering from the cancer a therapeutically effective amount of a compound according to any one of claims 1 to 54 or a pharmaceutical composition according to claim 55.

57. The method of claim 56, wherein the cancer is deficient in a HR-dependent DNA DSB repair pathway.

58. The method of claim 56, wherein the cancer comprises one or more cancer cells having a reduced or abrogated ability to repair DNA DSBs by HR relative to normal cells.

59. The method of claim 58, wherein the cancer cells have a BRCA1 or BRCA2 deficient phenotype.

60. The method of claim 59, wherein the cancer cells lack BRCA1 or BRCA2.

61. The method of any one of claims 56 to 60, wherein the subject is heterozygous for a mutation in a gene encoding a component of the HR-dependent DNA DSB repair pathway.

62. The method of claim 61, wherein the subject is heterozygous for a mutation in BRCA1 or BRCA2.

63. The method of any one of claims 56 to 62, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, lung cancer, or brain cancer.

64. A method of inhibiting a PARP1 protein, the method comprising contacting the PARP1 protein with an effective amount of a compound according to any one of claims 1 to 54 or a pharmaceutical composition according to claim 55.

65. The method of claim 64, wherein the inhibition occurs in a subject suffering from a PARP1 -mediated disease or condition.

66. The method of claim 65, wherein the disease or condition is cancer.

67. The method of claim 66, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, lung cancer, or brain cancer.

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