Compounds and methods for cd73 modulation and indications thereof

Abstract

Disclosed are compounds of Formula I: or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or deuterated analog thereof, wherein R 1 , R 2 , R 3 , A, E, L, and G are described in any of the embodiments described in the present disclosure; compositions thereof; and uses thereof.

Description

[0001] Cross-referencing of related patent applications

[0002] This application claims the benefit of U.S. Provisional Application 63 / 014,523, filed April 23, 2020, under 35 U.S.SC §119(e), which is incorporated herein by reference in its entirety. Technical Field

[0003] This invention relates to organic compounds for the treatment of mammals, particularly for regulating CD73 in various diseases associated with CD73 overexpression. Background Technology

[0004] CD73, an enzyme that catalyzes the breakdown of AMP into adenosine, has been found to be overexpressed in many types of cancer. CD73 is involved in the production of extracellular adenosine, which regulates tumor-induced immunosuppression mechanisms of T cells. Tumor-derived CD73 acts as an extracellular enzyme to produce extracellular adenosine, which promotes tumor growth by limiting anti-tumor T-cell immunity through adenosine receptor (AR) signaling. More specifically, CD73 is a highly conserved exonuclease, a dimerase expressed on the outer lobe of the plasma membrane. It catalyzes the dephosphorylation of a subset of 5'-nucleotides, with 5'-adenosine monophosphate (AMP) as the primary substrate. Adenosine is produced by the high-level catalytic hydrolysis of AMP by CD73 in the tumor microenvironment. It binds to A2a and A2b receptors on immune cells and inhibits immune surveillance against tumor cells. Blocking CD73 hydrolysis of AMP is a potential therapeutic approach to desuppress anti-tumor immunity. Results from small-molecule inhibitors targeting CD73 in mouse tumor models suggest that CD73-targeted therapy is an important and realistic option for effectively controlling tumor growth. In particular, it aids T-cell-based therapy by enhancing adaptive immune response mechanisms, which may increase the function of tumor-infiltrating T lymphocytes, thereby improving survival rates in cancer patients.

[0005] Based on clinical trial data, CD73 expression has been reported to be associated with poor prognosis and reduced antitumor immunity in human TNBC, and targeting CD73 may be a promising strategy for reprogramming the tumor microenvironment in this BC subtype. (See Bruissert et al., Clinical significance of CD73 in triple-negative breast cancer: multiplex analysis of a phase III clinical trial, Ann Oncol. 2018 Apr 1; ​​29(4):1056-1062.)

[0006] CD73 has also been reported as a target for immunotherapy, and clinical studies using CD73 inhibitors have demonstrated benefits for lung cancer patients. (See Hui et al., Evaluation of CD73 in lung cancer, Journal of Clinical Oncology 201735:15.)

[0007] Increasing evidence has been reported confirming that CD73 is a key regulatory molecule in cancer development. More specifically, CD73 is overexpressed in biopsies of many types of cancer cell lines and patients, including breast cancer, colorectal cancer, ovarian cancer, gastric cancer, and gallbladder cancer, and is also associated with clinical characteristics or prognosis in cancer patients. Furthermore, positive effects in tumor-bearing mouse models suggest that anti-CD73 therapy has become a promising approach for treating patients with these types of cancer. (See Zhao-wei Gao et al., The Roles of CD73 in Cancer, BioMed Research International, Volume 2014).

[0008] The host CD73 has been further demonstrated to play a crucial role in multiple areas of glioblastoma pathogenesis, including promoting glioblastoma growth, angiogenesis, and invasiveness. More specifically, studies have shown that A2B adenosine receptor (AR) expression on the GB increased 20-fold compared to sham surgery, and its inhibition increased the chemosensitivity of glioblastoma to temozolomide. These findings strongly suggest that blocking or inhibiting CD73 and A2B AR is a major target for future glioblastoma therapy. (See Yan.A et al., CD73 Promotes Glioblastoma Pathogenesis and Enhances Its Chemoresistance via A2B Adenosine Receptor Signaling, J Neurosci. 2019 May 29; 39(22):4387-4402).

[0009] Studies have shown that CD73 activity increases during the proliferation of glioma cell lines, indicating that this enzyme plays an important role in the development of brain tumors. In summary, these results suggest that extracellular -50-NT / CD73 plays an important role in glioma cell proliferation. (See Luci Bavaresco et al., The role of ecto-5′-nucleotidase / CD73 inglioma cell line proliferation, Mol Cell Biochem (2008) 319: 61–68).

[0010] Further investigation revealed that gastric cancer patients with high CD73 expression had lower overall survival rates, and demonstrated that CD73 expression is an independent predictor of gastric cancer. (See Lu XX et al., Expression and clinical significance of CD73 and hypoxia-inducible factor-1α in gastric carcinoma, World J Gastroenterol. 2013 Mar 28; 19(12):1912-8).

[0011] Other studies have found increased CD73 expression in certain disease patterns, such as the highly aggressive phenotype of melanoma cell lines, proliferative chronic lymphocytic leukemia cells, papillary carcinoma (the most common form of thyroid cancer), pancreatic ductal adenocarcinoma, and colorectal cancer stroma. Increased CD73 mRNA and activity have been found in glioma cell lines, lymph node metastatic prostate cancer, and human tumor bladder cell lines. (See Luca Antonioli et al., Anti-CD73 in cancer immunotherapy: awakening new opportunities, Trends Cancer. 2016 Feb 1; 2(2):95–,109).

[0012] Other reports suggest that inhibiting CD73 to prevent its immunosuppressive effects may be a promising therapeutic target, as it could potentially enhance control of leukemia. (See Paolo Bernasconi et al., Targeting Leukemia StemCell-Niche Dynamics: A New Challenge in AML Treatment, Journal of Oncology, Volume 2019).

[0013] Other studies have found that high CD73 expression in pancreatic cancer cells is associated with poor patient prognosis, independent of clinicopathological factors, suggesting that CD73 may be a relevant immunotherapy target and a promising immunoprognostic biomarker in pancreatic ductal adenocarcinoma. (See N. Messioudi et al., CD73 as a novel immune target and biomarker inpancreatic adenocarcinoma, HPB 2018, 20(S1), S5eS35).

[0014] Another report indicates that CD73 expression is higher in lymph node metastatic prostate cancer compared to non-metastatic prostate cancer, suggesting that CD73 may be a specific target for molecular therapy of prostate cancer metastases. (See Yang Q et al., Overexpression of CD73 in prostate cancer is associated with lymph node metastasis, Pathol Oncol Res. 2013 Oct; 19(4):811-4).

[0015] Other studies have reported that limiting CD73-derived adenosine significantly inhibits microglia-mediated neuroinflammation and improves the activity and motor behavior of dopaminergic neurons in Parkinson's disease models. The authors conclude that targeting nucleotide metabolic pathways (e.g., CD73) to limit adenosine production and neuroinflammation in Parkinson's disease may be a promising therapeutic strategy. (See Fan Meng et al., CD73-derived adenosine controls inflammation and neurodegeneration by modulating dopamine signaling, Brain, Volume 142, Issue 3, March 2019, Pages 700–718).

[0016] Liver fibrosis develops as a response to chronic inflammation and persistent liver damage. This pathological process is driven by the activation and accumulation of myofibroblasts. CD73 is upregulated in hepatic stellate cells, portal fibroblasts, and fibrous septa due to myofibroblast differentiation. CD73-deficient mice have been reported to be resistant to the development of liver fibrosis, suggesting its role in fibrosis and adenosine production. CD73 may contribute to the prevention of liver fibrosis.

[0017] Other studies have reported that CD73 is a novel target for regulating early Alzheimer's disease, in which synaptic and memory dysfunction in a β-amyloid model of early Alzheimer's disease depends on increased formation of extracellular adenosine derived from ATP generated by CD73. (See also...) et al., Synaptic and memory dysfunction in aβ-amyloid model of early Alzheimer's disease depends on increased formation of ATP-derived extracellular adenosine, Neurobiol Dis. 2019 Dec; 132:104570).

[0018] Therefore, compounds that can inhibit CD73 represent a new class of potential therapeutic agents capable of modulating immune responses and tumor growth. Since there are currently no approved CD73 inhibitors for the treatment or prevention of human diseases, the need for new compounds capable of modulating CD73 remains unmet. Summary of the Invention

[0019] One embodiment of this disclosure relates to novel compounds as described in any of the embodiments herein, or pharmaceutically acceptable salts, solvates, tautomers, stereoisomers, or deuterated analogs thereof, wherein these novel compounds can modulate CD73.

[0020] Another embodiment of this disclosure relates to compounds of formula I:

[0021]

[0022] Or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or deuterated analogue thereof, wherein R 1 R 2 R 3 A, E, L and G are as described in any embodiment (including any sub-embodiments) of this disclosure.

[0023] Other embodiments and sub-implementations of Formula I are further described in this disclosure.

[0024] Another embodiment of this disclosure relates to a pharmaceutical composition comprising a compound according to Formula I or any embodiment and sub-embodiments of Formula I described herein, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or deuterated analog of any of such compounds, and a pharmaceutically acceptable carrier or excipient.

[0025] Another embodiment of this disclosure relates to a pharmaceutical composition comprising a compound according to Formula I, or any embodiment of Formula I described herein, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or deuterated analog of any of these compounds, and another therapeutic agent.

[0026] Another embodiment of this disclosure relates to a method for treating a subject suffering from a CD73-mediated disease or symptom, the method comprising administering to the subject an effective amount of a compound according to Formula I, or any embodiment of Formula I as described in this disclosure, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or deuterated analog of any of these compounds, or a pharmaceutical composition of any of the compounds as described in this disclosure, wherein the disease or symptom abnormally or otherwise expresses CD73, or activates a mutation or translocation of any of the foregoing.

[0027] Further embodiments are described in the specific embodiments of this disclosure. Detailed Implementation

[0028] I. Definition

[0029] As used herein, unless otherwise expressly stated, the following definitions apply:

[0030] It should be noted here that, as used herein and in the appended claims, the singular forms “a” and “the” include plural references unless the context clearly specifies otherwise.

[0031] Unless otherwise specified by the attachment point, the chemical portions and all embodiments thereof listed in the definition of variables of Formula I of this disclosure shall be read from left to right, wherein the right-hand side is directly attached to the defined parent structure. However, if an attachment point (e.g., a dash "-") appears to the left of a chemical portion (e.g., -alkoxy-C1-C6 alkyl), then the left side of that chemical portion is directly attached to the defined parent portion.

[0032] It is assumed that, when considering the general description of the compounds described herein for the purpose of constructing the compounds, this construction results in stable structures. That is, those skilled in the art will recognize that, theoretically, some constructs would not generally be considered stable compounds (i.e., spatially useful and / or synthetically feasible).

[0033] "alkyl" itself, or as part of another substituent, unless otherwise specified, refers to a straight-chain or branched hydrocarbon having a specified number of carbon atoms (i.e., C1-C6 represents one to six carbon atoms). Representative alkyl groups include straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. Further representative alkyl groups include straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. For each definition herein (e.g., alkyl, alkoxy, arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, etc.), when excluding the prefix indicating the number of carbon atoms in the alkyl moiety, the alkyl moiety or a portion thereof will have 12 or fewer main chain carbon atoms, or 8 or fewer main chain carbon atoms, or 6 or fewer main chain carbon atoms. For example, C 1- C6 alkyl refers to straight-chain or branched hydrocarbons having 1, 2, 3, 4, 5, or 6 carbon atoms, including but not limited to -CH3, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, and C6 alkyl. 1- C2 alkyl, C2 alkyl, C3 alkyl, C 1- C3 alkyl, C 1- C4 alkyl, C 1- C5 alkyl, C 1- C6 alkyl, C 2- C3 alkyl, C 2- C4 alkyl, C 2- C5 alkyl, C 2- C6 alkyl, C 3- C4 alkyl, C 3- C5 alkyl, C 3- C6 alkyl, C 4- C5 alkyl, C 4- C6 alkyl, C 5- C6 alkyl and C6 alkyl. While it is understood that substitution can be attached to any available atom to produce a stable compound, when the optionally substituted alkyl group is a moiety (e.g., -OR (e.g., alkoxy), -SR (e.g., thioalkyl), -NHR (e.g., alkylamino), -C(O)NHR, etc.), substitution of the alkyl R group prevents substitution of any O, S, or N (except where N is a heteroaromatic ring atom) bonded to the alkyl carbon bonded to any O, S, or N of the moiety from causing any O, S, or N (except where N is a heteroaromatic ring atom) to bond to the substituent.

[0034] "alkylene" itself, or as part of another substituent, refers to a straight-chain or branched saturated divalent hydrocarbon portion derived from an alkane having the number of carbon atoms indicated in the prefix. For example, (i.e., C...1- C6 indicates one to six carbon atoms; C 1- C6 alkylene groups include methylene, ethylene, propylene, 2-methylpropylene, pentylene, and hexylene. 1-4 Alkylenes include methylene-CH2-, ethylene-CH2CH2-, propylene-CH2CH2CH2-, and isopropylene-CH(CH3)CH2-, -CH2CH(CH3)-, -CH2-(CH2)2CH2-, -CH2-CH(CH3)CH2-, and -CH2-C(CH3)2-CH2-CH2CH(CH3)-. Typically, alkyl (or alkylene) groups will have 1 to 24 carbon atoms, with these groups having 10 or fewer, 8 or fewer, or 6 or fewer carbon atoms. When no prefix is ​​included to indicate the number of carbon atoms in the alkylene moiety, the alkylene moiety or a portion thereof will have 12 or fewer main chain carbon atoms, or 8 or fewer main chain carbon atoms, 6 or fewer main chain carbon atoms, or 4 or fewer main chain carbon atoms, or 3 or fewer main chain carbon atoms, or 2 or fewer main chain carbon atoms, or 1 carbon atom.

[0035] "Alkenyl" refers to a straight-chain monovalent hydrocarbon group or a branched monovalent hydrocarbon group that has the number of carbon atoms indicated in the prefix and contains at least one double bond. For example, C2-C6 alkenyl is intended to include vinyl, propenyl, etc. "C2-C6 alkenyl C1-C6 alkylene" is a group -C1-C6 alkylene-C2-C6 alkenyl, where alkenyl and alkylene are as defined herein.

[0036] The term "alkenyl" refers to a straight-chain divalent hydrocarbon group or a branched divalent hydrocarbon group that contains at least one double bond and has the number of carbon atoms indicated in the prefix. Examples of such groups include vinyl, 2-propenyl, crotonyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), and higher homologues and isomers.

[0037] The term "alkynyl" refers to a monomole of an unsaturated hydrocarbon that, in some embodiments, has 2 to 20 carbon atoms (in some embodiments, 2 to 10 carbon atoms, e.g., 2 to 6 carbon atoms) and has 1 to 6 carbon-carbon triple bonds, e.g., 1, 2, or 3 carbon-carbon triple bonds. In some embodiments, alkynyl includes ethynyl (-C≡CH), propynyl (or propynyl, e.g., -C≡CCH3), etc. When no prefix is ​​included to indicate the number of carbon atoms in the alkenyl or alkynyl moiety, the alkenyl or alkynyl moiety or a portion thereof will have 12 or fewer main chain carbon atoms, or 8 or fewer main chain carbon atoms, 6 or fewer main chain carbon atoms, or 4 or fewer main chain carbon atoms.

[0038] The term "ethynyl" refers to a straight-chain divalent hydrocarbon group or a branched divalent hydrocarbon group that contains at least one triple bond and has the number of carbon atoms indicated in the prefix. Examples of such groups include ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologues and isomers.

[0039] “alkoxy” or “alkoxyl” refers to an -O-alkyl group, where the alkyl group is as defined herein. For example, “C1-C6 alkoxy” refers to an –O-C1-C6 alkyl group, where the alkyl group is as defined herein. While it is understandable that substitution on an alkoxy group is attached to any available atom to produce a stable compound, the substituent on the alkoxy group causes the O, S, or N (except where N is a heteroaromatic ring atom) to not bond to the alkyl carbon bonded to the alkoxy O. Furthermore, where the alkoxy group is described as a substituent on another part, the alkoxy oxygen does not bond to the carbon atom bonded to the O, S, or N (except where N is a heteroaromatic ring atom) of the other part, or to the carbon atom of the alkene or alkyne of the other part.

[0040] The terms “alkoxyalkyl” and “alkoxyalkylene” refer to alkyl groups substituted with alkoxy groups. For example, “C1-C6 alkoxyC1-C6 alkyl” refers to a C1-C6 alkyl group substituted with a C1-C6 alkoxy group, wherein the alkyl and alkoxy groups are as defined herein, while “C1-C3 alkoxyC1-C3 alkylene” refers to a C1-C3 alkyl group substituted with a C1-C3 alkoxy group, wherein the alkylene and alkoxy groups are as defined herein.

[0041] "Amino" or "amine" indicates the group -NH2.

[0042] Unless otherwise stated, “aryl” refers, either alone or as part of another substituent, to a monocyclic, bicyclic, or polycyclic polyunsaturated aromatic group containing 6 to 14 ring carbon atoms, which may be monocyclic or fused together or covalently linked polycyclic (up to three rings). However, aryl does not encompass or overlap in any way with heteroaryl as defined below. If one or more aryl rings are fused with a heteroaryl ring, the resulting ring system is a heteroaryl. Non-limiting examples of unsubstituted aryl groups include phenyl, 1-naphthyl, and 2-naphthyl. The term “arylene” refers to a divalent aryl group, wherein the aryl group is as defined herein.

[0043] "5-6 membered aromatic ring" refers to a benzene ring or a 5-6 membered heteroaromatic ring as defined herein. For the purposes of this disclosure, the bridgehead atom cannot be two adjacent atoms on any particular ring.

[0044] A “bridging ring” or “bridging compound” is a carbocyclic or heterocyclic compound or part thereof having two or more rings (containing bridges of one to four carbon atoms connecting two bridgehead atoms). In this disclosure, the phrase “bridging carbocyclic or heterocyclic” has the same meaning as the phrase “bridging carbocyclic or bridging heterocyclic.” For the purposes of this disclosure, the two bridgehead atoms in a bridging ring cannot be the same atom on any particular ring. A bridging heterocyclic compound refers to a bridging compound having at least one heteroatom. The bridgehead atom is part of the molecular skeleton. A bridging ring (or compound) can be a complete carbocyclic ring (all carbon skeleton atoms). The following are examples of bridging rings, showing each bridge atom and bridgehead atom.

[0045]

[0046] For the purposes of this disclosure, bridging rings are intended to include rings that may optionally have 1-2 C1-C3 alkyl groups not attached to their bridging atoms and bridgehead atoms, and these bridging rings may be substituted as described in this disclosure. Other non-limiting examples of bridging rings include bicyclo[1.1.1]pentane, adamantyl, (1s,5s)-bicyclo[3.3.1]nonane, (1R,5S)-6,6-dimethylbicyclo[3.1.1]heptane, (1R,5S)-6,6-dimethylbicyclo[3.1.1]heptane, (1r,2R,4S,5r,6R,8S)-tetracyclo[3.3.1.02,4.06,8]nonane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and 1-fluorobicyclo[2.2.2]octane.

[0047] Unless otherwise specified, "cycloalkyl," "carbocyclic," or "of a carbocyclic ring" on its own or as part of another substituent refers to a saturated or partially unsaturated non-aromatic monocyclic or fused ring, such as a bicyclic or tricyclic carbocyclic system or cubane, having the number of carbon atoms indicated in the prefix, or, if not specified, 36 or 46, and each ring having 5-6 ring members, such as cyclopropyl, cyclopentyl, cyclohexyl, where one or two ring carbon atoms may optionally be substituted with a carbonyl group. Furthermore, the term cycloalkyl is intended to cover ring systems fused to an aromatic ring (e.g., of an aryl group), regardless of the attachment point to the rest of the molecule. A cycloalkyl ring refers to a hydrocarbon ring having a specified number of ring atoms (e.g., C14, C24, C34, C44, C54, C6 ... 3-6 Cycloalkyl and 3-6 membered cycloalkyl both represent three to six cyclic carbon atoms. The term "cycloalkenyl" refers to a cycloalkyl group having at least one unsaturated unit. Substituents in cycloalkyl or cycloalkenyl groups can be located at the attachment sites of the cycloalkyl or cycloalkenyl groups, forming a quaternary center.

[0048] "Cycloalkylalkyl" and "cycloalkylalkylene" refer to -(alkylene)-cycloalkyl groups, wherein the alkylene group as defined herein has a specified number of carbon atoms, or six or fewer carbon atoms if not specified; and the cycloalkyl group as defined herein has a specified number of carbon atoms, or, if not specified, each ring has 310, 38, or 36 ring members. For example, 4-6 membered cycloalkyl-C1-C6 alkyl refers to a cycloalkyl group having 4-6 carbon atoms attached to an alkylene chain having 1-6 carbon atoms, wherein the alkylene chain is attached to a parent moiety. Other exemplary cycloalkylalkyl groups include, for example, cyclopropylmethylene, cyclobutylethylene, cyclobutylmethylene, etc. "Cycloalkylynylene" refers to -(ynylene)-cycloalkyl, for example, C3-C6 cycloalkyl-C2-C6 ynylene is the group -(C2-C6 ynylene)-C3-C6 cycloalkyl. "C3-C6 cycloalkylethynyl" is a group consisting of -C≡C-C3-C6 cycloalkyl.

[0049] The term "cyano" refers to the group -CN. The term "C1-C6 cyanoalkyl" refers to a C1-C6 alkyl group substituted with one, two, or three cyano groups as defined herein. "C1-C6 cyanoalkyl ethylene" is the group -C≡C-C1-C6 cyanoalkyl.

[0050] The term "haloalkyl" refers to an alkyl group substituted with one to seven halogen atoms. Haloalkyl includes monohaloalkyl or polyhaloalkyl. For example, the term "C1-C6 haloalkyl" is intended to include trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc. Furthermore, the term "haloalkylene" refers to an alkylene group substituted with one to seven halogen atoms.

[0051] The term "haloalkoxy" or "haloalkoxyl" refers to an -O-haloalkyl group, wherein the haloalkyl group is as defined herein. Haloalkoxy groups include monohaloalkoxy or polyhaloalkoxy groups. For example, the term "C1-C6 haloalkoxy" is intended to include trifluoromethoxy, difluoromethoxy, etc.

[0052] "Halogen" or "halo" refers to all halogens, namely chlorine (Cl), fluorine (F), bromine (Br), or iodine (I).

[0053] "Heteroatoms" are intended to include oxygen (O), nitrogen (N), and sulfur (S).

[0054] "Heteroaryl" refers to a monocyclic or bicyclic aromatic ring group containing 5-9 ring atoms (also referred to herein as a 5-9 membered heteroaryl, including monocyclic aromatic ring groups containing 5 or 6 ring atoms (also referred to herein as 5-6 membered heteroaryl), containing one or more, 14, 13, or 12 heteroatoms independently selected from the group consisting of O, S, and N. Any aromatic ring or ring system containing at least one heteroatom is a heteroaryl, regardless of the attachment point (i.e., through any fused ring). Heteroaryls are also intended to include a moiety having an oxidized S or N, such as a sulfinyl group, a sulfonyl group, and an N oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is the attachment point of the heteroaryl ring structure, thereby producing a stable compound. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, and pyrazine. The following groups are listed: [Aromatic group name], ...

[0055] "Heterocyclic alkyl" refers to a saturated or partially unsaturated non-aromatic cycloalkyl group containing one to five heteroatoms selected from N, O, S (including S(O) and S(O)2) or P (including phosphine oxide), wherein the nitrogen, sulfur, and phosphorus atoms are optionally oxidized, and the nitrogen atom is optionally quaternized, and the remaining ring atoms are C, with one or two C atoms optionally present as a carbonyl group. Furthermore, the term heterocyclic alkyl is intended to cover any ring or ring system containing at least one heteroatom that is not a heteroaryl group, regardless of its attachment point to the rest of the molecule. Heterocyclic alkyl groups include rings having formally charge-separated aromatic resonance structures, such as N-methylpyridinone groups. Heterocyclic alkyl groups may be substituted with one or two oxo groups and may include sulfone and sulfoxide derivatives. Heterocyclic alkyl groups can be monocyclic, fused bicyclic, or fused polycyclic systems with 3 to 12, 4 to 10, 5 to 10, or 5 to 6 ring atoms, wherein one to five ring atoms are heteroatoms selected from -N=, -N-, -O-, -S-, -S(O)-, or –S(O)2-, and one or two ring atoms are optionally substituted with a -C(O)- group. For example, a 4-6 membered heterocyclic alkyl group is a heterocyclic alkyl group having 4 to 6 ring members (having at least one heteroatom). Heterocyclic alkyl groups can also be heterocyclic alkyl rings fused with a cycloalkyl group. Non-limiting examples of heterocyclic alkyl groups include pyrrolidinyl, piperidinyl, morpholinyl, pyridoneyl, etc. Heterocyclic alkyl groups can be attached to the rest of the molecule via a ring carbon or heteroatom. "Heterocyclic alkenyl" refers to a heterocyclic alkyl group having at least one unsaturated unit. Substituents of heterocyclic alkyl or heterocyclic alkenyl groups can be located at the attachment site of the heterocyclic alkyl or heterocyclic alkenyl group, forming a quaternary center.

[0056] “Hydroxyl” or “hydroxy” refers to the OH group. The terms “hydroxyalkyl” or “hydroxyalkylene” refer to alkyl or alkylene groups substituted with 1 to 5 hydroxyl groups, as defined herein.

[0057] The term "oxo" refers to C (=O) or (O). In some embodiments, two possible attachment sites on the carbon form an oxo group.

[0058] As used throughout the disclosure, "optionally substituent" or "optionally substituted" means that substitution may or may not occur on the compound, and the description includes both cases where substitution occurs and instances where substitution does not occur. For example, the phrase "optionally substituted with 1-3 T" 1 "Group substitution" refers to T 1 Groups may be present, but are not required to be present. In this disclosure, it is assumed that optional substitutions on the compound will occur in a manner that yields a stable compound.

[0059] A "spiro carbon atom" is a carbon atom shared by two rings. A "carbocyclic spirocycle" consists of two cyclic alkyl rings connected at a common spiro carbon atom, as shown in this example: "Heterocyclic spirocyclic" refers to a cycloalkyl or heterocyclic alkyl ring attached to a heterocycle at a common spirocarbon atom, as shown in this example:

[0060] As used herein in conjunction with the compounds disclosed herein, the term "synthesis" and similar terms mean the chemical synthesis from one or more precursor materials.

[0061] As used herein, the term "composition" means a formulation suitable for administration to intended animal subjects for therapeutic purposes, which contains at least one pharmaceutically active compound and at least one pharmaceutically acceptable carrier or excipient.

[0062] The term "pharmaceutically acceptable" means that, taking into account the disease or symptom to be treated and the corresponding route of administration, the indicated material does not possess properties that would cause a physician with reasonable caution to avoid administering the material to a patient. For example, it is often required that the material be substantially sterile, such as for injectable formulations.

[0063] "Pharmaceutically acceptable salts" are salts that are acceptable for administration to patients (e.g., mammals) (e.g., salts with acceptable mammalian safety for a given dosage regimen). Envisioned pharmaceutically acceptable salt forms include, but are not limited to, monosalts, disalts, trisalts, tetrasalts, etc. Pharmaceutically acceptable salts are non-toxic at the amount and concentration in which they are administered. The preparation of such salts can facilitate pharmacological use by altering the physical properties of the compound without impairing its physiological effects. Useful alterations to physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate administration of higher drug concentrations. Depending on the specific substituents found on the compounds described herein, such salts can be derived from pharmaceutically acceptable inorganic or organic bases and pharmaceutically acceptable inorganic or organic acids.

[0064] Pharmaceutically acceptable salts can be prepared using standard techniques. For example, the free base form of a compound can be dissolved in a suitable solvent (e.g., an aqueous solution containing a suitable acid or an aqueous solution of alcohol), and then separated by evaporation of the solution. In another example, a salt can be prepared by reacting a free base with an acid in an organic solvent.

[0065] When the compounds of this disclosure contain relatively acidic functionality, a base addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of a desired base (i.e., primary amine, secondary amine, tertiary amine, quaternary amine, or cyclic amine; alkali metal hydroxide; alkaline earth metal hydroxide; etc.) in a pure solvent or a suitable inert solvent. The desired acid can be, for example, a pyranoside (e.g., glucuronic acid or galacturonic acid), an α-hydroxy acid (e.g., citric acid or tartaric acid), an amino acid (e.g., aspartic acid or glutamic acid), an aromatic acid (e.g., benzoic acid or cinnamic acid), a sulfonic acid (e.g., p-toluenesulfonic acid or ethanesulfonic acid), etc. In some embodiments, the salt may be derived from pharmaceutically acceptable acids, such as acetic acid, trifluoroacetic acid, propionic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glycolic acid, gluconic acid, glucuronic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroxyethylsulfonic acid, lactic acid, lactobionic acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, methanesulfonic acid, mucin, naphthalenesulfonic acid, nicotine, nitric acid, pamoic acid, pantothenic acid, etc. Phosphoric acid, succinic acid, sulfuric acid, aminosulfonic acid, hydroiodic acid, carbonic acid, tartaric acid, p-toluenesulfonic acid, pyruvic acid, aspartic acid, benzoic acid, cinnamic acid, anthranilic acid, methanesulfonic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, pamoic acid, ethylsulfonic acid, benzenesulfonic acid, 2-hydroxyethylsulfonic acid, p-aminobenzenesulfonic acid, stearic acid, cyclohexylsulfamic acid, cyclohexylsulfamic acid, quinic acid, algenic acid, hydroxybutyric acid, mucoic acid, and galacturonic acid, etc.

[0066] This also includes salts of amino acids (e.g., arginine salts) and salts of organic acids (e.g., glucuronic acid or galacturonic acid salts) (see, for example, Berge, SM et al., “Pharmaceutical Salts,” J. Pharmaceutical Science, 1977, 66: 1-19). Certain specific compounds of this disclosure contain both basic and acidic functional groups, which allows the compounds to be converted into base or acid addition salts.

[0067] The neutral form of a compound can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in some physical properties, such as solubility in polar solvents, but in other respects, for the purposes of this disclosure, the salt is equivalent to the parent form of the compound.

[0068] Pharmaceutically acceptable salts of different compounds can exist as complexes. Examples of complexes include 8-chlorotheophylline complexes (similar to, for example, the dimenhydrinate:diphenhydramine-8-chlorotheophylline (1:1) complex; dramamine) and various cyclodextrin inclusion complexes.

[0069] As used herein, either alone or as part of a group, the term "deuterated" refers to a substituted deuterium atom. As used herein, either alone or as part of a group, the term "deuterated analog" refers to a compound containing a substituted deuterium atom in place of a hydrogen atom. The deuterated analogs of the present invention can be fully or partially deuterated derivatives. In some embodiments, the deuterated derivatives of the present invention have fully or partially deuterated alkyl, aryl, or heteroaryl groups.

[0070] This disclosure also covers isotopically labeled compounds of this disclosure that are identical to those described herein, except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those normally found in nature. All isotopic variations of the compounds of this disclosure, whether or not radioactive, are intended to be covered within the scope of this disclosure. Examples of isotopes that may be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, isotopes of these elements. 2 H (deuterium, D) 3 H (tritium) 11 C 13 C 14 C 15 N、 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. Unless otherwise specified, when a position is specifically designated as “H” or “hydrogen”, that position is understood to have hydrogen or its isotopes in their naturally abundant isotopic composition, such as deuterium (D) or tritium (H). 3 H). Certain isotopically labeled compounds of this disclosure (e.g., 3 H and 14 Those labeled with C can be used for the determination of the tissue distribution of compounds and / or substrates. Tritium (i.e., 3 H) and carbon-14 (i.e., ... 14 C) and Fluorine-18 ( 18 F) Isotopes are available due to their ease of preparation and detectability. Furthermore, heavier isotopes (e.g., deuterium, i.e.,...) are also used. 2 H)) substitution can provide certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and may therefore be preferred in some cases. The isotopically labeled compounds of this disclosure can generally be prepared by replacing non-isotopically labeled reagents with isotopically labeled reagents through procedures similar to those described in the schemes and examples below.

[0071] "Prodrug" means any compound that releases an active parent drug of Formula I in vivo when administered to a subject. A prodrug of a Formula I compound is prepared by modifying functional groups present in the compound of Formula I in a manner that is conventional or in vivo such that the modification can be cleaved in vivo to release the parent compound. A prodrug can become the active form from the prodrug form in a single step, or it can have one or more intermediate forms, which may be active or inactive on their own. Some prodrugs are enzymatically activated to produce an active compound, or are compounds that produce an active compound after further chemical reactions. Prodrugs include compounds of Formula I, wherein the hydroxyl, amino, carboxyl, or thiol group in the compound of Formula I is bonded to any group that can be cleaved in vivo to regenerate a free hydroxyl, amino, or thiol group, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetates, formates, and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl), etc., of the hydroxyl functional group in the compound of Formula I. Other examples of prodrugs include, but are not limited to, carbonates, ureides, solvates, or hydrates of the active compound. The preparation, selection, and use of prodrugs are discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the ACSSymposium Series; “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985; and “Bioreversible Carriers in Drug Design,” ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is incorporated herein by reference in its entirety.

[0072] As described in *Medicinal Chemistry Practice*, Ch. 31-32 (edited Wermuth, Academic Press, San Diego, CA, 2001), prodrugs are conceptually classified into two non-exclusive categories: biological prodrugs and carrier prodrugs. Typically, biological prodrugs are compounds that are inactive or have low activity compared to the corresponding active pharmaceutical compound, containing one or more protecting groups and being converted to their active form through metabolism or solvent degradation. Both the active pharmaceutical form and any released metabolites should exhibit acceptable low toxicity. Generally, the formation of the active pharmaceutical compound involves one of the following types of metabolic processes or reactions:

[0073] (1) Oxidation reactions: Examples of oxidation reactions include, but are not limited to, the following reactions: oxidation of alcohols, carbonyl and acid functional groups, hydroxylation of aliphatic carbons, hydroxylation of alicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation of carbon-carbon double bonds, oxidation of nitrogen-containing functional groups, oxidation of silicon, phosphorus, arsenic and sulfur, oxidative dealkylation of N-, oxidative dealkylation of O- and S-, oxidative deamination, and other oxidation reactions.

[0074] (2) Reduction reaction: Examples of reduction reactions include, but are not limited to, the following: reduction of carbonyl functionality, reduction of alcohol functionality and carbon-carbon double bond, reduction of nitrogen-containing functional groups and other reduction reactions.

[0075] (3) Reactions that do not change the oxidation state: Examples of reactions that do not change the oxidation state include, but are not limited to, the following: hydrolysis of esters and ethers, hydrolytic cleavage of carbon-nitrogen single bonds, hydrolytic cleavage of non-aromatic heterocycles, hydration and dehydration of multiple bonds, dehydration reactions that produce new atomic bonds, hydrolytic dehalogenation, removal of hydrogen halide molecules and other such reactions.

[0076] A carrier prodrug is a pharmaceutical compound containing a transport moiety, for example, that improves absorption and / or local delivery to one or more sites of action. Ideally, for such carrier prodrugs, the bond between the pharmaceutical moiety and the transport moiety is covalent, the prodrug is inactive or less active than the pharmaceutical compound, and both the prodrug and any releasing transport moiety are acceptablely non-toxic. For prodrugs where the transport moiety is intended to enhance absorption, the release of the transport moiety is generally expected to be rapid. In other cases, it is desirable to utilize a moiety that provides sustained release, such as certain polymers or other moieties, such as cyclodextrins. (See, for example, Cheng et al., U.S. Patent Publication No. 2004 / 0077595, which is incorporated herein by reference.) Such carrier prodrugs are generally advantageous for orally administered pharmaceutical products. For example, carrier prodrugs can be used to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological action, increased site specificity, reduced toxicity and adverse reactions, and / or improved pharmaceutical formulations (e.g., stability, water solubility, inhibition of undesirable sensory or physicochemical properties). For example, lipophilicity can be increased by esterification of a hydroxyl group with a lipophilic carboxylic acid, or by esterification of a carboxylic acid group with an alcohol (e.g., an aliphatic alcohol).

[0077] The term "carrier" is also intended to include microspheres, liposomes, micelles, nanoparticles (naturally equipped nanocarriers, such as exosomes), etc. Exosomes are known to be highly efficient drug carriers, and drugs can be loaded into exosomes in a variety of ways, including those techniques described in J Control Release. 2015 December 10; 219:396–405, the contents of which are incorporated herein by reference in their entirety.

[0078] Metabolites, such as active metabolites, overlap with the aforementioned prodrugs (e.g., biological prodrugs). Therefore, such metabolites are pharmacologically active compounds or compounds that are further metabolized into pharmacologically active compounds, which are derivatives produced by metabolic processes within the subject's body. Active metabolites are these pharmacologically active derivatives. For prodrugs, the prodrug compound is typically inactive or less active than the metabolite. For active metabolites, the parent compound can be either an active compound or an inactive prodrug.

[0079] Prodrugs and active metabolites can be identified using conventional techniques known in the art. See, for example, Bertolini et al., 1997, J. Med. Chem., 40: 2011-2016; Shan et al., 1997, J Pharm Sci 86(7): 756-757; Bagshawe, 1995, Drug Dev. Res., 34: 220-230.

[0080] "Tautomerism" refers to a compound resulting from the transfer of a proton from one atom of a molecule to another. See Jerry March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structures, 4th Edition, John Wiley & Sons, pp. 69-74 (1992). Tautomerism also refers to one of two or more structural isomers that exist in equilibrium and readily transform from one isomer to another. Examples include keto-enol tautomers, such as acetone / propen-2-ol, imine-enamine tautomers, cyclic tautomers, such as glucose / 2,3,4,5,6-pentahydroxy-hexanal, and tautomers containing heteroaryl groups arranged in a -N=C(H)-NH- ring, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetraazoles. Tautomerism can occur when a compound contains, for example, a ketone or oxime group or an aromatic moiety ("tautomerism"). The compounds described herein may have one or more tautomers, and therefore include a variety of isomers. Those skilled in the art will recognize that other tautomeristic ring arrangements are possible. All such isomers of these compounds are explicitly included in this disclosure.

[0081] "Isomers" refer to compounds that have the same molecular formula but differ in the nature or order of their atomic bonding or in the spatial arrangement of their atoms. Isomers with different spatial arrangements of atoms are called "stereoisomers." "Stereoisomers" and "stereoisomers" refer to compounds that exist in different stereoisomeric forms, for example, if they have one or more asymmetric centers or asymmetric substituted double bonds, and therefore can occur as individual stereoisomers or as mixtures. Stereoisomers include enantiomers and diastereomers. Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are not superimposed mirror images of each other are called "enantiomers." Paired enantiomers are possible when a compound has an asymmetric center, for example, atoms bonded to four different groups (e.g., carbon). Enantiomers can be characterized by the absolute configuration of their asymmetric centers and can be described by the R- and S-sequencing rules of Cahn and Prelog, or by rotating the molecular polarization plane and specifying it as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a “racemic mixture.” As another example, stereoisomers include geometrical isomers, such as the cis or trans orientation of substituents on adjacent carbons of a double bond. Unless otherwise stated, the description is intended to include individual stereoisomers as well as mixtures. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (see discussion in Chapter 4 of Advanced Organic Chemistry, 6th Edition, J. March, John Wiley and Sons, New York, 2007), where the chirality of one or more stereocenters differs.

[0082] "Hydrate" refers to a complex formed by the combination of water molecules with molecules or ions of a solute. "Solvate" refers to a complex formed by the combination of solvent molecules with molecules or ions of a solute. A solvent can be an organic compound, an inorganic compound, or a mixture of both. Solvates are intended to include hydrates. Some examples of solvents include, but are not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and water. Generally, the solvated form is equivalent to the non-solvated form and is covered within the scope of this disclosure.

[0083] In the context of the use, testing, or screening of compounds that are or may be modulators, the term "contact" means bringing a compound into full proximity to a particular molecule, complex, cell, tissue, organism, or other particular material, such that a potential binding interaction and / or chemical reaction can occur between the compound and the other particular material.

[0084] "Assay" refers to the generation of experimental conditions and the collection of data about specific results from exposure to those conditions. For example, enzymes can be assayed based on their ability to act on detectable substrates. Compounds can be assayed based on their ability to bind to a specific target molecule or multiple target molecules.

[0085] As used herein, the terms “ligand” and “modifier” are used interchangeably to refer to compounds that alter (i.e., increase or decrease) the activity of a target biomolecule (e.g., enzymes such as those described herein). Typically, ligands or modifiers will be small molecules, where “small molecule” means a compound with a molecular weight of 1500 Daltons or less, 1000 Daltons or less, 800 Daltons or less, or 600 Daltons or less. Thus, an “improved ligand” is a ligand that has better pharmacological and / or pharmacokinetic properties than a reference compound, where “better” can be defined by a person skilled in the art for a particular biological system or therapeutic use.

[0086] The term "binding" in relation to the interaction between the target and the potential binding compound indicates the degree to which the potential binding compound associates with the target, compared to association with proteins normally (i.e., nonspecific binding). Therefore, the term "binding compound" refers to a compound that associates statistically significantly with the target molecule. In some embodiments, the binding compound has a dissociation constant (K0) of 10 mM or less, 1,000 μM or less, 100 μM or less, 10 μM or less, 1 μM or less, 1,000 nM or less, 100 nM or less, 10 nM or less, or 1 nM or less. D The compound interacts with the designated target. In the context of compound-target binding, the terms "greater affinity" and "selectivity" indicate that the compound binds more tightly than a reference compound or the same compound under reference conditions, i.e., has a lower dissociation constant. In some embodiments, greater affinity is at least 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500, 1000, or 10,000 times greater affinity.

[0087] The terms “modulate” and “modulation” refer to the ability of a compound to increase or decrease the function and / or expression of a target (e.g., CD73), where such function may include transcriptional regulatory activity and / or binding. Modulation can occur in vitro or in vivo. As described herein, modulation includes directly or indirectly inhibiting, antagonizing, partially antagonizing, activating, activating, or partially activating functions or features associated with CD73, and / or directly or indirectly upregulating or downregulating CD73 expression. In another embodiment, modulation is direct. Inhibitors or antagonists are compounds that, for example, bind, partially or completely block stimulation, reduce, prevent, inhibit, delay activation, inactivate, desensitize, or downregulate signal transduction. Activators or agonists are compounds that, for example, bind, stimulate, increase, open, activate, promote, enhance activation, activate, sensitize, or upregulate signal transduction.

[0088] As used herein, the terms “treat,” “treating,” “therapy,” “therapies,” and similar terms refer to the administration of a substance, such as any one or more compounds described herein, in an effective amount to prevent, alleviate, or improve one or more symptoms of a disease or condition (i.e., indications) and / or prolong the survival of a subject undergoing treatment.

[0089] As used herein, the terms “prevent,” “preventing,” “prevention,” and their grammatical variations refer to the partial or complete delay or exclusion of the onset or recurrence of a disease, symptom, or illness and / or one or more of its accompanying symptoms, or to the prevention of a subject from acquiring or re-acquiring a disease or illness, or to the reduction of the risk of a subject acquiring or re-acquiring a disease or illness or one or more of its accompanying symptoms.

[0090] As used herein, the terms “subject”, “animal subject”, etc., refer to living organisms, including but not limited to human and non-human vertebrates, such as any mammal (e.g., human), other primates, locomotion animals and commercially valuable animals such as cattle, horses, sheep or pigs, rodents or pets such as dogs and cats.

[0091] "Unit dosage form" refers to a composition intended for use in a single dose to treat a subject suffering from a disease or medical condition. Each unit dosage form typically comprises a compound of this disclosure plus one or more pharmaceutically acceptable excipients. Examples of unit dosage forms are single tablets, single capsules, bulk powders, liquid solutions, ointments, creams, eye drops, suppositories, emulsions, or suspensions. Treatment of a disease or condition may require periodic administration of the unit dosage form, such as: a unit dosage form, twice or more times a day, once with a meal, every four hours or other intervals, or once daily. The description "oral unit dosage form" indicates a unit dosage form designed for oral administration.

[0092] The term "administration" refers to oral administration to a subject, as a suppository, through external contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasal, or subcutaneous administration, or implantation of a sustained-release device (e.g., a micro-osmotic pump). Administration can be via any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or percutaneous). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intravenous, and intracranial administration. Other delivery methods include, but are not limited to, the use of liposomal formulations, intravenous infusion, and transdermal patches.

[0093] In the context of this document, the terms "therapeuticly effective" or "effective amount" mean that when administered, the amount of a compound or material is sufficient or effective to prevent, alleviate, or improve one or more symptoms of a disease, condition, or medical symptom being treated and / or prolong the survival of a subject being treated. Therapeuticly effective amounts will vary depending on the disease, condition, or symptom of the mammal to which the compound is to be treated, its severity, age, weight, etc. Generally, it indicates that satisfactory results were obtained in the subject at a daily dose of about 0.1 to about 10 g / kg of the subject's body weight. In some embodiments, the daily dose ranges from about 0.10 to 10.0 mg / kg of body weight, about 1.0 to 3.0 mg / kg of body weight, about 3 to 10 mg / kg of body weight, about 3 to 150 mg / kg of body weight, about 3 to 100 mg / kg of body weight, about 10 to 100 mg / kg of body weight, about 10 to 150 mg / kg of body weight, or about 150 to 1000 mg / kg of body weight. This dose can be conveniently administered, for example, in divided doses up to four times a day or in a sustained-release form.

[0094] The ability of compounds to inhibit CD73 function can be demonstrated in biochemical assays, such as binding assays or cell-based assays.

[0095] As used herein, the term "CD73-mediated disease or condition" refers to a disease or condition in which the biological function of CD73 influences the development and / or course of the disease or condition, and / or in which the regulation of CD73 alters the development, course, and / or symptoms. CD73-mediated diseases or conditions include those for which CD73 inhibition provides therapeutic benefit, for example, in which treatment with a CD73 inhibitor (including the compounds described herein) provides therapeutic benefit to a subject who has the disease or condition or is at risk of developing the disease or condition. CD73-mediated diseases or conditions are intended to include cancers with loss of CD73 function mutations or cancers with CD73 activation. CD73-mediated diseases or conditions are also intended to include various human cancers, including colon cancer, lung cancer, pancreatic cancer, and ovarian cancer, as well as diseases or conditions associated with tumor angiogenesis and invasiveness.

[0096] Similarly, in the context of compounds binding to biomolecular targets, the term "higher specificity" means that the compound binds to a specific target to a greater extent than it would bind to another biomolecule or multiple biomolecules that might be present under the relevant binding conditions, wherein binding to such other biomolecules produces a different biological activity than binding to the specific target. Typically, specificity is relative to a limited group of other biomolecules, for example, in the case of CD73. In specific embodiments, greater specificity is at least 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500, or 1000 times greater specificity.

[0097] As used herein with respect to binding compounds or ligands, the term "CD73-specific" and similar terms refer to a specific compound that binds to CD73 to a statistically greater extent than it binds to other targets that may be present in a particular sample. Furthermore, when referring to biological activities other than binding, the term "CD73-specific" indicates that the biological effects associated with binding to CD73 by a specific compound are greater than its biological effects on other enzymes, such as enzyme activity inhibition.

[0098] The term "first-line cancer therapy" refers to a therapy administered as an initial regimen to a subject to reduce the number of cancer cells. First-line therapy is also known as induction therapy, primary therapy, and primary treatment. First-line therapy can be administered in combination with one or more agents. A summary of currently accepted first-line treatments for certain diseases can be found in the NCI guidelines for such diseases.

[0099] The term "second-line cancer therapy" refers to the administration of cancer treatment to subjects who have not responded to first-line therapy, i.e., subjects who have typically received first-line therapy or whose cancer has relapsed after remission. In some implementations, second-line treatments that may be administered include repeating the initially successful cancer therapy, which can be any treatment described under "first-line cancer therapy." A summary of currently accepted second-line treatments for certain diseases is described in the NCI guidelines for such diseases.

[0100] The term "refractory" refers to a subject's lack of response to cancer therapy or treatment, or its intolerance in other ways. Cancer therapy can be first-line, second-line, or any subsequently administered treatment. In some implementations, refractory refers to a condition in which the subject has failed to achieve complete remission after two induction attempts. A subject may be refractory due to intrinsic resistance of cancer cells to a particular therapy, or due to acquired resistance developed during the course of a particular therapy.

[0101] In addition, the abbreviations used in this article have the following meanings:

[0102]

[0103]

[0104] II.Compounds

[0105] The compounds envisioned herein are described with reference to general formulas and specific compounds. Furthermore, the compounds described herein may exist in a variety of different forms or derivatives, all of which are within the scope of this disclosure. These include, for example, tautomers, stereoisomers, racemic mixtures, regioisomers, salts, prodrugs (e.g., carboxylic acid esters), solvated forms, and active metabolites.

[0106] It should be understood that some compounds may exhibit tautomerism. In such cases, the formulas provided herein explicitly describe only one possible tautomer form. Therefore, it should be understood that the formulas provided herein are intended to represent any tautomer form of the compound shown, and not only the specific tautomer form shown in the diagram of the formula.

[0107] Similarly, some compounds according to this disclosure can exist as stereoisomers as defined herein. All such single stereoisomers, racemates, and mixtures thereof are intended to fall within the scope of this disclosure. Unless otherwise stated, all such stereoisomers are included in the formulas provided herein.

[0108] In some embodiments, the chiral compounds of this disclosure are in the form containing at least 80% of a single isomer (60% enantiomer excess (“ee”) or diastereomeric excess (“de”)), or at least 85% (70% ee or de), 90% (80% ee or de), 95% (90% ee or de), 97.5% (95% ee or de), or 99% (98% ee or de). As is generally understood by those skilled in the art, an optically pure compound having one chiral center is a compound consisting essentially of one of two possible enantiomers (i.e., enantiomerically pure), and an optically pure compound having more than one chiral center is a compound that is both enantiomerically and diastereomeric pure. In some embodiments, the compound is present in an optically pure form.

[0109] For compounds in which the synthesis involves the addition of a single group to a double bond, particularly a carbon-carbon double bond, the addition may occur at any atom of either double bond. This disclosure includes such regioisomers for such compounds.

[0110] In addition to the formulas and compounds described herein, this disclosure also includes prodrugs (generally pharmaceutically acceptable prodrugs), active metabolic derivatives (active metabolites), and their pharmaceutically acceptable salts.

[0111] Unless otherwise stated, the description of the compounds herein includes pharmaceutically acceptable salts, solvates, tautomers, stereoisomers, or deuterated analogs of such compounds.

[0112] In some embodiments, the compounds of this disclosure are complexed with acids or bases, including base addition salts such as ammonium, diethylamine, ethanolamine, ethylenediamine, diethanolamine, tert-butylamine, piperazine, and meglumine; acid addition salts such as acetates, acetylsalicylates, benzenesulfonates, camphorsulfonates, citrates, formates, fumarates, glutarate, hydrochlorides, maleates, methanesulfonates, nitrates, oxalates, phosphates, succinates, sulfates, tartrates, thiocyanates, and toluenesulfonates; and amino acids such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine. In some instances, the amorphous form of the complex is promoted by additional treatments, such as spray drying, mechanochemical methods (e.g., rolling), or microwave irradiation of the parent compound mixed with an acid or base. Such methods may also include the addition of ionic and / or nonionic polymer systems, including but not limited to hydroxypropyl methylcellulose acetate succinate (HPMCAS) and methacrylic acid copolymers (e.g. L100-55), which further stabilizes the amorphous properties of the complex. This amorphous complex offers several advantages. For example, the lower melting temperature relative to the free base facilitates additional processing, such as hot melt extrusion, to further improve the biopharmaceutical properties of the compound. Furthermore, the amorphous complex is brittle, which provides improved compressibility for loading solids into capsule or tablet forms.

[0113] Compound Implementation

[0114] Embodiment 1 of this disclosure relates to compounds having Formula I;

[0115]

[0116] Or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or deuterated analogue thereof, wherein:

[0117] A is a 5-6 membered aromatic ring or a 4-7 membered nitrogen-containing heterocyclic alkyl group, wherein A is surrounded by 0-3 R groups. 4 Substitution occurs when ring A is a 4-7 member nitrogen-containing heterocyclic alkyl group, in which case the pyridazinone portion of formula I is attached to the nitrogen atom of A.

[0118] E is a phenyl or a 5- or 6-membered heteroaryl group, wherein E is surrounded by 0-3 Q groups and 0-1 R groups. 11 Substitution occurs when, if E is a 5- or 6-membered heteroaryl group, O does not attach to the heteroatom of E.

[0119] L is non-existent, -C(O)N(H)-, C0-C3 alkylene, -N(H)-, or -O-;

[0120] G is one of the following groups:

[0121] (a) by 0-4 T 1 and 0-1 T 2 Substituted cycloalkyl groups;

[0122] (b) by 0-4 T 1 and 0-1 T 2 Substituted cycloalkenyl groups;

[0123] (c) by 0-4 T 1 and 0-1 T 2 Replacement bridging carbon rings;

[0124] (d) A carbocyclic spirocycle containing two cycloalkyl groups linked by a common spirocarbon atom, wherein the carbocyclic spirocycle is surrounded by 0-4 T atoms. 1 and 0-1 T 2 replace;

[0125] (e) A heterocyclic spirocycle containing two cyclic groups having at least one heteroatom, wherein the two cyclic groups are linked by a common spirocarbon atom, and wherein the heterocyclic spirocycle is separated by 0-3 T atoms. 5 0-1 T 6 replace;

[0126] (f) by 0-4 T 1 and 0-1 T 4 Substituted phenyl;

[0127] (g) by 0-4 T 5 and 0-1 T 6 Substituted heterocyclic alkyl groups;

[0128] (h) is 0-4 T 5 and 0-1 T 6 Substituted heterocyclic alkenyl groups;

[0129] (i) by 0-4 T 5 and 0-1 T 6 Replacement bridging heterocycle; or

[0130] (j) is 0-3 T 5 and 0-1 T 3 Substituted heteroaryl groups;

[0131] Each Q is independently a halogen, CN, or an alkyl group optionally substituted with 1-3 halogens;

[0132] Each T 1 It is independently a halogen, hydroxyl group, optionally surrounded by 1-3 Rs. b Substituted alkyl groups, optionally with 1-3 R groups b The substituted alkenyl group, optionally surrounded by 1-3 R groups, b Substituted alkynyl, CN, cyanoalkyl, optionally with 1-3 R b Substituted alkoxy groups or optionally substituted with 1-3 R groups b Substituted alkoxyalkyl groups;

[0133] T 2 It is -(CH2) 0-3 -N(R 9 SO2-R 7 -(CH2) 0-3 -SO2-R 7 -(CH2) 0-3 -SO2N(R 8 )R 9 -(CH2) 0-3 -N(R 9 SO2N(R) 8 )R 9-(CH2) 0-3 -N(R 9 )C(O)N(R 8 )R 9 -(CH2) 0-3 -N(R 9 )C(O)R 8 -(CH2) 0-3 -N(R 9 )C(O)OR 9 -(CH2) 0-3 -N(R 8 )R 9 -(CH2) 0-3 -C(O)N(R 8 )R 9 -(CH2) 0-3 -C(O)OR 9 -(CH2) 0-3 -C(O)R 10 -(CH2) 0-3 -C(O)H, -(CH2) 0-3 -N(R 9 )C(O)R 10 Optionally selected by 1-4 Z 3 Substituted -(CH2) 0-3 cycloalkyl, optionally with 1-3 Z 5 Substituted -(CH2) 0-3 -Phenyl or optionally surrounded by 1-3 Z-peptides 5 Substituted -(CH2) 0-3 Mixed aromatics;

[0134] T 3 It is -(CH2) 0-3 -C(O)N(R 8 )R 9 -(CH2) 0-3 -N(R 8 )R 9 -(CH2) 0-3 -C(O)OR 9 -(CH2) 0-3 -cycloalkyl, -(CH2) 0-3 -cycloalkenyl, -(CH2) 0-3 -Heterocyclic alkyl, -(CH2) 0-3 -Heterocyclic alkenyl, -O-heterocyclic alkyl group optionally substituted with 4-chloropyridazin-3-one-5-yl, or -(CH2) 0-3 -Bridging carbon rings, wherein -(CH2) 0-3 -cycloalkyl, -(CH2) 0-3 -cycloalkenyl, -(CH2)0-3 -Heterocyclic alkyl, -(CH2) 0-3 -Heterocyclic alkenyl or -(CH2) 0-3 - Each bridging carbon ring is optionally connected by 1-3 Z-rings. 5 And 0-1 Z 1 Replacement, condition is when T 3 When a heteroatom of G is attached, G cannot be attached to T. 3 Oxygen or nitrogen atoms;

[0135] T 4 It is -(CH2) 0-3 C(O)OR 9 -(CH2) 0-3 -N(R 9 )C(O)R 8 -(CH2) 0-3 -N(R 9 SO2-R 7 -(CH2) 0-3 -SO2-R 7 -(CH2) 0-3 -SO2N(R 8 )R 9 -(CH2) 0-3 -N(R 9 )C(O)N(R 8 )R 9 or N(R) a )2;

[0136] Each T 5 It is independently a halogen, hydroxyl group, optionally surrounded by 1-3 Rs. b Substituted alkyl groups, optionally with 1-3 R groups b Substituted alkenyl groups, optionally surrounded by 1-3 RbR groups b Substituted alkynyl, CN, cyanoalkyl, optionally with 1-3 R b Substituted alkoxy groups or optionally surrounded by 1-3 R groups b Substituted alkoxyalkyl, under the condition that T 5 When attached to a heteroatom of G, T 5 It cannot be halogen, hydroxyl, CN, or optionally marked with 1-3 Rs. b Substituted alkoxy groups;

[0137] T 6 It is -(CH2) 0-3 -N(R 9 SO2-R 7 -(CH2) 0-3 -SO2-R 7 -(CH2) 0-3 -SO2N(R8 )R 9 -(CH2) 0-3 -N(R 9 SO2N(R) 8 )R 9 -(CH2) 0-3 -N(R 9 )C(O)N(R 8 )R 9 -(CH2) 0-3 -N(R 9 )C(O)R 8 -(CH2) 0-3 -N(R 9 )C(O)OR 9 -(CH2) 0-3 -N(R 8 )R 9 -(CH2) 0-3 -C(O)-N(R 8 )R 9 -(CH2) 0-3 -C(O)OR 9 -(CH2) 0-3 -C(O)R 10 -(CH2) 0-3 -N(R 9 )C(O)R 10 -N(H)C(H)C=O, optionally divided by 1-4 Z 3 Substituted -(CH2) 0-3 cycloalkyl, optionally with 1-4 Z 3 Substituted -(CH2) 0-2 Heterocyclic alkyl groups, optionally with 1-3 Z's 5 Substituted -(CH2) 0-3 Heteroaryl or 4-chloropyridazin-3-one-5-yl, under the condition that T 6 When a heteroatom of G is attached, G cannot be attached to T. 6 Nitrogen or oxygen atoms;

[0138] R a It is H or alkyl;

[0139] R b It is a halogen, CN, CF3, or hydroxyl group, provided that it does not exceed one R. b It could be CF3;

[0140] R 1 It is H, alkoxyalkyl, and surrounded by 0-4 Z. 2 Substituted alkenyl groups or 0-4 Z groups 2 Substituted C2-C6 alkyl groups;

[0141] R 2 It is H, halogen, alkyl, alkenyl, alkoxy, haloalkyl, CF3 or CN;

[0142] R 3 It is H, halogen, alkyl, CN or haloalkyl;

[0143] Each R 4 It is independently a halogen, CN, or an alkyl group optionally substituted with 1-3 halogens;

[0144] R 7 It is arbitrarily divided by 1-4 Z. 4 Substituted alkyl groups, optionally with 1-4 Z's 3 Substituted -C0-C3 alkyl-cycloalkyl, optionally with 1-4 Z-terminals 3 Substituted -C0-C3 alkyl-phenyl, optionally with 1-3 Z-terminals 5 Substituted -C0-C3 alkyl-heteroaryl groups or optionally with 1-3 Z groups 5 Substituted -C0-C3 alkyl-heterocyclic alkyl;

[0145] R 8 H, arbitrarily divided by 1-4 Z 4 Substituted alkyl groups, optionally with 1-4 Z-shaped radicals 4 Substituted alkenyl groups, optionally surrounded by 1-4 Z groups 3 Substituted -C0-C3 alkyl-cycloalkyl, optionally with 1-4 Z-terminals 3 Substituted -C0-C3 alkyl-phenyl, optionally with 1-3 Z-terminals 5 Substituted -C0-C3 alkyl-heteroaryl, optionally with 1-3 Z-terminals 5 Substituted -C0-C3 alkyl-heterocyclic alkyl or with 0-5 T 1 Replacement bridging carbon rings;

[0146] Each R 9 Independently H or optionally by 1-4 Z 4 Substituted alkyl groups;

[0147] R 10 It is 0-4 Z 4 Substituted alkyl groups, optionally with 1-4 Z-shaped radicals 3 Substituted -C0-C3 alkyl-cycloalkyl, optionally with 1-4 Z-terminals 3 Substituted -C0-C3 alkyl-phenyl, optionally with 1-3 Z-terminals 5 Substituted -C0-C3 alkyl-heteroaryl groups or optionally with 1-3 Z groups 5 Substituted -C0-C3 alkyl-heterocyclic alkyl;

[0148] R11 It is NH2;

[0149] Z 1 It is a cyanoalkyl group, -(CH2) 0-2 -C(O)OR 9 -(CH2) 0-2 -C(O)-N(R 8 )R 9 The condition is that when Z 1 When attached to a heteroatom, then Z 1 Not C(O)OR 9 ;

[0150] Each Z 2 It can be hydroxyl, halogen, NH2 or CN independently, provided that it does not exceed one Z. 2 It could be NH2;

[0151] Each Z 3 It is independently an alkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl or CN;

[0152] Each Z 4 Independently, it is hydroxyl, halogen, alkoxy, or CN; and

[0153] Each Z 5 Independently, it is an alkyl, haloalkyl, hydroxy, hydroxyalkyl, halogen, alkoxy, alkoxyalkyl, CN, or cyanoalkyl, provided that Z is... 5 When attached to a heteroatom, then Z 5 It is not halogen, hydroxyl, alkoxy or CN.

[0154] Sub-implementation of Implementation Method 1

[0155] Implementation 1(a) relates to Implementation 1, wherein A is a 5-6 quinone aromatic ring, wherein A is surrounded by 0-3 R... 4 replace.

[0156] Embodiment 1(b) relates to Embodiment 1, wherein A is a 4-7 member nitrogen-containing heterocyclic alkyl group, provided that the pyridazinone moiety of Formula I is attached to the nitrogen atom of A.

[0157] Implementation 1(c) relates to any one of Implementation 1, 1(a) or 1(b), wherein E is controlled by 0-3 Qs and 0-1 Rs. 11 Substituted phenyl groups.

[0158] Implementation 1(d) relates to any one of implementation 1, 1(a) or 1(b), wherein E is a 5- or 6-membered heteroaryl group, wherein E is separated by 0-3 Q groups and 0-1 R groups. 11 Substitution occurs when O is not attached to a heteroatom of E.

[0159] Implementation method 1(e) relates to any one of implementation methods 1, 1(a), 1(b), 1(c) or 1(d), wherein L is absent.

[0160] Implementation 1(f) relates to any one of Implementation 1, 1(a), 1(b), 1(c) or 1(d), wherein L is -C(O)N(H)-.

[0161] Embodiment 1(g) relates to any one of Embodiment 1, 1(a), 1(b), 1(c) or 1(d), wherein L is a C0-C3 alkylene group.

[0162] Implementation 1(h) relates to any one of Implementation 1, 1(a), 1(b), 1(c) or 1(d), where L is -N(H)-.

[0163] Implementation 1(i) relates to any one of Implementation 1, 1(a), 1(b), 1(c) or 1(d), where L is -O-.

[0164] Implementation 1(j) relates to any one of Implementation 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), or 1(i), where G is a subset of 0-4 T. 1 and 0-1 T 2 Substituted cycloalkyl groups.

[0165] Implementation 1(k) relates to any one of Implementation 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), or 1(i), where G is a subset of 0-4 T. 1 and 0-1 T 2 Substituted cycloalkenyl groups.

[0166] Implementation 1(l) relates to any one of Implementation 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h) or 1(i), where G is a subset of 0-4 T. 1 and 0-1 T 2 Replacement bridging carbon rings.

[0167] Embodiment 1(m) relates to any one of Embodiments 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), or 1(i), wherein G is a carbocyclic spirocycle containing two cycloalkyl groups linked by a common spirocarbon atom, wherein the carbocyclic spirocycle is surrounded by 0-4 T atoms. 1 and 0-1 T 2 replace.

[0168] Embodiment 1(n) relates to any one of Embodiments 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), or 1(i), wherein G is a heterocyclic spirocycle containing two cyclic groups having at least one heteroatom, wherein the two cyclic groups are connected by a common spirocarbon atom, and wherein the heterocyclic spirocycle is surrounded by 0-3 T atoms. 5 0-1 T 6 replace.

[0169] Implementation 1(o) relates to any one of Implementation 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), or 1(i), where G is a subset of 0-4 T. 1 and 0-1 T 4 Substituted phenyl groups.

[0170] Implementation 1(p) relates to any one of Implementation 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), or 1(i), where G is a subset of 0-4 T. 5 and 0-1 T 6 Substituted heterocyclic alkyl groups.

[0171] Implementation 1(q) relates to any one of Implementation 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), or 1(i), where G is a subset of 0-4 T. 5 and 0-1 T 6 Substituted heterocyclic alkenyl groups.

[0172] Implementation 1(r) relates to any one of Implementation 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), or 1(i), where G is a subset of 0-4 T. 5 and 0-1 T 6 Replacement bridging heterocycles.

[0173] Implementation 1(s) relates to any one of Implementation 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), or 1(i), where G is a subset of 0-3 T. 5 and 0-1 T 3 Substituted heteroaryl groups.

[0174] Implementation method 1(t) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), or 1(m), wherein T 2It is -(CH2) 0-3 -N(R 9 SO2-R 7 .

[0175] Implementation 1(u) relates to any one of Implementation 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), or 1(m), wherein T 2 It is -(CH2) 0-3 -SO2-R 7 .

[0176] Implementation method 1(v) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), or 1(m), wherein T 2 It is -(CH2) 0-3 -N(R 9 SO2N(R) 8 )R 9 .

[0177] Implementation 1(w) relates to any one of Implementation 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), or 1(m), wherein T 2 It is -(CH2) 0-3 -N(R 9 )C(O)N(R 8 )R 9 .

[0178] Implementation method 1(x) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), or 1(m), wherein T 2 It is -(CH2) 0-3 -N(R 9 )C(O)R 8 .

[0179] Implementation 1(y) relates to any one of Implementation 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), or 1(m), wherein T 2 It is -(CH2) 0-3 -N(R 9 )C(O)OR 9 .

[0180] Implementation method 1(z) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(1) or 1(m), wherein T 2 It is -(CH2) 0-3 -N(R 8 )R 9 .

[0181] Implementation method 1 (aa) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), or 1(m), wherein T 2 It is -(CH2) 0-3 -C(O)N(R 8 )R 9 .

[0182] Implementation method 1 (ab) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(1) or 1(m), wherein T 2 It is -(CH2) 0-3 -C(O)OR 9 9.

[0183] Implementation method 1(ac) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), or 1(m), wherein T 2 It is -(CH2) 0-3 -C(O)R 10 .

[0184] Implementation method 1 (ad) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), or 1(m), wherein T 2 It is -(CH2) 0-3 -C(O)H.

[0185] Implementation method 1(ae) ​​relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), or 1(m), wherein T 2 It is -(CH2)0-3 -N(R 9 )C(O)R 10 .

[0186] Implementation method 1(af) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), or 1(m), wherein T 2 It is arbitrarily divided by 1-4 Z. 3 Substituted -(CH2) 0-3 Cycloalkyl.

[0187] Implementation method 1 (ag) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), or 1(m), wherein T 2 It is arbitrarily divided by 1-3 Z. 5 Substituted -(CH2) 0-3 -Phenyl.

[0188] Implementation method 1(ah) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), or 1(m), wherein T 2 It is arbitrarily divided by 1-3 Z. 5 Substituted -(CH2) 0-3 -Phenyl.

[0189] Implementation method 1 (ai) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), or 1(m), wherein T 2 It is arbitrarily divided by 1-3 Z. 5 Substituted -(CH2) 0-3 Mixed aromatic compounds.

[0190] Implementation 1(aj) relates to any one of Implementation 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), or 1(s), wherein T 3 It is -(CH2) 0-3 -C(O)N(R 8 )R 9 .

[0191] Implementation 1 (ak) relates to any one of Implementation 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i) or 1(s), wherein T 3 It is -(CH2) 0-3 -N(R 8 )R 9 The condition is when T 3 When attached to a heteroatom of G, T 3 It cannot be -N(R) 8 )R 9 .

[0192] Implementation 1 (a1) relates to any one of Implementation 1, 1 (a), 1 (b), 1 (c), 1 (d), 1 (e), 1 (f), 1 (g), 1 (h), 1 (i), or 1 (s), wherein T 3 It is -(CH2) 0-3 -C(O)OR 9 .

[0193] Implementation 1 (am) relates to any one of Implementation 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), or 1(s), wherein T 3 It is arbitrarily divided by 1-3 Z. 5 And 0-1 Z 1 Substituted -(CH2) 0-3 -Cycloalkyl.

[0194] Implementation method 1(an) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), or 1(s), wherein T 3 It is arbitrarily divided by 1-3 Z. 5 And 0-1 Z 1 Substituted -(CH2) 0-3 - Heterocyclic alkyl, condition when T 3 When a heteroatom of G is attached, G cannot be attached to T. 3 Nitrogen or oxygen atoms.

[0195] Implementation method 1 (ao) relates to any one of implementation methods 1, 1 (a), 1 (b), 1 (c), 1 (d), 1 (e), 1 (f), 1 (g), 1 (h), 1 (i), or 1 (s), wherein T 3 It is an -O-heterocyclic alkyl group optionally substituted with 4-chloropyridazin-3-one-5-yl, provided that the -O-heterocyclic alkyl group is not attached to the heteroatom of G.

[0196] Implementation 1 (ap) relates to any one of Implementation 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), or 1(s), wherein T 3 It is arbitrarily divided by 1-3 Z. 5 And 0-1 Z 1 Substituted -(CH2) 0-3 -Bridging carbon rings.

[0197] Implementation method 1(aq) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h) or 1(i), wherein T 4 It is -(CH2) 0-3 C(O)OR 9 .

[0198] Implementation method 1 (ar) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), or 1(o), wherein T 4 It is -(CH2) 0-3 -N(R 9 SO2-R 7 .

[0199] Implementation method 1(as) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), or 1(o), wherein T 4 It is -(CH2) 0-3 -SO2-R 7 .

[0200] Implementation 1(at) relates to any one of Implementation 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), or 1(o), wherein T 4 It is -(CH2) 0-3 -SO2N(R 8 )R 9 .

[0201] Implementation 1 (au) relates to any one of Implementation 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), or 1(o), wherein T 4 It is -(CH2) 0-3 -N(R 9 )C(O)N(R 8 )R 9 .

[0202] Implementation method 1 (av) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), or 1(o), wherein T 4 It is N(R) a )2.

[0203] Implementation method 1 (aw) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(n), 1(p), 1(q), or 1(r), wherein T 6 It is -(CH2) 0-3 -N(R 9 SO2-R 7 The condition is when T 6 When attached to a heteroatom of G, T 6 It cannot be -N(R) 9 SO2-R 7 .

[0204] Implementation method 1(ax) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(n), 1(p), 1(q), or 1(r), wherein T 6 It is -(CH2) 0-3 -SO2-R 7 .

[0205] Implementation method 1(ay) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(n), 1(p), 1(q), or 1(r), wherein T 6 It is -(CH2) 0-3 -SO2N(R 8 )R 9 .

[0206] Implementation method 1 (az) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(n), 1(p), 1(q), or 1(r), wherein T 6 It is -(CH2) 0-3 -N(R 9 SO2N(R) 8 )R 9 The condition is when T 6 When attached to a heteroatom of G, T 6 It cannot be -N(R)9 SO2N(R) 8 )R 9 .

[0207] Implementation method 1 (ba) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(n), 1(p), 1(q), or 1(r), wherein T 6 It is -(CH2) 0-3 -N(R 9 )C(O)N(R 8 )R 9 The condition is when T 6 When attached to a heteroatom of G, T 6 It cannot be -N(R) 9 )C(O)N(R 8 )R 9 .

[0208] Implementation method 1 (bb) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(n), 1(p), 1(q), or 1(r), wherein T 6 It is -(CH2) 0-3 -N(R 9 )C(O)R 8 The condition is when T 6 When attached to a heteroatom of G, T 6 It cannot be N(R) 9 )C(O)R 8 .

[0209] Implementation method 1 (bc) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(n), 1(p), 1(q), or 1(r), wherein T 6 It is -(CH2) 0-3 -N(R 9 )C(O)OR 9 The condition is when T 6 When attached to a heteroatom of G, T 6 It cannot be -N(R) 9 )C(O)OR 9 .

[0210] Implementation method 1 (bd) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(n), 1(p), 1(q), or 1(r), wherein T 6 It is -(CH2) 0-3 -N(R 8 )R 9 The condition is when T 6 When attached to a heteroatom of G, T 6 It cannot be -N(R) 8 )R 9 .

[0211] Implementation 1 (be) relates to any one of Implementation 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(n), 1(p), 1(q), or 1(r), wherein T 6 It is -(CH2) 0-3 -C(O)-N(R 8 )R 9 .

[0212] Implementation method 1 (bf) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(n), 1(p), 1(q), or 1(r), wherein T 6 It is -(CH2) 0-3 -C(O)OR 9 .

[0213] Implementation method 1 (bg) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(n), 1(p), 1(q), or 1(r), wherein T 6 It is -(CH2) 0-3 -C(O)R 10 .

[0214] Implementation method 1 (bh) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(n), 1(p), 1(q), or 1(r), wherein T 6 It is -(CH2) 0-3 -N(R 9 )C(O)R 10 The condition is when T 6 When attached to a heteroatom of G, T 6 It cannot be -N(R)9 )C(O)R 10 .

[0215] Implementation method 1 (bi) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(n), 1(p), 1(q), or 1(r), wherein T 6 It is -N(H)C(H)C=O, the condition is T 6 Heteroatoms that do not attach to G.

[0216] Implementation method 1(bj) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(n), 1(p), 1(q), or 1(r), wherein T 6 It is arbitrarily divided by 1-4 Z. 3 Substituted -(CH2) 0-3 Cycloalkyl.

[0217] Implementation method 1 (bk) relates to any one of implementation methods 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(n), 1(p), 1(q), or 1(r), wherein T 6 It is arbitrarily divided by 1-4 Z. 3 Substituted -(CH2) 0-2 Heterocyclic alkyl, under the condition that T 6 When a heteroatom of G is attached, G cannot be attached to T. 6 Nitrogen or oxygen atoms.

[0218] Implementation 1 (bl) relates to any one of Implementation 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(n), 1(p), 1(q), or 1(r), wherein T 6 It is arbitrarily divided by 1-3 Z. 5 Substituted -(CH2) 0-3 heteroaryl, provided that T 6 When a heteroatom of G is attached, G cannot be attached to T. 6 Nitrogen or oxygen atoms.

[0219] Implementation method 1 (bm) relates to implementation method 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), 1(m), 1(n), 1(o), 1(p), 1(q), 1(r), 1(s), 1(t), 1(u), 1(v), 1(w), 1(x), 1(y), 1(z), 1(aa), 1(ab), 1(ac), 1(ad), 1(ae), 1(af), 1(ag), 1( ah), 1(ai), 1(aj), 1(ak), 1(al), 1(am), 1(an), 1(ao), 1(ap), 1(aq), 1(ar), 1(as), 1(at), 1(au), 1(av), 1(aw), 1(ax), 1(ay), 1(az), 1(ba), 1(bb), 1(bc), 1(bd), 1(be), 1(bf), 1(bg), 1(bh), 1(bi), 1(bj), (bk), or 1(bl), where R 1 It is hydrogen.

[0220] Implementation method 1(bn) relates to implementation method 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), 1(m), 1(n), 1(o), 1(p), 1(q), 1(r), 1(s), 1(t), 1(u), 1(v), 1(w), 1(x), 1(y), 1(z), 1(aa), 1(ab), 1(ac), 1(ad), 1(ae), 1(af), 1(ag), 1( ah), 1(ai), 1(aj), 1(ak), 1(al), 1(am), 1(an), 1(ao), 1(ap), 1(aq), 1(ar), 1(as), 1(at), 1(au), 1(av), 1(aw), 1(ax), 1(ay), 1(az), 1(ba), 1(bb), 1(bc), 1(bd), 1(be), 1(bf), 1(bg), 1(bh), 1(bi), 1(bj), (bk), or 1(bl), where R 1 It is a C2-C6 alkyl group substituted with 0-4 hydroxyl groups.

[0221] Implementation method 1 (bo) relates to implementation method 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), 1(m), 1(n), 1(o), 1(p), 1(q), 1(r), 1(s), 1(t), 1(u), 1(v), 1(w), 1(x), 1(y), 1(z), 1(aa), 1(ab), 1(ac), 1(ad), 1(ae), 1(af), 1(ag), 1(ah), 1( any one of ai), 1(aj), 1(ak), 1(al), 1(am), 1(an), 1(ao), 1(ap), 1(aq), 1(ar), 1(as), 1(at), 1(au), 1(av), 1(aw), 1(ax), 1(ay), 1(az), 1(ba), 1(bb), 1(bc), 1(bd), 1(be), 1(bf), 1(bg), 1(bh), 1(bi), 1(bj), (bk), 1(bl), 1(bm) or 1(bn), where R 2 It is halogen.

[0222] Implementation method 1 (bp) involves implementation method 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), 1(m), 1(n), 1(o), 1(p), 1(q), 1(r), 1(s), 1(t), 1(u), 1(v), 1(w), 1(x), 1(y), 1(z), 1(aa), 1(ab), 1(ac), 1(ad), 1(ae), 1(af), 1(ag), 1(ah), 1( any one of ai), 1(aj), 1(ak), 1(al), 1(am), 1(an), 1(ao), 1(ap), 1(aq), 1(ar), 1(as), 1(at), 1(au), 1(av), 1(aw), 1(ax), 1(ay), 1(az), 1(ba), 1(bb), 1(bc), 1(bd), 1(be), 1(bf), 1(bg), 1(bh), 1(bi), 1(bj), (bk), 1(bl), 1(bm) or 1(bn), where R 2 It's CN.

[0223] Implementation method 1 (bq) relates to implementation method 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), 1(m), 1(n), 1(o), 1(p), 1(q), 1(r), 1(s), 1(t), 1(u), 1(v), 1(w), 1(x), 1(y), 1(z), 1(aa), 1(ab), 1(ac), 1(ad), 1(ae), 1(af), 1(ag), 1(ah), 1(ai), 1( any one of the following: aj), 1(ak), 1(al), 1(am), 1(an), 1(ao), 1(ap), 1(aq), 1(ar), 1(as), 1(at), 1(au), 1(av), 1(aw), 1(ax), 1(ay), 1(az), 1(ba), 1(bb), 1(bc), 1(bd), 1(be), 1(bf), 1(bg), 1(bh), 1(bi), 1(bj), (bk), 1(bl), 1(bm), 1(bn), 1(bo) or 1(bp), where R 3 It's H.

[0224] Embodiment 2 of this disclosure relates to compounds according to Embodiment 1,1, wherein ring A is an azacyclobutane, pyrrolidine, piperidine, imidazole, thiazole, or pyrazolyl.

[0225] Sub-implementation of Implementation Method 2

[0226] Embodiment 2(a) of this disclosure relates to a compound according to Embodiment 2, wherein ring A is azacyclobutane.

[0227] Embodiment 2(b) of this disclosure relates to a compound according to Embodiment 2, wherein ring A is pyrrolidine.

[0228] Embodiment 2(c) of this disclosure relates to a compound according to Embodiment 2, wherein ring A is piperidine.

[0229] Embodiment 2(d) of this disclosure relates to a compound according to Embodiment 2, wherein ring A is an imidazole.

[0230] Embodiment 2(e) of this disclosure relates to a compound according to Embodiment 2, wherein ring A is a thiazole.

[0231] Embodiment 2(f) of this disclosure relates to a compound according to Embodiment 2, wherein ring A is azacyclobutane.

[0232] Embodiment 2(g) of this disclosure relates to a compound according to Embodiment 2, wherein ring A is a pyrazolyl group.

[0233] Embodiment 3 of this disclosure relates to a compound having Formula II according to Embodiment 1:

[0234]

[0235] Or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or deuterated analogue thereof, wherein L is absent, -N(H)-, or -O-; and m is 0-2.

[0236] Embodiment 4 of this disclosure relates to compounds having formula IIIa or IIIb according to Embodiment 1:

[0237]

[0238] Or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or deuterated analogue thereof, wherein:

[0239] E is a phenyl or a 6-membered heteroaryl group, wherein E is substituted by 0-2 Q atoms, provided that when E is a 6-membered heteroaryl group, O is not attached to the heteroatom of E;

[0240] G is one of the following groups:

[0241] (a) by 0-3 T 1 and 0-1 T 2 Substituted C3-C6 cycloalkyl groups;

[0242] (b) by 0-3 T 1 and 0-1 T 2 Substituted C3-C6 cycloalkenyl groups;

[0243] (c) by 0-3 T 1 and 0-1 T 2 Replacement of 5-9 bridging carbon rings;

[0244] (d) 5-9 membered carbocyclic spirocycles containing two cycloalkyl groups linked by a common spirocarbon atom, wherein the carbocyclic spirocycle is surrounded by 0-3 T atoms. 1 and 0-1 T 2 replace;

[0245] (e) A 6-9 membered heterocyclic spirocycle containing two cyclic groups having at least one heteroatom, wherein the two cyclic groups are linked by a common spirocarbon atom, and wherein the heterocyclic spirocycle is separated by 0-3 T atoms. 5 0-1 T 6 replace;

[0246] (f) by 0-3 T 1 and 0-1 T 4 Substituted phenyl;

[0247] (g) by 0-3 T 5 and 0-1 T 6 Substituted 4-6 membered heterocyclic alkyl groups;

[0248] (h) is 0-3 T 5 and 0-1 T 6 Substituted 4-6 membered heterocyclic alkenyl groups;

[0249] (i) by 0-3 T 5 and 0-1 T 6 Replacement of 5-9 bridging heterocyclic rings; or

[0250] (j) is 0-3 T 5 and 0-1 T 3 Substituted 5-6 aryl groups;

[0251] Each Q is independently a halogen, CN, or a C1-C3 alkyl group optionally substituted with 1-3 halogens;

[0252] Each T 1 It is independently a halogen, hydroxyl group, optionally surrounded by 1-3 Rs. b Substituted C1-C6 alkyl groups, optionally with 1-3 R groups b The substituted C2-C5 alkenyl group, optionally surrounded by 1-3 R groups, b Substituted C2-C5 ynyl, CN, C1-C6 cyanoalkyl, optionally with 1-3 R b Substituted C1-C6 alkoxy groups or optionally with 1-3 R groups b Substituted C1-C6 alkoxy-C1-C6 alkyl;

[0253] T 2 It is -(CH2) 0-2 -N(R 9 SO2-R 7 -(CH2) 0-2 -SO2-R 7 -(CH2) 0-2 -SO2N(R 8 )R 9 -(CH2) 0-2 -N(R 9 SO2N(R) 8 )R 9 -(CH2) 0-2 -N(R 9 )C(O)N(R 8 )R 9 -(CH2) 0-2 -N(R 9 )C(O)R 8 -(CH2)0-2 -N(R 9 )C(O)OR 9 -(CH2) 0-2 -N(R 8 )R 9 -(CH2) 0-2 -C(O)N(R 8 )R 9 -(CH2) 0-2 -C(O)OR 9 -(CH2) 0-2 -C(O)R 10 -(CH2) 0-2 -C(O)H, -(CH2) 0-2 -N(R 9 )C(O)R 10 Optionally selected by 1-4 Z 3 Substituted -(CH2) 0-2 C3-C6 cycloalkyl, optionally surrounded by 1-3 Z 5 Substituted -(CH2) 0-2 -Phenyl or optionally surrounded by 1-3 Z-peptides 5 Substituted -(CH2) 0-2 -5-6 membered heteroaryl;

[0254] T 3 It is -(CH2) 0-2 -C(O)N(R 8 )R 9 -(CH2) 0-2 -N(R 8 )R 9 -(CH2) 0-2 -C(O)OR 9 -(CH2) 0-2 -C3-C6 cycloalkyl, -(CH2) 0-2 -5-6-membered heterocyclic alkyl groups, -O-5-6-membered heterocyclic alkyl groups optionally substituted with 4-chloropyridazin-3-one-5-yl groups, or -(CH2) 0-2 -5-9 bridging carbon rings, where -(CH2) 0-2 -C3-C6 cycloalkyl, -(CH2) 0-2 -5-6 membered heterocyclic alkyl groups or -(CH2) 0-2 -5-9 yuan bridging carbon rings are each arbitrarily selected by 1-3 Z. 5 And 0-1 Z 1 Replacement, condition is when T 3 When a heteroatom is attached to G, G does not attach to T. 3 Oxygen or nitrogen atoms;

[0255] T4 It is -(CH2) 0-2 C(O)OR 9 -(CH2) 0-2 -N(R 9 )C(O)R 8 -(CH2) 0-2 -N(R 9 SO2-R 7 -(CH2) 0-2 -SO2-R 7 -(CH2) 0-2 -SO2N(R 8 )R 9 -(CH2) 0-2 -N(R 9 )C(O)N(R 8 )R 9 or N(R) a )2;

[0256] Each T 5 It is independently a halogen, hydroxyl group, optionally surrounded by 1-3 Rs. b Substituted C1-C6 alkyl groups, optionally with 1-3 R groups b The substituted C2-C6 alkenyl group, optionally surrounded by 1-3 R groups, b Substituted C2-C6 ynyl, CN, C1-C6 cyanoalkyl, optionally with 1-3 R b Substituted C1-C6 alkoxy groups or optionally with 1-3 R groups b Substituted C1-C6 alkoxy-C1-C6 alkyl, under the condition that T 5 When attached to a heteroatom of G, T 5 It cannot be halogen, hydroxyl, CN, or optionally marked with 1-3 Rs. b Substituted C1-C6 alkoxy groups;

[0257] T 6 It is -(CH2) 0-2 -N(R 9 SO2-R 7 -(CH2) 0-2 -SO2-R 7 -(CH2) 0-2 -SO2N(R 8 )R 9 -(CH2) 0-2 -N(R 9 SO2N(R) 8 )R 9 -(CH2) 0-2 -N(R 9 )C(O)N(R 8 )R9 -(CH2) 0-2 -N(R 9 )C(O)R 8 -(CH2) 0-2 -N(R 9 )C(O)OR 9 -(CH2) 0-2 -N(R 8 )R 9 -(CH2) 0-2 -C(O)-N(R 8 )R 9 -(CH2) 0-2 -C(O)OR 9 -(CH2) 0-2 -C(O)R 10 -(CH2) 0-2 -N(R 9 )C(O)R 10 -N(H)C(H)C=O, optionally divided by 1-4 Z 3 Substituted -(CH2) 0-2 -C3-C6 cycloalkyl, optionally surrounded by 1-4 Z 3 Substituted -(CH2) 0-2 -5-6 membered heterocyclic alkyl groups, optionally surrounded by 1-3 Z groups. 5 Substituted -(CH2) 0-3 -5-6-membered heteroaryl or 4-chloropyridazine-3-one-5-yl, under the condition that T 6 When a heteroatom is attached to G, G does not attach to T. 6 Oxygen or nitrogen atoms;

[0258] R a It is an H or C1-C6 alkyl group;

[0259] R b It is a halogen, CN, CF3, or hydroxyl group, provided that it does not exceed one R. b It could be CF3;

[0260] Each R 1 It is hydrogen, C1-C6 alkoxy, C1-C6 alkyl, surrounded by 1-4 Z. 2 Substituted C2-C6 alkenyl groups or 1-4 Z groups 2 Substituted C2-C6 alkyl groups;

[0261] R 2 It is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, CF3 or CN;

[0262] R 3It is H, halogen, C1-C6 alkyl, CN or C1-C6 haloalkyl;

[0263] Each R 4 It is independently a halogen, CN, or a C1-C3 alkyl group optionally substituted with 1-3 halogens;

[0264] R 7 It is arbitrarily divided by 1-4 Z. 4 Substituted C1-C6 alkyl groups, optionally with 1-4 Z-terminals 3 Substituted -C0-C2 alkyl-C3-C6 cycloalkyl, optionally with 1-4 Z-terminals 3 Substituted -C0-C2 alkyl-phenyl, optionally with 1-3 Z-terminals 5 Substituted -C0-C2 alkyl-5-6 heteroaryl groups or optionally surrounded by 1-3 Z groups 5 Substituted -C0-C2 alkyl-5-6 membered heterocyclic alkyl;

[0265] R 8 H, arbitrarily divided by 1-4 Z 4 Substituted C1-C6 alkyl groups, optionally with 1-4 Z-terminals 4 The substituted C2-C6 alkenyl group, optionally surrounded by 1-4 Z groups, 3 Substituted -C0-C2 alkyl-C3-C6 cycloalkyl, optionally with 1-4 Z-terminals 3 Substituted -C0-C2 alkyl-phenyl, optionally with 1-3 Z-terminals 5 Substituted -C0-C2 alkyl-5-6 heteroaryl, optionally with 1-3 Z-terminals 5 Substituted -C0-C2 alkyl-5-6-membered heterocyclic alkyl or substituted with 0-4 T 1 Replacement of 5-9 bridging carbon rings;

[0266] Each R 9 Independently H or optionally by 1-4 Z 4 Substituted C1-C6 alkyl groups;

[0267] R 10 It is 0-4 Z 4 Substituted C1-C6 alkyl groups, optionally with 1-4 Z-terminals 3 Substituted -C0-C2 alkyl-C3-C6 cycloalkyl, optionally with 1-4 Z-terminals 3 Substituted -C0-C2 alkyl-phenyl, optionally with 1-3 Z-terminals 5 Substituted -C0-C2 alkyl-5-6 heteroaryl groups or optionally surrounded by 1-3 Z groups 5 Substituted -C0-C2 alkyl-5-6 membered heterocyclic alkyl;

[0268] R 11It is NH2;

[0269] Z 1 It is a C1-C6 cyanoalkyl group, -(CH2) 0-2 -C(O)OR 9 -(CH2) 0-2 -C(O)-N(R 8 )R 9 The condition is that when Z 1 When attached to a heteroatom, then Z 1 Not -C(O)OR;

[0270] Each Z 2 Independently, it consists of hydroxyl, halogen, and CN;

[0271] Each Z 3 Independently, it is a C1-C6 alkyl, halogen, C1-C6 haloalkyl, hydroxyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, or CN;

[0272] Each Z 4 Independently, it is hydroxyl, halogen, C1-C6 alkoxy, or CN; and

[0273] Each Z 5 Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, halogen, C1-C6 alkoxy, CN, or C1-C6 cyanoalkyl, provided that Z is... 5 When attached to a heteroatom, then Z 5 It is not halogen, hydroxyl, C1-C6 alkoxy or CN.

[0274] Sub-implementation of Implementation Method 4

[0275] Embodiment 4(a) of this disclosure relates to a compound having formula IIIa according to Embodiment 4, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or deuterated analog thereof.

[0276] Embodiment 4(b) of this disclosure relates to a compound having formula IIIb according to Embodiment 4, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or deuterated analog thereof.

[0277] Embodiment 4(c) of this disclosure relates to a compound according to Embodiment 4, 4(a) or 4(b), wherein G is reacted with 0-3 T atoms. 1 and 0-1 T 2 Substituted C3-C6 cycloalkyl groups.

[0278] Embodiment 4(d) of this disclosure relates to a compound according to Embodiment 4, 4(a) or 4(b), wherein G is a compound formed by 0-3 T atoms.1 and 0-1 T 2 Substituted C3-C6 cycloalkenyl groups.

[0279] Embodiment 4(e) of this disclosure relates to a compound according to Embodiment 4, 4(a) or 4(b), wherein G is a compound formed by 0-3 T atoms. 1 and 0-1 T 2 Replaces the 5-9 bridging carbon ring.

[0280] Embodiment 4(f) of this disclosure relates to compounds according to Embodiments 4, 4(a) or 4(b), wherein G is a 5-9 membered carbocyclic spirocycle containing two cycloalkyl groups linked by a common spirocarbon atom, wherein the carbocyclic spirocycle is surrounded by 0-3 T groups. 1 and 0-1 T 2 replace.

[0281] Embodiment 4(g) of this disclosure relates to a compound according to Embodiments 4, 4(a) or 4(b), wherein G is a 6-9 membered heterocyclic spirocycle containing two cyclic groups having at least one heteroatom, wherein the two cyclic groups are linked by a common spirocarbon atom, and wherein the heterocyclic spirocycle is surrounded by 0-3 T atoms. 5 0-1 T 6 replace.

[0282] Embodiment 4(h) of this disclosure relates to a compound according to Embodiment 4, 4(a) or 4(b), wherein G is a compound formed by 0-3 T atoms. 1 and 0-1 T 4 Substituted phenyl groups.

[0283] Embodiment 4(i) of this disclosure relates to a compound according to Embodiment 4, 4(a) or 4(b), wherein G is a compound formed by 0-3 T atoms. 5 and 0-1 T 6 Substituted 4-6 membered heterocyclic alkyl groups.

[0284] Embodiment 4(j) of this disclosure relates to a compound according to Embodiment 4, 4(a) or 4(b), wherein G is a compound formed by 0-3 T atoms. 5 and 0-1 T 6 Substituted 4-6 membered heterocyclic alkenyl groups.

[0285] Embodiment 4(k) of this disclosure relates to a compound according to Embodiment 4, 4(a) or 4(b), wherein G is a compound formed by 0-3 T atoms. 5 and 0-1 T 6 Replaces the 5-9 bridging heterocyclic ring.

[0286] Embodiment 4(l) of this disclosure relates to a compound according to Embodiment 4, 4(a) or 4(b), wherein G is a compound formed by 0-3 T atoms.5 and 0-1 T 3 Substituted 5-6 heteroaryl groups.

[0287] Embodiment 4(m) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T 2 It is -(CH2) 0-2 -N(R 9 SO2-R 7 .

[0288] Embodiment 4(n) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T 2 It is -(CH2) 0-2 -SO2-R 7 .

[0289] Embodiment 4(o) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T 2 It is -(CH2) 0-2 -SO2N(R 8 )R 9 .

[0290] Embodiment 4(p) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T 2 It is -(CH2) 0-2 -N(R 9 SO2N(R) 8 )R 9 .

[0291] Embodiment 4(q) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T 2 It is -(CH2) 0-2 -N(R 9 )C(O)N(R 8 )R 9 .

[0292] Embodiment 4(r) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T 2 It is -(CH2) 0-2 -N(R 9 )C(O)R 8 .

[0293] Embodiment 4(s) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T 2 It is -(CH2) 0-2 -N(R 9 )C(O)OR 9 .

[0294] Embodiment 4(t) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T 2 It is -(CH2) 0-2 -N(R 8 )R 9 .

[0295] Embodiment 4(u) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T 2 It is -(CH2) 0-2 -C(O)N(R 8 )R 9 .

[0296] Embodiment 4(v) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T 2 It is -(CH2) 0-2 -C(O)OR 9 .

[0297] Embodiment 4(w) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T 2 It is -(CH2) 0-2 -C(O)R 10 .

[0298] Embodiment 4(x) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T 2 It is -(CH2) 0-2 -C(O)H.

[0299] Embodiment 4(y) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T 2 It is -(CH2) 0-2 -N(R 9 )C(O)R 10.

[0300] Embodiment 4(z) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(c), 4(d), 4(e), or 4(f), wherein T2 is optionally surrounded by 1-4 Z 3 Substituted -(CH2) 0-2 C3-C6 cycloalkyl groups.

[0301] Embodiment 4(aa) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T 2 It is arbitrarily divided by 1-3 Z. 5 Substituted -(CH2) 0-2 -Phenyl.

[0302] Embodiment 4(ab) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T 2 It is arbitrarily divided by 1-3 Z. 5 Substituted -(CH2) 0-2 -5-6 membered heteroaryl.

[0303] Embodiment 4(ac) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b) or 4(1), wherein T 3 It is -(CH2) 0-2 -C(O)N(R 8 )R 9 .

[0304] Embodiment 4(ad) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b) or 4(1), wherein T 3 It is -(CH2) 0-2 -N(R 8 )R 9 The condition is T 3 Heteroatoms attached to G, but G is not attached to N(R) 8 )R 9 .

[0305] Embodiment 4(ae) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b) or 4(1), wherein T 3 It is -(CH2) 0-2 -C(O)OR 9 .

[0306] Embodiment 4(af) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b) or 4(1), wherein T 3It is arbitrarily divided by 1-3 Z. 5 And 0-1 Z 1 Substituted -(CH2) 0-2 -C3-C6 cycloalkyl.

[0307] Embodiment 4(ag) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b) or 4(1), wherein T3 is optionally surrounded by 1-3 Z 5 and 0-1 Z 1 Substituted -(CH2) 0-2 -5-6 heterocyclic alkyl, condition when T 3 When it does not attach to the heteroatom of G.

[0308] Embodiment 4(ah) of this disclosure relates to compounds according to Embodiment 4, 4(a), 4(b) or 4(1), wherein T 3 It is an -O-5-6-membered heterocyclic alkyl group optionally substituted with 4-chloropyridazin-3-one-5-yl.

[0309] Embodiment 4(a) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b) or 4(1), wherein T 3 It can be arbitrarily divided by 1-3 Z. 5 And 0-1 Z 1 Substituted -(CH2) 0-2 -5-9 yuan bridging carbon ring.

[0310] Embodiment 4(aj) of this disclosure relates to a compound according to Embodiment 4, 4(a), 4(b) or 4(h), wherein T 4 It is -(CH2) 0-2 C(O)OR 9 .

[0311] Embodiment 4(ak) of this disclosure relates to a compound according to Embodiment 4, 4(a), 4(b) or 4(h), wherein T 4 It is -(CH2) 0-2 -N(R 9 )C(O)R 8 .

[0312] Embodiment 4(a1) of this disclosure relates to compounds according to Embodiment 4, 4(a), 4(b) or 4(h), wherein T 4 It is -(CH2) 0-2 -N(R 9 SO2-R 7 .

[0313] Embodiment 4(am) of this disclosure relates to a compound according to Embodiment 4, 4(a), 4(b) or 4(h), wherein T4 It is -(CH2) 0-2 -SO2-R 7 .

[0314] Embodiment 4(an) of this disclosure relates to a compound according to Embodiment 4, 4(a), 4(b) or 4(h), wherein T 4 It is -(CH2) 0-2 -SO2N(R 8 )R 9 .

[0315] Embodiment 4(a) of this disclosure relates to a compound according to Embodiment 4, 4(a), 4(b) or 4(h), wherein T 4 It is -(CH2) 0-2 -N(R 9 )C(O)N(R 8 )R 9 .

[0316] Embodiment 4(ap) of this disclosure relates to a compound according to Embodiment 4, 4(a), 4(b) or 4(h), wherein T 4 It is N(R) a )2.

[0317] Embodiment 4(aq) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T 6 It is -(CH2) 0-2 -N(R 9 SO2-R 7 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 SO2-R 7 .

[0318] Embodiment 4(ar) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T 6 It is -(CH2) 0-2 -SO2-R 7 .

[0319] Embodiment 4(as) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T 6 It is -(CH2) 0-2 -SO2N(R 8 )R.

[0320] Embodiment 4(at) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T 6 It is -(CH2) 0-2 -N(R 9 SO2N(R) 8 )R 9 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 SO2N(R) 8 )R 9 .

[0321] Embodiment 4 (au) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T 6 It is -(CH2) 0-2 -N(R 9 )C(O)N(R 8 )R 9 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 )C(O)N(R 8 )R 9 .

[0322] Embodiment 4 (av) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T 6 It is -(CH2) 0-2 -N(R 9 )C(O)R 8 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 )C(O)R 8 .

[0323] Embodiment 4 (aw) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T 6 It is -(CH2) 0-2 -N(R 9 )C(O)OR 9 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 )C(O)OR 9 .

[0324] Embodiment 4(ax) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T 6 It is -(CH2) 0-2 -N(R 8 )R 9 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 8 )R 9 .

[0325] Embodiment 4(ay) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T 6 It is -(CH2) 0-2 -C(O)-N(R 8 )R 9 .

[0326] Embodiment 4(az) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T 6 It is -(CH2) 0-2 -C(O)OR 9 .

[0327] Embodiment 4(ba) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T 6 It is -(CH2) 0-2 -C(O)R 10 .

[0328] Embodiment 4(bb) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T 6 It is -(CH2) 0-2 -N(R 9 )C(O)R 10 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 )C(O)R 10 .

[0329] Embodiment 4(bc) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T 6 It is -N(H)C(H)C=O, the condition is T 6 Heteroatoms that do not attach to G.

[0330] Embodiment 4(bd) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T 6 It can be arbitrarily divided by 1-4 Z. 3 Substituted -(CH2) 0-2 -C3-C6 cycloalkyl.

[0331] Embodiment 4(be) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T 6 It can be arbitrarily divided by 1-4 Z. 3 Substituted -(CH2) 0-2 -5-6 membered heterocyclic alkyl groups, under the condition that T 6 When attached to a heteroatom of G, G does not attach to the oxygen or nitrogen atom of a 5- or 6-membered heterocyclic alkyl group.

[0332] Embodiment 4(bf) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T 6 It can be arbitrarily divided by 1-3 Z. 5 Substituted -(CH2) 0-3 -5-6 aryl heteroaryl groups, provided that T 6 When attached to a heteroatom of G, G does not attach to the oxygen or nitrogen atom of a 5-6 membered heteroaryl group.

[0333] Embodiment 4(bg) of this disclosure relates to compounds according to Embodiments 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T 6 It is 4-chloropyridazine-3-one-5-yl.

[0334] Implementation method 4(bh) relates to implementation methods 4, 4(a), 4(b), 4(c), 4(d), 4(e), 4(f), 4(g), 4(h), 4(i), 4(j), 4(k), 4(l), 4(m), 4(n), 4(o), 4(p), 4(q), 4(r), 4(s), 4(t), 4(u), 4(v), 4(w), 4(x), 4(y), 4(z), 4(aa), 4(ab), 4(ac), 4(ad), and 4(ae). , 4(af), 4(ag), 4(ah), 4(ai), 4(aj), 4(ak), 4(al), 4(am), 4(an), 4(ao), 4(ap), 4(aq), 4(ar), 4(as), 4(at), 4(au), 4(av), 4(aw), 4(ax), 4(ay), 4(az), 4(ba), 4(bb), 4(bc), 4(bd), (be), 4(bf), or 4(bg), where R 1 It is hydrogen.

[0335] Implementation method 4(bi) relates to implementation methods 4, 4(a), 4(b), 4(c), 4(d), 4(e), 4(f), 4(g), 4(h), 4(i), 4(j), 4(k), 4(l), 4(m), 4(n), 4(o), 4(p), 4(q), 4(r), 4(s), 4(t), 4(u), 4(v), 4(w), 4(x), 4(y), 4(z), 4(aa), 4(ab), 4(ac), 4(ad), and 4(ae). , 4(af), 4(ag), 4(ah), 4(ai), 4(aj), 4(ak), 4(al), 4(am), 4(an), 4(ao), 4(ap), 4(aq), 4(ar), 4(as), 4(at), 4(au), 4(av), 4(aw), 4(ax), 4(ay), 4(az), 4(ba), 4(bb), 4(bc), 4(bd), (be), 4(bf), or 4(bg), where R 1 It is a C2-C6 alkyl group substituted with 0-4 hydroxyl groups.

[0336] Implementation method 4(bj) relates to implementation methods 4, 4(a), 4(b), 4(c), 4(d), 4(e), 4(f), 4(g), 4(h), 4(i), 4(j), 4(k), 4(l), 4(m), 4(n), 4(o), 4(p), 4(q), 4(r), 4(s), 4(t), 4(u), 4(v), 4(w), 4(x), 4(y), 4(z), 4(aa), 4(ab), 4(ac), 4(ad), and 4(ae). , 4(af), 4(ag), 4(ah), 4(ai), 4(aj), 4(ak), 4(al), 4(am), 4(an), 4(ao), 4(ap), 4(aq), 4(ar), 4(as), 4(at), 4(au), 4(av), 4(aw), 4(ax), 4(ay), 4(az), 4(ba), 4(bb), 4(bc), 4(bd), (be), 4(bf), or 4(bg), where R 2 It is halogen.

[0337] Implementation method 4(bk) relates to implementation methods 4, 4(a), 4(b), 4(c), 4(d), 4(e), 4(f), 4(g), 4(h), 4(i), 4(j), 4(k), 4(l), 4(m), 4(n), 4(o), 4(p), 4(q), 4(r), 4(s), 4(t), 4(u), 4(v), 4(w), 4(x), 4(y), 4(z), 4(aa), 4(ab), 4(ac), 4(ad), and 4(ae). , 4(af), 4(ag), 4(ah), 4(ai), 4(aj), 4(ak), 4(al), 4(am), 4(an), 4(ao), 4(ap), 4(aq), 4(ar), 4(as), 4(at), 4(au), 4(av), 4(aw), 4(ax), 4(ay), 4(az), 4(ba), 4(bb), 4(bc), 4(bd), (be), 4(bf), or 4(bg), where R 2 It's CN.

[0338] Implementation method 4(bl) relates to implementation methods 14, 4(a), 4(b), 4(c), 4(d), 4(e), 4(f), 4(g), 4(h), 4(i), 4(j), 4(k), 4(l), 4(m), 4(n), 4(o), 4(p), 4(q), 4(r), 4(s), 4(t), 4(u), 4(v), 4(w), 4(x), 4(y), 4(z), 4(aa), 4(ab), 4(ac), 4(ad), 4(ae) ), 4(af), 4(ag), 4(ah), 4(ai), 4(aj), 4(ak), 4(al), 4(am), 4(an), 4(ao), 4(ap), 4(aq), 4(ar), 4(as), 4(at), 4(au), 4(av), 4(aw), 4(ax), 4(ay), 4(az), 4(ba), 4(bb), 4(bc), 4(bd), (be), 4(bf), or 4(bg) are any one of the following, where R 3 It is H.

[0339] Embodiment 5 of this disclosure relates to a compound according to any of the foregoing embodiments, wherein:

[0340] E is a phenyl or a 6-membered heteroaryl group, wherein E is substituted by 0-1 Q atoms, provided that when E is a 6-membered heteroaryl group, O is not attached to the heteroatom of E;

[0341] G is one of the following groups:

[0342] (a) by 0-2 T 1 and 0-1 T 2 Substituted C3-C6 cycloalkyl groups;

[0343] (b) by 0-2 T 1 and 0-1 T 2 Substituted C3-C6 cycloalkenyl groups;

[0344] (c) by 0-2 T 1 and 0-1 T 2 Replacement of 5-9 bridging carbon rings;

[0345] (d) 5-9 membered carbon spirocyclic rings containing two cycloalkyl groups linked by a common spirocarbon atom, wherein the carbon spirocyclic ring is surrounded by 0-2 T atoms. 1 and 0-1 T 2 replace;

[0346] (e) A 6-9 membered heterocyclic spirocycle containing two cyclic groups having at least one heteroatom, wherein the two cyclic groups are linked by a common spirocarbon atom, and wherein the heterocyclic spirocycle is separated by 0-2 T atoms. 5 0-1 T6 replace;

[0347] (f) by 0-2 T 1 and 0-1 T 4 Substituted phenyl;

[0348] (g) by 0-2 T 5 and 0-1 T 6 Substituted 4-6 membered heterocyclic alkyl groups;

[0349] (h) is 0-2 T 5 and 0-1 T 6 Substituted 4-6 membered heterocyclic alkenyl groups;

[0350] (i) by 0-2 T 5 and 0-1 T 6 Replacement of 5-9 bridging heterocyclic rings; or

[0351] (j) is 0-2 T 5 and 0-1 T 3 Substituted 5-6 aryl groups;

[0352] Each Q is independently a halogen, CN, or a C1-C4 alkyl group optionally substituted with 1-3 halogens;

[0353] Each T 1 It is independently a halogen, hydroxyl group, optionally surrounded by 1-3 Rs. b Substituted C1-C4 alkyl groups, optionally with 1-3 R groups b The substituted C2-C4 alkenyl group, optionally surrounded by 1-3 R groups, b Substituted C2-C4 ynyl, CN, C1-C4 cyanoalkyl, optionally with 1-3 R b Substituted C1-C4 alkoxy groups or optionally with 1-3 R groups b Substituted C1-C4 alkoxy-C1-C4 alkyl;

[0354] T 2 It is -(CH2) 0-1 -N(R 9 SO2-R 7 -(CH2) 0-1 -SO2-R 7 -(CH2) 0-1 -SO2N(R 8 )R 9 -(CH2) 0-1 -N(R 9 SO2N(R) 8 )R 9 -(CH2) 0-1 -N(R 9)C(O)N(R 8 )R 9 -(CH2) 0-1 -N(R 9 )C(O)R 8 -(CH2) 0-1 -N(R 9 )C(O)OR 9 -(CH2) 0-1 -N(R 8 )R 9 -(CH2) 0-1 -C(O)N(R 8 )R 9 -(CH2) 0-1 -C(O)OR 9 -(CH2) 0-1 -C(O)R 10 -(CH2) 0-1 -C(O)H, -(CH2) 0-1 -N(R 9 )C(O)R 10 Optionally selected by 1-3 Z 3 Substituted -(CH2) 0-2 C3-C6 cycloalkyl, optionally surrounded by 1-3 Z 5 Substituted -(CH2) 0-1 Phenyl or optionally with 1-3 Z 5 Substituted -(CH2) 0-1 -5-6 membered heteroaryl;

[0355] T 3 It is -(CH2) 0-2 -C(O)N(R 8 )R 9 -(CH2) 0-2 -N(R 8 )R 9 -(CH2) 0-2 -C(O)OR 9 -(CH2) 0-2 -C3-C6 cycloalkyl, -(CH2) 0-2 -5-6-membered heterocyclic alkyl groups, -O-5-6-membered heterocyclic alkyl groups optionally substituted with 4-chloropyridazin-3-one-5-yl groups, or -(CH2) 0-2 -5-9 bridging carbon rings, where -(CH2) 0-2 -C3-C6 cycloalkyl, -(CH2) 0-1 -5-6 membered heterocyclic alkyl groups or -(CH2) 0-2 -5-9 yuan bridging carbon rings are each arbitrarily selected by 1-3 Z. 5 And 0-1 Z1 Replacement, condition is when T 3 When a heteroatom is attached to G, G does not attach to T. 3 Oxygen or nitrogen atoms;

[0356] T 4 It is -(CH2) 0-1 C(O)OR 9 -(CH2) 0-1 -N(R 9 )C(O)R 8 -(CH2) 0-1 -N(R 9 SO2-R 7 -(CH2) 0-1 -SO2-R 7 -(CH2) 0-1 -SO2N(R 8 )R 9 -(CH2) 0-1 -N(R 9 )C(O)N(R 8 )R 9 or N(R) a )2;

[0357] Each T 5 It is independently a halogen, hydroxyl group, optionally surrounded by 1-3 Rs. b Substituted C1-C4 alkyl groups, optionally with 1-3 R groups b The substituted C2-C4 alkenyl group, optionally surrounded by 1-3 R groups, b Substituted C2-C4 ynyl, CN, C1-C4 cyanoalkyl, optionally with 1-3 R b Substituted C1-C4 alkoxy groups or optionally with 1-3 R groups b Substituted C1-C4 alkoxy-C1-C4 alkyl, under the condition that T 5 When attached to a heteroatom of G, T 5 It cannot be halogen, hydroxyl, CN, or optionally marked with 1-3 Rs. b Substituted C1-C4 alkoxy groups;

[0358] T 6 It is -(CH2) 0-1 -N(R 9 SO2-R 7 -(CH2) 0-1 -SO2-R 7 -(CH2) 0-1 -SO2N(R 8 )R 9 -(CH2) 0-1 -N(R 9SO2N(R) 8 )R 9 -(CH2) 0-1 -N(R 9 )C(O)N(R 8 )R 9 -(CH2) 0-1 -N(R 9 )C(O)R 8 -(CH2) 0-1 -N(R 9 )C(O)OR 9 -(CH2) 0-1 -N(R 8 )R 9 -(CH2) 0-1 -C(O)-N(R 8 )R 9 -(CH2) 0-1 -C(O)OR 9 -(CH2) 0-1 -C(O)R 10 -(CH2) 0-1 -N(R 9 )C(O)R 10 -N(H)C(H)C=O, optionally divided by 1-4 Z 3 Substituted -(CH2) 0-1 -C3-C6 cycloalkyl, optionally surrounded by 1-4 Z 3 Substituted -(CH2) 0-1 -5-6 membered heterocyclic alkyl groups, optionally surrounded by 1-3 Z groups. 5 Substituted -(CH2) 0-1 -5-6-membered heteroaryl or 4-chloropyridazine-3-one-5-yl, under the condition that T 6 When a heteroatom is attached to G, G does not attach to T. 6 Oxygen or nitrogen atoms;

[0359] R a It is an H or C1-C4 alkyl group;

[0360] R b It is F, Cl, CN, CF3, or a hydroxyl group, provided that there is no more than one R. b It could be CF3;

[0361] R 1 It is H, C1-C4 alkoxy, C1-C4 alkyl, surrounded by 1-3 Z 2 Substituted C2-C4 alkenyl groups or 1-3 Z groups 2 Substituted C2-C4 alkyl groups;

[0362] R 2It is H, halogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, C1-C4 haloalkyl, CF3 or CN;

[0363] R 3 It is H, halogen, C1-C4 alkyl, CN or C1-C4 haloalkyl;

[0364] Each R 4 It is independently a halogen, CN, or a C1-C4 alkyl group optionally substituted with 1-3 halogens;

[0365] R 7 It can be arbitrarily divided by 1-3 Z. 4 Substituted C1-C4 alkyl groups, optionally with 1-3 Z-shaped radicals 3 Substituted -C0-C3 alkyl-C3-C6 cycloalkyl, optionally with 1-3 Z-terminals 3 Substituted -C0-C3 alkyl-phenyl, optionally with 1-3 Z-terminals 5 Substituted -C0-C1 alkyl-5-6 heteroaryl groups or optionally surrounded by 1-3 Z groups 5 Substituted -C0-C1 alkyl-5-6 membered heterocyclic alkyl;

[0366] R 8 H, arbitrarily divided by 1-3 Z 4 Substituted C1-C4 alkyl groups, optionally with 1-3 Z-shaped radicals 4 The substituted C2-C4 alkenyl group, optionally surrounded by 1-3 Z groups, 3 Substituted -C0-C1 alkyl-C3-C6 cycloalkyl, optionally with 1-3 Z-terminals 3 Substituted -C0-C1 alkyl-phenyl, optionally with 1-3 Z-terminals 5 Substituted -C0-C1 alkyl-5-6 heteroaryl groups, optionally with 1-3 Z-terminals 5 Substituted -C0-C1 alkyl-5-6-membered heterocyclic alkyl or substituted with 0-3 T 1 Replacement of 5-9 bridging carbon rings;

[0367] Each R 9 Independently H or optionally by 1-3 Z 4 Substituted C1-C4 alkyl groups;

[0368] R 10 It is 0-3 Z 4 Substituted C1-C4 alkyl groups, optionally with 1-3 Z-shaped radicals 3 Substituted -C0-C1 alkyl-C3-C6 cycloalkyl, optionally with 1-3 Z-terminals 3 Substituted -C0-C1 alkyl-phenyl, optionally with 1-3 Z-terminals 5Substituted -C0-C1 alkyl-5-6 heteroaryl groups or optionally surrounded by 1-3 Z groups 5 Substituted -C0-C1 alkyl-5-6 membered heterocyclic alkyl;

[0369] Z 1 It is a C1-C4 cyanoalkyl group, -(CH2) 0-1 -C(O)OR 9 -(CH2) 0-1 -C(O)-N(R 8 )R 9 The condition is that when Z 1 When attached to a heteroatom, then Z 1 Not -C(O)OR 9 ;

[0370] Each Z 2 Independently, it consists of hydroxyl, halogen, and CN;

[0371] Each Z 3 Independently, it is a C1-C4 alkyl, halogen, C1-C4 haloalkyl, hydroxyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, or CN;

[0372] Each Z 4 Independently, it is hydroxyl, halogen, C1-C4 alkoxy, or CN; and

[0373] Each Z 5 Independently, it is a C1-C4 alkyl, C1-C6 haloalkyl, hydroxy, C1-C4 hydroxyalkyl, halogen, C1-C4 alkoxy, CN, or C1-C4 cyanoalkyl, provided that Z is... 5 When attached to a heteroatom, Z 5 It is not halogen, hydroxyl, C1-C4 alkoxy or CN.

[0374] Sub-implementation of Implementation Method 5

[0375] Embodiment 5(a) of this disclosure relates to Embodiment 5, wherein E is a phenyl group substituted with 0-1 Q.

[0376] Embodiment 5(b) of this disclosure relates to Embodiment 5, wherein E is a 6-membered heteroaryl group substituted with 0-1 Q atoms, provided that O is not attached to the heteroatom of E.

[0377] Implementation 5(c) of this disclosure relates to implementation 5, 5(a) or 5(b), wherein G is controlled by 0-2 T 1 and 0-1 T 2 Substituted C3-C6 cycloalkyl groups.

[0378] Implementation 5(d) of this disclosure relates to implementation 5, 5(a) or 5(b), wherein G is controlled by 0-2 T 1 and 0-1 T 2 Substituted C3-C6 cycloalkenyl groups.

[0379] Implementation 5(e) of this disclosure relates to implementation 5, 5(a) or 5(b), wherein G is controlled by 0-2 T 1 and 0-1 T 2 Replaces the 5-9 bridging carbon ring.

[0380] Embodiment 5(f) of this disclosure relates to Embodiment 5, 5(a) or 5(b), wherein G is a 5-9 membered carbocyclic spirocycle containing two cycloalkyl groups linked by a common spirocarbon atom, wherein the carbocyclic spirocycle is surrounded by 0-2 T groups. 1 and 0-1 T 2 replace.

[0381] Embodiment 5(g) of this disclosure relates to Embodiments 5, 5(a) or 5(b), wherein G is a 6-9 membered heterocyclic spirocycle containing two cyclic groups having at least one heteroatom, wherein the two cyclic groups are linked by a common spirocarbon atom, and wherein the heterocyclic spirocycle is surrounded by 0-2 T atoms. 5 0-1 T 6 replace.

[0382] Implementation 5(h) of this disclosure relates to implementation 5, 5(a) or 5(b), wherein G is controlled by 0-2 T 1 and 0-1 T 4 Substituted phenyl groups.

[0383] Implementation 5(i) of this disclosure relates to implementation 5, 5(a) or 5(b), wherein G is controlled by 0-2 T 5 and 0-1 T 6 Substituted 4-6 membered heterocyclic alkyl groups.

[0384] Implementation 5(j) of this disclosure relates to implementation 5, 5(a) or 5(b), wherein G is controlled by 0-2 T 5 and 0-1 T 6 Substituted 4-6 membered heterocyclic alkenyl groups.

[0385] Implementation 5(k) of this disclosure relates to implementation 5, 5(a) or 5(b), wherein G is controlled by 0-2 T 5 and 0-1 T 6 Replaces the 5-9 bridging heterocyclic ring.

[0386] Embodiment 5(l) of this disclosure relates to Embodiment 5, 5(a) or 5(b), wherein G is a subset of 0-2 T.5 and 0-1 T 3 Substituted 5-6 heteroaryl groups.

[0387] Embodiment 5(m) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T 2 It is -(CH2) 0-1 -N(R 9 SO2-R 7 .

[0388] Embodiment 5(n) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T 2 It is -(CH2) 0-1 -SO2-R 7 .

[0389] Embodiment 5(o) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T 2 It is -(CH2) 0-1 -SO2N(R 8 )R 9 .

[0390] Embodiment 5(p) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T 2 It is -(CH2) 0-1 -N(R 9 SO2N(R) 8 )R 9 .

[0391] Embodiment 5(q) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T 2 It is -(CH2) 0-1 -N(R 9 )C(O)N(R 8 )R 9 .

[0392] Embodiment 5(r) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T 2 It is -(CH2) 0-1 -N(R 9 )C(O)R 8 .

[0393] Embodiment 5(s) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T 2 It is -(CH2) 0-1 -N(R 9 )C(O)OR 9 .

[0394] Embodiment 5(t) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T 2 It is -(CH2) 0-1 -N(R 8 )R 9 .

[0395] Embodiment 5(u) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T 2 It is -(CH2) 0-1 -C(O)N(R 8 )R 9 .

[0396] Embodiment 5(v) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T 2 It is -(CH2) 0-1 -C(O)OR 9 .

[0397] Embodiment 5(w) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T 2 It is -(CH2) 0-1 -C(O)R 10 .

[0398] Embodiment 5(x) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T 2 It is -(CH2) 0-1 -C(O)H.

[0399] Embodiment 5(y) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T 2 It is -(CH2) 0-1 -N(R 9 )C(O)R 10.

[0400] Embodiment 5(z) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(c), 5(d), 5(e), or 5(f), wherein T2 is optionally surrounded by 1-3 Z 3 Substituted -(CH2) 0-2 C3-C6 cycloalkyl groups.

[0401] Embodiment 5(aa) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T 2 It can be arbitrarily divided by 1-3 Z. 5 Substituted -(CH2) 0-1 -Phenyl.

[0402] Embodiment 5(ab) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T 2 It can be arbitrarily divided by 1-3 Z. 5 Substituted -(CH2) 0-1 -5-6 membered heteroaryl.

[0403] Embodiment 5(ac) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b) or 5(1), wherein T 3 It is -(CH2) 0-2 -C(O)N(R 8 )R 9 .

[0404] Embodiment 5(ad) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b) or 5(1), wherein T 3 It is -(CH2) 0-2 -N(R 8 )R 9 The condition is when T 3 When attached to a heteroatom of G, G does not attach to -N(R) 8 )R 9 .

[0405] Embodiment 5(ae) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b) or 5(1), wherein T 3 It is -(CH2) 0-2 -C(O)OR 9 .

[0406] Embodiment 5(af) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b) or 5(1), wherein T 3It can be arbitrarily divided by 1-3 Z. 5 And 0-1 Z 1 Substituted -(CH2) 0-2 -C3-C6 cycloalkyl.

[0407] Embodiment 5 (ag) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b) or 5(1), wherein T 3 It can be arbitrarily divided by 1-3 Z. 5 And 0-1 Z 1 Substituted -(CH2) 0-2 -5-6 heterocyclic alkyl, condition when T 3 When attached to a heteroatom of G, G does not attach to the oxygen or nitrogen atom of a 5- or 6-membered heterocyclic alkyl group.

[0408] Embodiment 5(ah) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b) or 5(1), wherein T 3 It is an -O-5-6-membered heterocyclic alkyl group optionally substituted with 4-chloropyridazin-3-one-5-yl.

[0409] Embodiment 5(a) of this disclosure relates to a compound according to Embodiment 5, 5(a), 5(b) or 5(1), wherein T 3 It can be arbitrarily divided by 1-3 Z. 5 And 0-1 Z 1 Substituted -(CH2) 0-2 -5-9 yuan bridging carbon ring.

[0410] Embodiment 5(aj) of this disclosure relates to a compound according to Embodiment 5, 5(a), 5(b) or 5(h), wherein T 4 It is -(CH2) 0-1 C(O)OR 9 .

[0411] Embodiment 5(ak) of this disclosure relates to a compound according to Embodiment 5, 5(a), 5(b) or 5(h), wherein T 4 It is -(CH2) 0-1 -N(R 9 )C(O)R 8 .

[0412] Embodiment 5(a1) of this disclosure relates to a compound according to Embodiment 5, 5(a), 5(b) or 5(h), wherein T 4 It is -(CH2) 0-1 -N(R 9 SO2-R

[0413] Embodiment 5(am) of this disclosure relates to a compound according to Embodiment 5, 5(a), 5(b) or 5(h), wherein T 4 It is -(CH2) 0-1 -SO2-R 7 .

[0414] Embodiment 5(an) of this disclosure relates to a compound according to Embodiment 5, 5(a), 5(b) or 5(h), wherein T 4 It is -(CH2) 0-1 -SO2N(R 8 )R 9 .

[0415] Embodiment 5(a) of this disclosure relates to a compound according to Embodiment 5, 5(a), 5(b) or 5(h), wherein T 4 It is -(CH2) 0-1 -N(R 9 )C(O)N(R 8 )R 9 .

[0416] Embodiment 5(ap) of this disclosure relates to a compound according to Embodiment 5, 5(a), 5(b) or 5(h), wherein T 4 It is N(R) a )2.

[0417] Embodiment 5(aq) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T 6 It is -(CH2) 0-1 -N(R 9 SO2-R 7 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 SO2-R 7 .

[0418] Embodiment 5(ar) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T 6 It is -(CH2) 0-1 -SO2-R 7 .

[0419] Embodiment 5(as) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T 6 It is -(CH2) 0-1 -SO2N(R8 )R 9 .

[0420] Embodiment 5(at) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T 6 It is -(CH2) 0-1 -N(R 9 SO2N(R) 8 )R 9 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 SO2N(R) 8 )R 9 .

[0421] Embodiment 5 (au) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T 6 It is -(CH2) 0-1 -N(R 9 )C(O)N(R 8 )R 9 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 )C(O)N(R 8 )R 9 .

[0422] Embodiment 5 (av) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T 6 It is -(CH2) 0-1 -N(R 9 )C(O)R 8 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 )C(O)R 8 .

[0423] Embodiment 5 (aw) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T 6 It is -(CH2) 0-1 -N(R 9 )C(O)OR 9 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 )C(O)OR 9 .

[0424] Embodiment 5(ax) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T 6 It is -(CH2) 0-1 -N(R 8 )R 9 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 8 )R 9 .

[0425] Embodiment 5(ay) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T 6 It is -(CH2) 0-1 -C(O)-N(R 8 )R 9 .

[0426] Embodiment 5 (az) of this disclosure relates to compounds according to Embodiments 5, 5 (a), 5 (b), 5 (g), 5 (i), 5 (j) or 5 (k), wherein T 6 It is -(CH2) 0-1 -C(O)OR 9 .

[0427] Embodiment 5(ba) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T 6 It is -(CH2) 0-1 -C(O)R 10 .

[0428] Embodiment 5(bb) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein TT 6 It is -(CH2) 0-1 -N(R 9 )C(O)R 10 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 )C(O)R 10 .

[0429] Embodiment 5(bc) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T 6 It is -N(H)C(H)C=O, the condition is T6 Heteroatoms that do not attach to G.

[0430] Embodiment 5(bd) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T 6 It can be arbitrarily divided by 1-4 Z. 3 Substituted -(CH2) 0-1 -C3-C6 cycloalkyl.

[0431] Embodiment 5(be) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T 6 It can be arbitrarily divided by 1-4 Z. 3 Substituted -(CH2) 0-1 -5-6 membered heterocyclic alkyl groups, under the condition that T 6 When attached to a heteroatom of G, G does not attach to heteroatoms of 5-6 membered heteroaryl groups.

[0432] Embodiment 5(bf) of this disclosure relates to compounds according to Embodiments 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T 6 It can be arbitrarily divided by 1-3 Z. 5 Substituted -(CH2) 0-1 -5-6 aryl heteroaryl groups, provided that T 6 When attached to a heteroatom of G, G does not attach to heteroatoms of 5-6 membered heteroaryl groups.

[0433] Implementation method 5(bg) relates to implementation methods 5, 5(a), 5(b), 5(c), 5(d), 5(e), 5(f), 5(g), 5(h), 5(i), 5(j), 5(k), 5(l), 5(m), 5(n), 5(o), 5(p), 5(q), 5(r), 5(s), 5(t), 5(u), 5(v), 5(w), 5(x), 5(y), 5(z), 5(aa), 5(ab), 5(ac), 5(ad), 5( any one of the following: ae), 5(af), 5(ag), 5(ah), 5(ai), 5(aj), 5(ak), 5(al), 5(am), 5(an), 5(ao), 5(ap), 5(aq), 5(ar), 5(as), 5(at), 5(au), 5(av), 5(aw), 5(ax), 5(ay), 5(az), 5(ba), 5(bb), 5(bc), 5(bd), 5(be), or 5(bf), where R 1 It is hydrogen.

[0434] Implementation 5(bh) relates to implementations 5, 5(a), 5(b), 5(c), 5(d), 5(e), 5(f), 5(g), 5(h), 5(i), 5(j), 5(k), 5(l), 5(m), 5(n), 5(o), 5(p), 5(q), 5(r), 5(s), 5(t), 5(u), 5(v), 5(w), 5(x), 5(y), 5(z), 5(aa), 5(ab), 5(ac), 5(ad), 5( any one of the following: ae), 5(af), 5(ag), 5(ah), 5(ai), 5(aj), 5(ak), 5(al), 5(am), 5(an), 5(ao), 5(ap), 5(aq), 5(ar), 5(as), 5(at), 5(au), 5(av), 5(aw), 5(ax), 5(ay), 5(az), 5(ba), 5(bb), 5(bc), 5(bd), 5(be), or 5(bf), where R 1 It is a C2-C4 alkyl group substituted with 0-4 hydroxyl groups.

[0435] Implementation method 5(bi) relates to implementation methods 5, 5(a), 5(b), 5(c), 5(d), 5(e), 5(f), 5(g), 5(h), 5(i), 5(j), 5(k), 5(l), 5(m), 5(n), 5(o), 5(p), 5(q), 5(r), 5(s), 5(t), 5(u), 5(v), 5(w), 5(x), 5(y), 5(z), 5(aa), 5(ab), 5(ac), 5(ad), 5( any one of the following: ae), 5(af), 5(ag), 5(ah), 5(ai), 5(aj), 5(ak), 5(al), 5(am), 5(an), 5(ao), 5(ap), 5(aq), 5(ar), 5(as), 5(at), 5(au), 5(av), 5(aw), 5(ax), 5(ay), 5(az), 5(ba), 5(bb), 5(bc), 5(bd), 5(be), or 5(bf), where R 2 It is halogen.

[0436] Implementation 5(bj) relates to implementations 5, 5(a), 5(b), 5(c), 5(d), 5(e), 5(f), 5(g), 5(h), 5(i), 5(j), 5(k), 5(l), 5(m), 5(n), 5(o), 5(p), 5(q), 5(r), 5(s), 5(t), 5(u), 5(v), 5(w), 5(x), 5(y), 5(z), 5(aa), 5(ab), 5(ac), 5(ad), 5( any one of the following: ae), 5(af), 5(ag), 5(ah), 5(ai), 5(aj), 5(ak), 5(al), 5(am), 5(an), 5(ao), 5(ap), 5(aq), 5(ar), 5(as), 5(at), 5(au), 5(av), 5(aw), 5(ax), 5(ay), 5(az), 5(ba), 5(bb), 5(bc), 5(bd), 5(be), or 5(bf), where R 2 It's CN.

[0437] Implementation method 5(bk) relates to implementation methods 5, 5(a), 5(b), 5(c), 5(d), 5(e), 5(f), 5(g), 5(h), 5(i), 5(j), 5(k), 5(l), 5(m), 5(n), 5(o), 5(p), 5(q), 5(r), 5(s), 5(t), 5(u), 5(v), 5(w), 5(x), 5(y), 5(z), 5(aa), 5(ab), 5(ac), 5(ad), 5( any one of the following: ae), 5(af), 5(ag), 5(ah), 5(ai), 5(aj), 5(ak), 5(al), 5(am), 5(an), 5(ao), 5(ap), 5(aq), 5(ar), 5(as), 5(at), 5(au), 5(av), 5(aw), 5(ax), 5(ay), 5(az), 5(ba), 5(bb), 5(bc), 5(bd), 5(be), or 5(bf), where R 3 It is H.

[0438] Embodiment 6 of this embodiment relates to a compound according to any one of embodiments 1, 2, 3, 4 or 5 above, wherein R 1 It is hydrogen.

[0439] Embodiment 7 of this embodiment relates to a compound according to any one of Embodiments 1, 2, 3, 4 or 5, wherein R 1 It is a C1-C4 alkoxy-C1-C4 alkyl group, surrounded by 1-3 Z groups. 2 Substituted C2-C4 alkenyl groups or 1-3 Z groups 2 Substituted C2-C4 alkyl groups;

[0440] Embodiment 8 of this embodiment relates to a compound according to Embodiments 1, 2, 3, 4 or 5, wherein

[0441] R 1 It is -CH2CH2OH, -CH2CH2CH2OH, -CH2CH(OH)CH2OH or -CH2CH(CH3)OH;

[0442] R 2 It is Cl, Br, CF3 or CN; and

[0443] E is pyridyl, phenyl, pyrimidinyl, or pyridazinyl.

[0444] Sub-implementation of Implementation Method 8

[0445] Embodiment 8(a) of this disclosure relates to embodiment 8, wherein R 1 It is -CH2CH2OH; R 2 It is Cl; and E is pyridyl.

[0446] Embodiment 8(b) of this disclosure relates to embodiment 8, wherein R 1 It is -CH2CH2CH2OH; R 2 It is Cl; and E is pyridyl.

[0447] Embodiment 8(c) of this disclosure relates to embodiment 8, wherein R 1 It is -CH2CH(OH)CH2OH; R 2 It is Cl; and E is pyridyl.

[0448] Embodiment 8(d) of this disclosure relates to Embodiment 8, wherein R 1 It is -CH2CH(CH3)OH; R 2 It is Cl; and E is pyridyl.

[0449] Embodiment 9 of this disclosure relates to a compound according to Embodiment 8, wherein R 2 It is Cl.

[0450] Embodiment 10 of this disclosure relates to a compound according to any one of Embodiments 1, 2, 3, 4 or 5, wherein

[0451] R 1 It is H;

[0452] R 2 It is Cl, Br, CF3 or CN;

[0453] R 4 It is halogen; and

[0454] E is pyridyl, phenyl, pyrimidinyl, or pyridazinyl.

[0455] Sub-implementation of Implementation Method 10

[0456] Embodiment 10(a) of this disclosure relates to Embodiment 10, wherein E is pyridyl.

[0457] Embodiment 11 of this disclosure relates to a compound according to Embodiment 10, wherein R 2 It is Cl.

[0458] Embodiment 12 of this disclosure relates to a compound according to any one of Embodiments 1-5, having any one of the following formulas:

[0459]

[0460] Sub-implementation of Implementation Method 12

[0461] Embodiment 12(a) of this disclosure relates to embodiment 12, wherein G is a subset of 0-2 T. 1 and 0-1 T 2 Substituted C3-C6 cycloalkyl groups.

[0462] Implementation 12(b) of this disclosure relates to implementation 12, wherein G is controlled by 0-2 T 1 and 0-1 T 2 Substituted C3-C6 cycloalkenyl groups.

[0463] Implementation 12(c) of this disclosure relates to implementation 12, wherein G is controlled by 0-2 T 1 and 0-1 T 2 Replaces the 5-9 bridging carbon ring.

[0464] Embodiment 12(d) of this disclosure relates to Embodiment 12, wherein G is a 5-9 membered carbocyclic spirocycle containing two cycloalkyl groups linked by a common spirocarbon atom, wherein the carbocyclic spirocycle is surrounded by 0-2 T groups. 1 and 0-1 T 2 replace.

[0465] Embodiment 12(e) of this disclosure relates to Embodiment 12, wherein G is a 6-9 membered heterocyclic spirocycle containing two cyclic groups having at least one heteroatom, wherein the two cyclic groups are connected by a common spirocarbon atom, and wherein the heterocyclic spirocycle is separated by 0-2 T atoms. 5 0-1 T 6 replace.

[0466] Implementation 12(f) of this disclosure relates to implementation 12, wherein G is controlled by 0-2 T 1 and 0-1 T4 Substituted phenyl groups.

[0467] Embodiment 12(g) of this disclosure relates to Embodiment 12, wherein G is a subset of 0-2 T. 5 and 0-1 T 6 Substituted 4-6 membered heterocyclic alkyl groups.

[0468] Implementation 12(h) of this disclosure relates to implementation 12, wherein G is controlled by 0-2 T 5 and T 6 Substituted 4-6 membered heterocyclic alkenyl groups.

[0469] Implementation 12(i) of this disclosure relates to implementation 12, wherein G is a subset of 0-2 T. 5 and 0-1 T 6 Replaces the 5-9 bridging heterocyclic ring.

[0470] Implementation 12(j) of this disclosure relates to implementation 12, wherein G is controlled by 0-2 T 5 and 0-1 T 3 Substituted 5-6 heteroaryl groups.

[0471] Embodiment 12(k) of this disclosure relates to a compound according to Embodiment 12, 12(a), 12(b), 12(c) or 12(d), wherein T 2 It is -(CH2) 0-1 -N(R 9 SO2-R 7 .

[0472] Embodiment 12(l) of this disclosure relates to a compound according to Embodiment 12, 12(a), 12(b), 12(c) or 12(d), wherein T 2 It is -(CH2) 0-1 -SO2-R 7 .

[0473] Embodiment 12(m) of this disclosure relates to compounds according to Embodiments 12, 12(a), 12(b), 12(c) or 12(d), wherein T 2 It is -(CH2) 0-1 -SO2N(R 8 )R 9 .

[0474] Embodiment 12(n) of this disclosure relates to compounds according to Embodiment 12, 12(a), 12(b), 12(c) or 12(d), wherein T 2 It is -(CH2) 0-1 -N(R 9 SO2N(R)8 )R 9 .

[0475] Embodiment 12(o) of this disclosure relates to a compound according to Embodiment 12, 12(a), 12(b), 12(c) or 12(d), wherein T 2 It is -(CH2) 0-1 -N(R 9 )C(O)N(R 8 )R 9 .

[0476] Embodiment 12(p) of this disclosure relates to compounds according to Embodiments 12, 12(a), 12(b), 12(c) or 12(d), wherein T 2 It is -(CH2) 0-1 -N(R 9 )C(O)R 8 .

[0477] Embodiment 12(q) of this disclosure relates to a compound according to Embodiment 12, 12(a), 12(b), 12(c) or 12(d), wherein T 2 It is -(CH2) 0-1 -N(R 9 )C(O)OR 9 .

[0478] Embodiment 12(r) of this disclosure relates to compounds according to Embodiments 12, 12(a), 12(b), 12(c) or 12(d), wherein T 2 It is -(CH2) 0-1 -N(R 8 )R 9 .

[0479] Embodiment 12(s) of this disclosure relates to compounds according to Embodiments 12, 12(a), 12(b), 12(c) or 12(d), wherein T 2 It is -(CH2) 0-1 -C(O)N(R 8 )R 9 .

[0480] Embodiment 12(t) of this disclosure relates to compounds according to Embodiments 12, 12(a), 12(b), 12(c) or 12(d), wherein T 2 It is -(CH2) 0-1 -C(O)OR 9 .

[0481] Embodiment 12(u) of this disclosure relates to compounds according to Embodiments 12, 12(a), 12(b), 12(c) or 12(d), wherein T 2 It is -(CH2) 0-1 -C(O)R 10 .

[0482] Embodiment 12(v) of this disclosure relates to compounds according to Embodiments 12, 12(a), 12(b), 12(c) or 12(d), wherein T 2 It is -(CH2) 0-1 -C(O)H.

[0483] Embodiment 12(w) of this disclosure relates to compounds according to Embodiments 12, 12(a), 12(b), 12(c) or 12(d), wherein T 2 It is -(CH2) 0-1 -N(R 9 )C(O)R 10 .

[0484] Embodiment 12(x) of this disclosure relates to compounds according to Embodiments 5, 12, 12(a), 12(b), 12(c) or 12(d), wherein T 2 It is arbitrarily divided by 1-3 Z. 3 Substituted -(CH2) 0-2 C3-C6 cycloalkyl groups.

[0485] Embodiment 12(y) of this disclosure relates to a compound according to 12, 12(a), 12(b), 12(c) or 12(d), wherein T 2 It is arbitrarily divided by 1-3 Z. 5 Substituted -(CH2) 0-1 -Phenyl.

[0486] Embodiment 12(z) of this disclosure relates to a compound according to 12, 12(a), 12(b), 12(c) or 12(d), wherein T 2 It is arbitrarily divided by 1-3 Z. 5 Substituted -(CH2) 0-1 -5-6 membered heteroaryl.

[0487] Embodiment 12(aa) of this disclosure relates to a compound according to Embodiment 12 or 12(j), wherein T 3 It is -(CH2) 0-2 -C(O)N(R 8 )R 9 .

[0488] Embodiment 12(ab) of this disclosure relates to a compound according to Embodiment 12 or 12(j), wherein T 3 It is -(CH2) 0-2 -N(R 8 )R 9 The condition is when T 3 Heteroatoms attached to G, but G is not attached to -N(R) 8 )R 9 .

[0489] Embodiment 12(ac) of this disclosure relates to a compound according to Embodiment 12 or 12(j), wherein T 3 It is -(CH2) 0-2 -C(O)OR 9 .

[0490] Embodiment 12(ad) of this disclosure relates to a compound according to Embodiment 12 or 12(j), wherein T 3 It is arbitrarily divided by 1-3 Z. 5 And 0-1 Z 1 Substituted -(CH2) 0-2 -C3-C6 cycloalkyl.

[0491] Embodiment 12(ae) of this disclosure relates to a compound according to Embodiment 12 or 12(j), wherein T 3 It is arbitrarily divided by 1-3 Z. 5 and 0-1 Z 1 Substituted -(CH2) 0-2 -5-6 membered heterocyclic alkyl groups, under the condition that T 3 When attached to a heteroatom of G, G does not attach to the oxygen or nitrogen atom of a 5- or 6-membered heterocyclic alkyl group.

[0492] Embodiment 12(af) of this disclosure relates to a compound according to Embodiment 12 or 12(j), wherein T 3 It is an -O-5-6-membered heterocyclic alkyl group optionally substituted with 4-chloropyridazin-3-one-5-yl.

[0493] Embodiment 12(ag) of this disclosure relates to a compound according to Embodiment 12 or 12(j), wherein T 3 It is arbitrarily divided by 1-3 Z. 5 and 0-1 Z 1 Substituted -(CH2) 0-2 -5-9 yuan bridging carbon ring.

[0494] Embodiment 12(ah) of this disclosure relates to a compound according to Embodiment 12 or 12(j), wherein T 4 It is -(CH2) 0-1 C(O)OR9 .

[0495] Embodiment 12(ai) of this disclosure relates to a compound according to Embodiment 12 or 12(j), wherein T 4 It is -(CH2) 0-1 -N(R 9 )C(O)R 8 .

[0496] Embodiment 12(aj) of this disclosure relates to a compound according to Embodiment 12 or 12(j), wherein T 4 It is -(CH2) 0-1 -N(R 9 SO2-R

[0497] Embodiment 12(ak) of this disclosure relates to a compound according to Embodiment 12 or 12(j), wherein T 4 It is -(CH2) 0-1 -SO2-R 7 .

[0498] Embodiment 12(a1) of this disclosure relates to a compound according to Embodiment 12 or 12(j), wherein T 4 It is -(CH2) 0-1 -SO2N(R 8 )R 9 .

[0499] Embodiment 12(am) of this disclosure relates to a compound according to Embodiment 12 or 12(j), wherein T 4 It is -(CH2) 0-1 -N(R 9 )C(O)N(R 8 )R 9 .

[0500] Embodiment 12(an) of this disclosure relates to a compound according to Embodiment 12 or 12(j), wherein T 4 It is N(R) a )2.

[0501] Embodiment 12(ao) of this disclosure relates to compounds according to Embodiments 12, 12(e), 12(g), 12(h) or 12(i), wherein T 6 It is -(CH2) 0-1 -N(R 9 SO2-R 7 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 SO2-R 7 .

[0502] Embodiment 12 (ap) of this disclosure relates to compounds according to Embodiments 12, 12 (e), 12 (g), 12 (h) or 12 (i), wherein T 6 It is -(CH2) 0-1 -SO2-R 7 .

[0503] Embodiment 12(aq) of this disclosure relates to compounds according to Embodiments 12, 12(e), 12(g), 12(h) or 12(i), wherein T 6 It is -(CH2) 0-1 -SO2N(R 8 )R 9 .

[0504] Embodiment 12(ar) of this disclosure relates to compounds according to Embodiments 12, 12(e), 12(g), 12(h) or 12(i), wherein T 6 It is -(CH2) 0-1 -N(R 9 SO2N(R) 8 )R 9 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 SO2N(R) 8 )R 9 .

[0505] Embodiment 12(as) of this disclosure relates to compounds according to Embodiments 12, 12(e), 12(g), 12(h) or 12(i), wherein T 6 It is -(CH2) 0-1 -N(R 9 )C(O)N(R 8 )R 9 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 )C(O)N(R 8 )R 9 .

[0506] Embodiment 12(at) of this disclosure relates to compounds according to Embodiments 12, 12(e), 12(g), 12(h) or 12(i), wherein T 6 It is -(CH2) 0-1 -N(R 9 )C(O)R 8 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 )C(O)R 8.

[0507] Embodiment 12 (au) of this disclosure relates to compounds according to Embodiments 12, 12 (e), 12 (g), 12 (h) or 12 (i), wherein T 6 It is -(CH2) 0-1 -N(R 9 )C(O)OR 9 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 )C(O)OR 9 .

[0508] Embodiment 12(av) of this disclosure relates to compounds according to Embodiments 12, 12(e), 12(g), 12(h) or 12(i), wherein T 6 It is -(CH2) 0-1 -N(R 8 )R 9 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 8 )R 9 .

[0509] Embodiment 12 (aw) of this disclosure relates to compounds according to Embodiments 12, 12 (e), 12 (g), 12 (h) or 12 (i), wherein T 6 It is -(CH2) 0-1 -C(O)-N(R 8 )R 9 .

[0510] Embodiment 12(ax) of this disclosure relates to compounds according to Embodiments 12, 12(e), 12(g), 12(h) or 12(i), wherein T 6 It is -(CH2) 0-1 -C(O)OR 9 .

[0511] Embodiment 12(ay) of this disclosure relates to compounds according to Embodiments 12, 12(e), 12(g), 12(h) or 12(i), wherein T 6 It is -(CH2) 0-1 -C(O)R 10 .

[0512] Embodiment 12(az) of this disclosure relates to compounds according to Embodiments 12, 12(e), 12(g), 12(h) or 12(i), wherein T 6 It is -(CH2) 0-1 -N(R 9 )C(O)R10 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 )C(O)R 10 .

[0513] Embodiment 12(ba) of this disclosure relates to compounds according to Embodiments 12, 12(e), 12(g), 12(h) or 12(i), wherein T 6 It is -N(H)C(H)C=O, the condition is T 6 Heteroatoms that do not attach to G.

[0514] Embodiment 12(bb) of this disclosure relates to compounds according to Embodiments 12, 12(e), 12(g), 12(h) or 12(i), wherein T 6 It can be arbitrarily divided by 1-4 Z. 3 Substituted -(CH2) 0-1 -C3-C6 cycloalkyl.

[0515] Embodiment 12(bc) of this disclosure relates to compounds according to Embodiments 12, 12(e), 12(g), 12(h) or 12(i), wherein T 6 It can be arbitrarily divided by 1-4 Z. 3 Substituted -(CH2) 0-1 -5-6 membered heterocyclic alkyl groups, under the condition that T 6 When attached to a heteroatom of G, G does not attach to heteroatoms of 5-6 membered heteroaryl groups.

[0516] Embodiment 12(bd) of this disclosure relates to compounds according to Embodiments 12, 12(e), 12(g), 12(h) or 12(i), wherein T 6 It can be arbitrarily divided by 1-3 Z. 5 Substituted -(CH2) 0-1 -5-6 aryl heteroaryl groups, provided that T 6 When attached to a heteroatom of G, G does not attach to heteroatoms of 5-6 membered heteroaryl groups.

[0517] Implementation method 12(be) relates to implementation methods 12, 12(a), 12(b), 12(c), 12(d), 12(e), 12(f), 12(g), 12(h), 12(i), 12(j), 12(k), 12(l), 12(m), 12(n), 12(o), 12(p), 12(q), 12(r), 12(s), 12(t), 12(u), 12(v), 12(w), 12(x), 12(y), 12(z), 12(aa), 12(ab), and 12(ac). Any one of the following: 12(ad), 12(ae), 12(af), 12(ag), 12(ah), 12(ai), 12(aj), 12(ak), 12(al), 12(am), 12(an), 12(ao), 12(ap), 12(aq), 12(ar), 12(as), 12(at), 12(au), 12(av), 12(aw), 12(ax), 12(ay), 12(az), 12(ba), 12(bb), 12(bc), or 12(bd), where R 1 It is hydrogen.

[0518] Implementation method 12(bf) relates to implementation methods 12, 12(a), 12(b), 12(c), 12(d), 12(e), 12(f), 12(g), 12(h), 12(i), 12(j), 12(k), 12(l), 12(m), 12(n), 12(o), 12(p), 12(q), 12(r), 12(s), 12(t), 12(u), 12(v), 12(w), 12(x), 12(y), 12(z), 12(aa), 12(ab), and 12(ac). Any one of the following: 12(ad), 12(ae), 12(af), 12(ag), 12(ah), 12(ai), 12(aj), 12(ak), 12(al), 12(am), 12(an), 12(ao), 12(ap), 12(aq), 12(ar), 12(as), 12(at), 12(au), 12(av), 12(aw), 12(ax), 12(ay), 12(az), 12(ba), 12(bb), 12(bc), or 12(bd), where R 1 It is a C2-C4 alkyl group substituted with 0-4 hydroxyl groups.

[0519] Implementation method 12(bg) relates to implementation methods 12, 12(a), 12(b), 12(c), 12(d), 12(e), 12(f), 12(g), 12(h), 12(i), 12(j), 12(k), 12(l), 12(m), 12(n), 12(o), 12(p), 12(q), 12(r), 12(s), 12(t), 12(u), 12(v), 12(w), 12(x), 12(y), 12(z), 12(aa), 12(ab), and 12(ac). Any one of the following: 12(ad), 12(ae), 12(af), 12(ag), 12(ah), 12(ai), 12(aj), 12(ak), 12(al), 12(am), 12(an), 12(ao), 12(ap), 12(aq), 12(ar), 12(as), 12(at), 12(au), 12(av), 12(aw), 12(ax), 12(ay), 12(az), 12(ba), 12(bb), 12(bc), or 12(bd), where R 2 It is Cl.

[0520] Implementation method 12(bh) relates to implementation methods 12, 12(a), 12(b), 12(c), 12(d), 12(e), 12(f), 12(g), 12(h), 12(i), 12(j), 12(k), 12(l), 12(m), 12(n), 12(o), 12(p), 12(q), 12(r), 12(s), 12(t), 12(u), 12(v), 12(w), 12(x), 12(y), 12(z), 12(aa), 12(ab), and 12(ac). Any one of the following: 12(ad), 12(ae), 12(af), 12(ag), 12(ah), 12(ai), 12(aj), 12(ak), 12(al), 12(am), 12(an), 12(ao), 12(ap), 12(aq), 12(ar), 12(as), 12(at), 12(au), 12(av), 12(aw), 12(ax), 12(ay), 12(az), 12(ba), 12(bb), 12(bc), or 12(bd), where R 2 It's CN.

[0521] Embodiment 13 relates to a compound according to any one of Embodiments 1-5, having any one of the following formulas:

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530] Or a pharmaceutically acceptable salt thereof, wherein R 2 It is Cl, Br, CF3 or CN.

[0531] Sub-implementation of Implementation Method 13

[0532] Embodiment 13(a) of this disclosure relates to embodiment 13, wherein G is controlled by 0-2 T 1 and 0-1 T 2 Substituted C3-C6 cycloalkyl groups.

[0533] Implementation 13(b) of this disclosure relates to implementation 13, wherein G is controlled by 0-2 T. 1 and 0-1 T 2 Substituted C3-C6 cycloalkenyl groups.

[0534] Implementation 13(c) of this disclosure relates to implementation 13, wherein G is controlled by 0-2 T 1 and 0-1 T 2 Replaces the 5-9 bridging carbon ring.

[0535] Embodiment 13(d) of this disclosure relates to Embodiment 13, wherein G is a 5-9 membered carbocyclic spirocycle containing two cycloalkyl groups linked by a common spirocarbon atom, wherein the carbocyclic spirocycle is surrounded by 0-2 T groups. 1 and 0-1 T 2 replace.

[0536] Embodiment 13(e) of this disclosure relates to Embodiment 13, wherein G is a 6-9 membered heterocyclic spirocycle containing two cyclic groups having at least one heteroatom, wherein the two cyclic groups are connected by a common spirocarbon atom, and wherein the heterocyclic spirocycle is surrounded by 0-2 T atoms. 5 0-1 T 6 replace.

[0537] Implementation 13(f) of this disclosure relates to implementation 13, wherein G is controlled by 0-2 T 1 and 0-1 T 4Substituted phenyl groups.

[0538] Embodiment 13(g) of this disclosure relates to embodiment 13, wherein G is a subset of 0-2 T. 5 and 0-1 T 6 Substituted 4-6 membered heterocyclic alkyl groups.

[0539] Embodiment 13(h) of this disclosure relates to embodiment 13, wherein G is controlled by 0-2 T 5 and T 6 Substituted 4-6 membered heterocyclic alkenyl groups.

[0540] Implementation 13(i) of this disclosure relates to implementation 13, wherein G is controlled by 0-2 T 5 and 0-1 T 6 Replaces the 5-9 bridging heterocyclic ring.

[0541] Implementation 13(j) of this disclosure relates to implementation 13, wherein G is controlled by 0-2 T 5 and 0-1 T 3 Substituted 5-6 aryl groups.

[0542] Embodiment 13(k) of this disclosure relates to compounds according to Embodiments 13, 13(a), 13(b), 13(c) or 13(d), wherein T 2 It is -(CH2) 0-1 -N(R 9 SO2-R 7 .

[0543] Embodiment 13(l) of this disclosure relates to compounds according to Embodiments 13, 13(a), 13(b), 13(c) or 13(d), wherein T 2 It is -(CH2) 0-1 -SO2-R 7 .

[0544] Embodiment 13(m) of this disclosure relates to compounds according to Embodiments 13, 13(a), 13(b), 13(c) or 13(d), wherein T 2 It is -(CH2) 0-1 -SO2N(R 8 )R 9 .

[0545] Embodiment 13(n) of this disclosure relates to compounds according to Embodiments 13, 13(a), 13(b), 13(c) or 13(d), wherein T 2 It is -(CH2) 0-1 -N(R 9 SO2N(R) 8 )R9 .

[0546] Embodiment 13(o) of this disclosure relates to a compound according to Embodiment 13, 13(a), 13(b), 13(c) or 13(d), wherein T 2 It is -(CH2) 0-1 -N(R 9 )C(O)N(R 8 )R 9 .

[0547] Embodiment 13(p) of this disclosure relates to compounds according to Embodiments 13, 13(a), 13(b), 13(c) or 13(d), wherein T 2 It is -(CH2) 0-1 -N(R 9 )C(O)R 8 .

[0548] Embodiment 13(q) of this disclosure relates to compounds according to Embodiments 13, 13(a), 13(b), 13(c) or 13(d), wherein T 2 It is -(CH2) 0-1 -N(R 9 )C(O)OR 9 .

[0549] Embodiment 13(r) of this disclosure relates to compounds according to Embodiments 13, 13(a), 13(b), 13(c) or 13(d), wherein T 2 It is -(CH2) 0-1 -N(R 8 )R 9 .

[0550] Embodiment 13(s) of this disclosure relates to compounds according to Embodiments 13, 13(a), 13(b), 13(c) or 13(d), wherein T 2 It is -(CH2) 0-1 -C(O)N(R 8 )R 9 .

[0551] Embodiment 13(t) of this disclosure relates to compounds according to Embodiments 13, 13(a), 13(b), 13(c) or 13(d), wherein T 2 It is -(CH2) 0-1 -C(O)OR 9 .

[0552] Embodiment 13(u) of this disclosure relates to compounds according to Embodiments 13, 13(a), 13(b), 13(c) or 13(d), wherein T2 It is -(CH2) 0-1 -C(O)R 10 .

[0553] Embodiment 13(v) of this disclosure relates to compounds according to Embodiments 13, 13(a), 13(b), 13(c) or 13(d), wherein T 2 It is -(CH2) 0-1 -C(O)H.

[0554] Embodiment 13(w) of this disclosure relates to compounds according to Embodiments 13, 13(a), 13(b), 13(c) or 13(d), wherein T 2 It is -(CH2) 0-1 -N(R 9 )C(O)R 10 .

[0555] Embodiment 13(x) of this disclosure relates to compounds according to Embodiments 5, 13, 13(a), 13(b), 13(c) or 13(d), wherein T 2 It is arbitrarily divided by 1-3 Z. 3 Substituted -(CH2) 0-2 C3-C6 cycloalkyl groups.

[0556] Embodiment 13(y) of this disclosure relates to a compound according to 13, 13(a), 13(b), 13(c) or 13(d), wherein T 2 It is arbitrarily divided by 1-3 Z. 5 Substituted -(CH2) 0-1 -Phenyl.

[0557] Embodiment 13(z) of this disclosure relates to a compound according to 13, 13(a), 13(b), 13(c) or 13(d), wherein T 2 It is arbitrarily divided by 1-3 Z. 5 Substituted -(CH2) 0-1 -5-6 membered heteroaryl.

[0558] Embodiment 13(aa) of this disclosure relates to a compound according to Embodiment 13 or 13(j), wherein T 3 It is -(CH2) 0-2 -C(O)N(R 8 )R 9 .

[0559] Embodiment 13(ab) of this disclosure relates to a compound according to Embodiment 13 or 13(j), wherein T 3 It is -(CH2) 0-2 -N(R8 )R 9 The condition is when T 3 Heteroatoms attached to G, but G is not attached to -N(R) 8 )R 9 .

[0560] Embodiment 13(ac) of this disclosure relates to a compound according to Embodiment 13 or 13(j), wherein T 3 It is -(CH2) 0-2 -C(O)OR 9 .

[0561] Embodiment 13(ad) of this disclosure relates to a compound according to Embodiment 13 or 13(j), wherein T 3 It is arbitrarily divided by 1-3 Z. 5 and 0-1 Z 1 Substituted -(CH2) 0-2 -C3-C6 cycloalkyl.

[0562] Embodiment 13(ae) of this disclosure relates to a compound according to Embodiment 13 or 13(j), wherein T 3 It is arbitrarily divided by 1-3 Z. 5 and 0-1 Z 1 Substituted -(CH2) 0-2 -5-6 membered heterocyclic alkyl groups, under the condition that T 3 When attached to a heteroatom of G, G does not attach to the oxygen or nitrogen atom of a 5- or 6-membered heterocyclic alkyl group.

[0563] Embodiment 13(af) of this disclosure relates to a compound according to Embodiment 13 or 13(j), wherein T 3 It is an -O-5-6-membered heterocyclic alkyl group optionally substituted with 4-chloropyridazin-3-one-5-yl.

[0564] Embodiment 13(ag) of this disclosure relates to a compound according to Embodiment 13 or 13(j), wherein T 3 It is arbitrarily divided by 1-3 Z. 5 and 0-1 Z 1 Substituted -(CH2) 0-2 -5-9 yuan bridging carbon ring.

[0565] Embodiment 13(ah) of this disclosure relates to a compound according to Embodiment 13 or 13(j), wherein T 4 It is -(CH2) 0-1 C(O)OR 9 .

[0566] Embodiment 13(ai) of this disclosure relates to a compound according to Embodiment 13 or 13(j), wherein T 4 It is -(CH2) 0-1 -N(R 9 )C(O)R 8 .

[0567] Embodiment 13(aj) of this disclosure relates to a compound according to Embodiment 13 or 13(j), wherein T 4 It is -(CH2) 0-1 -N(R 9 )SO2-R.

[0568] Embodiment 13(ak) of this disclosure relates to a compound according to Embodiment 13 or 13(j), wherein T 4 It is -(CH2) 0-1 -SO2-R 7 .

[0569] Embodiment 13(a1) of this disclosure relates to a compound according to Embodiment 13 or 13(j), wherein T 4 It is -(CH2) 0-1 -SO2N(R 8 )R 9 .

[0570] Embodiment 13(am) of this disclosure relates to a compound according to Embodiment 13 or 13(j), wherein T 4 It is -(CH2) 0-1 -N(R 9 )C(O)N(R 8 )R 9 .

[0571] Embodiment 13(an) of this disclosure relates to a compound according to Embodiment 13 or 13(j), wherein T 4 It is N(R) a )2.

[0572] Embodiment 13(ao) of this disclosure relates to compounds according to Embodiments 13, 13(e), 13(g), 13(h) or 13(i), wherein T 6 It is -(CH2) 0-1 -N(R 9 SO2-R 7 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 SO2-R 7 .

[0573] Embodiment 13(ap) of this disclosure relates to compounds according to Embodiments 13, 13(e), 13(g), 13(h) or 13(i), wherein T 6 It is -(CH2) 0-1 -SO2-R 7 .

[0574] Embodiment 13(aq) of this disclosure relates to compounds according to Embodiments 13, 13(e), 13(g), 13(h) or 13(i), wherein T 6 It is -(CH2) 0-1 -SO2N(R 8 )R 9 .

[0575] Embodiment 13(ar) of this disclosure relates to compounds according to Embodiments 13, 13(e), 13(g), 13(h) or 13(i), wherein T 6 It is -(CH2) 0-1 -N(R 9 SO2N(R) 8 )R 9 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 SO2N(R) 8 )R 9 .

[0576] Embodiment 13(as) of this disclosure relates to compounds according to Embodiments 13, 13(e), 13(g), 13(h) or 13(i), wherein T 6 It is -(CH2) 0-1 -N(R 9 )C(O)N(R 8 )R 9 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 )C(O)N(R 8 )R 9 .

[0577] Embodiment 13(at) of this disclosure relates to compounds according to Embodiments 13, 13(e), 13(g), 13(h) or 13(i), wherein T 6 It is -(CH2) 0-1 -N(R 9 )C(O)R 8 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 )C(O)R 8 .

[0578] Embodiment 13(au) of this disclosure relates to compounds according to Embodiments 13, 13(e), 13(g), 13(h) or 13(i), wherein T 6 It is -(CH2) 0-1 -N(R 9 )C(O)OR 9 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 )C(O)OR 9 .

[0579] Embodiment 13(av) of this disclosure relates to compounds according to Embodiments 13, 13(e), 13(g), 13(h) or 13(i), wherein T 6 It is -(CH2) 0-1 -N(R 8 )R 9 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 8 )R 9 .

[0580] Embodiment 13 (aw) of this disclosure relates to compounds according to Embodiments 13, 13 (e), 13 (g), 13 (h) or 13 (i), wherein T 6 It is -(CH2) 0-1 -C(O)-N(R 8 )R 9 .

[0581] Embodiment 13(ax) of this disclosure relates to compounds according to Embodiments 13, 13(e), 13(g), 13(h) or 13(i), wherein T 6 It is -(CH2) 0-1 -C(O)OR 9 .

[0582] Embodiment 13(ay) of this disclosure relates to compounds according to Embodiments 13, 13(e), 13(g), 13(h) or 13(i), wherein T 6 It is -(CH2) 0-1 -C(O)R 10 .

[0583] Embodiment 13(az) of this disclosure relates to compounds according to Embodiments 13, 13(e), 13(g), 13(h) or 13(i), wherein T 6 It is -(CH2) 0-1 -N(R 9 )C(O)R10 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 )C(O)R 10 .

[0584] Embodiment 13(ba) of this disclosure relates to compounds according to Embodiments 13, 13(e), 13(g), 13(h) or 13(i), wherein T 6 It is -N(H)C(H)C=O, the condition is T 6 Heteroatoms that do not attach to G.

[0585] Embodiment 13(bb) of this disclosure relates to compounds according to Embodiments 13, 13(e), 13(g), 13(h) or 13(i), wherein T 6 It can be arbitrarily divided by 1-4 Z. 3 Substituted -(CH2) 0-1 -C3-C6 cycloalkyl.

[0586] Embodiment 13(bc) of this disclosure relates to compounds according to Embodiments 13, 13(e), 13(g), 13(h) or 13(i), wherein T 6 It can be arbitrarily divided by 1-4 Z. 3 Substituted -(CH2) 0-1 -5-6 membered heterocyclic alkyl groups, under the condition that T 6 When attached to a heteroatom of G, G does not attach to heteroatoms of 5-6 membered heteroaryl groups.

[0587] Embodiment 13(bd) of this disclosure relates to compounds according to Embodiments 13, 13(e), 13(g), 13(h) or 13(i), wherein T 6 It can be arbitrarily divided by 1-3 Z. 5 Substituted -(CH2) 0-1 -5-6 aryl heteroaryl groups, provided that T 6 When attached to a heteroatom of G, G does not attach to heteroatoms of 5-6 membered heteroaryl groups.

[0588] Implementation method 13(be) relates to implementation methods 13, 13(a), 13(b), 13(c), 13(d), 13(e), 13(f), 13(g), 13(h), 13(i), 13(j), 13(k), 13(l), 13(m), 13(n), 13(o), 13(p), 13(q), 13(r), 13(s), 13(t), 13(u), 13(v), 13(w), 13(x), 13(y), 13(z), 13(aa), 13(ab), and 13(ac). Any one of the following: 13(ad), 13(ae), 13(af), 13(ag), 13(ah), 13(ai), 13(aj), 13(ak), 13(al), 13(am), 13(an), 13(ao), 13(ap), 13(aq), 13(ar), 13(as), 13(at), 13(au), 13(av), 13(aw), 13(ax), 13(ay), 13(az), 13(ba), 13(bb), 13(bc), or 13(bd), where R 2 It is Cl.

[0589] Implementation method 13(bf) relates to implementation methods 13, 13(a), 13(b), 13(c), 13(d), 13(e), 13(f), 13(g), 13(h), 13(i), 13(j), 13(k), 13(l), 13(m), 13(n), 13(o), 13(p), 13(q), 13(r), 13(s), 13(t), 13(u), 13(v), 13(w), 13(x), 13(y), 13(z), 13(aa), 13(ab), and 13(ac). Any one of the following: 13(ad), 13(ae), 13(af), 13(ag), 13(ah), 13(ai), 13(aj), 13(ak), 13(al), 13(am), 13(an), 13(ao), 13(ap), 13(aq), 13(ar), 13(as), 13(at), 13(au), 13(av), 13(aw), 13(ax), 13(ay), 13(az), 13(ba), 13(bb), 13(bc), or 13(bd), where R 2 It's CN.

[0590] Embodiment 14 relates to a compound according to any one of Embodiments 1-5, having any one of the following formulas:

[0591]

[0592]

[0593] Or a pharmaceutically acceptable salt thereof, wherein R 2 It is Cl, Br, CF3 or CN.

[0594] Sub-implementation of Implementation Method 14

[0595] Embodiment 14(a) of this disclosure relates to embodiment 14, wherein G is controlled by 0-2 T 1 and 0-1 T 2 Substituted C3-C6 cycloalkyl groups.

[0596] Implementation 14(b) of this disclosure relates to implementation 14, wherein G is controlled by 0-2 T. 1 and 0-1 T 2 Substituted C3-C6 cycloalkenyl groups.

[0597] Implementation 14(c) of this disclosure relates to implementation 14, wherein G is controlled by 0-2 T 1 and 0-1 T 2 Replaces the 5-9 bridging carbon ring.

[0598] Embodiment 14(d) of this disclosure relates to Embodiment 14, wherein G is a 5-9 membered carbocyclic spirocycle containing two cycloalkyl groups linked by a common spirocarbon atom, wherein the carbocyclic spirocycle is surrounded by 0-2 T groups. 1 and 0-1 T 2 replace.

[0599] Embodiment 14(e) of this disclosure relates to Embodiment 14, wherein G is a 6-9 membered heterocyclic spirocycle containing two cyclic groups having at least one heteroatom, wherein the two cyclic groups are connected by a common spirocarbon atom, and wherein the heterocyclic spirocycle is surrounded by 0-2 T atoms. 5 0-1 T 6 replace.

[0600] Implementation 14(f) of this disclosure relates to implementation 14, wherein G is controlled by 0-2 T 1 and 0-1 T 4 Substituted phenyl groups.

[0601] Embodiment 14(g) of this disclosure relates to embodiment 14, wherein G is a subset of 0-2 T. 5 and 0-1 T 6 Substituted 4-6 membered heterocyclic alkyl groups.

[0602] Embodiment 14(h) of this disclosure relates to embodiment 14, wherein G is a subset of 0-2 T. 5 and 0-1 T 6 Substituted 4-6 membered heterocyclic alkenyl groups.

[0603] Implementation 14(i) of this disclosure relates to implementation 14, wherein G is controlled by 0-2 T 5 and 0-1 T 6 Replaces the 5-9 bridging heterocyclic ring.

[0604] Implementation 14(j) of this disclosure relates to implementation 14, wherein G is controlled by 0-2 T 5 and 0-1 T 3 Substituted 5-6 aryl groups.

[0605] Embodiment 14(k) of this disclosure relates to compounds according to Embodiments 14, 14(a), 14(b), 14(c) or 14(d), wherein T 2 It is -(CH2) 0-1 -N(R 9 SO2-R 7 .

[0606] Embodiment 14(l) of this disclosure relates to compounds according to Embodiments 14, 14(a), 14(b), 14(c) or 14(d), wherein T 2 It is -(CH2) 0-1 -SO2-R 7 .

[0607] Embodiment 14(m) of this disclosure relates to compounds according to Embodiments 14, 14(a), 14(b), 14(c) or 14(d), wherein T 2 It is -(CH2) 0-1 -SO2N(R 8 )R 9 .

[0608] Embodiment 14(n) of this disclosure relates to compounds according to Embodiments 14, 14(a), 14(b), 14(c) or 14(d), wherein T 2 It is -(CH2) 0-1 -N(R 9 SO2N(R) 8 )R 9 .

[0609] Embodiment 14(o) of this disclosure relates to a compound according to Embodiments 14, 14(a), 14(b), 14(c) or 14(d), wherein T 2 It is -(CH2) 0-1 -N(R 9 )C(O)N(R 8 )R 9 .

[0610] Embodiment 14(p) of this disclosure relates to compounds according to Embodiments 14, 14(a), 14(b), 14(c) or 14(d), wherein T 2 It is -(CH2) 0-1 -N(R 9 )C(O)R 8 .

[0611] Embodiment 14(q) of this disclosure relates to compounds according to Embodiments 14, 14(a), 14(b), 14(c) or 14(d), wherein T 2 It is -(CH2) 0-1 -N(R 9 )C(O)OR 9 .

[0612] Embodiment 14(r) of this disclosure relates to compounds according to Embodiments 14, 14(a), 14(b), 14(c) or 14(d), wherein T 2 It is -(CH2) 0-1 -N(R 8 )R 9 .

[0613] Embodiment 14(s) of this disclosure relates to compounds according to Embodiments 14, 14(a), 14(b), 14(c) or 14(d), wherein T 2 It is -(CH2) 0-1 -C(O)N(R 8 )R 9 .

[0614] Embodiment 14(t) of this disclosure relates to compounds according to Embodiments 14, 14(a), 14(b), 14(c) or 14(d), wherein T 2 It is -(CH2) 0-1 -C(O)OR 9 .

[0615] Embodiment 14(u) of this disclosure relates to compounds according to Embodiments 14, 14(a), 14(b), 14(c) or 14(d), wherein T 2 It is -(CH2) 0-1 -C(O)R 10 .

[0616] Embodiment 14(v) of this disclosure relates to compounds according to Embodiments 14, 14(a), 14(b), 14(c) or 14(d), wherein T 2 It is -(CH2) 0-1 -C(O)H.

[0617] Embodiment 14(w) of this disclosure relates to compounds according to Embodiments 14, 14(a), 14(b), 14(c) or 14(d), wherein T 2 It is -(CH2) 0-1 -N(R 9 )C(O)R 10 .

[0618] Embodiment 14(x) of this disclosure relates to compounds according to Embodiments 5, 14, 14(a), 14(b), 14(c) or 14(d), wherein T 2 It can be arbitrarily divided by 1-3 Z. 3 Substituted -(CH2) 0-2 C3-C6 cycloalkyl groups.

[0619] Embodiment 14(y) of this disclosure relates to a compound according to 14, 14(a), 14(b), 14(c) or 14(d), wherein T 2 It can be arbitrarily divided by 1-3 Z. 5 Substituted -(CH2) 0-1 -Phenyl.

[0620] Embodiment 14(z) of this disclosure relates to a compound according to 14, 14(a), 14(b), 14(c) or 14(d), wherein T 2 It can be arbitrarily divided by 1-3 Z. 5 Substituted -(CH2) 0-1 -5-6 membered heteroaryl.

[0621] Embodiment 14(aa) of this disclosure relates to a compound according to Embodiment 14 or 14(j), wherein T 3 It is -(CH2) 0-2 -C(O)N(R 8 )R 9 .

[0622] Embodiment 14(ab) of this disclosure relates to a compound according to Embodiment 14 or 14(j), wherein T 3 It is -(CH2) 0-2 -N(R 8 )R 9 The condition is when T 3 Heteroatoms attached to G, but G is not attached to -N(R) 8 )R 9 .

[0623] Embodiment 14(ac) of this disclosure relates to a compound according to Embodiment 14 or 14(j), wherein T 3 It is -(CH2) 0-2 -C(O)OR9 .

[0624] Embodiment 14(ad) of this disclosure relates to a compound according to Embodiment 14 or 14(j), wherein T 3 It can be arbitrarily divided by 1-3 Z. 5 and 0-1 Z 1 Substituted -(CH2) 0-2 -C3-C6 cycloalkyl.

[0625] Embodiment 14(ae) of this disclosure relates to a compound according to Embodiment 14 or 14(j), wherein T 3 It can be arbitrarily divided by 1-3 Z. 5 and 0-1 Z 1 Substituted -(CH2) 0-2 -5-6 membered heterocyclic alkyl groups, under the condition that T 3 When attached to a heteroatom of G, G does not attach to the oxygen or nitrogen atom of a 5- or 6-membered heterocyclic alkyl group.

[0626] Embodiment 14(af) of this disclosure relates to a compound according to Embodiment 14 or 14(j), wherein T 3 It is an -O-5-6-membered heterocyclic alkyl group optionally substituted with 4-chloropyridazin-3-one-5-yl.

[0627] Embodiment 14(ag) of this disclosure relates to a compound according to Embodiment 14 or 14(j), wherein T 3 It can be arbitrarily divided by 1-3 Z. 5 and 0-1 Z 1 Substituted -(CH2) 0-2 -5-9 yuan bridging carbon ring.

[0628] Embodiment 14(ah) of this disclosure relates to a compound according to Embodiment 14 or 14(j), wherein T 4 It is -(CH2) 0-1 C(O)OR 9 .

[0629] Embodiment 14(ai) of this disclosure relates to a compound according to Embodiment 14 or 14(j), wherein T 4 It is -(CH2) 0-1 -N(R 9 )C(O)R 8 .

[0630] Embodiment 14(aj) of this disclosure relates to a compound according to Embodiment 14 or 14(j), wherein T 4 It is -(CH2) 0-1 -N(R 9 )SO2-R.

[0631] Embodiment 14(ak) of this disclosure relates to a compound according to Embodiment 14 or 14(j), wherein T 4 It is -(CH2) 0-1 -SO2-R 7 .

[0632] Embodiment 14(a1) of this disclosure relates to a compound according to Embodiment 14 or 14(j), wherein T 4 It is -(CH2) 0-1 -SO2N(R 8 )R 9 .

[0633] Embodiment 14(am) of this disclosure relates to a compound according to Embodiment 14 or 14(j), wherein T 4 It is -(CH2) 0-1 -N(R 9 )C(O)N(R 8 )R 9 .

[0634] Embodiment 14(an) of this disclosure relates to a compound according to Embodiment 14 or 14(j), wherein T 4 It is N(R) a )2.

[0635] Embodiment 14(ao) of this disclosure relates to compounds according to Embodiments 14, 14(e), 14(g), 14(h) or 14(i), wherein T 6 It is -(CH2) 0-1 -N(R 9 SO2-R 7 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 SO2-R 7 .

[0636] Embodiment 14(ap) of this disclosure relates to compounds according to Embodiments 14, 14(e), 14(g), 14(h) or 14(i), wherein T 6 It is -(CH2) 0-1 -SO2-R 7 .

[0637] Embodiment 14(aq) of this disclosure relates to compounds according to Embodiments 14, 14(e), 14(g), 14(h) or 14(i), wherein T 6 It is -(CH2) 0-1 -SO2N(R 8 )R 9.

[0638] Embodiment 14(ar) of this disclosure relates to compounds according to Embodiments 14, 14(e), 14(g), 14(h) or 14(i), wherein T 6 It is -(CH2) 0-1 -N(R 9 SO2N(R) 8 )R 9 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 SO2N(R) 8 )R 9 .

[0639] Embodiment 14(as) of this disclosure relates to compounds according to Embodiments 14, 14(e), 14(g), 14(h) or 14(i), wherein T 6 It is -(CH2) 0-1 -N(R 9 )C(O)N(R 8 )R 9 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 )C(O)N(R 8 )R 9 .

[0640] Embodiment 14(at) of this disclosure relates to compounds according to Embodiments 14, 14(e), 14(g), 14(h) or 14(i), wherein T 6 It is -(CH2) 0-1 -N(R 9 )C(O)R 8 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 )C(O)R 8 .

[0641] Embodiment 14(au) of this disclosure relates to compounds according to Embodiments 14, 14(e), 14(g), 14(h) or 14(i), wherein T 6 It is -(CH2) 0-1 -N(R 9 )C(O)OR 9 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 )C(O)OR 9 .

[0642] Embodiment 14(av) of this disclosure relates to compounds according to Embodiments 14, 14(e), 14(g), 14(h) or 14(i), wherein T 6 It is -(CH2) 0-1 -N(R 8 )R 9 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 8 )R 9 .

[0643] Embodiment 14 (aw) of this disclosure relates to compounds according to Embodiments 14, 14 (e), 14 (g), 14 (h) or 14 (i), wherein T 6 It is -(CH2) 0-1 -C(O)-N(R 8 )R 9 .

[0644] Embodiment 14(ax) of this disclosure relates to compounds according to Embodiments 14, 14(e), 14(g), 14(h) or 14(i), wherein T 6 It is -(CH2) 0-1 -C(O)OR 9 .

[0645] Embodiment 14(ay) of this disclosure relates to compounds according to Embodiments 14, 14(e), 14(g), 14(h) or 14(i), wherein T 6 It is -(CH2) 0-1 -C(O)R 10 .

[0646] Embodiment 14(az) of this disclosure relates to compounds according to Embodiments 14, 14(e), 14(g), 14(h) or 14(i), wherein T 6 It is -(CH2) 0-1 -N(R 9 )C(O)R 10 The condition is when T 6 When attached to a heteroatom of G, G does not attach to -N(R) 9 )C(O)R 10 .

[0647] Embodiment 14(ba) of this disclosure relates to compounds according to Embodiments 14, 14(e), 14(g), 14(h) or 14(i), wherein T 6 It is -N(H)C(H)C=O, the condition is T 6 Heteroatoms that do not attach to G.

[0648] Embodiment 14(bb) of this disclosure relates to compounds according to Embodiments 14, 14(e), 14(g), 14(h) or 14(i), wherein T 6 It can be arbitrarily divided by 1-4 Z. 3 Substituted -(CH2) 0-1 -C3-C6 cycloalkyl.

[0649] Embodiment 14(bc) of this disclosure relates to compounds according to Embodiments 14, 14(e), 14(g), 14(h) or 14(i), wherein T 6 It can be arbitrarily divided by 1-4 Z. 3 Substituted -(CH2) 0-1 -5-6 membered heterocyclic alkyl groups, under the condition that T 6 When attached to a heteroatom of G, G does not attach to heteroatoms of 5-6 membered heteroaryl groups.

[0650] Embodiment 14(bd) of this disclosure relates to compounds according to Embodiments 14, 14(e), 14(g), 14(h) or 14(i), wherein T 6 It can be arbitrarily divided by 1-3 Z. 5 Substituted -(CH2) 0-1 -5-6 aryl heteroaryl groups, provided that T 6 When attached to a heteroatom of G, G does not attach to heteroatoms of 5-6 membered heteroaryl groups.

[0651] Implementation method 14(be) relates to implementation methods 14, 14(a), 14(b), 14(c), 14(d), 14(e), 14(f), 14(g), 14(h), 14(i), 14(j), 14(k), 14(l), 14(m), 14(n), 14(o), 14(p), 14(q), 14(r), 14(s), 14(t), 14(u), 14(v), 14(w), 14(x), 14(y), 14(z), 14(aa), 14(ab), 14(ac). Any one of the following: 14(ad), 14(ae), 14(af), 14(ag), 14(ah), 14(ai), 14(aj), 14(ak), 14(al), 14(am), 14(an), 14(ao), 14(ap), 14(aq), 14(ar), 14(as), 14(at), 14(au), 14(av), 14(aw), 14(ax), 14(ay), 14(az), 14(ba), 14(bb), 14(bc), or 14(bd), where R 2 It is Cl.

[0652] Implementation method 14(bf) relates to implementation methods 14, 14(a), 14(b), 14(c), 14(d), 14(e), 14(f), 14(g), 14(h), 14(i), 14(j), 14(k), 14(l), 14(m), 14(n), 14(o), 14(p), 14(q), 14(r), 14(s), 14(t), 14(u), 14(v), 14(w), 14(x), 14(y), 14(z), 14(aa), 14(ab), and 14(ac). Any one of the following: 14(ad), 14(ae), 14(af), 14(ag), 14(ah), 14(ai), 14(aj), 14(ak), 14(al), 14(am), 14(an), 14(ao), 14(ap), 14(aq), 14(ar), 14(as), 14(at), 14(au), 14(av), 14(aw), 14(ax), 14(ay), 14(az), 14(ba), 14(bb), 14(bc), or 14(bd), where R 2 It's CN.

[0653] Embodiment 15 relates to a compound according to Embodiment 12 having one of Formula IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), or a pharmaceutically acceptable salt thereof, or any sub-embodiment of Formula IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), or a pharmaceutically acceptable salt thereof.

[0654] Embodiment 16 relates to a compound according to Embodiment 13, having one of the following formulas: V(a), V(b), V(c), V(d), V(e), V(f), V(g), V(h), V(i), V(j), V(k), V(l), V(m), V(n), V(o), V(p), V(q), V(r), V(s), V(t), V(u), V(v), V(w), V(af), V(ag), V(ah), V(ai), V(aj), V(ak), V(al), V(am), V(an), V(ao), V(ap), V(aq), V(ar), V(as), V(at), V(au), V(av), V(aw), V(ay), V(az), V(ba), V(bb), or Pharmaceutically acceptable salts thereof, or any sub-implementation of formula V(a), V(b), V(c), V(d), V(e), V(f), V(g), V(h), V(i), V(j), V(k), V(l), V(m), V(n), V(o), V(p), V(q), V(r), V(s), V(t), V(u), V(v), V(w), V(af), V(ag), V(ah), V(ai), V(aj), V(ak), V(al), V(am), V(an), V(ao), V(ap), V(aq), V(ar), V(as), V(at), V(au), V(av), V(aw), V(ay), V(az), V(ba), V(bb), or pharmaceutically acceptable salts thereof.

[0655] Embodiment 17 relates to a compound according to Embodiment 14 having one of the formulas VI(a), VI(b), VI(c), VI(d), VI(e), VI(f), VI(g), VI(h), VI(i), VI(j), VI(k), VI(l), VI(m), VO(n), VI(o), or a pharmaceutically acceptable salt thereof, or any sub-embodiment of the formulas VI(a), VI(b), VI(c), VI(d), VI(e), VI(f), VI(g), VI(h), VI(i), VI(j), VI(k), VI(l), VI(m), VO(n), VI(o), or a pharmaceutically acceptable salt thereof.

[0656] Embodiment 18 relates to a compound according to any of the foregoing embodiments, wherein

[0657] G is one of the following groups:

[0658] (a) by 0-2 T 1 and 0-1 T 2 Substituted C3-C6 cycloalkyl groups;

[0659] (b) by 0-2 T 1 and 0-1 T 2 Substituted C3-C6 cycloalkenyl groups;

[0660] (c) A 6-9 membered heterocyclic spirocycle containing two cyclic groups having at least one heteroatom, wherein the two cyclic groups are linked by a common spirocarbon atom, and wherein the heterocyclic spirocycle is separated by 0-2 T atoms. 5 0-1 T 6 replace;

[0661] (d) by 0-2 T 1 and 0-1 T 4 Substituted phenyl;

[0662] (e) by 0-2 T 5 and 0-1 T 6 Substituted 5-6 membered heterocyclic alkyl groups;

[0663] (f) by 0-2 T 5 and 0-1 T 6 Substituted 5-6 membered heterocyclic alkenyl groups;

[0664] (g) by 0-2 T 5 and 0-1 T 6 Replacement of 5-9 bridging heterocyclic rings; or

[0665] (h) is 0-2 T 5 and 0-1 T 3 Substituted 5-6 aryl groups.

[0666] Embodiment 19 relates to a compound according to Embodiment 16, wherein G is pyrazolyl, isoxazolyl, indolyl, 1,2,3-triazolyl, imidazolyl, thiazolyl, or pyrroleyl, each being radicalized by 0-2 T groups. 5 and 0-1 T 3 replace.

[0667] Sub-implementation of Implementation Method 19

[0668] Embodiment 19(a) relates to a compound according to Embodiment 19, wherein G is reacted with 0-2 T atoms. 5 and 0-1 T 3 Substituted pyrazol group.

[0669] Embodiment 19(b) relates to a compound according to Embodiment 19, wherein G is reacted with 0-2 T atoms. 5 and 0-1 T 3 Substituted isoxazolyl group.

[0670] Embodiment 19(c) relates to a compound according to Embodiment 19, wherein G is reacted with 0-2 T atoms. 5 and 0-1 T 3 Substituted indole group.

[0671] Embodiment 19(d) relates to a compound according to Embodiment 19, wherein G is reacted with 0-2 T atoms. 5 and 0-1 T 3 Substituted 1,2,3-triazolyl.

[0672] Embodiment 19(e) relates to a compound according to Embodiment 19, wherein G is reacted with 0-2 T atoms. 5 and 0-1 T 3 Substituted imidazole group.

[0673] Embodiment 19(f) relates to a compound according to Embodiment 19, wherein G is reacted with 0-2 T atoms. 5 and 0-1 T 3 Substituted thiazole group.

[0674] Embodiment 19(g) relates to a compound according to Embodiment 19, wherein G is reacted with 0-2 T atoms. 5 and 0-1 T 3 Substituted pyrrole group.

[0675] Embodiment 20 relates to a compound according to Embodiment 16, wherein G is 2,5-dihydropyrrole or 3,6-dihydropyranyl, each being separated by 0-2 T atoms. 5 and 0-1 T 6 replace.

[0676] Sub-implementation of Implementation 20

[0677] Embodiment 20(a) relates to a compound according to Embodiment 20, wherein G is reacted with 0-2 T atoms. 5 and 0-1 T 6 Substituted piperazine group.

[0678] Embodiment 20(b) relates to a compound according to Embodiment 20, wherein G is reacted with 0-2 T atoms. 5 and 0-1 T 6 Substituted piperidine.

[0679] Embodiment 20(c) relates to a compound according to Embodiment 20, wherein G is reacted with 0-2 T atoms. 5 and 0-1 T 6 Substituted pyrrolidines.

[0680] Embodiment 20(d) relates to a compound according to Embodiment 20, wherein G is reacted with 0-2 T atoms. 5and 0-1 T 6 Substituted tetrahydropyran.

[0681] Embodiment 20(e) relates to a compound according to Embodiment 20, wherein G is reacted with 0-2 T atoms. 5 and 0-1 T 6 Substituted morpholino group.

[0682] Embodiment 20(f) relates to a compound according to Embodiment 20, wherein G is reacted with 0-2 T atoms. 5 and 0-1 T 6 Substituted 1,2,3,6-tetrahydropyridinyl.

[0683] Embodiment 20(g) relates to a compound according to Embodiment 20, wherein G is reacted with 0-2 T atoms. 5 and 0-1 T 6 Substituted 2,5-dihydropyrrole group.

[0684] Embodiment 20(h) relates to a compound according to Embodiment 20, wherein G is reacted with 0-2 T atoms. 5 and 0-1 T 6 Substituted 3,6-dihydropyranyl.

[0685] Embodiment 21 relates to a compound according to Embodiment 16, wherein G is (1R,5S)-3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3-diazabicyclo[3.2.1]octyl, or (1R,5S)-8-diazabicyclo[3.2.1]octyl, each being separated by 0-2 T atoms. 5 and 0-1 T 6 replace.

[0686] Sub-implementation of Implementation Method 21

[0687] Embodiment 21(a) relates to a compound according to Embodiment 21, wherein G is reacted with 0-2 T atoms. 5 and 0-1 T 6 Substituted (1R,5S)-3,8-diazabicyclo[3.2.1]octyl.

[0688] Embodiment 21(b) relates to a compound according to Embodiment 21, wherein G is reacted with 0-2 T atoms. 5 and 0-1 T 6 Substituted (1R,5S)-3-azabicyclo[3.2.1]octyl.

[0689] Embodiment 21(c) relates to a compound according to Embodiment 21, wherein G is reacted with 0-2 T atoms. 5 and 0-1 T 6Substituted (1R,5S)-8-azabicyclo[3.2.1]octyl.

[0690] Embodiment 22 relates to a compound according to Embodiment 16, wherein G is cyclohexyl, cyclopentyl, cyclohexenyl, or cyclopentenyl, each being separated by 0-2 T atoms. 1 and 0-1 T 2 replace.

[0691] Sub-implementation of Implementation 22

[0692] Embodiment 22(a) relates to a compound according to Embodiment 22, wherein G is reacted with 0-2 T atoms. 1 and 0-1 T 2 Substituted cyclohexyl groups.

[0693] Embodiment 22(b) relates to a compound according to Embodiment 22, wherein G is reacted with 0-2 T atoms. 1 and 0-1 T 2 Substituted cyclopentyl group.

[0694] Embodiment 22(c) relates to a compound according to Embodiment 22, wherein G is reacted with 0-2 T atoms. 1 and 0-1 T 2 Substituted cyclohexene group.

[0695] Embodiment 22(d) relates to a compound according to Embodiment 22, wherein G is reacted with 0-2 T atoms. 1 and 0-1 T 2 Substituted cyclopentenyl group.

[0696] Embodiment 23 relates to a compound according to any one of Embodiments 1-17, wherein T 3 It is -CH2C(O)N(H)cyclopropyl, -CH2C(O)N(H)CH3, -CH2-COOH, oxetyl, -(CH2) 0-2 Cyclopropyl, -(CH2) 0-2 Cyclobutyl, -(CH2) 0-2 -Tetrahydropyran, -(CH2) 0-2 -Tetrahydrofuran, -(CH2) 0-2 Azahexacyclic butyl, -(CH2) 0-2 Pyrroloalkyl or -(CH2) 0-2 Morpholinyl.

[0697] Embodiment 24 relates to a compound according to any one of Embodiments 1-17, wherein G is one of the following formulas:

[0698]

[0699]

[0700] Embodiment 25 relates to a compound according to any one of Embodiments 1-17, wherein G is one of the following formulas:

[0701]

[0702]

[0703]

[0704] Each T 1a It is F, Cl, or CH3 independently; and

[0705] Each T 5a It can be F, Cl, or CH3 independently.

[0706] Embodiment 26 relates to a compound according to Embodiment 25, wherein G is one of formulas (a), (b), (c), (d), (e), (f), (g), or (H).

[0707] Embodiment 27 relates to a compound according to Embodiment 25, wherein G is one of the formulas (i), (j), (k), (l), (m), (n), (o), (p), (q), (r), (s), (t), (u), (v), (w), (x), (y), (z), (aa), (ab), (ac), or (ad).

[0708] Embodiment 28 relates to a compound according to Embodiment 25, wherein G is one of the formulas (ae), (af), (ag), (ah), (ai), (aj), (ak), (al), (am), (an), (ao), (ap), or (aq).

[0709] Embodiment 29 relates to a compound according to Embodiment 25, wherein G is one of formulas (ar) or (as).

[0710] Embodiment 30 relates to a compound according to Embodiment 25, wherein G is one of the formulas (at) or (au).

[0711] Embodiment 31 relates to a compound according to Embodiment 25, wherein G is one of the formulas (av), (aw), (ax), (ay), or (az).

[0712] Embodiment 32 relates to a compound according to any one of Embodiments 1-25 or 27, wherein T 6Oxycyclobutylmethylene, -C(O)CH2OH, -C(O)OH, -SO2CH3, -C(O)cyclopropyl, -C(O)CH3, -N(H)SO2-cyclopropyl, -N(H)C(O)cyclopropyl, -SO2N(H)CH2CH2CH3, -SO2NHcyclopropyl or -SO2CH2CH2CH3.

[0713] Embodiment 33 relates to a compound according to any one of Embodiments 1-25, 27 or 29, wherein T 5 is F, Cl, CH2Cl, CH2F, CH3, -CH2CH3, -CH(CH3)2, CH2OH, -CH2CH2OH, -CH2C(CH3)2OH, -CH(CH2OH)2, -CH2CH(OH)CF3, CH2CF3, CN, -C H2CN, -OCH3, -CH2OCH3, -CHF2, -CH2CHF2, -CH2CH(OH)CH2CH2Cl, -CH(CH2OH)CH2Cl, -CH(CH2OH)CH2I or -CH2C(CH3)(CH2OH)CH2Cl.

[0714] Embodiment 34 relates to a compound according to any one of Embodiments 1-25, wherein Z 5 It can be CH3, F, Cl, CN, -CH2CN, -CH2CH3 or OH.

[0715] Embodiment 35 relates to compounds according to Embodiment 1, selected from Table 1, or pharmaceutically acceptable salts thereof.

[0716] Furthermore, these formulas are intended to cover both hydrated and solvated forms of the identified structures, as well as non-hydrated and non-solventized forms. For example, the compounds shown include both hydrated and non-hydrated forms. Other examples of solvates include structures combined with suitable solvents such as isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, or ethanolamine.

[0717] III. Preparation and Administration

[0718] Embodiment 36 of this disclosure relates to a pharmaceutical composition comprising a compound of any one of the embodiments of this disclosure, such as a compound of any one of embodiments 1-35, including any sub-embodiments thereof, and a pharmaceutically acceptable carrier.

[0719] Embodiment 37 of this disclosure relates to the pharmaceutical composition of Embodiment 36, further comprising a second pharmaceutical agent.

[0720] A suitable dosage form depends in part on the intended use or route of administration, such as oral, transdermal, transmucosal, inhalation, or injection (parenteral). Such dosage forms should allow the compound to reach target cells. Other factors are well known in the art and include considerations such as toxicity and dosage form factors that hinder the compound or composition from exerting its effect. Techniques and formulations are commonly found in Pharmaceutical Science and Practice, 21st Edition, Lippincott, Williams, and Wilkins, Philadelphia, PA, 2005 (incorporated herein by reference).

[0721] The compounds disclosed herein (i.e., any of the compounds described in embodiments 1-36, including any of their sub-embodiments) can be formulated into pharmaceutically acceptable salts.

[0722] A carrier or excipient may be used to generate the composition. The carrier or excipient can be selected to facilitate the administration of the compound. Examples of carriers include calcium carbonate, calcium phosphate, various sugars (e.g., lactose, glucose, or sucrose) or starch types, cellulose derivatives, gelatin, vegetable oils, polyethylene glycol, and physiologically compatible solvents. Examples of physiologically compatible solvents include water for injection (WFI), saline solutions, and sterile solutions of glucose.

[0723] The compound can be administered via various routes, including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, mucosal, rectal, transdermal, or inhalation. In some embodiments, the compound can be administered orally. For example, for oral administration, the compound can be formulated into conventional oral dosage forms, such as capsules, tablets, and liquid formulations, such as syrups, elixirs, and concentrated drops.

[0724] For inhalation formulations, the compounds disclosed herein can be formulated as dry powders or suitable solutions, suspensions, or aerosols. Powders and solutions can be formulated with suitable additives known in the art. For example, powders may include suitable powder matrices such as lactose or starch, and solutions may contain propylene glycol, sterile water, ethanol, sodium chloride, and other additives such as acids, bases, and buffer salts. Such solutions or suspensions can be administered by inhalation via sprays, pumps, nebulizers, or nebulizers. The compounds disclosed herein can also be used in combination with other inhaled therapies such as corticosteroids, such as fluticasone propionate, beclomethasone dipropionate, triamcinolone acetonide, budesonide, and mometasone furoate; beta agonists, such as salbutamol, salmeterol, and formoterol; anticholinergic drugs, such as ipratropium bromide or tiotropium bromide; vasodilators, such as treprostinal and iloprost; enzymes, such as DNase; therapeutic proteins; immunoglobulin antibodies; oligonucleotides, such as single-stranded or double-stranded DNA or RNA, siRNA; antibiotics, such as tobramycin; muscarinic receptor antagonists; leukotriene antagonists; cytokine antagonists; protease inhibitors; cromolyn sodium; nedocril sodium; and sodium cromoglycate.

[0725] For example, a pharmaceutical formulation for oral administration can be obtained by combining an active compound with solid excipients, optionally grinding the resulting mixture and processing it into a granular mixture, and adding suitable excipients, if necessary, to obtain tablets or sugar-coated cores. Suitable excipients, especially fillers, include sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose formulations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose (CMC), and / or polyvinylpyrrolidone (PVP; povidone). If necessary, disintegrants, such as cross-linked polyvinylpyrrolidone, agar, or alginate, or salts thereof, such as sodium alginate, can be added.

[0726] The sugar-coated core is provided with a suitable coating. For this purpose, a concentrated sugar solution may be used, which may optionally contain, for example, gum arabic, talc, polyvinylpyrrolidone, carbomer gel, polyethylene glycol (PEG) and / or titanium dioxide, lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the coating of the tablet or sugar-coated pill for the purpose of identifying or characterizing different combinations of active compound dosages.

[0727] Orally administered pharmaceutical formulations include push-fit capsules (“soft gelcaps”) made of gelatin, and soft-sealable capsules made of gelatin and plasticizers (such as glycerin or sorbitol). Push-fit capsules may contain an active ingredient mixed with a filler (such as lactose), a binder (such as starch), and / or a lubricant (such as talc or magnesium stearate) and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol (PEG). Additionally, stabilizers may be added.

[0728] Alternatively, the compound can be administered by injection (parenteral administration), for example, intramuscular, intravenous, intraperitoneal, and / or subcutaneous administration. For injection, the disclosed compounds are formulated as sterile liquid solutions, such as physiologically compatible buffers or solutions, such as saline, Hank's solution, or Ringer's solution. Furthermore, the compounds can be formulated as solids and immediately reconstituted or suspended prior to use. Lyophilized forms are also possible.

[0729] Application can also be made via mucosal, topical, transdermal, or inhalation routes. For mucosal, topical, or transdermal application, the formulation uses a penetrant suitable for the target permeability barrier. Such penetrants are generally known in the art and include, for example, bile salts and fusidic acid derivatives for mucosal application. Additionally, detergents may be used to facilitate penetration. For example, mucosal application can be made via nasal sprays or suppositories (rectal or vaginal).

[0730] The topical compositions disclosed herein are formulated into oils, creams, lotions, ointments, etc., using suitable carriers known in the art. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched-chain fatty acids or oils, animal fats, and high molecular weight alcohols (greater than C10). 12 In another embodiment, the carrier is one in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants, antioxidants, and colorants or fragrances may also be included, if desired. Creams for topical application are formulated from a mixture of mineral oil, self-emulsifying beeswax, and water, wherein the active ingredient is mixed in a small amount of solvent (e.g., oil). Furthermore, transdermal application may comprise transdermal patches or dressings, such as bandages impregnated with the active ingredient and optionally one or more carriers or diluents known in the art. For application in the form of a transdermal delivery system, dosage administration is, of course, continuous rather than intermittent throughout the administration regimen.

[0731] The amounts of various compounds to be applied can be determined through standard procedures, considering, for example, compound IC. 50Factors such as the compound's biological half-life, the subject's age, height, weight, and the indication being treated are considered. The importance of these and other factors is well known to those skilled in the art. Typically, the dosage will be from about 0.01 to 50 mg / kg, or 0.1 to 20 mg / kg for the treated subject. Multiple dosages may be used.

[0732] The compounds disclosed herein can also be used in combination with other therapies for treating the same disease. Such combination use includes administering the compound and one or more other therapeutic agents at different times, or administering the compound and one or more other therapeutic agents together. In some embodiments, the dosage of one or more of the compounds disclosed herein or other therapeutic agents used in combination can be modified by methods well known to those skilled in the art, for example, by reducing the dosage relative to the compound or therapeutic agent used alone.

[0733] It should be understood that combined use includes use with other therapies, drugs, medical procedures, etc., wherein the other therapies or procedures may be administered at different times (e.g., within a short period of time, such as within several hours (e.g., 1, 2, 3, 4-24 hours), or for a longer period of time than the compounds of this disclosure (e.g., 1-2 days, 2-4 days, 4-7 days, 1-4 weeks), or concurrently with the compounds of this disclosure. Combined use also includes use with a therapy or medical procedure (e.g., surgery) that is administered once or infrequently, and administration of the compounds of this disclosure for a short or longer period of time before or after other therapies or procedures. In some embodiments, this disclosure provides the compounds of this disclosure and one or more other pharmaceutical therapeutic agents delivered via different routes of administration or via the same route of administration. Combined use for any route of administration includes delivery of the compounds of this disclosure and one or more other pharmaceutical therapeutic agents together in any formulation via the same route of administration, including chemically linked two of the compounds in a manner that maintains their therapeutic activity upon administration. Co-administration of the compounds disclosed herein. In one aspect, other drug therapies may be co-administered with one or more of the compounds disclosed herein. Co-administration includes administration of a co-administered formulation or a formulation of chemically bound compounds, or administration of two or more compounds in separate formulations over short periods of time (e.g., within 1 hour, 2 hours, 3 hours, up to 24 hours), via the same or different routes. Co-administration of separate formulations includes delivery via a single device (e.g., the same inhalation device, the same syringe, etc.), or administration from separate devices over short periods of time. Co-administration of the compounds disclosed herein and one or more other drug therapies delivered via the same route includes materials prepared together such that they can be administered via a single device, including separate compounds combined in a formulation, or compounds modified such that they are chemically bound but still retain their biological activity. Such chemically linked compounds may have a link that is substantially maintained in vivo, or the link may be broken down in vivo, thereby separating the two active ingredients.

[0734] IV. Instructions for Use

[0735] The methods and compounds are typically used to treat human subjects. However, they can also be used to treat similar or identical indications in other animal subjects.

[0736] In some implementations, the patient is 60 years of age or older and has relapsed after first-line cancer treatment. In some implementations, the patient is 18 years of age or older and has relapsed or is refractory after second-line cancer treatment. In some implementations, the patient is 60 years of age or older and is primary refractory to first-line cancer treatment. In some implementations, the patient is 70 years of age or older and has not previously received treatment. In some implementations, the patient is 70 years of age or older and is ineligible and / or unlikely to benefit from cancer treatment.

[0737] In some embodiments, the therapeutically effective dose used in the methods provided herein is at least 10 mg per day. In some embodiments, the therapeutically effective dose is 10, 50, 90, 100, 135, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, or 2500 mg per day. In other embodiments, the therapeutically effective dose is 10, 50, 90, 100, 135, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2500, 3000, 3500, 4000, 4500, 5000 mg or more per day. In some embodiments, the compound is administered continuously.

[0738] In some embodiments, this document provides a method for treating CD73-mediated diseases or symptoms by administering to a mammal suffering from the disease or symptoms at least 10, 50, 90, 100, 135, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2500, 3000, 3500, 4000, 4500, or 5000 mg daily of any compound described in any one of embodiments 1-36, or a pharmaceutically acceptable salt, deuterated analog, tautomer, or stereoisomer thereof, and wherein the compound is administered on an empty stomach.

[0739] Embodiment 38 of this disclosure relates to a method for treating a subject suffering from a CD73-mediated disease or condition, the method comprising administering to the subject an effective amount of a compound of one of Embodiments 1-35 (or any sub-embodiment thereof, as applicable), a pharmaceutically acceptable salt, deuterated analog, tautomer or stereoisomer thereof, or a pharmaceutical composition of one of Embodiments 36-37.

[0740] Embodiment 39 of this disclosure relates to a method for treating a disease or condition according to embodiment 38, wherein the disease or condition is a neoplastic condition, cancer, age-related disease, inflammatory condition, cognitive impairment, and / or neurodegenerative disease.

[0741] Embodiment 40 of this disclosure relates to a method for treating a disease or symptom according to Embodiment 38, wherein the disease or symptom is bladder cancer, colorectal cancer, gastric cancer, gallbladder cancer, glioblastoma multiforme, glioma, leukemia, lymphoma, lung cancer, breast cancer, melanoma, multiple myeloma, ovarian cancer, prostate cancer, pancreatic cancer, thyroid cancer, liver fibrosis, Alzheimer's disease, multiple sclerosis, or Parkinson's disease.

[0742] Embodiment 40(a) of this disclosure relates to a method for treating a disease or condition according to Embodiment 38, wherein the disease or condition is bladder cancer, colorectal cancer, gastric cancer, gallbladder cancer, glioblastoma multiforme, glioma, leukemia, lymphoma, lung cancer, breast cancer, melanoma, multiple myeloma, ovarian cancer, prostate cancer, pancreatic cancer, thyroid cancer, pulmonary fibrosis, liver fibrosis, Alzheimer's disease, multiple sclerosis, or Parkinson's disease.

[0743] Embodiment 41 of this disclosure relates to a method for treating a disease or symptom according to Embodiment 40, wherein the lymphoma is adult T-cell lymphoma, AIDS-related lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, B-cell lymphoma, Burkitt lymphoma, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, enteropathy-associated T-cell lymphoma, follicular lymphoma, hepatosplenic T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, MALT lymphoma, mantle cell lymphoma, marginal zone B-cell lymphoma, primary exudative lymphoma, or T-cell lymphoma.

[0744] Embodiment 42 of this disclosure relates to a method for treating a disease or symptom according to Embodiment 40, wherein the leukemia is adult T-cell leukemia, aggressive NK-cell leukemia, B-cell chronic lymphocytic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, B-cell prolymphocytic leukemia, acute eosinophilic leukemia, acute erythroleukemia, acute lymphoblastic leukemia, acute megakaryocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, or mast cell leukemia.

[0745] Embodiment 43 of this disclosure relates to a method for treating a disease or condition according to Embodiment 38, wherein the disease or condition is renal cell carcinoma, small cell lung cancer, non-small cell lung cancer, acute myeloid leukemia, multiple myeloma, diffuse large B-cell lymphoma, breast cancer, or prostate cancer.

[0746] Sub-implementation of Implementation Method 43

[0747] Embodiment 43(a) of this disclosure relates to a method for treating a disease or symptom according to embodiment 43, wherein the disease or symptom is kidney cancer.

[0748] Embodiment 43(b) of this disclosure relates to a method for treating a disease or symptom according to embodiment 43, wherein the disease or symptom is small cell lung cancer.

[0749] Embodiment 43(c) of this disclosure relates to a method for treating a disease or symptom according to embodiment 43, wherein the disease or symptom is non-small cell lung cancer.

[0750] Embodiment 43(d) of this disclosure relates to a method for treating a disease or condition according to embodiment 43, wherein the disease or condition is acute myeloid leukemia.

[0751] Embodiment 43(e) of this disclosure relates to a method for treating a disease or symptom according to embodiment 43, wherein the disease or symptom is multiple myeloma.

[0752] Embodiment 43(f) of this disclosure relates to a method for treating a disease or symptom according to embodiment 43, wherein the disease or symptom is diffuse large B-cell lymphoma.

[0753] Embodiment 43(g) of this disclosure relates to a method for treating a disease or symptom according to Embodiment 43, wherein the disease or symptom is breast cancer.

[0754] Embodiment 43(h) of this disclosure relates to a method for treating a disease or symptom according to Embodiment 43, wherein the disease or symptom is prostate cancer.

[0755] V. Combination Therapy

[0756] CD73 modulators can be effectively used in combination with another pharmacologically active compound or two or more other pharmacologically active compounds, particularly in cancer treatment. In one embodiment, the composition comprises any one or more compounds described herein, and one or more compounds that are therapeutically effective for the same disease indication, wherein the compounds have a synergistic effect on the disease indication. In one embodiment, the composition comprises any one or more compounds as described herein that are effective in treating cancer, and one or more other compounds that are effective in treating the same cancer, further wherein the compounds are synergistically effective in treating cancer.

[0757] In combination with other adenosine axis blockers (e.g., agents targeting CD39, CD38, A2AR, or A2BR):

[0758] Under physiological conditions, ATP and NAD in biological fluids and extracellular space +These substances are present at low concentrations (30-100 nM), while their intracellular concentrations are in the mM range. They are released from cells during cell activation, stress, hypoxia, and tissue damage. Excess extracellular ATP is rapidly hydrolyzed by exonucleases (e.g., CD39) or exonuclease / phosphodiesterase (ENPP1) to generate ADP, which ultimately generates AMP. Alternatively, AMP can be generated from extracellular nicotinamide adenine dinucleotide (NAD+) through the coordinated action of exonuclease CD38 and ENPP1. AMP is further hydrolyzed to adenosine primarily by CD73, with alkaline phosphatase being less efficient. Adenosine activates signaling pathways via G protein-coupled receptors A1, A2a, A2b, and A3. Upon binding to A2a or A2b receptors, which are upregulated in response to immune cell activation, adenosine triggers an increase in intracellular cAMP and leads to severe suppression of immune function. Preclinical studies support that targeting multiple points in the adenosine pathway may provide significant therapeutic benefits for cancer treatment. Perrot, I. et al. Blocking Antibodies Targeting the CD39 / CD73Immunosuppressive Pathway Unleash Immune Responses in Combination CancerTherapies. Cell Rep. 27, 2411-2425.e9 (2019), Young, A. et al. Co-inhibition of CD73and A2AR Adenosine Signaling Improves Anti-tumor Immune Responses. Cancer Cell30,391–403(2016).

[0759] Combined with immune checkpoint blockade:

[0760] Anti-PD-1 and anti-CTLA4 checkpoint blockade can be synergistic with anti-CD73 or anti-A2a therapy. Allard, B. et al. Targeting CD73 Enhances the Antitumor Activity of Anti-PD-1and Anti-CTLA-4mAbs. Clin. Cancer Res. 19, 5626–5636 (2013); Hay, CM et al. Targeting CD73 in thetumor microenvironment with MEDI9447. Oncoimmunology 5,1–10(2016); Willingham, SB et al. Access.61,917–926(2013);Beavis,PA et al.Adenosine Receptor 2ABlockade Increases the Efficiency of Anti–PD-1 through Enhanced Antitumor T-cell Responses. 3, (2015); Mittal, D. et al. Antimetastatic Effects of Blocking PD-1 and the Adenosine A2A Receptor. 3, 3652–3659 (2014). In some tumor models, the synergistic effect, in a CD8+ T cell and IFN-γ dependent manner, has shown to promote growth delay or even complete rejection.Allard, B. et al. Targeting CD73 Enhances the Antitumor Activity of Anti-PD-1and Anti-CTLA-4mAbs. Clin Cancer Res. 19, 5626–5636 (2013); Hay, CM et al. Targeting CD73 in the tumor microenvironment with MEDI9447. Oncoimmunology 5,1–10(2016); Willingham, SB et al. of Anti–PD-1through Enhanced Antitumor T-cell Responses. 3, (2015). Potential CD73 inhibitors can synergize with other agents that target T-cell-related inhibitory molecules (such as PDL1, LAG-3, TIGIT, TIM-3, VISTA, B7-H3, etc.).

[0761] Combined with agonists of the TNFA superfamily:

[0762] Agonist antibodies targeting members of the tumor necrosis factor receptor (TNFR) superfamily (e.g., 4-1BB, GITR, and OX40) on the surface of antigen-induced T cells are at various stages of preclinical and clinical trials. However, they have shown limited therapeutic benefit as single agents. CD73 expression on T cells maintained by TGF-β in the tumor microenvironment hinders the therapeutic activity of these agonist antibodies. CD73 inhibitors could overcome resistance to TNFR agonists and enhance their efficacy.

[0763] In combination with targeted therapy:

[0764] High expression of CD73 in breast cancer is associated with resistance to trastuzumab (anti-HER2 / ErbB2 mAb). Turcotte, M. et al. CD73 promotes resistance to HER2 / ErbB2 antibody therapy. Cancer Res. 77, 5652–5663 (2017). Blocking CD73 has been shown to enhance the activity of anti-ErbB2 mAb in treating breast cancer and lung metastases. Ibid.

[0765] Elevated CD73 expression has been observed in melanoma patients with BRAF-mutant tumors. A2AR antagonists have been shown to enhance the efficacy of BRAF and MEK inhibition in mice with BRAF-mutant tumors. (Young, A. et al. Targeting adenosine in BRAF-mutant melanoma reduces tumor growth and metastasis. Cancer Res. 77, 4684–4696 (2017)). Similarly, CD73 inhibitors can enhance the therapeutic benefit of BRAF and MEK inhibitors.

[0766] CD73 is overexpressed in NSCLC carrying EGFR mutations. (Inoue, Y. et al. Prognostic impact of CD73 and A2A adenosine receptor expression in non-small-cell lung cancer. Oncotarget 8,8738–8751 (2017)). Similarly, CD73 inhibitors can enhance the therapeutic benefit of BRAF and MEK inhibitors. CD73 is overexpressed in non-small cell lung cancer (NSCLC) carrying EGFR mutations (Inoue, Y. et al. Prognostic impact of CD73 and A2A adenosine receptor expression in non-small-cell lung cancer. Oncotarget 8,8738–8751 (2017)), and its expression is positively correlated with EGFR expression in NSCLC, hepatocellular carcinoma, breast cancer, and glioblastoma. Zhu, J. et al. CD73 / NT5E is a target ofmiR-30a-5p and plays an important role in the pathogenesis of non-small celllung cancer. Mol. Cancer 16,1–15(2017); Shali, S. et al. Ecto-5′-nucleotidase(CD73) is a potential target of hepatocellular carcinoma.J.Cell.Physiol.234,10248–10259(2019); Zhi, 73(ecto-5'-nucleotidase)in 165glioblastomas by immunohistochemistry and electronmicroscopichistochemistry Anticancer Res. 19, 1747–52 (1999).CD73 has been found to promote EGFR expression in several types of cancer cells, including NSCLC, hepatocellular carcinoma, and breast cancer cells. Zhu, J. et al. CD73 / NT5E is a target of miR-30a-5p and plays an important role in the pathogenesis of non-small cell lung cancer. Mol. Cancer 16, 1–15 (2017); Shali, S. et al. Ecto-5′-nucleotidase (CD73) is a potential target of hepatocellular carcinoma. J. Cell. Physiol. 234, 10248–10259 (2019); Zhi, X. et al. Potential Prognostic Biomarker CD73 Regulates Epidermal Growth Factor Receptor Expression in Human Breast Cancer. IUBMBLife. 64, 911–920 (2012). Previous studies have shown that inhibiting CD73 can reduce the proliferation of NSCLC and hepatocellular carcinoma cells (Zhu, J. et al. CD73 / NT5E is a target of miR-30a-5p and plays an important role in the pathogenesis of non-small cell lung cancer. Mol. Cancer 16, 1–15 (2017); Shali, S. et al. Ecto-5′-nucleotidase (CD73) is a potential target of hepatocellular carcinoma. J. Cell. Physiol. 234, 10248–10259 (2019)) and the migration and invasion of breast cancer cells. Zhi, X. et al. Potential Prognostic Biomarker CD73 Regulates Epidermal Growth Factor Receptor Expression in Human Breast Cancer. IUBMB Life 64, 911–920 (2012). CD73 inhibition may improve the therapeutic outcomes of EGFR inhibitors in these cancers. The combination of CD73 inhibitors and EGFR inhibitors can produce better therapeutic benefits than single agents.

[0767] Combined with radiotherapy and chemotherapy:

[0768] Radiotherapy and chemotherapy can induce ATP release from cancer cells. They also enhance the expression of CD73 and other members of the adenosine axis. The activity of the CD73 / adenosine system in the tumor microenvironment is not only associated with increased tumor growth and tumor immune escape, but also with radiation-induced adverse late effects such as pulmonary fibrosis. Wirsdorfer, F. et al. Extracellular adenosine production by ecto-50-nucleotidase (CD73) enhances radiation-induced lung fibrosis. Cancer Res. 76, 3045–3056 (2016). Blocking CD73 activity can enhance the antitumor efficacy of radiotherapy (Wennerberg, E. et al. Adenosine regulates radiation therapy-induced anti-tumor immunity. J. Immunother. Cancer 3, P378 (2015); Wennerberg, E. et al. Adenosine generation limits radiation-induced tumor immunogenicity by abrogating recruitment and activation of CD103+ DCs. J. Immunol. 198, 154. 6 (2017)) and chemotherapeutic agents (e.g., doxorubicin, paclitaxel) (Loi, S. et al. CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer. doi:10.1073 / pnas.1222251110.) and mitoxantrone, and can also reduce radiotherapy-induced late toxicity to normal tissues (Wirsdorfer, F. et al. Extracellular adenosine production by ecto-50-nucleotidase (CD73) enhances radiation-induced lung fibrosis. Cancer Res. 76, 3045–3056 (2016); de Leve, S. et al. The CD73 / Ado System—A New Player in RT Induced Adverse Late Effects. Cancer (Basel) 11, 1578 (2019), thus improving the therapeutic gain of radiotherapy and chemotherapy.

[0769] Combined with adoptive T-cell transfer or DC vaccine:

[0770] Adoptive T-cell transfer (tumor-infiltrating lymphocyte therapy and CAR-T therapy) has produced unprecedented clinical effects against certain types of malignancies. A synergistic effect between CD73 blockade and adoptive T-cell transfer in mice has been demonstrated. (Wang, L. et al. CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice. J. Clin. Invest. 121, 2371–2382 (2011); Jin, D. et al. CD73 on tumor cells impairs anti-tumor T cell responses: a novel mechanism of tumor-induced immune suppression. Cancer Res. 70, 2245–2255 (2011)). This can be explained by CD73 blockade promoting the homing of tumor-specific T cells at the tumor site. Wang, L. et al. CD73 has distinct roles in nonhematopoietic and hematopoietic cells topromote tumor growth in mice. J. Clin. Invest. 121, 2371–2382 (2011).

[0771] Dendritic cell (DC) vaccination, aimed at inducing tumor-specific effector T cells with immune memory, is a promising approach to cancer immunotherapy. It needs to be combined with other therapies targeting immunosuppressive mechanisms to improve outcomes. Targeting CD73 has been shown to enhance the efficacy of DC vaccines by inducing tumor-specific T cell activity. (Ara, S. et al. Increased efficacy of a dendritic cell–based therapeutic cancer vaccine with adenosine receptor antagonist and CD73 inhibitor. Tumor Biol. 1–8 (2017) doi:10.1177 / 1010428317695021.)

[0772] In another embodiment, this disclosure provides a method for treating CD73-mediated diseases or symptoms by administering an effective amount of a composition to a subject, the composition comprising any one or more compounds described herein and one or more other therapies suitable for treating the disease.

[0773] liver fibrosis

[0774] Liver fibrosis develops as a response to chronic inflammation and persistent liver damage caused by alcohol or viral infection. This pathological process is driven by the activation and accumulation of myofibroblasts. CD73 is upregulated in hepatic stellate cells, portal fibroblasts, and fibrous septa due to myofibroblast differentiation. Fausther, M. et al. Activated hepaticstellate cells upregulate transcription of ecto-5′-nucleotidase / CD73 via specific SP1 and SMAD promoter elements. Am. J. Physiol.-Gastrointest. Liver Physiol. 303, (2012). CD73-deficient mice are protected from the development of liver fibrosis, suggesting its role in fibrosis and adenosine production. Peng, Z. et al. Ecto-5′-nucleotidase (CD73)-mediated extracellular adenosine production plays a critical role in hepatic fibrosis. FASEB J. 22, 2263–2272 (2008). CD73 may contribute to the prevention of liver fibrosis.

[0775] Multiple sclerosis (MS)

[0776] MS is an autoimmune disease affecting the central nervous system (CNS). In animal models of MS, experimental autoimmune encephalomyelitis (EAE), myelin antigen-specific CD4+ T cells have been shown to play a role in inducing CNS inflammation, demyelination, and neurodegeneration. Although CD73 is known for its central role in immunosuppression, CD73- / - mice are highly resistant to EAE induction. Mills, JH et al. CD73 is required for efficient entry of lymphocytes into the central nervous system during experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA 105, 9325–9330 (2008). This can be explained by the fact that CD73 and adenosine play a more significant role in CNS lymphocyte infiltration during EAE induction than in regulating neuroinflammation. Ibid. CD73 inhibition may be helpful in treating MS and other neuroinflammatory diseases.

[0777] Embodiment 44 of this disclosure relates to a method according to any one of embodiments 38-43 or any sub-embodiments thereof, further comprising the application of one or more additional therapeutic agents.

[0778] Embodiment 45 of this disclosure relates to a method according to Embodiment 44, wherein i) one or more alkylating agents are selected from adozelesin, hexamethylmelamine, bizelesin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estradiol, formustine, hepsulfam, ifosfamide, improsulfan, ilofofen. (ii) Antibiotics selected from bleomycin, actinomycin D, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinosin. iii) antimetabolites selected from the group consisting of: azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, fluorouracil, fludarabine, 5-fluorouracil, tegafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelabine, pemetrexed, raltitrexed, thioguanine, and trimetrexate. iv) Immunotherapy agents selected from PD-1 or PD-L1 inhibitors; v) Hormones or hormone antagonists selected from the group consisting of: enzalutamide, abiraterone, anastrozole, androgens, busherin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprorelin, magestrol, raloxifene, tamoxifen, and toremifene; vi) Taxanes selected from DJ-927, docetaxel, and TPIs. 287. Paclitaxel and DHA-paclitaxel; vii) Retinoids selected from aliretinoin, bexarotene, fenretinide, isotretinoin, and retinoic acid; viiii) Alkaloids selected from etoposide, homoharringtonine, teniposide, vincristine, vinblastine, vinorelbine, and vinorelbine; ix) Antiangiogenic agents selected from AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide; x) Topoisomerase inhibitors selected from acridine, aetaline, exatecan, irinotecan, SN-38 (7-ethyl-10-hydroxycamptothecin), rubitecan, topotecan, and 9-aminocamptothecin;xi) kinase inhibitors, selected from erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, AEE-788, AG-013736, and AMG. 706, AMN107, BMS-354825, BMS-599626, UCN-01 (7-hydroxyastrosporin), vemurafenib, dabrafenib, trametinib, cobimetinib, selumetinib, and vatalanib; xii) signal transduction inhibitors selected from bortezomib, geldanamycin, and rapamycin; xiii) biological response modifiers selected from imiquimod, interferon-α, and interleukin-2; xiv) IDO inhibitors; and xv) chemotherapeutic agents selected from 3-AP (3-amino-2-carboxyaldehyde thiourea), atrasentan, aminoglutethimide, anagrelide, asparaginase, lichenin-1, and cephalosporin. Clinigide, elesclomol, eribulin mesylate (E7389), ixabepilone, lonidamine, masoprocol, mitoguanazone, oblimersen, sulindac, testrolide, tiazofurin, mTOR inhibitors, PI3K inhibitors, Cdk4 inhibitors, Akt inhibitors, Hsp90 inhibitors, farnesyltransferase inhibitors, or aromatase inhibitors (anastrozole, letrozole, exemestane); xvi) Mek inhibitors; xvii) tyrosine kinase inhibitors; xviii) c-Kit mutation inhibitors; xix) EGFR inhibitors; PD-1 inhibitors; or xx) epigenetic regulators.

[0779] Embodiment 46 of this disclosure relates to a method according to embodiment 45, wherein the one or more additional therapeutic agents are PD-1 or PD-L1 inhibitors.

[0780] Embodiment 47 of this disclosure relates to a method according to Embodiment 46, wherein the PD-1 or PD-L1 inhibitor is nivolumab, pembrolizumab, cimipril, atezolizumab, avelumab, or durvalumab.

[0781] Embodiment 47(a) of this disclosure relates to a method according to Embodiment 46, wherein the PD-1 or PD-L1 inhibitor is nivolumab, pembrolizumab, cimipril, atezolizumab, acimetab, durvalumab, or zimberelimab.

[0782] Embodiment 48 of this disclosure relates to a method according to Embodiment 44, wherein the one or more additional therapeutic agents are PD-1 inhibitors and the disease or symptom is colorectal cancer.

[0783] Embodiment 49 of this disclosure relates to a method according to Embodiment 44, including the application of first and second additional therapeutic agents.

[0784] Embodiment 50 of this disclosure relates to a method according to Embodiment 49, wherein the first additional therapeutic agent is a PD-1 inhibitor, the second additional therapeutic agent is a chemotherapeutic agent, and the disease or symptom is adenocarcinoma.

[0785] Embodiment 50(a) of this disclosure relates to a method according to Embodiment 50, wherein the adenocarcinoma is metastatic pancreatic ductal adenocarcinoma.

[0786] In another embodiment, this disclosure provides a method for treating cancer in a subject of need by administering to the subject an effective amount of a composition comprising any one or more compounds described herein in combination with one or more other therapies or medical procedures effective in treating cancer. Other therapies or medical procedures include suitable anticancer therapies (e.g., drug therapy, vaccine therapy, gene therapy, photodynamic therapy) or medical procedures (e.g., surgery, radiation therapy, hyperthermia, bone marrow or stem cell transplantation). In one embodiment, one or more suitable anticancer therapies or medical procedures are selected from treatment with chemotherapy agents (e.g., chemotherapeutic drugs), radiation therapy (e.g., X-rays, gamma rays, or electron, proton, neutron, or alpha particle beams), hyperthermia (e.g., microwaves, ultrasound, radiofrequency ablation), vaccine therapy (e.g., AFP gene hepatocellular carcinoma vaccine, AFP adenovirus vector vaccine, AG-858, allogeneic GM-CSF secretory breast cancer vaccine, dendritic cell peptide vaccine), gene therapy (e.g., Ad5CMV-p53 vector, adenovirus vector encoding MDA7, adenovirus 5-tumor necrosis factor α), photodynamic therapy (e.g., aminolevulinic acid, motexatin lutetium), surgery, or bone marrow and stem cell transplantation.

[0787] VI. Reagent Kit

[0788] In another aspect, this disclosure provides a kit comprising one or more compounds as described in any one of embodiments 1-35, or a pharmaceutically acceptable salt, deuterated analog, tautomer, or stereoisomer thereof, or a pharmaceutical composition of any one of embodiments 36-37. In some embodiments, the compound or composition is packaged in, for example, vials, bottles, or flasks, which may be further packaged in, for example, boxes, envelopes, or bags. The compound or composition may be approved by the U.S. Food and Drug Administration or a similar regulatory agency for administration to mammals (e.g., humans). The compound or composition may be approved for administration to mammals (e.g., humans) for the treatment of CD73-mediated diseases or conditions. The kit described herein may include written instructions for use and / or other instructions that the compound or composition is suitable or approved for administration to mammals (e.g., humans) for the treatment of CD73-mediated diseases or conditions. The compound or composition may be packaged in unit dose or single-dose form, such as single-dose pills, capsules, etc.

[0789] VII. Combined with determination

[0790] The methods disclosed herein may involve assays capable of detecting the binding of a compound to a target molecule. Such binding is statistically significant, with a confidence level of at least 90%, or at least 95, 97, 98, 99%, or higher, meaning the measured signal indicates binding to the target molecule, distinct from background. In some embodiments, a control is used to distinguish target binding from nonspecific binding. Various assays indicating binding are known for different target types and may be used in this disclosure.

[0791] Conjugated compounds can be characterized by their effect on the activity of target molecules. Therefore, "low-activity" compounds exhibit inhibitory concentrations (IC50) greater than 1 μM under standard conditions. 50 ) or effective concentration (EC 50 "Very low activity" means that ICs under standard conditions... 50 or EC 50 Above 100 μM. "Extremely low activity" means that under standard conditions, IC... 50 or EC 50 Above 1 mM. "Moderate activity" means IC under standard conditions. 50 or EC 50 The range is 200 nM to 1 μM. "Moderately high activity" refers to IC... 50 or EC 50 The range is from 1 nM to 200 nM. "High activity" means that the IC operates under standard conditions. 50 or EC 50 Below 1 nm. IC 50 or EC 50Defined as the concentration of a compound at which the activity of a target molecule (e.g., an enzyme or other protein) decreases or increases by 50% relative to the range of activity observed in the absence of the compound. Activity can be measured using methods known to those skilled in the art, such as by measuring any detectable product or signal produced by the occurrence of an enzyme reaction, or other activities of the protein being measured.

[0792] The term "background signal" in binding assays refers to the signal recorded under specific assay conditions in the absence of a test compound, molecular scaffold, or ligand binding to the target molecule. Those skilled in the art will recognize that recognized methods exist and are widely used to determine the background signal.

[0793] "Standard deviation" refers to the square root of the variance. Variance is a measure of how spread out a distribution. It is calculated as the average variance of each value relative to its mean. For example, for the values ​​1, 2, and 3, the mean is 2, and the variance is:

[0794]

[0795] Surface Plasmon Resonance

[0796] Binding parameters can be measured using surface plasmon resonance, for example, using a coating to immobilize the binding components. Chip (Biacore, Japan). Surface plasmon resonances are used to characterize the microscopic binding and dissociation constants of sFv or reactions between other ligands for target molecules. Such methods are broadly described in the following references, which are incorporated herein by reference. Vely F. et al., (2000) 用于测试磷酸化肽与SH2结构域相互作用的分析,《分子生物学方法》。121:313 - 21;Liparoto等人,(1999年)白细胞介素-2受体复合物的生物传感器分析,《分子识别杂志》。12:316 - 21;Lipschultz等人,(2000年)使用表面等离子体共振分析复杂动力学的实验设计,《方法》。20(3):310 - 8;Malmqvist.,(1999年)BIACORE:一种用于表征生物分子相互作用的亲和生物传感器系统,《生物化学学会会刊》27:335 - 40;Alfthan,(1998年)表面等离子体共振生物传感器作为抗体工程中的一种工具,《生物传感器与生物电子学》。13:653 - 63;Fivash等人,(1998年)用于大分子相互作用的BIAcore,《生物技术当前观点》。9:97 - 101;Price等人;(1998年)关于ISOBM TD - 4研讨会的总结报告:56种抗MUC1粘蛋白单克隆抗体的分析。《肿瘤生物学》19增刊1:1 - 20;Malmqvist等人,(1997年)生物分子相互作用分析:用于蛋白质功能分析的亲和生物传感器技术,《化学生物学当前观点》。1:378-83; O'Shannessy et al., (1996) Interpretation of deviations from pseudo-first-order kinetic behavior in the characterization of ligand binding by biosensor technology, Analytical Biochemistry. 236:275-83; Malmborg et al., (1995) BIAcore as a tool in antibody engineering, Journal of Immunological Methods.183:7-13; Van Regenmortel, (1994) Use of biosensors to characterize recombinant proteins, Developments in BiologicalStandardization.83:143-51; and O'Shannessy, (1994) Determination of kinetic rate and equilibrium binding constants for macromolecular interactions: a critique of the surface plasmon literature, Current Opinions resonance resonance inBiotechnology.5:65-71. .

[0797] The optical properties of surface plasmon resonance (SPR) are used to detect changes in the concentration of proteins bound to a dextran matrix located at the gold / glass sensor chip interface on the surface of a dextran biosensor matrix. In short, proteins are covalently bound to the dextran matrix at a known concentration, and protein ligands are injected through the dextran matrix. Near-infrared light directed towards the other side of the sensor chip surface is reflected, inducing evanescent waves in the gold film, which in turn causes a decrease in the intensity of the reflected light at a specific angle (called the resonance angle). If the refractive index of the sensor chip surface changes (e.g., through ligand binding to the bound protein), the resonance angle changes. This angular shift can be measured and expressed as resonance units (RUs), so 1000 RUs corresponds to a change in surface protein concentration of 1 ng / mm². 2 These changes are shown along the y-axis of the sensor plot over time, describing the association and dissociation of any biological reaction.

[0798] High-throughput screening (HTS) assay

[0799] High-throughput assays (HTS) typically use automated assays to search large numbers of compounds for desired activity. Often, HTS assays are used to find new drugs by screening chemicals that act on specific enzymes or molecules. For example, if a chemical inactivates an enzyme, it may prove to be effective in preventing disease-causing processes in cells. High-throughput methods enable researchers to analyze thousands of different chemicals very quickly for each target molecule using robotic processing systems and automated analysis of results.

[0800] As used in this article, "high-throughput screening" or "HTS" refers to rapid in vitro screening of large numbers of compounds (libraries); robotic screening assays are typically used to analyze tens of thousands to hundreds of thousands of compounds. Ultra-high-throughput screening (uHTS) typically refers to high-throughput screening accelerated to more than 100,000 tests per day.

[0801] To achieve high-throughput screening, it is advantageous to place samples on multi-container supports or platforms. Multi-container supports facilitate the simultaneous measurement of reactions of multiple candidate compounds. Porous microplates can be used as supports. Such porous microplates and their methods of use in numerous assays are known in the art and are commercially available.

[0802] Screening assays may include controls for calibrating and confirming the correct operation of the assay components. These typically include blank wells containing all reactants but excluding members of the chemical library. As another example, a known inhibitor (or activator) of an enzyme used to find modulators may be incubated with a sample to be assayed, and the resulting decrease (or increase) in enzyme activity serves as a comparison or control. It should be understood that incubation may also be combined with enzyme activators or inhibitors to identify modulators that inhibit enzyme activation or inhibition caused by the presence of known enzyme modulators.

[0803] Enzyme-catalyzed and binding reactions were measured during the screening assay.

[0804] Techniques for measuring the progress of enzyme-catalyzed and binding reactions, such as in multi-container carriers, are known in the art and include, but are not limited to, the following.

[0805] Spectrophotometry and spectrofluorescence assays are well known in the art. Examples of such assays include the use of colorimetric methods to detect peroxides, as described in Gordon, A.J. and Ford, RA, (1972) The Chemist's Companion: A Handbook of Practical Data, Techniques, and References, John Wiley and Sons, NY, Page 437.

[0806] Fluorescence spectroscopy can be used to monitor the generation of reaction products. Fluorescence methods are generally more sensitive than absorption methods. The use of fluorescent probes is well known to those skilled in the art. For reviews, see Bashford et al., (1987) Spectrophotometry and Spectrofluorometry: A Practical Approach, pp. 91-114, IRL Press Ltd.; and Bell, (1981) Spectroscopy in Biochemistry, Vol. I, pp. 155-194, CRC Press.

[0807] In fluorescence spectrophotometry, enzymes are exposed to substrates, and when treated by the target enzyme, the substrates alter their intrinsic fluorescence. Typically, substrates are non-fluorescent and are converted into fluorophores through one or more reactions. As a non-limiting example, SMase activity can be used... Red reagent (Molecular Probes, Eugene, OR) detection. For use... Red measured sphingomyelinase activity, which involved the following reactions: First, SMase hydrolyzed sphingomyelin to produce ceramide and phosphocholine. Second, alkaline phosphatase hydrolyzed phosphocholine to produce choline. Third, choline was oxidized to betaine by choline oxidase. Finally, in the presence of horseradish peroxidase, H2O2 reacted with… The Red reaction generates a fluorescent product, halogen, and the signal is detected by fluorescence spectrophotometry.

[0808] Fluorescence polarization (FP) is based on the decrease in the rotational speed of the fluorophore molecule, which occurs when it binds to a larger molecule (such as a receptor protein), resulting in polarized fluorescence emission from the bound ligand. FP is empirically determined by measuring the vertical and horizontal components of the fluorophore emission after excitation with plane-polarized light. Polarized emission increases as the fluorophore's molecular rotation decreases. The binding of the fluorophore to a larger molecule (i.e., the receptor) produces a larger polarization signal, thus slowing down the fluorophore's molecular rotation. The magnitude of the polarization signal is quantitatively related to the degree of fluorescent ligand binding. Therefore, the polarization of the "binding" signal depends on the maintenance of high-affinity binding.

[0809] FP is a homogeneous technique and the reaction is very rapid, requiring seconds to minutes to reach equilibrium. The reagents are stable and can be prepared in large quantities with high reproducibility. Due to these characteristics, FP has proven to be highly automated, typically using a single premixed tracer acceptor reagent for a single incubation. For a review, see Owicki et al., (1997), Application of Fluorescence Polarization Assays in High-Throughput Screening, Genetic Engineering News, 17:27.

[0810] FP is particularly desirable because its readings are independent of emission intensity (Checovich, WJ, et al., (1995) Nature 375:254-256; Dandliker, WB, et al., (1981) Methods in Enzymology 74:3-28), and therefore insensitive to the presence of colored compounds that quench fluorescence emission. FP and FRET (see below) are well-suited for identifying compounds that block the interaction between sphingolipid receptors and their ligands. See, for example, Parker et al., (2000) Development of high throughput screening assays using fluorescence polarization: nuclear receptor-ligand-binding and kinase / phosphatase assays, J Biomol Screen 5:77-88.

[0811] Fluorescein-derived sphingolipids suitable for FP assays are commercially available. For example, Molecular Probes (Eugene, OR) currently sells sphingolipids and a ceramide fluorophore. These are N-(4,4-difluoro-5,7-dimethyl-4-boronic acid-3a,4a-diaza-s-indacene-3-pentanoyl)sphingosine phosphate choline (SPO) FLC5-sphingomyelin); N-(4,4-difluoro-5,7-dimethyl-4-boronic acid-3a,4a-diaza-s-indan-3-dodecanoyl)sphingosine phosphate choline ( FL C12-sphingomyelin); and N-(4,4-difluoro-5,7-dimethyl-4-boron-3a,4a-diaza-s-indan-3-pentanoyl)sphingosine ( FL C5-ceramide). US Patent No. 4,150,949 (Immunoassay of Gentamicin) discloses fluorescein-labeled gentamicin, including fluorescein thiocarbonyl gentamicin. Additional fluorophores can be prepared using methods well known to those skilled in the art.

[0812] Exemplary normal and polarized fluorescence microplate readers include Fluorescence polarization system (Tecan AG, Hombrechtikon, Switzerland). Universal multi-well plate readers for other assays are also available, such as... ELISA reader and Multi-well plate spectrophotometers (all from Molecular Devices).

[0813] Fluorescence resonance energy transfer (FRET) is another useful assay for detecting interactions and has been described. See, for example, Heim et al., (1996) Curr. Biol. 6:178-182; Mitra et al., (1996) Gene 173:13-17; and Selvin et al., (1995) Meth. Enzymol. 246:300-345. FRET detects energy transfer between two fluorescent substances with known excitation and emission wavelengths. For example, a protein can be expressed as a fusion protein with green fluorescent protein (GFP). When the two fluorescent proteins are close together, such as when the protein specifically interacts with a target molecule, resonance energy can transfer from one excited molecule to the other. As a result, the emission spectrum of the sample shifts, which can be measured by a fluorometer, such as the fMAX porous fluorometer (Molecular Devices, Sunnyvale Calif.).

[0814] Scintillation proximity assay (SPA) is a particularly useful assay for detecting interactions with target molecules. SPA is widely used in the pharmaceutical industry and has been described (Hanselman et al., (1997) J. Lipid Res. 38:2365-2373; Kahl et al., (1996) Anal. Biochem. 243:282-283; Undenfriend et al., (1987) Anal. Biochem. 161:494-500). See also U.S. Patent Nos. 4,626,513 and 4,568,649, and European Patent No. 0,154,734. A commercially available system uses... Scintillator coated plate (NEN Life Science Products, Boston, MA).

[0815] Target molecules can bind to scintillator plates in a variety of well-known ways. Scintillator plates that have been derivatized to bind to fusion proteins such as GST, His6, or Flag fusion proteins can be used. In cases where the target molecule is a protein complex or multimer, a protein or subunit can be first attached to the plate, followed by the addition of other components of the complex under binding conditions, thereby producing a bound complex.

[0816] In a typical SPA assay, the gene product in the expression pool is radiolabeled and added to the wells, where it interacts with a solid phase, which is a target molecule and scintillator coating immobilized in the wells. The assay can be performed immediately or allowed to reach equilibrium. Either way, when the radiolabeled material gets sufficiently close to the scintillator coating, it produces an effect that can be controlled by a device such as… The signal detected by a microplate scintillation counter (Packard BioScience Co., Meriden Conn.). If the radiolabeled expression product binds to the target molecule, the radiolabel remains near the scintillator long enough to produce a detectable signal.

[0817] Conversely, labeled proteins that do not bind to the target molecule or bind only briefly do not remain near the scintillator long enough to produce a signal above the background. Any time spent near the scintillator due to random Brownian motion also does not produce a significant signal. Similarly, residual unbound radiolabeled material used in the expression step may be present but does not produce a significant signal because it is in solution rather than interacting with the target molecule. Therefore, these non-binding interactions will result in a certain level of background signal, which can be mathematically removed. If too much signal is obtained, salt or other modifiers can be added directly to the assay plate until the desired specificity is achieved (Nichols et al., (1998) Anal. Biochem. 257:112-119).

[0818] General Synthesis

[0819] Compounds can be prepared using the methods disclosed herein and their conventional modifications, as will be apparent given the disclosure herein and methods well-known in the art. In addition to the teachings herein, conventional and well-known synthetic methods can also be used. The synthesis of typical compounds described herein can be carried out as illustrated in the following examples. Reagents are commercially available, for example, from Sigma Aldrich or other chemical suppliers, if available.

[0820] The compounds disclosed herein can be prepared from readily available starting materials using, for example, the following general methods and procedures. It should be understood that, given typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), other process conditions may be used unless otherwise stated. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through conventional optimization procedures.

[0821] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, many protecting groups are described in Wuts, PGM, Greene, TW, & Greene, TW (2006). Greene's protective groups in organic synthesis. Hoboken, NJ, Wiley-Interscience, and references thereto.

[0822] The compounds disclosed herein may contain one or more asymmetric or chiral centers. Therefore, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as mixtures rich in stereoisomers, if desired. Unless otherwise stated, all such stereoisomers (and enriched mixtures) are included within the scope of this disclosure. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Optionally, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, supercritical fluid chromatography, chiral seeds, chiral resolving agents, etc.

[0823] The starting materials used in the following reactions are generally known compounds or can be prepared by known procedures or by obvious modifications thereof. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce, or Sigma (St. Louis, Missouri, USA). Others can be prepared by procedures or obvious modifications, as described in standard references, such as Fieser and Fieser's Organic Synthetic Reagents, Volumes 1–15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1–5 and Supplements (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1–40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0824] It should also be understood that, in each scheme, the addition of any substituent may result in the formation of numerous isomers (including, but not limited to, enantiomers or one or more diastereomers), which can be separated and purified using conventional techniques. When enantiomerically pure or enriched compounds are required, chiral chromatography and / or enantiomerically pure or enriched starting materials may be used as conventionally in the art or as described in the examples.

[0825] The compounds disclosed herein can be synthesized according to the general reaction scheme and / or examples described below. The general scheme can be modified to produce the corresponding products by substituting other materials having similar structures for the starting materials. The desired structure of the product usually makes the required starting materials clear to those skilled in the art.

[0826] Scheme 1 provides an exemplary synthetic route for synthesizing compounds provided herein (e.g., compounds of Formula I). ​​Compounds of Formula I or other formulas or compounds disclosed herein are generally prepared by first providing a core formula X(a) and then attaching a desired substituent using suitable conditions (e.g., conjugated addition; formation of carbonates, carbamates or ureas; or cross-coupling).

[0827] In some embodiments, the synthesis of the compound of formula I is carried out according to scheme 1.

[0828] Option I

[0829]

[0830] In Scheme 1, A, E, G, L, R 1 R 2 and R 3 As defined in Formula I. In Scheme 1, the compound of Formula X(a) is converted into the compound of Formula X(b). The compound of Formula X(b) can then be converted into the compound of Formula X(d), optionally via Formula X(c), which can be converted into the compound of Formula I. A 1 E 1 E 11 G 1 L 1 L 2 L 11 P 1 R 15 R 21 R 31 Z 1 and Z 2 As described below.

[0831] In Scheme 1, Z 1 and Z 2 Each is an independent leaving group, for example, a halide or a suitable coupling partner, or Z. 2 It is R 21 For example, Z 1 and / or Z 2 It can be a chloride or a bromide. As a coupling partner, Z... 1 or Z 2 It can be activated in situ, for example, by reducing a zinc reagent (e.g., metallic zinc). The compound of formula X(a) can react with compound 101 under conjugate addition conditions.

[0832] In Scheme 1, P 1 It is H, R 15 Or an N-protecting group. For example, P 1 It can be an N-protecting group that forms an acetal or amidal with the parent structure (e.g., P...). 1 It can be a tetrahydropyran, such as tetrahydro-2H-pyran-2-yl (“THP”). When P 1 When it is H, R 15 It can be added in a conventional manner, for example by nucleophilic addition of the parent structure to halides such as primary halides (e.g., when R...). 15 It is R 1 When P is a protected precursor, it is a halide such as 2-(2-bromoethoxy)tetrahydro-2H-pyran. 1When pyran is present, it can be removed by conventional pyran deprotection conditions, such as those described herein or known in the art. When P 1 When it is not H, P 1 P can be added in conventional ways, such as through protecting group chemistry as described herein or known in the art. For example, P can be added by catalytic addition of the parent structural acid to dihydro-2H-pyran. 1 .

[0833] In Scheme 1, R 15 It is R 1 Or R 1 Derivatives, such as R 1 Protected derivatives. In some embodiments, R 15 It is R 1 Hydroxyl-protected derivatives. For example, R 1 Hydroxyl-protected derivatives may include silyl ethers, acetates, benzyl, benzoyl, acetone compounds, or tetrahydropyran derivatives (e.g., wherein R...). 1 It is ethanol-2-ol, R 15 It can be 2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl). In some embodiments, R 15 Includes corresponding to R 1 Protected diols at the site of diols (e.g., when R...) 1 When containing vicinal diols, R 15 It may contain dioxolane.

[0834] In Option 1, A 1 It is A or its derivatives. A in A 1 The derivative at the site may further include substituents, and A may be derived from it through oxidation, reduction, and / or protection (e.g., A). 1 It may contain cyano substituents, where A contains an amide. For example, A 1 It can be pyrrolidine-1-yl, such as (R)-3-hydroxypyrrolidine-1-yl or (3S,4S)-3-hydroxy-4-fluoropyrrolidine-1-yl.

[0835] In Scheme 1, E 1 It is E or its derivatives, or E 1 It could be H. E in E 1 The derivative may contain a leaving group or a suitable coupling partner (e.g., E 1 It may contain halogens, such as bromine or iodine. E in E 1 The derivatives at the site may further include substituents, and E can be derived from it through oxidation, reduction, and / or protection (e.g., E1). 1It may include a cyano substituent, wherein E comprises an amide. Compounds of formula X(b) may be reacted with compound 102 or compound 104 under nucleophilic aromatic substitution conditions or copper coupling conditions described herein or known in the art. In some embodiments, E 1 It may contain phenyl, pyridazin-4-yl, pyrimidin-4-yl, pyrimidin-6-yl, pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl. In some embodiments, L 1 -E 11 It is 4-bromopyridin-2-yl, 4-bromo-5-chloro-2-fluoropyridine, 3-bromo-5-iodopyridine, 1-bromo-3-iodobenzene, 5-bromo-3-chloropyridazine, or 4,6-dichloropyrimidine. When compound X(b) is directly converted to formula X(d), formula X(b) can react with compound 104. In this embodiment, G 1 -L 2 -E 11 It can be 4-(2-fluoro-4-pyridinyl)-3,5-dimethyl-isoxazole or 4-(6-chloropyridazin-4-yl)-3,5-dimethyl-isoxazole.

[0836] In Scheme 1, E 11 It is E 1 Derivatives of E, suitable for reacting with compound 102 or 104 to produce E 1 Attached to the parent structure of formula X(b). For example, compounds of formula X(b) can react with compound 102 or compound 104 under nucleophilic substitution conditions (e.g., nucleophilic aromatic substitution conditions).

[0837] In Scheme 1, L 1 and L 2 Each of them is independently a part or derivative of L, or L 1 It can be H or L 2 It can be L. L in L 1 Parts or derivatives at the location can be in the remainder of L or G 1 The attachment points include hydrogen atoms (e.g., when L includes oxygen or nitrogen atoms bonded to the parent structure, A...). 1 -L 1 It can be the corresponding hydroxyl group, amine, or -C(O)NH2). L in L 1 Parts or derivatives at the location can be found in G 1 The attachment site contains a protecting group (e.g., a hydroxyl protecting group, such as p-nitrophenoxycarbonyl or tetrahydropyran, or an amine protecting group, such as tert-butyloxycarbonyl). In some embodiments, L 1 or L 2 It can be non-existent.

[0838] In Scheme 1, L 11 It is L2 Derivatives of [the compound] are suitable for reacting with compound 103 to [react with] L [the compound]. 2 Attached to the parent structure of formula X(c). L 11 This can be a suitable coupling partner or leaving group (e.g., boric acid, borate ester (e.g., 4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl), pseudohalide, or halide (e.g., chlorine, bromine, or iodine)). For example, a compound of formula X(c) can react with compound 103 under nucleophilic substitution conditions (e.g., nucleophilic aromatic substitution conditions) or under coupling conditions (e.g., palladium coupling conditions or copper coupling conditions). In some embodiments, L 11 It is hydrogen.

[0839] In Scheme 1, G 1 It is G or a derivative of G. A derivative of G may contain one or more components suitable for attaching T. 1 T 2 T 3 T 4 T 5 and / or T 6 ("T" 1 -T 6 The portion of G and / or derivatives of G may contain nitrogen or oxygen protecting groups (e.g., THP). Therefore, derivatives of G may contain amines (e.g., cyclic amines in which G contains piperidinyl, piperazine, or pyrrolidinyl groups) or protected amines (e.g., containing tert-butoxycarbonyl protecting groups). 1 The transformation to G can be included in T. 1 -T 6 The substitution reaction of the carbonyl or sulfonyl group to form carbonates, carbamates, ureas, or sulfonamides (e.g., when G...). 1 When amines are included, G can be... 1 The addition of amine to aminosulfonyl chloride or T 1 -T 6 The corresponding acyl chloride). G 1 The transformation to G may optionally include T 1 -T 6 Nucleophilic substitution reactions at a portion of the site (e.g., Sn1 or Sn2 type reactions). For example, when T 1 -T 6 When an α-carbonyl group is present, the reaction can be carried out by Sn2 substitution of a pseudohalide (e.g., a sulfonate, such as 4-methylbenzenesulfonic acid (3-cyanobicyclo[1.1.1]pent-1-yl)methyl) or a halide (e.g., bromine, such as tert-butyl 2-bromoacetate).

[0840] In Scheme 1, R 21 Is it H, or R? 2Protected derivatives, or suitable coupling partners (e.g., pseudohalides or halides such as chlorine, bromine, or iodine), or R 21 It is R 2 .

[0841] In Scheme 1, R 31 It is R 3 .

[0842] Conjugate addition condition

[0843] In appropriate circumstances, for example, when compound 101(OH-A) is used... 1 When -H) is added to a compound of formula X(a), a conjugate addition reaction can occur. The conjugate addition reaction is carried out under nucleophilic addition conditions (e.g., in the presence of a base such as triethylamine, N,N-diisopropyl-N-ethylamine, or a carbonate such as potassium carbonate) in a suitable solvent (e.g., a polar aprotic solvent, tetrahydrofuran, DMF, etc.), optionally under an inert atmosphere. The reaction is typically carried out at a temperature of about 20 to 100 °C for about 10 minutes to about 7 days. When the reaction is substantially complete, the product is isolated by conventional methods. In some embodiments, compound 101 is (R)-pyrrolidine-3-ol or (3S,4S)-4-fluoropyrrolidine-3-ol, or a salt thereof.

[0844] Nucleophilic aromatic substitution conditions

[0845] In appropriate circumstances, for example, when compound 102 (L 1 -E 11 When added to a compound of formula X(b), a nucleophilic aromatic substitution reaction can occur. The nucleophilic aromatic substitution reaction is carried out under nucleophilic addition conditions (e.g., in the presence of a base (e.g., sodium hydride or cesium carbonate)) in a suitable solvent (e.g., a polar aprotic solvent, 1,4-dioxane, tetrahydrofuran, DMF, etc.), optionally under an inert atmosphere. The reaction is typically carried out at a temperature of about 20 to 120 °C for about 10 minutes to about 7 days. Conditions may include discrete deprotonation steps (e.g., where the base is sodium hydride). When the reaction is substantially complete, the product is isolated by conventional methods. In some embodiments, compound 102 is 2-fluoropyridine, 3-fluoropyridine, or 4-fluoropyridine (e.g., 4-bromo-5-chloro-2-fluoropyridine).

[0846] Palladium coupling conditions

[0847] In appropriate cases, such as compounds of formula X(a), X(b), X(c) or X(d), compound 102, compound 103 or compound 104, wherein Z 1 Z 2 E 11 L 1 L 11 or G1 Each of the components contains a suitable coupling partner, such as a pseudohalide or halide (e.g., chlorine) or a zinc reagent (e.g., zinc cyanide), and is carried out under standard metal-catalyzed cross-coupling conditions (e.g., using a palladium catalyst) in a suitable solvent (e.g., toluene, N,N-dimethylacetamide, dioxane, acetonitrile, water, etc.), optionally under an inert atmosphere. The coupling reaction is carried out in an inert solvent (e.g., an aqueous solution of 1,4-dioxane or an aqueous solution of N,N-dimethylformamide) in the presence of a weak base (e.g., pyridine, potassium carbonate, sodium carbonate, sodium bicarbonate, or sodium tert-butoxide). The reaction is typically carried out in the presence of a metal catalyst such as tris(dibenzylacetone)palladium(0), dichlorobis(triphenylphosphine)palladium(II), or dichloro-1,1'-bis(diphenylphosphino)ferrocenepalladium(II), ruphos cyclic palladium GEN 4, optionally with a suitable ligand (e.g., 1,1'-bis(diphenylphosphino)ferrocene), optionally under microwave irradiation, at a temperature of about 60 to 160 °C, for about 10 minutes to about 24 hours. The reaction can be sealed. When the reaction is substantially complete, the product is separated by conventional methods.

[0848] Copper coupling conditions

[0849] In appropriate cases, for example, compounds of formula X(b), where E 1 or Z 2 Including suitable coupling partners, such as halides (e.g., chlorine, bromine, or iodine), under copper-catalyzed cross-coupling conditions, in a suitable solvent, optionally under an inert atmosphere, to form formula X(c) or X(d). The coupling reaction is carried out in an inert solvent (e.g., toluene or DMF), in the presence of a weak base (e.g., cesium carbonate), optionally in a sealed container. The reaction is typically carried out in the presence of a copper catalyst (e.g., copper iodide (I) (cuprous iodide)), optionally using a suitable ligand (e.g., 3,4,7,8-tetramethyl-1,10-phenanthroline), at a temperature of about 60 to 150 °C for about 10 minutes to about 24 hours. When the reaction is substantially complete, the product is isolated by conventional methods.

[0850] Nucleophilic aromatic substitution conditions

[0851] Under suitable conditions, such as when a compound of formula X(d) is converted to a compound of formula (I), a nucleophilic substitution reaction can be carried out. The nucleophilic substitution reaction is carried out under nucleophilic addition conditions (e.g., in the presence of a base (e.g., sodium hydride, sodium tert-butoxide, or cesium carbonate)) in a suitable solvent (e.g., a polar aprotic solvent, 1,4-dioxane, tetrahydrofuran, DMF, etc.), optionally under an inert atmosphere. The reaction is typically carried out at temperatures from about 20 to 160 °C for about 10 minutes to about 7 days. Conditions may include discrete deprotonation steps (e.g., where the base is sodium hydride), which can be carried out at temperatures from -78 °C to 0 °C. When the reaction is substantially complete, the product is separated by conventional methods. In some embodiments, T 1 -T 6 The corresponding electrophilic reagents are primary pseudohalides (e.g., benzenesulfonyl) or halides (e.g., bromine).

[0852] Pyran deprotection conditions

[0853] In appropriate cases, such as when compounds of formula X(c) or X(d) contain a pyran protecting group, for example in P 1 or R 15 The compound can be reacted under standard acid-catalyzed deprotection conditions (e.g., using Lewis acids or protic acids) in a suitable solvent (e.g., 1,4-dioxane, dichloromethane, ethyl acetate, acetonitrile, water, methanol, ethanol, etc.), optionally under an inert atmosphere, to form R. 15 or R 1 The reaction is typically carried out in the presence of an acid catalyst (e.g., HCl or trifluoroacetic acid) at a temperature of about 0 to 100°C for about 10 minutes to about 24 hours. When the reaction is substantially complete, the product is separated by conventional methods. In some embodiments, the starting material used for pyran deprotection can be reused from previous steps without purification.

[0854] Those skilled in the art will understand that any compound of formula X(a), X(b), or X(c) is available from commercial suppliers for use in a particular embodiment. Optional synthesis of compounds of formula X(a), X(b), or X(c) may be as described herein or as known to those skilled in the art.

[0855] Intermediate 1

[0856]

[0857] Step 1: Preparation of 4,5-dichloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one 2: 4,5-dichloropyridazin-3(2H)-one (1,30 g, 182 mmol) and p-toluenesulfonic acid (1.6 g, 9.1 mmol) were combined in a 250 mL flask and tetrahydrofuran (100 mL) was added. Then, 3,4-dihydro-2H-pyran (18.4 g, 218 mmol) was added via syringe and the reaction was heated to reflux for 15 hours. LCMS analysis showed conversion to the product and the remaining starting material. The reaction was concentrated onto 50 g silica gel and purified by normal-phase rapid column chromatography (120 g column, 0-100% ethyl acetate in hexane) to provide 4,5-dichloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (2). MS (ESI) [M+H + -THP] + =248.9.

[0858] Step 2: Preparation of 4-chloro-5-((R)-3-hydroxypyrrolidone-1-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one 3: 4,5-dichloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (2, 9.35 g, 37.5 mmol) and (R)-pyrrolidone-3-ol hydrochloride (5.6 g, 45.0 mmol) were added to a 250 mL round-bottom flask. Then, potassium carbonate (15.6 g, 113 mmol) and N,N-dimethylformamide (100 mL) were added, and the reaction was stirred at room temperature for 15 hours. LCMS analysis showed conversion to the desired product. The reaction was concentrated onto 40 g silica gel and purified by normal-phase rapid column chromatography (40 g column, 0-100% ethyl acetate in hexane) to provide 4-chloro-5-((R)-3-hydroxypyrrolidone-1-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (3). MS (ESI) [M+H + ] + =300.2.

[0859] Intermediate 2

[0860]

[0861] Step 1: Preparation of 5-((R)-3-((4-bromopyridin-2-yl)oxy)pyrrolidine-1-yl)-4-chloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one 4: 4-chloro-5-((R)-3-hydroxypyrrolidine-1-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (3, 4.0 g, 13.3 mmol), 4-bromo-2-fluoropyridine (2.8 g, 16.0 mmol), cesium carbonate (8.7 g, 26.7 mmol), and N,N-dimethylformamide (50 mL) were added to a 250 mL round-bottom flask. The reaction was stirred in an oil bath at 80 °C for 18 hours. LCMS analysis showed conversion to the desired product. The reaction was concentrated onto 20 g of silica gel and purified by normal-phase rapid column chromatography (120 g silica gel column, 0 to 100% ethyl acetate in hexane) to give 5-((R)-3-((4-bromopyridin-2-yl)oxy)pyrrolidine-1-yl)-4-chloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (4). MS(ESI)[M+H + ] + =455.1.

[0862] Example 1

[0863]

[0864] Step 1: Preparation of 4-chloro-5-((3S,4S)-3-fluoro-4-hydroxypyrrolidine-1-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one 5: 4,5-dichloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (2,7.2 g, 28.9 mmol) and (3S,4S)-4-fluoropyrrolidine-3-ol hydrochloride (4.5 g, 31.8 mmol) were added to a 250 mL round-bottom flask. Then, potassium carbonate (16.0 g, 116 mmol) and N,N-dimethylformamide (100 mL) were added, and the reaction was stirred at room temperature for 15 hours. LCMS analysis showed conversion to the desired product. The reaction was concentrated onto 40 g silica gel and purified by normal-phase rapid column chromatography (120 g column, 0-100% ethyl acetate in hexane) to provide 4-chloro-5-((3S,4S)-3-fluoro-4-hydroxypyrrolidone-1-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (5). MS (ESI) [M+H + -THP] + =234.1.

[0865] Step 2: Preparation of 5-[(3S,4S)-3-[(4-bromo-2-pyridinyl)oxy]-4-fluoropyrrolidine-1-yl]-4-chloro-2-tetrahydropyran-2-yl-pyridazin-3-one 6: 4-chloro-5-[(3S,4S)-3-fluoro-4-hydroxypyrrolidine-1-yl-2-tetrahydropyran-2-yl-pyridazin-3-one (5, 4.0 g, 12.6 mmol), 4-bromo-2-fluoropyridine (2.7 g, 15.1 mmol), cesium carbonate (8.2 g, 25.2 mmol), and N,N-dimethylformamide (50 mL) were added to a 250 mL round-bottom flask. The reaction was stirred in an oil bath at 80 °C for 18 hours. LC-MS analysis showed conversion to the desired product. The reaction was concentrated onto 20 g of silica gel and purified by normal-phase chromatography (120 g silica gel column, 0 to 100% ethyl acetate in hexane) to give 5-[(3S,4S)-3-[(4-bromo-2-pyridinyl)oxy]-4-fluoropyrrolidine-1-yl]-4-chloro-2-tetrahydropyran-2-yl-pyridazin-3-one (6). MS (ESI) [M+H + ] + =473.0.

[0866] Step 3: Preparation of 4-chloro-5-((3S,4S)-3-((4-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)oxy)-4-fluoropyrrolidine-1-yl)pyridazin-3(2H)-one 7: In a 250 mL round-bottom flask, 5-((3S,4S)-3-((4-bromopyridin-2-yl)oxy)-4-fluoropyrrolidine-1-yl)-4-chloro-2-(tetrahydro-2-yl)-pyridoxane (90 mL) was added to the mixture. H-pyran-2-yl)pyridazin-3(2H)-one (6, 4.6 g, 9.8 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)isoxazole (3.3 g, 14.7 mmol), and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium(II)acetone adduct (772 mg, 0.98 mmol) were added to 1M potassium carbonate in water (29 mL). The reaction mixture was immediately heated to 100°C in an oil bath preheated to 100°C. The reaction was stirred at this temperature for two hours. The reaction was cooled to room temperature and concentrated onto 20 g of silica gel. The reaction was purified by normal-phase rapid column chromatography (120 g silica column, 0 to 100% ethyl acetate in hexane) to give the intermediate. The material was then dissolved in 20 mL of dichloromethane and hydrochloric acid (4 M, 20 mL, 80 mmol in 1,4-dioxane) was added. The reaction was stirred at room temperature for 30 minutes. The reaction was concentrated to give 4-chloro-5-((3S,4S)-3-((4-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)oxy)-4-fluoropyrrolidine-1-yl)pyridazin-3(2H)-one (7). MS(ESI)[M+H + ] + =406.2.

[0867] Step 4: Preparation of 4-chloro-5-((3S,4S)-3-((4-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)oxy)-4-fluoropyrrolidine-1-yl)-2-(2-hydroxyethyl)pyridazin-3(2H)-one (P-0179): 4-chloro-5-((3S,4S)-3-((4-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)oxy)-4-fluoropyrrolidine-1-yl)pyridazin-3(2H)-one (7,4.0 g, 9.9 mmol) was dissolved in N,N-dimethylformamide (40 mL) and potassium carbonate (2.7 g, 19.7 mmol) was added. Then 2-(2-bromoethoxy)tetrahydro-2H-pyran (2.7 g, 12.8 mmol) was added and the reaction was stirred at 60 °C for 15 h. LC-MS showed conversion to 4-chloro-5-((3S,4S)-3-((4-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)oxy)-4-fluoropyrrolidine-1-yl)-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridazine-3(2H)-one. Solid potassium carbonate was filtered off and the crude reactant was mixed with hydrochloric acid (4 M, 20 mL, 80 mmol in 1,4-dioxane). The reaction was stirred at room temperature for two h. The reaction was quenched with 20 mL of methanol and concentrated onto 60 g of silica gel. The material was then purified by reversed-phase rapid chromatography (415 g C18 column; 0-45% B; A: 99.9% H2O, 0.1% HCO2H; B: 99.9% CH3CN, 0.1% HCO2H). This purification yielded a still impure product. The material was then purified by normal-phase chromatography (40 g silica gel column, 0-100% ethyl acetate in hexane). This purification yielded 4-chloro-5-((3S,4S)-3-((4-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)oxy)-4-fluoropyrrolidine-1-yl)-2-(2-hydroxyethyl)pyridazine-3(2H)-one (P-0179). MS (ESI) [M+H + ] + =450.1.

[0868] Example 2

[0869]

[0870] Step 1: Preparation of 4,5-dibromo-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one 9: 4,5-dibromo-1H-pyridazin-6-one (8, 1.00 g, 3.95 mmol), 3,4-dihydro-2H-pyran (1.00 g, 11.9 mmol), DCE (25 mL), and PTSA monohydrate (0.195 g, 1.03 mmol) were charged into a screw-cap reaction vessel. The reaction vessel was sealed and stirred in an oil bath at 70 °C for 16 hours. The reaction was then cooled and extracted with ethyl acetate and water, filtered twice to remove particles. The organic layer was separated, dried over magnesium sulfate, and filtered. Volatiles were removed by rotary evaporation, and the residue was purified by rapid silica gel column chromatography (40 g silica gel column, 0 to 60% ethyl acetate in hexane). This purification yielded 4,5-dibromo-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (9). MS(ESI)[M+H + ] + =338.8.

[0871] Step 2: Preparation of 4-bromo-5-((R)-3-hydroxypyrrolidone-1-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one 10: To a round-bottom flask containing 4,5-dibromo-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (9, 0.43 g, 1.27 mmol), (3R)-pyrrolidone-3-ol hydrochloride (0.189 g, 1.53 mmol) was added, followed by N,N-dimethylformamide (10 mL). Triethylamine (0.27 mL, 1.91 mmol) was added to the solution. The reaction was stirred at room temperature for four days. All volatiles were removed under reduced pressure, and the residue was extracted with ethyl acetate and water. The aqueous layer was extracted four more times until no product was detected by TLC. The combined organic layers were dried over magnesium sulfate and filtered. Volatile substances were removed by rotary evaporation, and the resulting residue was purified by rapid silica gel column chromatography (24 g silica gel column, 0 to 6% methanol in dichloromethane). This purification yielded 4-bromo-5-((R)-3-hydroxypyrrolidone-1-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (10). MS (ESI) [M+H + ] + =344.0.

[0872] Step 3: Preparation of 4-bromo-5-[(3R)-3-[[4-(3,5-dimethylisoxazol-4-yl)-2-pyridinyl]oxy]pyrrolidine-1-yl]-2-tetrahydropyran-2-yl-pyridazin-3-one 11: Sodium hydride (60% in mineral oil, 25 mg, 0.62 mmol) was added to 4-bromo-5-((R)-3-hydroxypyrrolidine-1-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (10,195 mg, 0.567 mmol) in 1,4-dioxane (10 ml). After the gas escaping stopped, 4-(2-fluoro-4-pyridinyl)-3,5-dimethyl-isoxazole (122 mg, 0.635 mmol) was added, and the reaction was stirred in an oil bath at 60 °C for 6 hours under an argon atmosphere, followed by stirring at 80 °C for another 17 hours. The volatiles were removed under reduced pressure, and the resulting residue was dried from THF / MeOH and loaded onto silica, and purified by silica gel rapid column chromatography (24 g column, 50-100% ethyl acetate in hexane). This purification yielded 4-bromo-5-[(3R)-3-[[4-(3,5-dimethylisoxazole-4-yl)-2-pyridinyl]oxy]pyrrolidine-1-yl]-2-tetrahydropyran-2-yl-pyridazin-3-one (11). MS (ESI) [M+H + ] + =515.5.

[0873] Step 4: Preparation of 5-[(3R)-3-[[4-(3,5-dimethylisoxazol-4-yl)-2-pyridyl]oxy]pyrrolidine-1-yl]-2-tetrahydropyran-2-yl-4-(trifluoromethyl))pyridazin-3-one 12: Copper iodide (I) (122 mg, 0.383 mmol) was added to methyl 2,2-difluoro-2-fluorosulfonyl acetate (79 mg, 0.41 mmol) in N,N-dimethylformamide (2 ml) and 4-bromo-5-[(3R)-3-[[4-(3,5-dimethylisoxazol-4-yl)-2-pyridyl]oxy]pyrrolidine-1-yl]-2-tetrahydropyran-2-yl-pyridazin-3-one (11,101 mg, 0.196 mmol). The mixture was heated at 100 °C for 15 hours. The reaction was cooled and diluted with THF. The THF-insoluble fraction was allowed to precipitate, and the soluble fraction was dried, loaded onto silica gel, and purified by rapid silica gel column chromatography (12 g silica gel column, 0-100% ethyl acetate in hexane). This purification yielded 5-[(3R)-3-[[4-(3,5-dimethylisoxazo-4-yl)-2-pyridinyl]oxy]pyrrolidine-1-yl]-2-tetrahydropyran-2-yl-4-(trifluoromethyl)pyridazin-3-one (12). MS (ESI) [M+H + ] + =506.1.

[0874] Step 5: Preparation of (R)-5-(3-((4-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)oxy)pyrrolidine-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (P-0053): Dichloromethane (5 ml) was added to a round-bottom flask containing 5-[(3R)-3-[[4-(3,5-dimethylisoxazol-4-yl)-2-pyridinyl]oxy]pyrrolidine-1-yl]-2-tetrahydropyran-2-yl-4-(trifluoromethyl)pyridazin-3-one (12, 6.0 mg, 0.01 mmol), followed by trifluoroacetic acid (0.5 ml, 6.53 mmol). The solution was stirred at ambient temperature for 2 hours. The volatiles were removed under reduced pressure to give (R)-5-(3-((4-(3,5-dimethylisoxazo-4-yl)pyridin-2-yl)oxy)pyrrolidine-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (P-0053). MS(ESI)[M+H + ] + =422.0.

[0875] Example 3

[0876]

[0877] Step 1: Preparation of 5-((R)-3-((4-bromo-5-chloropyridin-2-yl)oxy)pyrrolidine-1-yl)-4-chloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one 13: In a vial, 4-bromo-5-chloro-2-fluoropyridine (0.27 g, 1.28 mmol) was added to 4-chloro-5-[(3R)-3-hydroxypyrrolidine-1-yl]-2-tetrahydropyran-2-yl-pyridazin-3-one (3, 0.30 g, 1.0 mmol) and cesium carbonate (1.27 g, 4.0 mmol) in N,N-dimethylformamide (5 ml). The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was filtered to remove cesium carbonate. Volatile substances were removed under vacuum. The material was directly loaded onto silica gel and purified by normal-phase rapid column chromatography (12 g silica gel column, 0 to 100% ethyl acetate in hexane). This purification yielded 5-((R)-3-((4-bromo-5-chloropyridin-2-yl)oxy)pyrrolidine-1-yl)-4-chloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (13). MS (ESI) [M+H + ] + =488.8.

[0878] Step 2: Preparation of 4-chloro-5-((R)-3-((5-chloro-4-(4-(pyrrolidin-1-ylsulfonyl)phenyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one 14: In a 10 mL microwave-safe vial, 5-[(3R)-3-[(4-bromo-5-chloro-2-pyridinyl)oxy] in 1,4-dioxane (2 mL) [Pyrrolidine-1-yl]-4-chloro-2-tetrahydropyran-2-yl-pyridazin-3-one (13,50 mg, 0.1 mmol), (4-pyrrolidine-1-ylsulfonylphenyl)boronic acid (40 mg, 0.16 mmol), and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium(II)acetone adduct (15 mg, 0.019 mmol) were added to 1 M potassium carbonate in water (1 ml, 1 mmol). The reaction mixture was immediately heated to 100°C in an oil bath preheated to 100°C. The reaction was stirred at this temperature for five minutes. Water and ethyl acetate were added to the cooled reaction mixture. The organic layer was separated and washed with water and brine, then dried over magnesium sulfate. Volatiles were removed under vacuum onto 5 g silica gel. The crude material was then purified by normal-phase rapid column chromatography (12 g silica gel column, 0 to 100% ethyl acetate in dichloromethane). This purification yielded 4-chloro-5-[(3R)-3-[[5-chloro-4-(4-pyrrolidone-1-ylsulfonylphenyl)-2-pyridinyl]oxy]pyrrolidone-1-yl]-2-tetrahydropyran-2-ylpyridazin-3-one (14). MS(ESI)[M+H + ] + =620.0.

[0879] Step 3: Preparation of (R)-4-chloro-5-(3-((5-chloro-4-(4-(pyrrolidine-1-ylsulfonyl)phenyl)pyridin-2-yl)oxy)pyrrolidine-1-yl)pyridazin-3(2H)-one (P-0250): In a 40 mL vial, hydrochloric acid (4 M, 9 mL, 36 mmol in 1,4-dioxane) was added to 4-chloro-5-[(3R)-3-[[5-chloro-4-(4-pyrrolidine-1-ylsulfonylphenyl)-2-pyridinyl]oxy]pyrrolidine-1-yl]-2-tetrahydropyran-2-yl-pyridazin-3-one (14,40 mg, 0.064 mmol) in 1,4-dioxane (2 mL). The reaction mixture was stirred at room temperature for 2 hours. Volatile substances were removed under vacuum. The crude material was directly purified by preparative HPLC (C18 column; 0-60% B; A: 99.9% H2O, 0.1% HCO2H; B: 99.9% CH3CN, 0.1% HCO2H). This purification yielded (R)-4-chloro-5-(3-((5-chloro-4-(4-(pyrrolidine-1-ylsulfonyl)phenyl)pyridin-2-yl)oxy)pyrrolidine-1-yl)pyridazin-3(2H)-one (P-0250). MS (ESI) [M+H + ] + =535.9.

[0880] Example 4

[0881]

[0882] Step 1: Preparation of 5-[(3R)-3-(3-bromophenoxy)pyrrolidone-1-yl]-4-chloro-2-tetrahydropyran-2-yl-pyridazin-3-one 15: 4-chloro-5-[(3R)-3-hydroxypyrrolidone-1-yl]-2-tetrahydropyran-2-yl-pyridazin-3-one (3, 0.30 g, 1.0 mmol), 1-bromo-3-iodobenzene (0.19 mL, 1.5 mmol), cuprous iodide (10 mg, 0.05 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (24 mg, 0.1 mmol), cesium carbonate (489 mg, 1.5 mmol), and toluene (5 mL) were added to a 20 mL microwave-safe vial. The vial was sealed, degassed, and stirred at 120 °C for 18 hours under a nitrogen atmosphere. The reaction mixture was poured onto brine and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated onto silica gel. The reaction was purified by normal-phase rapid column chromatography (24 g silica gel column, 0 to 100% ethyl acetate in hexane) to give 5-[(3R)-3-(3-bromophenoxy)pyrrolidone-1-yl]-4-chloro-2-tetrahydropyran-2-yl-pyridazin-3-one (15). MS (ESI) [M+H + ] + =453.9.

[0883] Step 2: Preparation of (R)-4-chloro-5-(3-(3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenoxy)pyrrolidone-1-yl)pyridazin-3(2H)-one (P-0200): Add 5-[(3R)-3-(3-bromophenoxy)pyrrolidone-1-yl]-4-chloro-2-tetrahydropyran-2-yl-pyridazin-3-one (15g, 0.15g, 0.33mmol) to a 5mL microwave-safe vial. The reaction mixture consisted of 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyrazole (0.12 g, 0.50 mmol), dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium(II)acetone adduct (0.026 g, 0.033 mmol), potassium carbonate aqueous solution (1 M, 0.66 ml, 0.66 mmol), and 1,4-dioxane (2 ml). The vials were sealed and irradiated at 100 °C for 30 min. The reaction mixture was filtered, evaporated onto silica gel, and purified by reversed-phase rapid column chromatography (30 g C18 column; 0-70% B; A: 99.9% H₂O, 0.1% HCO₂H; B: 99.9% CH₃CN, 0.1% HCO₂H). This purification yielded a THP-protected intermediate. The protected intermediate was dissolved in dichloromethane (2 mL) and treated with hydrochloric acid (4 M in 1,4-dioxane, 0.80 mL, 3.2 mmol). The reaction was stirred at room temperature for 2 hours and evaporated to dryness to give (R)-4-chloro-5-(3-(3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenoxy)pyrrolidine-1-yl)pyridazin-3(2H)-one (P-0200). MS(ESI)[M+H + ] + =400.0.

[0884] Example 5

[0885]

[0886] Step 1: Preparation of 4-(6-chloropyridazine-4-yl)-3,5-dimethylisoxazole 17: Add 5-bromo-3-chloropyridazine (16, 0.1 g, 0.52 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)isoxazole (0.14 g, 0.62 mmol), dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium(II)acetone adduct (0.04 g, 0.05 mmol), 1M potassium carbonate aqueous solution (1.03 ml), and 1,4-dioxane (2 ml) to a 5 mL microwave-safe vial. Seal the vial, degas, and irradiate at 100 °C for 30 minutes. The reactants were evaporated onto silica gel and purified by reversed-phase rapid column chromatography (30 g C18 column; 0-70% B; A: 99.9% H2O, 0.1% HCO2H; B: 99.9% CH3CN, 0.1% HCO2H) to give 4-(6-chloropyridazine-4-yl)-3,5-dimethylisoxazole (17). MS (ESI) [M+H + ] + =210.0.

[0887] Step 2: Preparation of (R)-4-chloro-5-(3-((5-(3,5-dimethylisoxazol-4-yl)pyridazin-3-yl)oxy)pyrrolidine-1-yl)pyridazin-3(2H)-one (P-0160): 4-chloro-5-[(3R)-3-hydroxypyrrolidine-1-yl]-2-tetrahydropyran-2-yl-pyridazin-3-one (3, 0.10 g, 0.33 mmol), 4-(6-chloropyridazin-4-yl)-3,5-dimethylisoxazole (17, 0.070 g, 0.33 mmol), and N,N-dimethylformamide (5 mL) were added to a 20 mL scintillation flask. Sodium hydride (60% in mineral oil, 16 mg, 0.67 mmol) was added, and the reaction was stirred at room temperature for 2 hours. The reactants were evaporated onto silica gel and purified by reversed-phase rapid column chromatography (30 g C18 column; 0-70% B; A: 99.9% H2O, 0.1% HCO2H; B: 99.9% CH3CN, 0.1% HCO2H) to provide a THP-protected intermediate. The THP-protected intermediate was dissolved in dichloromethane (5 mL), treated with hydrochloric acid (4 M in 1,4-dioxane, 0.83 mL, 3.3 mmol), and stirred at room temperature for 2 hours. The reactants were evaporated onto silica gel and purified by reversed-phase rapid column chromatography (30 g C18 column; 0-50% B; A: 99.9% H2O, 0.1% HCO2H; B: 99.9% CH3CN, 0.1% HCO2H) to give (R)-4-chloro-5-(3-((5-(3,5-dimethylisoxazol-4-yl)pyridazin-3-yl)oxy)pyrrolidine-1-yl)pyridazin-3(2H)-one (P-0160). MS (ESI) [M+H + ] + =389.0.

[0888] Example 6

[0889]

[0890] Step 1: Preparation of 4-chloro-5-((R)-3-((6-chloropyrimidin-4-yl)oxy)pyrrolidine-1-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one 18: In a 250 mL round-bottom flask, combine 4-chloro-5-[(3R)-3-hydroxypyrrolidine-1-yl]-2-tetrahydropyran-2-yl-pyridazin-3-one (3, 3.0 g, 10.0 mmol), 4,6-dichloropyrimidine (2.98 g, 20.0 mmol), and N,N-dimethylformamide (100 mL). Cool the reaction mixture to 0 °C and add sodium hydride (60% in mineral oil, 0.48 g, 20.0 mmol) in portions. Stir the reaction mixture while slowly heating to room temperature over 2 hours. Pour the mixture into cold saturated ammonium chloride and extract with ethyl acetate. The organic layer was washed with brine, filtered, and evaporated onto silica gel. The product was separated by normal-phase rapid column chromatography (40 g silica gel column, 0-100% ethyl acetate in hexane) to give 4-chloro-5-[(3R)-3-(6-chloropyrimidin-4-yl)hydroxypyrrolidone-1-yl]-2-tetrahydropyran-2-yl-pyridazin-3-one (18). MS (ESI) [M+H] + ] + =412.0.

[0891] Step 2: Preparation of (R)-4-chloro-5-(3-((6-(3-(methoxymethyl)-5-methylisoxazol-4-yl)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)pyridazin-3(2H)-one 19: Combine 4-chloro-5-[(3R)-3-(6-chloropyrimidin-4-yl)oxypyrrolidine-1-yl]-2-tetrahydropyran-2-yl-pyridazin-3-one (18, 0.10 g (0.24 mmol), [3-(methoxymethyl)-5-methyl-isoxazol-4-yl]boric acid (0.050 g (0.29 mmol), dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium(II)acetone adduct (0.020 g (0.02 mmol), 1 M potassium carbonate aqueous solution (0.49 mL (0.49 mmol), and 1,4-dioxane (3 mL). The vials were placed under a nitrogen atmosphere and irradiated at 100 °C for 40 min. The reactants were evaporated onto silica gel and separated by reversed-phase rapid column chromatography (30 g C18 column; 0-70% B; A: 99.9% H2O, 0.1% HCO2H; B: 99.9% CH3CN, 0.1% HCO2H). The THP-protected intermediate was separated. The intermediate was dissolved in dichloromethane (5 mL), treated with hydrochloric acid (4 M in 1,4-dioxane, 0.61 mL, 2.4 mmol), and stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness, dissolved in N,N-dimethylformamide (2 mL), and purified by reversed-phase column chromatography (30 g C18 column; 0-50% B; A: 99.9% H2O, 0.1% HCO2H; B: 99.9% CH3CN, 0.1% HCO2H) to give (R)-4-chloro-5-(3-((6-(3-(methoxymethyl)-5-methylisoxazol-4-yl)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)pyridazin-3(2H)-one (19). MS (ESI) [M+H + ] + = 419.0.

[0892] Step 3: Preparation of (R)-4-chloro-2-(2-hydroxyethyl)-5-(3-((6-(3-(methoxymethyl)-5-methylisoxazol-4-yl)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)pyridazin-3(2H)-one (P-0126): Combine (R)-4-chloro-5-(3-((6-(3-(methoxymethyl)-5-methylisoxazol-4-yl)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)pyridazin-3(2H)-one (19, 0.040 g, 0.080 mmol), N,N-dimethylformamide (3 mL), potassium carbonate (0.020 g, 0.17 mmol) and 2-(2-bromoethoxy)tetrahydro-2H-pyran (0.030 mL, 0.17 mmol) in a 20 mL scintillation bottle. The reaction was stirred at 70 °C for 3 hours. The reaction was cooled to room temperature and hydrochloric acid (4 M, 0.42 mL, 1.68 mmol in 1,4-dioxane) was added, and the reaction was stirred for 2 hours. The reaction mixture was evaporated onto silica gel and separated by reversed-phase rapid column chromatography (30 g C18 column; 0-50% B; A: 99.9% H₂O, 0.1% HCO₂H; B: 99.9% CH₃CN, 0.1% HCO₂H) to give (R)-4-chloro-2-(2-hydroxyethyl)-5-(3-((6-(3-(methoxymethyl)-5-methylisoxazol-4-yl)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)pyridazin-3(2H)-one (P-0126). MS (ESI) [M+H + ] + =463.0.

[0893] Example 7

[0894]

[0895] Step 1: Preparation of (R)-4-chloro-5-(3-((4-(piperazin-1-yl)pyridin-2-yl)oxy)pyrrolidine-1-yl)pyridazin-3(2H)-one 20: Add 5-[(3R)-3-[(4-bromo-2-pyridinyl)oxy]pyrrolidine-1-yl]-4-chloro-2-tetrahydropyran-2-yl-pyridazin-3-one (4,0.30 g) to a dry 5 mL microwave-safe vial. 0.66 mmol), piperazine-1-carboxylic acid tert-butyl ester (0.25 g, 1.32 mmol), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) chloride (0.050 g, 0.07 mmol), cesium carbonate (0.32 g, 0.99 mmol), and 1,4-dioxane (5 mL). The vials were sealed and heated in an oil bath to 80 °C for 12 hours. The reactants were evaporated onto silica gel and purified by reversed-phase rapid column chromatography (50 g C18 column; 0-70% B; A: 99.9% H2O, 0.1% HCO2H; B: 99.9% CH3CN, 0.1% HCO2H) to give a double-protected intermediate. The substance was dissolved in dichloromethane (5 mL) and treated with hydrochloric acid (4 M in 1,4-dioxane, 0.82 mL, 3.3 mmol). After stirring at room temperature for 2 hours, the reaction was evaporated to dryness to give (R)-4-chloro-5-(3-((4-(piperazin-1-yl)pyridin-2-yl)oxy)pyrrolidine-1-yl)pyridin-3(2H)-one (20). MS(ESI)[M+H + ] + =377.0.

[0896] Step 2: Preparation of (R)-4-(2-((1-(5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)pyrrolidine-3-yl)oxy)pyridin-4-yl)-N-cyclopropylpiperazine-1-sulfonamide (P-0231): Add (R)-4-chloro-5-(3-((4-(pyrazin-1-yl)pyridin-2-yl)oxy)pyrrolidine-1-yl)pyridazin-3(2H)-one (20, 0.050 g, 0.11 mmol), pyridine (0.88 mL, 10.9 mmol), and N-cyclopropylaminosulfonyl chloride (0.020 g, 0.13 mmol) to a 20 mL scintillation vial. Stir the reaction at room temperature for 2 hours. The reactants were evaporated onto silica gel and purified by reversed-phase rapid column chromatography (30 g C18 column; 0-50% B; A: 99.9% H2O, 0.1% HCO2H; B: 99.9% CH3CN, 0.1% HCO2H) to give (R)-4-(2-((1-(5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)pyrrolidine-3-yl)oxy)pyridin-4-yl)-N-cyclopropylpiperazine-1-sulfonamide (P-0231). MS (ESI) [M+H + ] + =496.0.

[0897] Example 8

[0898]

[0899] Step 1: Preparation of 5-((R)-3-((4-(4-amino-2-fluorophenyl)pyridin-2-yl)oxy)pyrrolidine-1-yl)-4-chloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one 21: In a 20 mL microwave-safe vial, 5-[(3R)-3-[(4-bromo-2-pyridinyl)oxy]pyrrolidine-1-yl]-4-chloro- 2-Tetrahydropyran-2-yl-pyridazin-3-one (4, 0.50 g, 1.1 mmol), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)aniline (0.46 g, 1.9 mmol), and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium(II)acetone adduct (0.15 g, 0.19 mmol) were added to a 1M aqueous solution of potassium carbonate (5 mL). The reaction mixture was immediately heated to 100°C in an oil bath preheated to 100°C. The reaction was completed in less than 5 minutes. The reaction was concentrated onto 10 g of silica gel and purified by reversed-phase rapid column chromatography (50 g C18 column; 0-60% B; A: 99.9% H2O, 0.1% HCO2H; B: 99.9% CH3CN, 0.1% HCO2H) to give 5-((R)-3-((4-(4-amino-2-fluorophenyl)pyridin-2-yl)oxy)pyrrolidine-1-yl)-4-chloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (21). MS (ESI) [M+H + ] + =486.0.

[0900] Step 2: Preparation of (R)-N-(4-(2-((1-(5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)pyrrolidine-3-yl)oxy)pyridin-4-yl)-3-fluorophenyl)benzamide (P-0216): 5-((R)-3-((4-(4-amino-2-fluorophenyl)pyridin-2-yl)oxy)pyrrolidine-1-yl)-4-chloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (21.40 mg, 0.082 mmol) was dissolved in dichloromethane (2 mL), and triethylamine (25 mg, 0.25 mmol) was added. Benzoyl chloride (14 mg, 0.099 mmol) was added in one part while stirring vigorously at room temperature, and the reaction was stirred at room temperature for 2 hours. Hydrochloric acid (4 M, 2 mL, 8 mmol in 1,4-dioxane) was added to the crude reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction was then concentrated onto 10 g silica gel and purified by reversed-phase chromatography (50 g C18 column; 0-60% B; A: 99.9% H2O, 0.1% HCO2H; B: 99.9% CH3CN, 0.1% HCO2H). This purification yielded (R)-N-(4-(2-((1-(5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)pyrrolidine-3-yl)oxy)pyridin-4-yl)-3-fluorophenyl)benzamide (P-0216). MS (ESI) [M+H + ] + =506.0.

[0901] Example 9

[0902]

[0903] Step 1: Preparation of 5,5'-((3R,3'R)-(pyridin-3,5-diylbis(oxy))bis(pyrrolidine-3,1-diyl))bis(4-chloro-2-(tetrahydro-2H-)pyran-2-yl)pyridazin-3(2H)-one)22: In a vial, 4-chloro-5-[(3R)-3-hydroxypyrrolidine-1-yl]-2-tetra-dimethylformamide (5 mL) was added to the vial. Hydropyran-2-ylpyridazin-3-one (3,500 mg, 1.67 mmol), cuprous iodide (20.0 mg, 0.11 mmol), and 3,4,7,8-tetramethyl-1,10-phenanthroline (0.04 mL, 0.17 mmol) were added to 3-bromo-5-iodopyridine (500 mg, 1.76 mmol) and cesium carbonate (850 mg, 2.61 mmol). The reaction mixture was heated to 100 °C for 16 hours. Three products were detected, including a small amount of the desired product. The crude reaction mixture was filtered and concentrated onto silica gel. The substance was then purified by normal-phase rapid column chromatography (24 g silica gel column, 0 to 100% ethyl acetate gradient in dichloromethane). This purification yielded 5,5'-((3R,3'R)-(pyridin-3,5-diylbis(oxy))bis(pyrrolidine-3,1-diyl))bis(4-chloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one)(22). MS(ESI)[M+H + ] + =674.1.

[0904] Step 2: Preparation of 5,5'-((3R,3'R)-(pyridin-3,5-diylbis(oxy))bis(pyrrolidine-3,1-diyl))bis(4-chloropyridazin-3(2H)-one) (P-0165): In a 40 mL vial, 5,5'-((3R,3'R)-(pyridin-3,5-diylbis(oxy))bis(pyrrolidine-3,1-diyl))bis(4-chloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one) (22.40 mg, 0.060 mmol) in 1,4-dioxane (2 mL) was added to hydrochloric acid (4 M, 6 mL, 24 mmol in 1,4-dioxane). The reaction mixture was stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure, and the substance was dissolved in 2 mL of N,N-dimethylformamide. The substance was then purified by reversed-phase rapid column chromatography (30 g C18 column; 0-50% B; A: 99.9% H2O, 0.1% HCO2H; B: 99.9% CH3CN, 0.1% HCO2H). This purification yielded 5,5'-((3R,3'R)-(pyridine-3,5-diylbis(oxy))bis(pyrrolidine-3,1-diyl))bis(4-chloropyridazine-3(2H)-one) (P-0165). MS (ESI) [M+H + ]+ =505.9.

[0905] Example 10

[0906]

[0907] Step 1: Preparation of 4-chloro-5-((R)-3-((4-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)oxy)pyrrolidine-1-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one 23: In a 10 mL microwave-safe vial, 5-[(3R)-3-[(4-bromo-2-pyridinyl)oxy]pyrrolidine-1-yl]-4-chloro-2-tetrahydropyran-2-yl]pyrrolidine-1-yl]-4-chloro-2-tetrahydropyran-2-yl]pyrrolidine-1-yl]-4-chloro-2-tetrahydropyran-2-yl]pyrrolidine-1-yl]-4-chloro-2-tetrahydropyran-2-yl]pyrrolidine-1-yl]-4-chloro-2-tetrahydropyran-2-yl]pyrrolidine-1-yl]pyrrolidine-1-yl]pyrrolidine-2 ...2-yl]pyrrolidine-1-yl]pyrrolidine-2-yl]pyrrolidine-2-yl]pyrrolidine-2-yl]pyrrolidine-2-yl]pyrrolidine-2-yl]pyrrolidine-2-yl]pyrrolidine-2 3,5-dimethyl-4-(4,4,5,5-tetramethyl)-1,3,2-dioxane-2-yl)isoxazole (0.20 g, 0.90 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium(II)acetone adduct (0.050 g, 0.060 mmol) were added to a 1M aqueous solution of potassium carbonate (2 mL, 2.0 mmol). The reaction mixture was immediately heated to 100°C in an oil bath preheated to 100°C. The reaction was completed in less than 5 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over magnesium sulfate. The organic layer was concentrated onto silica gel and purified by normal-phase rapid column chromatography (12 g silica gel column, 0 to 100% ethyl acetate gradient in dichloromethane). This purification yielded 4-chloro-5-((R)-3-((4-(3,5-dimethylisoxazo-4-yl)pyridin-2-yl)oxy)pyrrolid-1-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (23). MS(ESI)[M+H + ] + =472.3.

[0908] Step 2: Preparation of (R)-5-(3-((4-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)oxy)pyrrolidine-1-yl)-3-oxo-2,3-dihydropyridazin-4-onitrile (P-0065): In a vial, N,N-dimethylacetamide (5 mL) was added to 4-chloro-5-((R)-3-((4-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)oxy)pyrrolidine-1-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (23,156 mg, 0.33 mmol). The solution was degassed by bubbling with argon. Zinc powder (10 mg, 0.15 mmol), 1,1'-bis(diphenylphosphino)ferrocene (16 mg, 0.030 mmol), tris(dibenzylacetone)dipalladium(0) (15 mg, 0.030 mmol), and zinc cyanide (50 mg, 0.43 mmol) were added to the solution at room temperature under argon atmosphere. The mixture was heated at 120 °C for 20 hours. After cooling to room temperature, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over magnesium sulfate. The solution was concentrated onto silica gel and purified by normal-phase rapid column chromatography (12 g silica gel column, 0 to 80% ethyl acetate gradient in dichloromethane, then 0 to 10% methanol in dichloromethane). The crude THP-protected product was collected and the residue was dissolved in 1,4-dioxane (2 mL) and hydrochloric acid (4 M, 8 mL, 32 mmol in 1,4-dioxane) was added. The mixture was stirred at room temperature for 2 hours. The reaction was concentrated and then dissolved in 2 mL of N,N-dimethylformamide. The solution was purified by reversed-phase rapid column chromatography (30 g C18 column; 0-50% B; A: 99.9% H₂O, 0.1% HCO₂H; B: 99.9% CH₃CN, 0.1% HCO₂H) to provide (R)-5-(3-((4-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)oxy)pyrrolidine-1-yl)-3-oxo-2,3-dihydropyridazine-4-onitrile (P-0065). MS (ESI) [M+H + ] + =379.3.

[0909] Example 11

[0910]

[0911] Step 1: Preparation of 4-chloro-5-[(3R)-3-[[4-(3,5-dimethyl-1H-pyrazol-4-yl)-2-pyridinyl]oxy]pyrrolidine-1-yl]-2-tetrahydropyran-2-yl-pyridazin-3-one 24: In a 250 mL round-bottom flask, 5-[(3R)-3-[(4-bromo-2-pyridinyl)oxy]pyrrolidine-1-yl]-4-chloro-2-tetrahydropyran-24 in 1,4-dioxane (50 mL) 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrazole (1.46 g, 6.6 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium(II)acetone adduct (0.35 g, 0.44 mmol) were added to a 1M potassium carbonate aqueous solution (13 mL, 13 mmol). The reaction mixture was immediately heated to 100°C in an oil bath preheated to 100°C. The reaction was stirred at 100°C for 4 hours. The reaction mixture was concentrated onto 50 g silica gel and purified by reversed-phase rapid column chromatography (150 g C18 column; 0-50% B; A: 99.9% H2O, 0.1% HCO2H; B: 99.9% CH3CN, 0.1% HCO2H). This purification yielded 4-chloro-5-[(3R)-3-[[4-(3,5-dimethyl-1H-pyrazol-4-yl)-2-pyridinyl]oxy]pyrrolidin-1-yl]-2-tetrahydropyran-2-yl-pyridazin-3-one (24). MS(ESI)[M+H + ] + =471.3.

[0912] Step 2: Preparation of 2-[4-[2-[(3R)-1-(5-chloro-6-oxo-1H-pyridazin-4-yl)pyrrolidine-3-yl]oxy-4-pyridinyl]-3,5-dimethyl-pyrazol-1-yl]acetic acid 25: 4-chloro-5-[(3R)-3-[[4-(3,5-dimethyl-1H-pyrazol-4-yl)-2-pyridinyl]oxy]pyrrolidine-1-yl]-2-tetrahydropyran-2-yl-pyridazin-3-one (24,250 mg, 0.53 mmol) and tert-butyl 2-bromoacetate (207 mg, 1.1 mmol) were dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (60% in mineral oil, 42 mg, 1.1 mmol) was added. The reaction was stirred overnight at room temperature for 15 hours. The reaction was concentrated onto 10 g silica gel and purified by normal-phase rapid column chromatography (12 g silica gel column, 0 to 100% ethyl acetate in hexane). This purification yielded a product with double protection of the intermediate. This substance was dissolved in 20 mL of dichloromethane and hydrochloric acid (4 M, 5 mL, 20 mmol in 1,4-dioxane). The reaction was stirred at room temperature for 30 min. The reaction was concentrated to give 2-[4-[2-[(3R)-1-(5-chloro-6-oxo-1H-pyridazin-4-yl)pyrrolidine-3-yl]oxy-4-pyridinyl]-3,5-dimethyl-pyrazol-1-yl]acetic acid (25). MS (ESI) [M+H + ] + =445.2.

[0913] Step 3: Preparation of (R)-2-(4-(2-((1-(5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)pyrrolidine-3-yl)oxy)pyridin-4-yl)-3,5-dimethyl-1H-pyrazole-1-yl)-N-cyclopropylacetamide P-0042: 2-[4-[2-[(3R)-1-(5-chloro-6-oxo-1H-pyridazin-4-yl)pyrrolidine-3-yl]oxy-4-pyridinyl]-3,5-dimethyl-pyrazole-1-yl]acetic acid (25,50 mg, 0.112 mmol) was dissolved in N,N-dimethylformamide (1 mL), and HBTU (55 mg, 0.10 mmol) and cyclopropylamine (26 mg, 0.45 mmol) were added. While stirring vigorously at room temperature, triethylamine (45 mg, 0.45 mmol) was added in one part and the reaction was stirred overnight for 15 hours. The reaction was then directly purified by reversed-phase rapid column chromatography (50 g C18 column; 0-50% B; A: 99.9% H2O, 0.1% HCO2H; B: 99.9% CH3CN, 0.1% HCO2H). This purification yielded (R)-2-(4-(2-((1-(5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)pyrrolidine-3-yl)oxy)pyridin-4-yl)-3,5-dimethyl-1H-pyrazol-1-yl)-N-cyclopropylacetamide (P-0042). MS (ESI) [M+H + ] + =484.3.

[0914] Example 12

[0915]

[0916] Step 1: Preparation of 4-chloro-5-[(3R)-3-[[4-(3,5-dimethyl-1H-pyrazol-4-yl)-2-pyridinyl]oxy]pyrrolidine-1-yl]-2-tetrahydropyran-2-yl-pyridazin-3-one 24: In a 250 mL round-bottom flask, 5-[(3R)-3-[(4-bromo-2-pyridinyl)oxy]pyrrolidine-1-yl]-4-chloro-2-tetrahydropyran-24 in 1,4-dioxane (50 mL) 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrazole (1.46 g, 6.6 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium(II)acetone adduct (0.35 g, 0.44 mmol) were added to a 1M potassium carbonate aqueous solution (13 mL, 13 mmol). The reaction mixture was immediately heated to 100°C in an oil bath preheated to 100°C. The reaction was stirred at 100°C for 4 hours. The reaction mixture was concentrated onto 50 g silica gel and purified by reversed-phase rapid column chromatography (150 g C18 column; 0-50% B; A: 99.9% H2O, 0.1% HCO2H; B: 99.9% CH3CN, 0.1% HCO2H). This purification yielded 4-chloro-5-[(3R)-3-[[4-(3,5-dimethyl-1H-pyrazol-4-yl)-2-pyridinyl]oxy]pyrrolidin-1-yl]-2-tetrahydropyran-2-yl-pyridazin-3-one (24). MS(ESI)[M+H + ] + =471.3.

[0917] Step 2: Preparation of 3-((4-(2-(((3R)-1-(5-chloro-6-oxo-1-(tetrahydro-2H-pyran-2-yl)-1,6-dihydropyridazin-4-yl)pyrrolidine-3-yl)oxy)pyridin-4-yl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)bicyclo[1.1.1]pentane-1-onitrile 26: In a vial, to N,N-dimethyl 4-chloro-5-[(3R)-3-[[4-(3,5-dimethyl-1H-pyrazol-4-yl)-2-pyridinyl]oxy]pyrrolidine-1-yl]-2-tetrahydropyran-2-yl-pyridazin-3-one (24, 0.060 g, 0.13 mmol) in methylformamide (2 mL) was added to sodium hydride (60% in mineral oil, 0.010 g, 0.34 mmol). The reaction was stirred at room temperature for 15 minutes. At this point, 4-methylbenzenesulfonic acid (3-cyanobicyclo[1.1.1]pent-1-yl)methyl ester (0.060 g, 0.22 mmol) was added and the reaction was stirred at room temperature for 16 hours. The reaction mixture was filtered to remove insoluble substances and concentrated onto silica gel. The substance was then purified by normal-phase rapid column chromatography (12 g silica gel column, 0 to 100% ethyl acetate gradient in dichloromethane). This purification yielded 3-((4-(2-(((3R)-1-(5-chloro-6-oxo-1-(tetrahydro-2H-pyran-2-yl)-1,6-dihydropyridazin-4-yl)pyrrolidine-3-yl)oxy)pyridin-4-yl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)bicyclo[1.1.1]pentane-1-nitrile (26). MS(ESI)[M+H + ] + =576.3.

[0918] Step ...

Claims

1. A compound having formula II: Or a pharmaceutically acceptable salt or deuterated analogue thereof, wherein: E is phenyl, pyridinyl, pyrimidinyl, or pyridazinyl, wherein E is surrounded by 0-3 Qs and 0-1 Rs. 11 Substitution occurs when E is a heteroaryl group and O does not attach to the heteroatom of E. L is non-existent, -N(H)- or -O-; m is 0-2; G is one of the following terms: Each Q is independently either halogen or CN; Each T 1 It is independently a halogen, hydroxyl group, optionally surrounded by 1-3 Rs. b Substituted C1-C6 alkyl groups, optionally with 1-3 R groups b The substituted C2-C5 alkenyl group, optionally surrounded by 1-3 R groups, b Substituted C2-C5 ynyl, CN, C1-C6 cyanoalkyl, optionally with 1-3 R b Substituted C1-C6 alkoxy groups or optionally with 1-3 R groups b Substituted C1-C6 alkoxy-C1-C6 alkyl; T 2 It is -(CH2) 0-2 -N(R 9 SO2-R 7 -(CH2) 0-2 -SO2-R 7 -(CH2) 0-2 -SO2N(R 8 )R 9 -(CH2) 0-2 -N(R 9 SO2N(R) 8 )R 9 -(CH2) 0-2 -N(R 9 )C(O)N(R 8 )R 9 -(CH2) 0-2 -N(R 9 )C(O)R 8 -(CH2) 0-2 -N(R 9 )C(O)OR 9 -(CH2) 0-2 -N(R 8 )R 9 -(CH2) 0-2 -C(O)N(R 8 )R 9 -(CH2) 0-2 -C(O)OR 9 -(CH2) 0-2 -C(O)R 10 -(CH2) 0-2 -C(O)H, -(CH2) 0-2 -N(R 9 )C(O)R 10 Optionally selected by 1-4 Z 3 Substituted -(CH2) 0-2 C3-C6 cycloalkyl, optionally surrounded by 1-3 Z 5 Substituted -(CH2) 0-2 -Phenyl or optionally surrounded by 1-3 Z-peptides 5 Substituted -(CH2) 0-2 -5-6 membered heteroaryl; T 3 It is -(CH2) 0-2 -C(O)N(R 8 )R 9 -(CH2) 0-2 -N(R 8 )R 9 -(CH2) 0-2 -C(O)OR 9 -(CH2) 0-2 -C3-C6 cycloalkyl, -(CH2) 0-2 -5-6-membered heterocyclic alkyl groups, -O-5-6-membered heterocyclic alkyl groups optionally substituted with 4-chloropyridazin-3-one-5-yl groups, or -(CH2) 0-2 -5-9 bridging carbon rings, wherein -(CH2) 0-2 -C3-C6 cycloalkyl, -(CH2) 0-2 -5-6 membered heterocyclic alkyl groups or -(CH2) 0-2 -5-9 yuan bridging carbon rings are each arbitrarily selected by 1-3 Z. 5 And 0-1 Z 1 Replacement, condition is when T 3 When a heteroatom of G is attached, G cannot be attached to T. 3 Oxygen or nitrogen atoms; Each T 5 It is independently a halogen, hydroxyl group, optionally surrounded by 1-3 Rs. b Substituted C1-C6 alkyl groups, optionally with 1-3 R groups b The substituted C2-C6 alkenyl group, optionally surrounded by 1-3 R groups, b Substituted C2-C6 ynyl, CN, C1-C6 cyanoalkyl, optionally with 1-3 R b Substituted C1-C6 alkoxy groups or optionally with 1-3 R groups b Substituted C1-C6 alkoxy-C1-C6 alkyl, under the condition that T 5 When attached to a heteroatom of G, T 5 It cannot be halogen, hydroxyl, CN, or optionally marked with 1-3 Rs. b Substituted C1-C6 alkoxy groups; T 6 It is -(CH2) 0-2 -N(R 9 SO2-R 7 -(CH2) 0-2 -SO2-R 7 -(CH2) 0-2 -SO2N(R 8 )R 9 -(CH2) 0-2 -N(R 9 SO2N(R) 8 )R 9 -(CH2) 0-2 -N(R 9 )C(O)N(R 8 )R 9 -(CH2) 0-2 -N(R 9 )C(O)R 8 -(CH2) 0-2 -N(R 9 )C(O)OR 9 -(CH2) 0-2 -N(R 8 )R 9 -(CH2) 0-2 -C(O)-N(R 8 )R 9 -(CH2) 0-2 -C(O)OR 9 -(CH2) 0-2 -C(O)R 10 -(CH2) 0-2 -N(R 9 )C(O)R 10 -N(H)C(H)C=O, optionally divided by 1-4 Z 3 Substituted -(CH2) 0-2 -C3-C6 cycloalkyl, optionally surrounded by 1-4 Z 3 Substituted -(CH2) 0-2 -5-6 membered heterocyclic alkyl groups, optionally surrounded by 1-3 Z groups. 5 Substituted -(CH2) 0-3 -5-6-membered heteroaryl, or 4-chloropyridazine-3-one-5-yl, provided that T 6 When a heteroatom of G is attached, G cannot be attached to T. 6 Oxygen or nitrogen atoms; R b It is a halogen, CN, CF3, or hydroxyl group, provided that it does not exceed one R. b It's CF3; R 1 It is H or is influenced by 1-3 Zs. 2 Substituted C2-C4 alkyl groups; R 2 It is H, halogen, or CN; R 3 It is H; R 4 It is halogen; R 7 It can be arbitrarily divided by 1-4 Z. 4 Substituted C1-C6 alkyl groups, optionally with 1-4 Z-terminals 3 Substituted -C0-C2 alkyl-C3-C6 cycloalkyl, optionally with 1-4 Z-terminals 3 Substituted -C0-C2 alkyl-phenyl, optionally with 1-3 Z-terminals 5 Substituted -C0-C2 alkyl-5-6 heteroaryl groups or optionally surrounded by 1-3 Z groups 5 Substituted -C0-C2 alkyl-5-6 membered heterocyclic alkyl; R 8 H, arbitrarily divided by 1-4 Z 4 Substituted C1-C6 alkyl groups, optionally with 1-4 Z-terminals 4 The substituted C2-C6 alkenyl group, optionally surrounded by 1-4 Z groups, 3 Substituted -C0-C2 alkyl-C3-C6 cycloalkyl, optionally with 1-4 Z-terminals 3 Substituted -C0-C2 alkyl-phenyl, optionally with 1-3 Z-terminals 5 Substituted -C0-C2 alkyl-5-6 heteroaryl, optionally with 1-3 Z-terminals 5 Substituted -C0-C2 alkyl-5-6-membered heterocyclic alkyl or substituted with 0-4 T 1 Replacement of 5-9 bridging carbon rings; Each R 9 Independently H or optionally by 1-4 Z 4 Substituted C1-C6 alkyl groups; R 10 It is 0-4 Z 4 Substituted C1-C6 alkyl groups, optionally with 1-4 Z-terminals 3 Substituted -C0-C2 alkyl-C3-C6 cycloalkyl, optionally with 1-4 Z-terminals 3 Substituted -C0-C2 alkyl-phenyl, optionally with 1-3 Z-terminals 5 Substituted -C0-C2 alkyl-5-6 heteroaryl groups or optionally surrounded by 1-3 Z groups 5 Substituted -C0-C2 alkyl-5-6 membered heterocyclic alkyl; R 11 It is NH2; Z 1 It is a C1-C6 cyanoalkyl group, -(CH2) 0-2 -C(O)OR 9 -(CH2) 0-2 -C(O)-N(R 8 )R 9 The condition is that when Z 1 When attached to a heteroatom, then Z 1 Not -C(O)OR 9 ; Each Z 2 It is independently a hydroxyl group or NH2, provided that it does not exceed one Z. 2 It is NH2; Each Z 3 Independently, it is a C1-C6 alkyl, halogen, C1-C6 haloalkyl, hydroxyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, or CN; Each Z 4 Independently, it is hydroxyl, halogen, C1-C6 alkoxy, or CN; and Each Z 5 Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, halogen, C1-C6 alkoxy, CN, or C1-C6 cyanoalkyl, provided that Z is... 5 When attached to a heteroatom, then Z 5 It is not halogen, hydroxyl, C1-C6 alkoxy or CN.

2. The compound according to claim 1, having formula IIIa or IIIb: Or its pharmaceutically acceptable salts or deuterated analogues.

3. The compound according to claim 1, wherein: Each T 1 It is independently a halogen, hydroxyl group, optionally surrounded by 1-3 Rs. b Substituted C1-C4 alkyl groups, optionally with 1-3 R groups b The substituted C2-C4 alkenyl group, optionally surrounded by 1-3 R groups, b Substituted C2-C4 ynyl, CN, C1-C4 cyanoalkyl, optionally with 1-3 R b Substituted C1-C4 alkoxy groups or optionally with 1-3 R groups b Substituted C1-C4 alkoxy-C1-C4 alkyl; T 2 It is -(CH2) 0-1 -N(R 9 SO2-R 7 -(CH2) 0-1 -SO2-R 7 -(CH2) 0-1 -SO2N(R 8 )R 9 -(CH2) 0-1 -N(R 9 SO2N(R) 8 )R 9 -(CH2) 0-1 -N(R 9 )C(O)N(R 8 )R 9 -(CH2) 0-1 -N(R 9 )C(O)R 8 -(CH2) 0-1 -N(R 9 )C(O)OR 9 -(CH2) 0-1 -N(R 8 )R 9 -(CH2) 0-1 -C(O)N(R 8 )R 9 -(CH2) 0-1 -C(O)OR 9 -(CH2) 0-1 -C(O)R 10 -(CH2) 0-1 -C(O)H, -(CH2) 0-1 -N(R 9 )C(O)R 10 Optionally selected by 1-3 Z 3 Substituted -(CH2) 0-2 C3-C6 cycloalkyl, optionally surrounded by 1-3 Z 5 Substituted -(CH2) 0-1 Phenyl or optionally with 1-3 Z 5 Substituted -(CH2) 0-1 -5-6 membered heteroaryl; T 3 It is -(CH2) 0-2 -C(O)N(R 8 )R 9 -(CH2) 0-2 -N(R 8 )R 9 -(CH2) 0-2 -C(O)OR 9 -(CH2) 0-2 -C3-C6 cycloalkyl, -(CH2) 0-2 -5-6-membered heterocyclic alkyl groups, -O-5-6-membered heterocyclic alkyl groups optionally substituted with 4-chloropyridazin-3-one-5-yl groups, or -(CH2) 0-2 -5-9 bridging carbon rings, wherein -(CH2) 0-2 -C3-C6 cycloalkyl, -(CH2) 0-1 -5-6 membered heterocyclic alkyl groups or -(CH2) 0-2 -5-9 yuan bridging carbon rings are each arbitrarily selected by 1-3 Z. 5 And 0-1 Z 1 Replacement, condition is when T 3 When a heteroatom of G is attached, G cannot be attached to T. 3 Oxygen or nitrogen atoms; Each T 5 It is independently a halogen, hydroxyl group, optionally surrounded by 1-3 Rs. b Substituted C1-C4 alkyl groups, optionally with 1-3 R groups b The substituted C2-C4 alkenyl group, optionally surrounded by 1-3 R groups, b Substituted C2-C4 ynyl, CN, C1-C4 cyanoalkyl, optionally with 1-3 R b Substituted C1-C4 alkoxy groups or optionally with 1-3 R groups b Substituted C1-C4 alkoxy-C1-C4 alkyl, under the condition that T 5 When attached to a heteroatom of G, T 5 It cannot be halogen, hydroxyl, CN, or optionally marked with 1-3 Rs. b Substituted C1-C4 alkoxy groups; T 6 It is -(CH2) 0-1 -N(R 9 SO2-R 7 -(CH2) 0-1 -SO2-R 7 -(CH2) 0-1 -SO2N(R 8 )R 9 -(CH2) 0-1 -N(R 9 SO2N(R) 8 )R 9 -(CH2) 0-1 -N(R 9 )C(O)N(R 8 )R 9 -(CH2) 0-1 -N(R 9 )C(O)R 8 -(CH2) 0-1 -N(R 9 )C(O)OR 9 -(CH2) 0-1 -N(R 8 )R 9 -(CH2) 0-1 -C(O)-N(R 8 )R 9 -(CH2) 0-1 -C(O)OR 9 -(CH2) 0-1 -C(O)R 10 -(CH2) 0-1 -N(R 9 )C(O)R 10 -N(H)C(H)C=O, optionally divided by 1-4 Z 3 Substituted -(CH2) 0-1 -C3-C6 cycloalkyl, optionally surrounded by 1-4 Z 3 Substituted -(CH2) 0-1 -5-6 membered heterocyclic alkyl groups, optionally surrounded by 1-3 Z groups. 5 Substituted -(CH2) 0-1 -5-6-membered heteroaryl or 4-chloropyridazine-3-one-5-yl, under the condition that T 6 When a heteroatom of G is attached, G cannot be attached to T. 6 Oxygen or nitrogen atoms; R b It is F, Cl, CN, CF3, or a hydroxyl group, provided that there is no more than one R. b It's CF3; R 7 It can be arbitrarily divided by 1-3 Z. 4 Substituted C1-C4 alkyl groups, optionally with 1-3 Z-shaped radicals 3 Substituted -C0-C3 alkyl-C3-C6 cycloalkyl, optionally with 1-3 Z-terminals 3 Substituted -C0-C3 alkyl-phenyl, optionally with 1-3 Z-terminals 5 Substituted -C0-C1 alkyl-5-6 heteroaryl groups or optionally surrounded by 1-3 Z groups 5 Substituted -C0-C1 alkyl-5-6 membered heterocyclic alkyl; R 8 H, arbitrarily divided by 1-3 Z 4 Substituted C1-C4 alkyl groups, optionally with 1-3 Z-shaped radicals 4 The substituted C2-C4 alkenyl group, optionally surrounded by 1-3 Z groups, 3 Substituted -C0-C1 alkyl-C3-C6 cycloalkyl, optionally with 1-3 Z-terminals 3 Substituted -C0-C1 alkyl-phenyl, optionally with 1-3 Z-terminals 5 Substituted -C0-C1 alkyl-5-6 heteroaryl groups, optionally with 1-3 Z-terminals 5 Substituted -C0-C1 alkyl-5-6-membered heterocyclic alkyl or substituted with 0-3 T 1 Replacement of 5-9 bridging carbon rings; Each R 9 Independently H or optionally by 1-3 Z 4 Substituted C1-C4 alkyl groups; R 10 It is 0-3 Z 4 Substituted C1-C4 alkyl groups, optionally with 1-3 Z-shaped radicals 3 Substituted -C0-C1 alkyl-C3-C6 cycloalkyl, optionally with 1-3 Z-terminals 3 Substituted -C0-C1 alkyl-phenyl, optionally with 1-3 Z-terminals 5 Substituted -C0-C1 alkyl-5-6 heteroaryl groups or optionally surrounded by 1-3 Z groups 5 Substituted -C0-C1 alkyl-5-6 membered heterocyclic alkyl; Z 1 It is a C1-C4 cyanoalkyl group, -(CH2) 0-1 -C(O)OR 9 -(CH2) 0-1 -C(O)-N(R 8 )R 9 The condition is that when Z 1 When attached to a heteroatom, then Z 1 Not -C(O)OR 9 ; Each Z 3 Independently, it is a C1-C4 alkyl, halogen, C1-C4 haloalkyl, hydroxyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, or CN; Each Z 4 Independently, it is hydroxyl, halogen, C1-C4 alkoxy, or CN; and Each Z 5 Independently, it is a C1-C4 alkyl, C1-C6 haloalkyl, hydroxy, C1-C4 hydroxyalkyl, halogen, C1-C4 alkoxy, CN, or C1-C4 cyanoalkyl, provided that Z is... 5 When attached to a heteroatom, Z 5 It is not halogen, hydroxyl, C1-C4 alkoxy or CN.

4. The compound according to any one of claims 1, 2 or 3, wherein R 1 It is hydrogen.

5. The compound according to any one of claims 1, 2 or 3, wherein R 1 It is by 1-3 Z 2 Substituted C2-C4 alkyl groups.

6. The compound according to any one of claims 1, 2 or 3, wherein R 1 It is -CH2CH2OH, -CH2CH2CH2OH, -CH2CH(OH)CH2OH or -CH2CH(CH3)OH; and R 2 It is Cl, Br, CF3 or CN.

7. The compound according to claim 6, wherein R 2 It is Cl.

8. The compound according to any one of claims 1, 2 or 3, wherein R 1 It is H; and R 2 It is Cl, Br, CF3 or CN.

9. The compound according to claim 8, wherein R 2 It is Cl.

10. The compound according to any one of claims 1-3, having any one of the following formulas: Or a pharmaceutically acceptable salt thereof, wherein R 2 It is Cl, Br, CF3 or CN, and m is 0-1.

11. The compound according to any one of claims 1-3, having any one of the following formulas: Or a pharmaceutically acceptable salt thereof, wherein R 2 It is Cl, Br, CF3 or CN.

12. The compound according to any one of claims 1-3, having any one of the following formulas: Or a pharmaceutically acceptable salt thereof, wherein R 2 It is Cl, Br, CF3 or CN.

13. The compound according to claim 10, having one of formula IV(a), IV(b), IV(c), IV(d), IV(e), IV(f) or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 11, having one of the formulas V(a), V(b), V(c), V(d), V(e), V(f), V(g), V(h), V(i), V(j), V(k), V(l), V(m), V(n), V(o), V(p), V(q), V(r), V(s), V(t), V(u), V(v), V(w), V(af), V(ag), V(ah), V(ai), V(aj), V(ak), V(al), V(am), V(an), V(ao), V(ap), V(aq), V(ar), V(as), V(at), V(au), V(av), V(aw), V(ay), V(az), V(ba), V(bb) or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 12, having one of formula VI(a), VI(b), VI(c), VI(d), VI(e), VI(f), VI(g), VI(h), VI(i), VI(j), VI(k), VI(l), VI(m), VI(o) or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 14, wherein G is pyrazolyl, isoxazolyl, indolyl, 1,2,3-triazolyl, imidazolyl, thiazolyl, or pyrroleyl, each being radicalized by 0-2 T groups. 5 and 0-1 T 3 replace.

17. The compound according to claim 14, wherein G is piperazinyl, piperidine, pyrrolidine, tetrahydropyran, morpholinyl, 1,2,3,6-tetrahydropyridinyl, 2,5-dihydropyrrolyl, or 3,6-dihydropyranyl, each being surrounded by 0-2 T atoms. 5 and 0-1 T 6 replace.

18. The compound according to claim 14, wherein G is (1R,5S)-3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3-diazabicyclo[3.2.1]octyl, or (1R,5S)-8-diazabicyclo[3.2.1]octyl, each being separated by 0-2 T atoms. 5 and 0-1 T 6 replace.

19. The compound according to claim 14, wherein G is cyclohexyl, cyclopentyl, cyclohexenyl, or cyclopentenyl, each being radicalized by 0-2 T atoms. 1 and 0-1 T 2 replace.

20. The compound according to claim 1, wherein T 3 It is -CH2C(O)N(H)cyclopropyl, -CH2C(O)N(H)CH3, -CH2-COOH, oxetyl, -(CH2) 0-2 Cyclopropyl, -(CH2) 0-2 Cyclobutyl, -(CH2) 0-2 -Tetrahydropyran, -(CH2) 0-2 -Tetrahydrofuran, -(CH2) 0-2 Azahexacyclic butyl, -(CH2) 0-2 Pyrroloalkyl or -(CH2) 0-2 Morpholinyl.

21. The compound according to any one of claims 1, 2 or 3, wherein G is one of the following formula: Each T 1a It is F, Cl, or CH3 independently; and Each T 5a It can be F, Cl, or CH3 independently.

22. The compound according to claim 21, wherein G is one of formula (a), (b), (c), (d), (e), (f), (g), or (h).

23. The compound according to claim 21, wherein G is one of formula (i), (j), (k), (l), (m), (n), (o), (p), (q), (r), (s), (t), (u), (v), (w), (x), (y), (z), (aa), (ab), (ac), or (ad).

24. The compound according to claim 21, wherein G is one of the formulas (ae), (af), (ag), (ah), (ai), (aj), (ak), (al), (am), (an), (ao), (ap), or (aq).

25. The compound according to claim 21, wherein G is one of formula (ar) or (as).

26. The compound according to claim 21, wherein G is one of formula (at) or (au).

27. The compound according to claim 21, wherein G is one of the formulas (av), (aw), (ax), (ay), or (az).

28. The compound according to claim 21, wherein G is one of the formulas (ag), (ah), (ai), (aj), (ak), (al).

29. The compound according to claim 21, wherein G is one of formula (ag) or (ah).

30. The compound according to claim 1, wherein T 6 Oxycyclobutylmethylene, -C(O)CH2OH, -C(O)OH, -SO2CH3, -C(O)cyclopropyl, -C(O)CH3, -N(H)SO2-cyclopropyl, -N(H)C(O)cyclopropyl, -SO2N(H)CH2CH2CH3, -SO2NHcyclopropyl or -SO2CH2CH2CH3.

31. The compound according to claim 1, wherein T 5 is F, Cl, CH2Cl, CH2F, CH3, -CH2CH3, -CH(CH3)2, CH2OH, -CH2CH2OH, -CH2C(CH3)2OH, -CH(CH2OH)2, -CH2CH(OH)CF3, CH2CF3, CN, -C H2CN, -OCH3, -CH2OCH3, -CHF2, -CH2CHF2, -CH2CH(OH)CH2CH2Cl, -CH(CH2OH)CH2Cl, -CH(CH2OH)CH2I or -CH2C(CH3)(CH2OH)CH2Cl.

32. The compound according to any one of claims 1, 2 or 3, wherein Z 5 It can be CH3, F, Cl, CN, -CH2CN, -CH2CH3 or OH.

33. The compound according to claim 6, wherein R 1 It is -CH2CH2OH; R 2 It is Cl; and E is pyridyl.

34. The compound according to claim 33, wherein G is reacted with 0-2 T atoms. 5 and 0-1 T 3 Substituted pyrazol group.

35. The compound according to claim 34, wherein T 5 is F, Cl, CH2Cl, CH2F, CH3, -CH2CH3, -CH(CH3)2, CH2OH, -CH2CH2OH, -CH2C(CH3)2OH, -CH(CH2OH)2, -CH2CH(OH)CF3, CH2CF3, CN, -CH 2CN, -OCH3, -CH2OCH3, -CHF2, -CH2CHF2, -CH2CH(OH)CH2CH2Cl, -CH(CH2OH)CH2Cl, -CH(CH2OH)CH2I, or -CH2C(CH3)(CH2OH)CH2Cl.

36. The compound according to claim 35, wherein T 3 It is -CH2C(O)N(H)cyclopropyl, -CH2C(O)N(H)CH3, -CH2-COOH, oxetyl, -(CH2) 0-2 Cyclopropyl, -(CH2) 0-2 Cyclobutyl, -(CH2) 0-2 -Tetrahydropyran, -(CH2) 0-2 -Tetrahydrofuran, -(CH2) 0-2 Azahexacyclic butyl, -(CH2) 0-2 Pyrroloalkyl or -(CH2) 0-2 Morpholinyl.

37. The compound according to claim 1, wherein the compound is selected from the group consisting of compounds or pharmaceutically acceptable salts thereof: 。 38. A pharmaceutical composition comprising a compound of any one of claims 1 to 37 and a pharmaceutically acceptable carrier.

39. The pharmaceutical composition according to claim 38, further comprising a second pharmaceutical agent.

40. Use of a compound of any one of claims 1-37, or a pharmaceutically acceptable salt or deuterated analog thereof, or a pharmaceutical composition of any one of claims 38-39 in the preparation of a medicament for treating CD73-mediated diseases or symptoms.

41. The use according to claim 40, wherein the disease or symptom is a neoplastic condition, an inflammatory condition, a cognitive impairment, or a neurodegenerative disease.

42. The use according to claim 40, wherein the disease or symptom is cancer.

43. The use according to claim 40, wherein the disease or symptom is bladder cancer, colorectal cancer, gastric cancer, gallbladder cancer, glioma, leukemia, lymphoma, lung cancer, breast cancer, melanoma, multiple myeloma, ovarian cancer, prostate cancer, pancreatic cancer, thyroid cancer, pulmonary fibrosis, liver fibrosis, Alzheimer's disease, multiple sclerosis, or Parkinson's disease.

44. The use according to claim 40, wherein the disease or symptom is glioblastoma multiforme.

45. The use according to claim 43, wherein the lymphoma is adult T-cell lymphoma, AIDS-related lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, B-cell lymphoma, Burkitt lymphoma, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, enteropathy-associated T-cell lymphoma, follicular lymphoma, hepatosplenic T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, MALT lymphoma, mantle cell lymphoma, marginal zone B-cell lymphoma, primary exudative lymphoma, or T-cell lymphoma.

46. ​​The use according to claim 43, wherein the leukemia is adult T-cell leukemia, aggressive NK-cell leukemia, B-cell chronic lymphocytic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, B-cell prolymphocytic leukemia, acute eosinophilic leukemia, acute erythroleukemia, acute megakaryocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, or mast cell leukemia.

47. The use according to claim 43, wherein the leukemia is acute lymphoblastic leukemia.

48. The use according to claim 40, wherein the disease or symptom is renal cell carcinoma, small cell lung cancer, non-small cell lung cancer, acute myeloid leukemia, multiple myeloma, diffuse large B-cell lymphoma, breast cancer, or prostate cancer.

49. The use according to any one of claims 40-48, further comprising the application of one or more additional therapeutic agents.

50. The use according to claim 49, wherein the one or more additional therapeutic agents are one or more of the following: i) an alkylating agent selected from adorexin, hexamethylmelamine, biferexin, busulfan, carboplatin, carboquinone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estradiol, formustine, hepsulfam, ifosfamide, inprofen, ilofofen, lomustine, nitrogen mustard, melphalan, oxaliplatin, piperazine, semustine, streptozotocin, temozolomide, thiotepa, and treoxazine; ii) an antibiotic selected from bleomycin, actinomycin D, daunorubicin, doxorubicin, epirubicin, idarubicin, metronidazole, mitomycin, mitoxantrone, neo-carcinomacin, pentostatin, and procainoxam; iii) an antimetabolite. The following are selected from the group consisting of: azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, fluorouracil, fludarabine, 5-fluorouracil, tegafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nerabine, pemetrexed, raltitrexed, thioguanine, and trimethoprim; iv) immunotherapeutic agents selected from PD-1 or PD-L1 inhibitors; v) hormones or hormone antagonists selected from the group consisting of: enzalutamide, abiraterone, anastrozole, androgens, buserreline, diethylstilbestrol, exemestane, flutamide, fulvestrant, gosereline, edoxifene, letrozole, leuproreline, magestrol, raloxifene, tamoxifen, and toremifene; vi) taxanes selected from DJ-927, docetaxel, and TPIs.

287. Paclitaxel and DHA-paclitaxel; vii) Retinoids selected from aliretinoin, bexarotine, fenvitamin A, isotretinoin, and retinoic acid; viii) Alkaloids selected from etoposide, homoharringtonine, teniposide, vincristine, vinblastine, vinorelbine, vinorelbine, and vinorelbine; ix) Antiangiogenic agents selected from AE-941, ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide; x) Topoisomerase inhibitors selected from acridine, atecarin, eczema, irinotecan, and SN-38. 7-Ethyl-10-hydroxycamptothecin, rubitecan, topotecan, and 9-aminocamptothecin; xi) kinase inhibitors selected from erlotinib, gefitinib, flapindole, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, AEE-788, AG-013736, AMG 706, AMN107, BMS-354825, BMS-599626, UCN-01; 7-hydroxyastrosporin, vemurafenib, dabrafenib, trametinib, cobimetinib, sumetinib, and vatarani; xii) targeted signal transduction inhibitors selected from bortezomib, geldmycin, and rapamycin; xiii) biological response modifiers selected from imiquimod, interferon-α, and interleukin-2; xiv) IDO inhibitors;(xv) Chemotherapy agents selected from 3-AP 3-amino-2-carboxyl thiocarbamate, atrasentan, aminoglutethimide, anagrelide, asparaginase, lichenstatin-1, silengiptide, irismo, eribulin mesylate E7389, ixaprone, clonidine, masorofol, mitoxantrone, olimol, sulindac, testrolide, thiazolidinone, mTOR inhibitors, PI3K inhibitors, Cdk4 inhibitors, Akt inhibitors, Hsp90 inhibitors, farnesyltransferase inhibitors, or aromatase inhibitors such as anastrozole, letrozole, and exemestane; (xvi) Mek inhibitors; (xvii) tyrosine kinase inhibitors; (xviii) c-Kit mutation inhibitors; (xix) EGFR inhibitors; PD-1 inhibitors; or (xx) epigenetic regulators.

51. The use according to claim 50, wherein the one or more additional therapeutic agents are PD-1 or PD-L1 inhibitors.

52. The use according to claim 51, wherein the PD-1 or PD-L1 inhibitor is nivolumab, pembrolizumab, cimipril, atezolizumab, acimetab, or durvalumab.

Images