Trpm8 antagonists for the treatment of cancer

Abstract

A method of treating cancer in a subject, the method comprising administering 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3,diazaspiro[4.5]decane-2,4-dione, a TRPM8 antagonist.

Description

[0001] Cross-references This application claims the benefit of U.S. Provisional Application Serial No. 63 / 583,688, filed on September 19, 2023, which is incorporated herein by reference in its entirety. Background Technology

[0002] Cancer is characterized by the development of abnormal cells that divide uncontrollably and have the ability to infiltrate and destroy normal body tissues. Cancer is a major public health problem in many parts of the world and is the second leading cause of death globally. However, due to current advances in cancer screening, treatment, and prevention, survival rates are improving for many types of cancer.

[0003] Transient receptor potential (TRP) channels are one of the largest groups of ion channels, and they are divided into six subfamilies (TRPV, TRPM, TRPA, TRPC, TRPP, and TRPML). TRP channels are cation-selective channels activated by a variety of physical (e.g., temperature, osmotic pressure, mechanical) and chemical stimuli. Transient receptor potential melastatin subfamily member 8 (TRPM8) is a member of the TRP channel family. TRPM8 can sense harmless cold (15–28 °C) (McKeny et al.). Nature 2002, 416 ,52; Peier et al. Cell 2002, 108 Temperature variations in two ranges: 705 and harmful cold (<15 °C), as well as temperature variations caused by chemical agents such as menthol and icilin (Chuang et al.). Neuron 2004, 43 ,859). Summary of the Invention

[0004] TRPM8 has been found to be expressed in a variety of cancers, particularly metastatic and drug-resistant cancers. In recent years, a growing body of literature has demonstrated that TRPM8 is involved in tumorigenesis and progression, and studies have found that TRPM8 expression is significantly upregulated in prostate cancer (PC) and many other tumors, indicating its important role in the development of human cancers. The accumulated evidence from the past decade strongly supports the hypothesis that TRPM8, which plays a significant role in thermoregulation, could be one of the most promising new therapeutic targets in cancer treatment.

[0005] This article discloses a method for treating cancer in a subject of need, the method comprising administering to the subject 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione: (Compound 1), or a pharmaceutically acceptable salt thereof.

[0006] In some implementations, compound 1 is in the form of a salt.

[0007] In some embodiments, compound 1 is in the form of benzenesulfonate.

[0008] In some implementations, the cancer is bladder cancer, breast cancer, bile duct cancer, colorectal cancer, kidney cancer, liver cancer, lung cancer, lymphoma, myeloma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, or skin cancer.

[0009] In some implementations, the breast cancer is ER-positive breast cancer, ER-positive metastatic breast cancer, or triple-negative breast cancer (TNB).

[0010] In some implementations, the myeloma is multiple myeloma (MM).

[0011] In some implementations, the skin cancer is melanoma.

[0012] In some implementations, the lung cancer is small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC).

[0013] In some implementations, the method further includes the application of an additional therapeutic agent.

[0014] In some implementations, the additional therapeutic agent is a targeted agent, chemotherapy, immunotherapy (IO), radiotherapy, gene therapy, or cell therapy, or any combination thereof.

[0015] In some embodiments, the additional therapeutic agent is a targeted agent selected from the following: apalutamide, dabrafenib, enzalutamide, fulvestrant, ibrutinib, lenalidomide, palbociclib, pomalidomide, sorafenib, tamoxifen, and thalidomide.

[0016] In some embodiments, the additional therapeutic agent is a chemotherapeutic agent selected from the following: 5-fluorouracil, bleomycin, capecitabine, carboplatin, cisplatin, cyclophosphamide, dacarbazine, docetaxel, doxorubicin, epirubicin, etoposide, folinic acid, gemcitabine, ifosfamide, methotrexate, mustine, oxaliplatin, prednisolone, procarbazine, vinorelbine, and vinorelbine.

[0017] In some embodiments, the additional therapeutic agent is a CTLA-4 blocker, a PD-1 blocker, or a PD-L1 blocker.

[0018] In some implementations, the CTLA-4 blocker is ipilimumab or tremelimumab.

[0019] In some implementations, the PD-1 blocker is nivolumab or pembrolizumab.

[0020] In some implementations, the PD-L1 blocker is atezolizumab, avelumab, cemiplimab, or durvalumab.

[0021] Incorporation All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the same extent that each individual publication, patent or patent application is expressly and individually indicated to be incorporated by reference. Attached Figure Description

[0022] The novel features of this disclosure are described in detail in the appended claims. The features and advantages of this disclosure will be better understood by referring to the following detailed description and accompanying drawings, which illustrate illustrative embodiments utilizing the principles of this disclosure, in which: Figure 1 The cell proliferation inhibition of compound 1, lenalidomide, and compound 1 in combination with lenalidomide in the KMS-26 cell line is shown.

[0023] Figure 2 The cell proliferation inhibition of compound 1, lenalidomide, and compound 1 in combination with lenalidomide in the JJN-3 cell line is shown.

[0024] Figure 3 The cell proliferation inhibition of compound 1, lenalidomide, and compound 1 in combination with lenalidomide in the OPM-2 cell line is shown.

[0025] Figure 4 The cell proliferation inhibition of compound 1, tamoxifen, and compound 1 in combination with tamoxifen in the MCF7 cell line is shown.

[0026] Figure 5 The cell proliferation inhibition of compound 1, gemcitabine, and compound 1 in combination with gemcitabine in the MDA-MB-231 cell line was demonstrated.

[0027] Figure 6 The cell proliferation inhibition of compound 1, sorafenib, and compound 1 in combination with sorafenib in the HMC-1-8 cell line is shown.

[0028] Figure 7 The inhibition of cell proliferation in the SK-MEL-28 cell line by compound 1, dabrafenib, and compound 1 in combination with dabrafenib is shown.

[0029] Figure 8 The inhibition of cell proliferation in the A101D cell line was demonstrated by compound 1, dabrafenib, and compound 1 in combination with dabrafenib.

[0030] Figure 9 The cell proliferation inhibition of compound 1, dabrafenib, and compound 1 in combination with dabrafenib in the Hs 294T cell line is shown.

[0031] Figure 10 The cell proliferation inhibition of compound 1, dabrafenib, and compound 1 in combination with dabrafenib in the MDA-MB-435S cell line was demonstrated.

[0032] Figure 11 The cell proliferation inhibition of compound 1, cisplatin, and compound 1 in combination with cisplatin in the HOS cell line was demonstrated.

[0033] Figure 12 The inhibition of cell proliferation in the Saos-2 cell line by compound 1, cisplatin, and compound 1 in combination with cisplatin is shown.

[0034] Figure 13 The cell proliferation inhibition of compound 1, cisplatin, and compound 1 in combination with cisplatin in the NCI-H2081 cell line was demonstrated.

[0035] Figure 14 The inhibition of cell proliferation in the ACHN cell line by compound 1, sorafenib, and compound 1 in combination with sorafenib is shown.

[0036] Figure 15 The cell proliferation inhibition of compound 1, sorafenib, and compound 1 in combination with sorafenib in the G-402 cell line is shown.

[0037] Figure 16 The cell proliferation inhibition of compound 1, gemcitabine, and compound 1 in combination with gemcitabine in the T24 cell line was demonstrated.

[0038] Figure 17 The cell proliferation inhibition of compound 1, carboplatin, and compound 1 in combination with carboplatin in the OAW28 cell line is shown.

[0039] Figure 18 The cell proliferation inhibition of compound 1, enzalutamide, and compound 1 in combination with enzalutamide in the LNCaP cell line is shown.

[0040] Figure 19 The cell proliferation inhibition of compound 1, oxaliplatin, and compound 1 in combination with oxaliplatin in the Caco-2 cell line is shown.

[0041] Figure 20 The cell proliferation inhibition of compound 1, ibrutinib, and compound 1 in combination with ibrutinib in the SU-DHL-1 cell line was demonstrated. Detailed Implementation

[0042] As used herein and in the appended claims, the singular forms “an,” “a,” and “the” include plural references unless the context clearly specifies otherwise. Thus, for example, referring to “an agent” includes a variety of such agents, and referring to “the cell” includes referring to one or more cells and their equivalents known to those skilled in the art, and so on. When scopes are used herein to refer to physical properties (such as molecular weight) or chemical properties (such as chemical formula), all combinations and sub-combinations of scopes, as well as specific embodiments thereof, should be included. When referring to numerical or numerical ranges, the term “about” means that the referenced number or numerical range is an approximation within experimental variability (or statistical experimental error), and therefore, in some cases, the number or numerical range may deviate from the stated number or numerical range by 1% to 15%. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including)” is not intended to exclude embodiments in which, for example, any embodiment of a substance composition, composition, method or process described herein is “composed of” or “substantially composed of” the described features.

[0043] Unless otherwise specified, the following terms shall have the meanings indicated below as used in the specification and appended claims.

[0044] As used herein, the term "therapeutic agent" means an agent used to treat, counteract, improve, prevent, or enhance a patient's adverse condition or disease. In some implementations, therapeutic agents (such as TRPM8 antagonists) are used to treat and / or improve cancer.

[0045] When used in conjunction with a therapeutic approach, “application” means the systemic or local administration of a therapeutic agent (e.g., direct administration into or onto a target tissue) or the administration of a therapeutic agent to a patient, thereby causing the therapeutic agent to have a positive effect on the tissue to which it is targeted. Therefore, as used herein, when used in conjunction with the compositions described herein, the term “application” may include, but is not limited to, providing the composition into or onto a target tissue; or providing the composition systemically to a patient, for example, through oral administration, thereby allowing the therapeutic agent to reach the target tissue or cells. An “application” composition may be achieved by injection, local administration, and oral administration, or by other methods, alone or in combination with other known techniques.

[0046] As used herein, the term "animal" includes, but is not limited to, human and non-human vertebrates, such as wild animals, domesticated animals, and farm animals. As used herein, the terms "patient," "object," and "individual" are intended to include any living organism capable of developing some of the conditions described herein. Examples include humans, monkeys, cattle, sheep, goats, dogs, cats, mice, rats, and their transgenic species. In a preferred embodiment, the patient is a primate. In some embodiments, the primate or object is a human. In some cases, the human is an adult. In some cases, the human is a child. In a further case, the human is under 12 years of age. In some cases, the human is an elderly person. In other cases, the human is 60 years of age or older. Other examples of objects include laboratory animals such as mice, rats, dogs, cats, goats, sheep, pigs, and cattle. Laboratory animals can be animal models of a condition, such as transgenic mice suffering from a hypertensive pathology.

[0047] "Pharmaceutical acceptable" means that the carrier, diluent, or excipient must be compatible with other components in the formulation and will not cause harm to the recipient.

[0048] The term "pharmaceutical composition" refers to a composition comprising at least one active ingredient, such that the composition is suitable for studies of a specific therapeutic effect in mammals (e.g., but not limited to humans). Those skilled in the art will understand and master appropriate techniques for determining whether an active ingredient possesses the desired therapeutic effect, as required by their skill.

[0049] As used herein, “therapeutic effective amount” or “effective amount” means the amount of an active compound or agent that elicits a biological or medical response sought by a researcher, veterinarian, physician or other clinician in a tissue, system, animal, individual or human body, including one or more of the following: (1) prevention of disease; for example, prevention of a disease, condition or symptom in an individual who may be susceptible to the disease, condition or symptom but has not yet developed or exhibited the pathology or symptoms of the disease; (2) inhibition of disease; for example, inhibition of a disease, condition or symptom in an individual who is developing or exhibiting the pathology or symptoms of the disease (i.e., prevention of further development of the pathology and / or symptoms); and (3) improvement of disease; for example, improvement of a disease, condition or symptom in an individual who is developing or exhibiting the pathology or symptoms of the disease (i.e., reversal of the pathology and / or symptoms).

[0050] As used herein, the terms “treat,” “treated,” “treatment,” or “treating” refer to therapeutic treatment aimed at alleviating (reducing) an adverse physical condition, symptom, or disease, or achieving a beneficial or desired clinical outcome. For the purposes described herein, a beneficial or desired clinical outcome includes, but is not limited to: relieving symptoms; reducing the severity of a condition, symptom, or disease; stabilizing (i.e., not worsening) the state of a condition, symptom, or disease; delaying the onset of a condition, symptom, or disease or slowing its progression; improving the state of a condition, symptom, or disease; and whether detectably or undetectably alleviating (partially or completely) or enhancing or improving a condition, symptom, or disease. Treatment includes eliciting a clinically meaningful response without producing excessive levels of side effects. Treatment also includes extending survival compared to expected survival without treatment.

[0051] Unless otherwise stated, the following terms as used herein have the following meanings: "Oxytochemical" refers to O.

[0052] "Amine" refers to -NH2; "Hydroxy group" refers to -OH; "Carboxyl group" refers to -COOH.

[0053] "alkyl" refers to a straight-chain or branched monovalent hydrocarbon group having one to about ten carbon atoms (more preferably one to six carbon atoms). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, etc. Whenever a numerical range such as "C1-C6 alkyl" appears in this document, it means that the alkyl group can consist of 1, 2, 3, 4, 5, or 6 carbon atoms, but this definition also covers the occurrence of the term "alkyl" without a specified numerical range. In some embodiments, alkyl is C1-C6. 10Alkyl group. In some embodiments, the alkyl group is C1-C6 alkyl. In some embodiments, the alkyl group is C1-C5 alkyl. In some embodiments, the alkyl group is C1-C4 alkyl. In some embodiments, the alkyl group is C1-C3 alkyl. Unless otherwise expressly specified in the specification, the alkyl group may optionally be substituted with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl groups. In some embodiments, the alkyl group is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl group is optionally substituted with one or more halogens, -CN, -OH, or -OMe. In some embodiments, the alkyl group is optionally substituted with a halogen.

[0054] "Alkenyl" refers to a straight-chain or branched hydrocarbon monovalent group having one or more carbon-carbon double bonds and having two to about ten carbon atoms (more preferably two to about six carbon atoms). This group may be in cis or trans or Z or E conformations around the double bond, and should be understood to include both isomers. Examples include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. Whenever a numerical range such as "C2-C6 alkenyl" appears herein, it means that the alkenyl group may consist of 2, 3, 4, 5, or 6 carbon atoms, but this definition also covers the occurrence of the term "alkenyl" where no numerical range is specified. Unless otherwise expressly specified in the specification, the alkenyl group may optionally be substituted with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl groups. In some embodiments, the alkenyl group is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2 groups. In some embodiments, the alkenyl group is optionally substituted with one or more halogens, -CN, -OH, or -OMe groups. In some embodiments, the alkenyl group is optionally substituted with a halogen.

[0055] "Alynyl" refers to a straight-chain or branched hydrocarbon monovalent group having one or more carbon-carbon triple bonds and having two to about ten carbon atoms (more preferably two to about six carbon atoms). Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. Whenever a numerical range such as "C2-C6 alkynyl" appears herein, it means that the alkynyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, but this definition also covers the occurrence of the term "alkynyl" where no numerical range is specified. Unless otherwise expressly specified in the specification, the alkynyl group may optionally be substituted with, for example, one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl groups. In some embodiments, the alkynyl group may optionally be substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2 groups. In some embodiments, the alkynyl group is optionally substituted with one or more halogens, -CN, -OH, or -OMe. In some embodiments, the alkynyl group is optionally substituted with a halogen.

[0056] "alkylene" refers to a straight-chain or branched divalent hydrocarbon chain. Unless otherwise expressly specified in the specification, the alkylene group may optionally be substituted with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl groups. In some embodiments, the alkylene group is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2 groups. In some embodiments, the alkylene group is optionally substituted with one or more halogens, -CN, -OH, or -OMe groups. In some embodiments, the alkylene group is optionally substituted with a halogen.

[0057] "Alkoxy" refers to a free radical of the formula -O alkyl, where alkyl is defined as above. Unless otherwise expressly specified in the specification, the alkoxy group may optionally be substituted with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl groups. In some embodiments, the alkoxy group is optionally substituted with one or more halogens, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy group is optionally substituted with one or more halogens, -CN, -OH, or -OMe. In some embodiments, the alkoxy group is optionally substituted with a halogen.

[0058] "Aryl" refers to a free radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. Aryl free radicals can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which can include fused ring systems (where the aryl group is bonded via aromatic ring atoms when fused with a cycloalkyl or heterocyclic alkyl ring) or bridged ring systems. In some embodiments, the aryl group is a 6- to 10-membered aryl group. In some embodiments, the aryl group is a 6-membered aryl (phenyl). Aryl free radicals include, but are not limited to, anthracene, naphthyl, phenanthryl, azulel, phenyl, phenanthyl, fluorenyl, as-indacenyl, s-indacenyl, indenyl, phenalenyl, phenanthryl, pleiadenyl, pyrene, and triphenylenyl. Unless otherwise expressly specified in the specification, the aryl group may optionally be substituted with, for example, one or more halogens, amino groups, nitriles, nitro groups, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups. In some embodiments, the aryl group is optionally substituted with one or more halogens, methyl groups, ethyl groups, -CN groups, -COOH groups, -COOMe groups, -CF3 groups, -OH groups, -OMe groups, -NH2 groups, or -NO2 groups. In some embodiments, the aryl group is optionally substituted with one or more halogens, methyl groups, ethyl groups, -CN groups, -CF3 groups, -OH groups, or -OMe groups. In some embodiments, the aryl group is optionally substituted with a halogen.

[0059] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbon ring, which can include fused ring systems (where the cycloalkyl group is bonded by non-aromatic atoms when fused with an aryl or heteroaryl ring), spirocyclic systems, and / or bridged ring systems. In some embodiments, the cycloalkyl group is fully saturated. Representative cycloalkyl groups include, but are not limited to, cycloalkyl groups having three to fifteen carbon atoms (e.g., C3-C5). 15 Fully saturated cycloalkyl or C3-C 15 Cycloalkenyl), cycloalkyl groups having three to ten carbon atoms (e.g., C3-C10), and cycloalkyl groups having three to ten carbon atoms. 10 Fully saturated cycloalkyl or C3-C 10The cycloalkyl group is a 3- to 10-membered fully saturated cycloalkyl group or a 3- to 6-membered cycloalkyl group. In some embodiments, the cycloalkyl group is a 3- to 6-membered fully saturated cycloalkyl group or a 3- to 6-membered cycloalkyl group. In some embodiments, the cycloalkyl group is a 5- to 6-membered fully saturated cycloalkyl group or a 5- to 6-membered cycloalkyl group. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornel, decahydronaphthyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cis-decahydronaphthyl, trans-decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl and bicyclo[3.3.2]decyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[3.1.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, spiro[4.2]heptyl, spiro[4.3]octyl, spiro[5.2]octyl, spiro[3.3]heptyl and spiro[5.3]nonyl. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise expressly specified in the specification, the cycloalkyl group is optionally substituted with, for example, one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl groups. In some embodiments, the cycloalkyl group is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2 groups. In some embodiments, the cycloalkyl group is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe groups. In some embodiments, the cycloalkyl group is optionally substituted with a halogen.

[0060] "Halogen" or "halogen" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

[0061] "Halogenated alkyl" refers to an alkyl radical as defined above that is substituted by one or more halogenated radicals as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 2-fluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0062] "Heterocyclic alkyl" refers to a 3- to 24-membered partially or fully saturated cyclic radical comprising 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocyclic alkyl is fully saturated. In some embodiments, the heterocyclic alkyl is C-linked. In some embodiments, the heterocyclic alkyl is N-linked. In some embodiments, the heterocyclic alkyl contains 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic alkyl contains 1 to 3 heteroatoms selected from nitrogen and oxygen. In some embodiments, the heterocyclic alkyl contains 1 to 3 nitrogen atoms. In some embodiments, the heterocyclic alkyl contains 1 or 2 nitrogen atoms. In some embodiments, the heterocyclic alkyl contains 1 nitrogen atom. In some embodiments, the heterocyclic alkyl contains 1 nitrogen atom and 1 oxygen atom. Unless otherwise expressly specified in the specification, heterocyclic alkyl radicals can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused ring systems (where the heterocyclic alkyl group is bonded through non-aromatic atoms when fused with an aryl or heteroaryl ring), spirocyclic, or bridged ring systems; and the nitrogen, carbon, or sulfur atom in the heterocyclic alkyl radical may optionally be oxidized; the nitrogen atom may optionally be quaternized. Representative heterocyclic alkyl groups include, but are not limited to, heterocyclic alkyl groups having two to fifteen carbon atoms (e.g., C2-C15). 15 Fully saturated heterocyclic alkyl or C2-C 15 Heterocyclic alkenyl groups, heterocyclic alkyl groups having two to ten carbon atoms (e.g., C2-C10) 10 Fully saturated heterocyclic alkyl or C2-C 10Heterocyclic alkenyl groups, heterocyclic alkyl groups having two to eight carbon atoms (e.g., fully saturated C2-C8 heterocyclic alkyl groups or C2-C8 heterocyclic alkenyl groups), heterocyclic alkyl groups having two to seven carbon atoms (e.g., fully saturated C2-C7 heterocyclic alkyl groups or C2-C7 heterocyclic alkenyl groups), heterocyclic alkyl groups having two to six carbon atoms (e.g., fully saturated C2-C6 heterocyclic alkyl groups or C2-C7 heterocyclic alkenyl groups), heterocyclic alkyl groups having two to five carbon atoms (e.g., fully saturated C2-C5 heterocyclic alkyl groups or C2-C5 heterocyclic alkenyl groups), or heterocyclic alkyl groups having two to four carbon atoms (e.g., fully saturated C2-C4 heterocyclic alkyl groups or C2-C4 heterocyclic alkenyl groups). Examples of such heterocyclic alkyl radicals include, but are not limited to, aziridinyl, aziridine, oxadiazinyl, dioxopentyl, thienyl[1,3]dithioheterocyclicbutyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, oxazolyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolyl, pyrazolyl. Quinoyl, thiazolyl, tetrahydrofuranyl, trithiayl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxacyclopenten-4-yl, and 2-oxo-1,3-dioxacyclopenten-4-yl. The term heterocyclic alkyl also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In some embodiments, the heterocyclic alkyl has 2 to 10 carbon atoms in the ring. It should be understood that when referring to the number of carbon atoms in a heterocyclic alkyl group, the number of carbon atoms in the heterocyclic alkyl group is different from the total number of atoms constituting the heterocyclic alkyl group (including heteroatoms) (i.e., the skeletal atoms of the heterocyclic alkyl ring). In some embodiments, the heterocyclic alkyl group is a 3- to 8-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 7-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 6-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 4- to 6-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 5- to 6-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 8-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 7-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 6-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 4- to 6-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 5- to 6-membered heterocyclic alkenyl group.Unless otherwise expressly specified in the specification, the heterocyclic alkyl group is optionally substituted with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocyclic alkyl, heteroaryl, etc. In some embodiments, the heterocyclic alkyl group is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocyclic alkyl group is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocyclic alkyl group is optionally substituted with a halogen.

[0063] "Heteroaryl" refers to a 5- to 14-membered cyclic radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl radical comprises one to three heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl radical comprises one to three heteroatoms selected from nitrogen and oxygen. In some embodiments, the heteroaryl radical comprises one to three nitrogen atoms. In some embodiments, the heteroaryl radical comprises one or two nitrogen atoms. In some embodiments, the heteroaryl radical comprises one nitrogen atom. In some embodiments, the heteroaryl radical is C-linked. In some embodiments, the heteroaryl radical is N-linked. The heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic cyclic system, which can include fused-ring systems (where the heteroaryl radical is bonded by aromatic ring atoms when fused with a cycloalkyl or heterocycloalkyl ring) or bridged-ring systems; and the nitrogen, carbon, or sulfur atom in the heteroaryl radical can optionally be oxidized; the nitrogen atom can optionally be quaternized. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl group, comprising one, two, or three heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl group, comprising one, two, or three heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl group is a 6-membered heteroaryl group, comprising one, two, or three heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group, comprising one, two, or three heteroatoms selected from oxygen, nitrogen, and sulfur. Examples include, but are not limited to, azatriyl, acridine, benzimidazolyl, benzothiazolyl, benzoindolyl, benzom-dioxacyclopentenyl, benzofuranyl, benzooxazolyl, benzothiadiazolyl, benzo[b][1,4]dioxacycloheptadienyl, 1,4-benzodioxaneyl, benzonaphthofuranyl, benzodioxinyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothienyl (benzothienyl (benzothiophenyl)), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, cenyl, dibenzofuranyl, dibenzothienyl, furanyl, isothiazolyl Imidazolyl, indazolyl, indolyl, isoindolyl, indololinyl, isoindololinyl, isoquinolinyl, inazinyl, isoxazolyl, naphridinyl, oxadiazolyl, 2-oxoazapyridine, oxazolyl, 1-pyridinyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide, 1-pyridazinyl oxide, 1-phenyl-1H-pyrroleyl, phenazinyl, phenothiazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl).Unless otherwise expressly specified in the specification, the heteroaryl group is optionally substituted with, for example, one or more halogens, amino groups, nitriles, nitro groups, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups. In some embodiments, the heteroaryl group is optionally substituted with one or more halogens, methyl groups, ethyl groups, -CN groups, -COOH groups, -COOMe groups, -CF3 groups, -OH groups, -OMe groups, -NH2 groups, or -NO2 groups. In some embodiments, the heteroaryl group is optionally substituted with one or more halogens, methyl groups, ethyl groups, -CN groups, -CF3 groups, -OH groups, or -OMe groups. In some embodiments, the heteroaryl group is optionally substituted with a halogen.

[0064] TRPM8 antagonist In some implementations, the TRPM8 antagonist is a compound of formula (I): ; in: A is aryl and heteroaryl; B represents aryl and heteroaryl groups; L is independently selected from chemical bonds, oxygen, sulfur, and -NR. 4 -、-(CR C R D ) t -、-O(CR C R D ) t -、-(CR C R D ) t O-、-N(R 4 (CR) C R D ) t -、-(CR C R D ) t N(R 4 )-、-N(R 4 (CR) C R D ) t O- and -O(CR) C R D ) t N(R 4 )- X is independently selected from -CH2-, oxygen, sulfur, and NH; R A and R B Selected independently; (1) Hydrogen, (2) Halogen, (3) (C1-C) 10 )alkyl, (4) (C3-C 10 )cycloalkyl and (5) (C1-C10 ) Haloalkyl; Or R A and R B It can form an oxo group (=O); or R A and R B It can form a 3- to 8-membered ring, which may contain one or more heteroatoms independently selected from oxygen, sulfur, and nitrogen; and the ring may optionally be substituted by one to six substituents independently selected from: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) (C1-C) 10 )alkyl, (5) (C3-C 10 )cycloalkyl, (6) (C1-C 10 ) Haloalkyl, (7) (C1-C 10 )alkoxy and (8) ((C1-C 10 ) Haloalkoxy groups; R C and R D Independently selected from (1) hydrogen, (2) halogen, (3) (C1-C) 10 )alkyl, (4) (C3-C 10 )cycloalkyl and (5) (C1-C 10 ) Haloalkyl; or R C and R D It can form a 3- to 8-membered ring, which may contain one or more heteroatoms independently selected from oxygen, sulfur, and nitrogen; and the ring may optionally be substituted by one to six substituents independently selected from: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) (C1-C) 10 )alkyl, (5) (C3-C 10 )cycloalkyl, (6) (C1-C 10 ) Haloalkyl, (7) (C1-C 10 )alkoxy and (8) (C1-C 10 ) Haloalkoxy groups; R 1 Independently selected from (1) hydrogen, (2) halogen, (3) amino, (4) cyano, (5) hydroxyl, (6) (C1-C) 10 )alkyl, (7) (C3-C 10 )cycloalkyl, (8) (C1-C 10 ) Haloalkyl, (9) (C1-C 10 )alkoxy and (10) (C1-C 10) Haloalkoxy group; two R1s on the same or different carbons may form a 3- to 8-membered ring, which may contain atoms selected from oxygen, sulfur and nitrogen; and said ring is optionally substituted by one to six substituents independently selected from the following: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) (C1-C 10 )alkyl, (5) (C3-C 10 )cycloalkyl, (6) (C1-C 10 ) Haloalkyl, (7) (C1-C 10 )alkoxy and (8) (C1-C 10 ) Haloalkoxy groups; R 2 Independently selected from (1) hydrogen, (2) halogen, (3) amino, (4) -NH(C1-C6)alkyl, (5) -N[(C1-C6)alkyl]2 (wherein the alkyl groups are the same or different), (6) cyano, (7) hydroxyl, (8) nitro, (9) (C1-C6) alkylthio, (10) (C1-C 10 )alkyl, (11) (C3-C 10 )cycloalkyl, (12) (C1-C 10 )alkoxy, (13) (C1-C 10 ) Haloalkyl and (14) (C1-C 10 ) Haloalkoxy groups; R 3 Independently selected from (1) hydrogen, (2) halogen, (3) cyano, (4) nitro, (5) hydroxyl, (6) (C1-C6) alkylthio, (7) (C1-C6) alkylsulfinyl, (8) (C1-C6) alkylsulfonyl, (9) -NR 5 R 6 (10)-C(=O)NR 5 R 6 (11) Tri(C1-C6)alkylsilyl, (12) (C1-C6)alkylsilyl 10 )alkyl, (13) (C3-C 10 )cycloalkyl, (14) (C1-C6)alkoxy (C0-C6)alkyl, (15) (C3-C 10 )cycloalkoxy, (16)-C(=O)(C1-C6)alkyl, (17)-C(=O)O(C1-C6)alkyl and (18)-C(=O)OH; the (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C1-C6)alkoxy, (C0-C6)alkyl and (C3-C 10The cycloalkoxy group is optionally substituted by one to six substituents independently selected from the following: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) cyano, (5) (C3-C) 10 )cycloalkyl, (6) (C1-C 10 ) Haloalkyl, (7) (C1-C 10 )alkoxy, (8) (C1-C 10 ) Haloalkoxy and (9)-NR 6 R 5 ; Where R 5 and R 6 They can form 3- to 10-membered rings together with the nitrogen atoms to which they are attached, the 3- to 10-membered rings may contain atoms selected from oxygen, sulfur and nitrogen; and said rings may optionally be substituted by one to six substituents independently selected from the following: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) (C1-C) 10 )alkyl, (5) (C3-C 10 )cycloalkyl, (6) (C1-C 10 ) Haloalkyl, (7) (C1-C 10 )alkoxy and (8) (C1-C10) haloalkoxy; R 4 R 5 and R 6 Independently selected from (1) hydrogen, (2) (C1-C 10 )alkyl, (3) (C3-C 10 )cycloalkyl, (4) (C1-C 10 ) Haloalkyl, (5) hydroxyl (C1-C 10 )alkyl, (6) (C1-C 10 )alkoxy (C1-C 10 )alkyl, (7)H2N-(C1-C 10 )alkyl, (8)[(C1-C 10 )alkyl]NH-(C1-C 10 )alkyl, (9) [(C1-C 10 )alkyl]2N-(C1-C 10 )alkyl, (10) (C1-C 10 )alkyl carbonyl and (11) (C1-C 10 )alkylsulfonyl; p is 1, 2, 3 or 4; q is 1, 2, 3, or 4; when q is two or greater than two, R 1 Same or different, r is 1, 2, 3, or 4; when r is two or greater than two, R 2 Same or different, s is 1, 2, 3, 4, 5, 6, or 7; when s is two or greater than two, R 3 Same or different, t is 1, 2, or 3; when t is two or greater than two, R C and R D Same or different, Or its pharmaceutically acceptable salt.

[0065] In some implementations, the TRPM8 antagonist is a compound selected from the following: 3-(2-(2,5-dimethyl-l-(5-methylisoxazol-3-yl)-1H-pyrrolo-3-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione; 3-(2-(2,5-dimethyl-1-phenyl-1H-imidazol-4-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro-[4,5]decane-2,4-dione; 6-(4-(2-(2,4-dioxo-1,3-diazaspiro[4.5]decane-3-yl)acetyl)phenyl)pyridinecarboxylonitrile; 3-(2-(l-(3-chlorophenyl)-2,5-dimethyl-1H-imidazol-4-yl)-2-oxoethyl)-8,8-difluoro-1,3-di-azaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-(l-(3-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-yl)-2-oxoethyl)-1,3-di-azaspiro[4.5]decane-2,4-dione; 3-(2-(l,4-dimethyl-5-phenyl-1H-pyrazol-3-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro-[4,5]decane-2,4-dione; 8,8-Difluoro-3-(2-(4-(6-methylpyrazin-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 6-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decane-3-yl)acetyl)phenyl)pyridinecarboxylonitrile; 8,8-Difluoro-3-(2-(2'-(hydroxymethyl)-[l,r-biphenyl]-4-yl)-2-oxoethyl)-1,3-diazaspiro-[4,5]decane-2,4-dione; 8,8-Difluoro-3-(2-(4-(3-methylpyrazin-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 3-(2-(2,5-dimethyl-l-phenyl-1H-imidazol-4-yl)-2-oxoethyl)-8,8-difluoro-l-oxa-3-azaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-(4-(2-(hydroxymethyl)pyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro-[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-(4-(4-(hydroxymethyl)pyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro-[4.5]decane-2,4-dione; 3-(2-(2,5-dimethyl-l-(5-methylisoxazol-3-yl)-1H-pyrrolo-3-yl)-2-oxoethyl)-8,8-difluoro-l-oxa-3-azaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-(5-(2-(hydroxymethyl)phenyl)-4-methylthiophen-2-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 3-(2-(4-(3-(hydroxymethyl)pyrazin-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 3-(2-(1,4-dimethyl-5-phenyl-1H-pyrazol-3-yl)-2-oxoethyl)-8,8-difluoro-1-oxa-3-azaspiro-[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 3-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decane-3-yl)acetyl)phenyl)pyrazine-2-carboxylonitrile; 3-(2-(l,4-dimethyl-5-phenyl-1H-pyrrolo-2-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-(4-(3-(hydroxymethyl)pyrazin-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro-[4.5]decane-2,4-dione; 3-(2-(6-(methyl(pyridin-2-yl)amino)pyridin-3-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 3-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decane-3-yl)acetyl)phenyl)pyridinecarboxylonitrile; 8,8-Difluoro-3-(2-oxo-2-(4-(quinolin-8-yl)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 3-(2-(4-(1H-indol-4-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-oxo-2-(4-(quinolin-2-yl)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-(4-(isoquinoline-8-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-(4-(isoquinoline-1-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-(4-(furano[3,2-c]pyridin-4-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-(6-(methyl(pyridin-2-yl)amino)pyridin-3-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-(6-(methyl(phenyl)amino)pyridin-3-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-(4-(3-fluoropyridin-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 3-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decane-3-yl)acetyl)phenyl)isonicotinonitrile; 8,8-Difluoro-3-(2-(4-(2-methoxypyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-(4-(4-methoxypyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-oxo-2-(4-(2-oxoindoline-4-yl)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 3-(2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione; 3-(2-(4-(1H-pyrrolo[3,2-c]pyridin-4-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro-[4,5]decane-2,4-dione; 3-(2-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro-[4,5]decane-2,4-dione; 3-(2-(4-(3-chloropyridin-2-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-(4-(2-methyl-1H-benzo[d]imidazol-1-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 3-(2-(4-(1H-indazol-4-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione; 3-(2-(6-(1H-indazol-4-yl)pyridin-3-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione; 3-(2-(4-(1H-benzo[d]imidazol-1-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione; 3-(5-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decane-3-yl)acetyl)-1,3-dimethyl-1H-pyrrole-2-yl)benzylnitrile; 3-(2-(4-(1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro-[4,5]decane-2,4-dione; 8,8-Difluoro-3-(2-(3-fluoro-4-(quinolin-8-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 3-(5-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decane-3-yl)acetyl)-1-methyl-1H-pyrrole-2-yl)benzylnitrile; 3-(5-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decane-3-yl)acetyl)-3-methylthiophene-2-yl)benzylnitrile; 8,8-Difluoro-3-(2-(4-(2-(2-(2-hydroxyethoxy)pyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-(5-(3-fluorophenyl)-1,4-dimethyl-1H-pyrrolo-2-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 3-(2-(5-(3-chlorophenyl)-1,4-dimethyl-1H-pyrrolo-2-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione; 3-(5-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decane-3-yl)acetyl)-1,3-dimethyl-1H-pyrrole-2-yl)benzamide; 8,8-Difluoro-3-(2-(5-(2-fluorophenyl)-1,4-dimethyl-1H-pyrrolo-2-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 3-(2-(4-(1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro-[4,5]decane-2,4-dione; 3-(2-(4-(1H-pyrazolo[4,3-c]pyridin-4-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro-[4,5]decane-2,4-dione; 3-(2-(4-(1H-indazol-1-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-(5-(3-fluorophenyl)-1-methyl-1H-imidazol-2-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-(4-(2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4,5]decane-2,4-dione; 8,8-Difluoro-3-(2-oxo-2-(4-(pyridin-2-yloxy)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 3-(2-(5-(3,5-difluorophenyl)-1,4-dimethyl-1H-pyrrolo-2-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-(2'-methyl-[3,3'-bipyridin]-6-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 3-(2-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione; 3-(2-(6-(1H-pyrrolo[2,3-c]pyridin-4-yl)pyridin-3-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-(4-(3-(2-hydroxyethoxy)pyrazin-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-oxo-2-(4-(phthalazin-1-yl)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 3-(2-(4-(3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro-[4,5]decane-2,4-dione; 3-(2-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decane-3-yl)acetyl)-4-methylthiazolyl-5-yl)benzylnitrile; 3-(2-(l,4-dimethyl-5-phenyl-1H-imidazol-2-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro-[4,5]decane-2,4-dione; 8,8-Difluoro-3-(2-(5-(3-fluorophenyl)-1,4-dimethyl-1H-imidazol-2-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 3-(2-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decane-3-yl)acetyl)-1,4-dimethyl-1H-imidazol-5-yl)benzylnitrile; 8,8-Difluoro-3-(2-(5-(isoquinolin-8-yl)-1,4-dimethyl-1H-imidazol-2-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-(5-(2-(hydroxymethyl)phenyl)-1,4-dimethyl-1H-imidazol-2-yl)-2-oxo-ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-(4-(2-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-(5-(3-fluorophenyl)-1,4-dimethyl-1H-pyrrolo-3-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 3-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decane-3-yl)acetyl)-1,3-dimethyl-1H-pyrrole-2-yl)benzylnitrile; 3-(2-(5-(1H-benzo[d]imidazol-1-yl)pyrazin-2-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro-[4,5]decane-2,4-dione; 3-(2-(4-(2,7-naphthid-1-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-oxo-2-(4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-(5-(2-(hydroxymethyl)phenyl)pyrazin-2-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-(5-(4-methoxypyridin-3-yl)pyrazin-2-yl)-2-oxoethyl)-1,3-diazaspiro-[4,5]decane-2,4-dione; 3-(5-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decane-3-yl)acetyl)-2,4-dimethylthiophene-3-yl)benzamide; 3-(2-(5-(3,5-difluorophenyl)-1,4-dimethyl-1H-imidazol-2-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-oxo-2-(4-(pyridazin-3-yloxy)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-oxo-2-(4-(2-oxo-1H-imidazo[4,5-b]pyridin-3(2H)-yl)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 3-(2-(5-(3,5-difluorophenyl)-4-methylthiazolyl-2-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione; 4'-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decane-3-yl)acetyl)-2'-methoxy-[l,r-biphenyl]-2-carboxynitrile; 2-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decane-3-yl)acetyl)phenoxy)nicotinonitrile; 3-(2-(4-((3-chloropyridin-2-yl)oxy)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-(4-(3-(hydroxymethyl)pyridin-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro-[4.5]decane-2,4-dione; 3-(2-(2'-(aminomethyl)-[l,r-biphenyl]-4-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]-decane-2,4-dione; 8,8-Difluoro-3-(2-oxo-2-(6-(quinolin-8-yl)pyridin-3-yl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-(5-(2-methylpyridin-3-yl)pyrazin-2-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 3-(2-(4-(2,7-naphthid-1-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1-oxa-3-azaspiro[4.5]decane-2,4-dione; 3-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decane-3-yl)acetyl)phenyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylonitrile; 8,8-Difluoro-3-(2-oxo-2-(4-(2-oxobenzo[d]oxazol-3(2H)-yl)phenyl)ethyl)-1,3-diazaspiro-[4.5]decane-2,4-dione; 3-(2-(4-(2,5-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4,5]decane-2,4-dione; 8,8-Difluoro-3-(2-(5-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrazin-2-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-(4-(2-methoxy-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-2-oxo-ethyl)-1,3-diazaspiro[4,5]decane-2,4-dione; 8,8-Difluoro-3-(2-(4-(5-methyl-2-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4,5]decane-2,4-dione; 3-(2-(4-(2-(difluoromethyl)-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4,5]decane-2,4-dione; 8,8-Difluoro-3-(2-(4-(5-methyl-2-oxo-1H-imidazo[4,5-b]pyridin-3(2H)-yl)phenyl)-2-oxo-ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 6-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decane-3-yl)acetyl)phenoxy)pyridinecarboxylon; 8,8-Difluoro-3-(2-(4-(5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4,5]decane-2,4-dione; 8,8-Difluoro-3-(2-(4-(3-methoxypyrazin-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 3-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decane-3-yl)acetyl)-3-fluorophenyl)pyrazine-2-carboxylonitrile; 8,8-Difluoro-3-(2-(4-(imidazo[l,2-b]pyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro-[4,5]decane-2,4-dione; 8,8-Difluoro-3-(2-(2'-(2-hydroxyethyl)-[l,r-biphenyl]-4-yl)-2-oxoethyl)-1,3-diazaspiro-[4,5]decane-2,4-dione; 2-(4'-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decane-3-yl)acetyl)-[l,r-biphenyl]-2-yl)acetonitrile; 3-(2-(4-(1H-imidazo[4,5-b]pyrazin-1-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro-[4,5]decane-2,4-dione; 8,8-Difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-l-oxa-3-azaspiro[4.5]decane-2,4-dione; 3-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decane-3-yl)acetyl)phenoxy)pyridazine-4-carboxylonitrile; 8,8-Difluoro-3-(2-(4-(2-(hydroxymethyl)-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4,5]decane-2,4-dione; 8,8-Difluoro-3-(2-oxo-2-(4-(pyrazolo[l,5-a]pyrimidin-3-yl)phenyl)ethyl)-1,3-diazaspiro-[4,5]decane-2,4-dione; 4-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decane-3-yl)acetyl)phenyl)nicotinonitrile; 8,8-Difluoro-3-(2-(2-fluoro-4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 8,8-Difluoro-3-(2-(2-fluoro-4-(3-(hydroxymethyl)pyrazin-2-yl)phenyl)-2-oxoethyl)-1,3-di-azaspiro[4.5]decane-2,4-dione; and 2-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decane-3-yl)acetyl)phenyl)nicotinonitrile; Or its pharmaceutically acceptable salt.

[0066] Compound 1 In some embodiments, the TRPM8 antagonist is compound 1 or a pharmaceutically acceptable salt thereof. Compound 1 is 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione: In some embodiments, compound 1 is in the form of a salt. In some embodiments, compound 1 is in the form of a benzenesulfonate.

[0067] In some embodiments, the TRPM8 antagonist is AMG-333, elismetrep, M8-B, PF-05105679, RGM8-51, or RQ-00203078. In some embodiments, the TRPM8 antagonist is... , , , , or .

[0068] Further forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds provided herein include all cis, trans, cis, trans, engegen (E), and zusammen (Z) isomers and corresponding mixtures thereof. In some cases, the compounds described herein have one or more chiral centers, and each center exists independently in an R or S configuration. The compounds described herein include all diastereomers, enantiomers, and epimers and corresponding mixtures thereof. In other embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers obtained by a single preparation step, combination, or interconversion can be used for the applications described herein. In some embodiments, the compounds described herein are prepared as single stereoisomers of themselves as follows: a racemic mixture of the compounds is reacted with an optically active resolving agent to generate a pair of diastereomer compounds, the diastereomers are separated, and the optically pure enantiomer is recovered. In some embodiments, a dissociable complex is preferred. In some embodiments, diastereomers possess different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.), and these differences are utilized for separation. In some embodiments, diastereomers are separated by chiral chromatography, or preferably by a separation / resolution technique based on solubility differences. In some embodiments, the optically pure enantiomers and the resolving agent are then recovered by any practical method that does not cause racemization.

[0069] Labeled compounds In some embodiments, the compounds described herein are present in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds as a pharmaceutical composition. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to the compounds 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. Examples of isotopes that may be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, respectively. 2 H, 3 H, 13 C 14 C l5 N、 18 O、 17 O、 31 P, 32 P, 35 S,18 F and 36 Cl. Other isotopes containing the aforementioned isotopes and / or other atoms, as well as their pharmaceutically acceptable salts, are within the scope of this invention. Certain isotope-labeled compounds (e.g., those doped with radioactive isotopes such as...) 3 H and 14 Compounds of type C) can be used for drug and / or substrate tissue distribution determination. Tritium isotopes (i.e. 3 H) and carbon-14 isotopes (i.e. 14 C) is particularly preferred due to its ease of preparation and detectability. Furthermore, heavy isotopes (such as deuterium, i.e., 2 H) Substitution brings certain therapeutic advantages due to improved metabolic stability, such as increased in vivo half-life or reduced dose requirement. In some embodiments, one or more hydrogen atoms in the compounds disclosed herein have been replaced by deuterium atoms. In some embodiments, one or more alkyl substituents in the compounds disclosed herein have been replaced by deuterated alkyl substituents.

[0070] In some embodiments, the compounds described herein are labeled in other ways, including but not limited to using chromophores or fluorescent moieties, bioluminescent markers, or chemiluminescent markers.

[0071] Pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts as a pharmaceutical composition.

[0072] In some embodiments, the compounds described herein have acidic or basic groups and thus react with a variety of inorganic or organic bases, as well as inorganic and organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by reacting the purified compounds in their free form with a suitable acid or base alone and separating the resulting salts.

[0073] Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with minerals, organic acids, or inorganic bases. These salts include, but are not limited to, acetates, acrylates, adipates, alginates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, bisulfites, bromides, butyrates, butyn-1,4-dicitates, camphorates, camphorsulfonates, hexanoates, octanoates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, disglucurons, gluconates, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucono-2-glucose, glycerophosphates, glycolates, hemisulfates, heptahydrates, hexyn-1,6-dicitates, hydroxybenzoates, γ-hydroxybenzoates, etc. 2-Hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, pyrosulfonate, pyrophosphate, propynate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, octanoate, sebacic acid salt, sulfonate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and xylenesulfonate.

[0074] Furthermore, the compounds described herein can be prepared into pharmaceutically acceptable salts by reacting their free base form with the following pharmaceutically acceptable inorganic or organic acids: including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, metaphosphoric acid, etc.; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, etc. -(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-en-1-carboxylic acid, glucoheponic acid, 4,4'-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecyl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and mucoconic acid. In some embodiments, other acids (such as oxalic acid), although not pharmaceutically acceptable on their own, are used to prepare salts that can serve as intermediates to obtain the compounds disclosed herein and their pharmaceutically acceptable acid addition salts.

[0075] In some embodiments, the compounds described herein containing free acid groups react with suitable bases (such as hydroxides, carbonates, bicarbonates, and sulfates of pharmaceutically acceptable metal cations), with ammonia, or with pharmaceutically acceptable primary, secondary, tertiary, or quaternary organic amines. Representative salts include alkali metal or alkaline earth metal salts, such as lithium, sodium, potassium, calcium, and magnesium salts, as well as aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and N2SO4. + (C 1- C4 alkyl)4 hydroxides, etc.

[0076] Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. It should be understood that the compounds described herein also include quaternization of any basic nitrogen-containing group they contain. In some embodiments, such quaternization yields water-soluble, oil-soluble, or dispersible products.

[0077] Treatment This article discloses a method for treating cancer in subjects of need, which involves administering a TRPM8 antagonist to the subject.

[0078] In some implementation schemes for treating cancer, the cancer is bladder cancer, breast cancer, bile duct cancer, colorectal cancer, kidney cancer, liver cancer, lung cancer, lymphoma, myeloma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, or skin cancer.

[0079] In some implementations of methods for treating cancer, the cancer is prostate cancer.

[0080] In some implementations of methods for treating cancer, breast cancer is defined as ER-positive breast cancer, ER-positive metastatic breast cancer, or triple-negative breast cancer (TNB).

[0081] In some implementations of methods for treating cancer, myeloma is referred to as multiple myeloma (MM).

[0082] In some implementations of methods for treating cancer, skin cancer is melanoma.

[0083] In some implementations of methods for treating cancer, lung cancer is referred to as small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC).

[0084] In some implementation methods for treating cancer, the cancer is multiple myeloma.

[0085] In some implementations of methods for treating cancer, the cancer is breast cancer.

[0086] In some implementations of methods for treating cancer, the cancer is triple-negative breast cancer (TNB).

[0087] In some implementations of methods for treating cancer, the cancer is melanoma.

[0088] In some implementation methods for treating cancer, the cancer is osteosarcoma.

[0089] In some implementation methods for treating cancer, the cancer is small cell lung cancer (SCLC).

[0090] In some implementations of methods for treating cancer, the cancer is kidney cancer.

[0091] In some implementations of methods for treating cancer, the cancer is bladder cancer.

[0092] In some implementation methods for treating cancer, the cancer is ovarian cancer.

[0093] In some implementations of methods for treating cancer, the cancer is prostate cancer.

[0094] In some implementation methods for treating cancer, the cancer is colorectal cancer.

[0095] In some implementations of methods for treating cancer, the cancer is lymphoma.

[0096] In some embodiments, the compounds and pharmaceutical compositions disclosed herein can be used to treat or prevent cancer progression. In some embodiments, the cancer is a hematologic malignancy or a solid tumor. Hematologic malignancies include leukemia, lymphoma, multiple myeloma, and their subtypes. Lymphomas can be classified in a variety of ways, typically based on the underlying malignant cell type, including Hodgkin lymphoma (typically a cancer of Reed-Sternberg cells, but sometimes also originating from B cells; all other lymphomas are non-Hodgkin lymphomas), B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, Burkitt lymphoma, follicular lymphoma, and other lymphomas as defined herein and known in the art.

[0097] B-cell lymphomas include, but are not limited to, diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), and other B-cell lymphomas as defined herein and known in the art.

[0098] T-cell lymphomas include T-cell acute lymphoblastic leukemia / lymphoma (T-ALL), peripheral T-cell lymphoma (PTCL), T-cell chronic lymphocytic leukemia (T-CLL), Sezary syndrome, and other T-cell lymphomas as defined herein and known in the art.

[0099] Leukemia includes acute myeloid (or myeloid cell) leukemia (AML), chronic myeloid (or myeloid cell) leukemia (CML), acute lymphoblastic (or lymphoblastic) leukemia (ALL), chronic lymphocytic leukemia (CLL), hairy cell leukemia (sometimes classified as lymphoma), and other leukemias as defined herein and known in the art.

[0100] Plasma cell malignancies include lymphoplasmacytic lymphoma, plasmacytoma, and multiple myeloma.

[0101] Solid tumors include melanoma, neuroblastoma, glioma, or five types of carcinoma, such as tumors of the brain, head and neck, breast, lung (e.g., non-small cell lung cancer, NSCLC), reproductive tract (e.g., ovary), upper digestive tract, pancreas, liver, renal system (e.g., kidney), bladder, prostate, and colorectal.

[0102] In some implementations of methods for treating cancer, the cancer is metastatic. In some implementations of methods for treating cancer, the cancer is drug-resistant cancer.

[0103] combination This article discloses a method for treating cancer in subjects of need, which involves administering a combination of a TRPM8 antagonist and an adjunct therapy to the subject.

[0104] In some embodiments, the adjunctive therapeutic agent is a targeted agent, chemotherapy, immunotherapy (IO), radiotherapy, gene therapy, or cell therapy, or any combination thereof. In some embodiments, the adjunctive therapeutic agent is a targeted agent. In some embodiments, the adjunctive therapeutic agent is chemotherapy. In some embodiments, the adjunctive therapeutic agent is immunotherapy (IO). In some embodiments, the adjunctive therapeutic agent is radiotherapy. In some embodiments, the adjunctive therapeutic agent is gene therapy. In some embodiments, the adjunctive therapeutic agent is cell therapy.

[0105] In some implementations, the adjunctive therapeutic agent is a targeted agent selected from the following: apalutamide, dabrafenib, enzalutamide, fulvestrant, ibrutinib, lenalidomide, palbociclib, pomalidomide, sorafenib, tamoxifen, and thalidomide.

[0106] In some implementations, the adjunctive treatment is dabrafenib.

[0107] In some implementations, the additional treatment agent is enzalutamide.

[0108] In some implementations, the additional treatment is ibrutinib.

[0109] In some implementations, the additional treatment agent is lenalidomide.

[0110] In some implementations, the additional treatment agent is sorafenib.

[0111] In some implementations, the additional treatment is tamoxifen.

[0112] In some implementations, the adjunctive therapeutic agent is a chemotherapeutic agent selected from the following: 5-fluorouracil, bleomycin, capecitabine, carboplatin, cisplatin, cyclophosphamide, dacarbazine, docetaxel, doxorubicin, epirubicin, etoposide, etoposide, leucovorin, gemcitabine, ifosfamide, methotrexate, nitrogen mustard, oxaliplatin, prednisolone, procarbazine, vinorelbine, and vinorelbine.

[0113] In some implementations, the additional treatment agent is cisplatin.

[0114] In some implementations, gemcitabine is used as an adjunct therapy.

[0115] In some implementations, the additional treatment agent is oxaliplatin.

[0116] In some implementations, the additional treatment agent is a CTLA-4 blocker, a PD-1 blocker, or a PD-L1 blocker.

[0117] In some implementations, the CTLA-4 blocker is ipilimumab or trimemumab.

[0118] In some implementations, the PD-1 blocker is nivolumab or pembrolizumab.

[0119] In some implementations, the PD-L1 blocker is atezolizumab, avelumab, cimiprimab, or durvalumab.

[0120] As used herein, the terms “combination,” “treatment combination,” or “drug combination” refer to a fixed combination or non-fixed combination in the form of a single dose unit, or a kit of components for combined administration, wherein two or more therapeutic agents may be administered together, simultaneously or independently, or separately at time intervals, particularly where such time intervals allow the combination partners to exhibit synergistic (e.g., co-existing) effects.

[0121] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat the therapeutic condition or symptom described in this disclosure. Such administration includes co-administering these therapeutic agents in a substantially simultaneous manner, such as administration as a single formulation having a fixed proportion of active ingredients, or administration as separate formulations targeting each active ingredient (e.g., capsules and / or intravenous formulations). Furthermore, such administration also includes using each type of therapeutic agent sequentially or separately, whether at approximately the same time or at different times. Regardless of whether the active ingredients are administered as a single formulation or as separate formulations, these medications are administered to the same patient as part of the same course of treatment. In any case, the treatment regimen will provide a beneficial effect in treating the condition or symptom described herein.

[0122] In some embodiments, the combination is used for simultaneous, sequential, or separate administration. Within the meaning of this embodiment, simultaneous therapeutic use refers to the administration of at least two active ingredients via the same route and simultaneously or substantially simultaneously.

[0123] Within the meaning of this implementation scheme, separate use specifically refers to the simultaneous or substantially simultaneous application of at least two active ingredients through different routes.

[0124] Sequential therapeutic use refers to the application of at least two active ingredients at different times, via the same or different routes of administration. More specifically, the method of administration refers to the complete application of one active ingredient before the application of any other active ingredient or ingredient.

[0125] In some embodiments, the combination is a fixed combination. In some embodiments, the combination is a non-fixed combination. As used herein, the terms "fixed combination," "fixed dose," and "single formulation" refer to a single carrier or mediator or dosage form formulated to deliver two therapeutic agents to a patient in a combination therapeutically effective amount for treating cancer. A single mediator is designed to deliver a specific amount of each agent along with any pharmaceutically acceptable carrier or excipient. In some embodiments, the mediator is a tablet, capsule, pill, or patch. In other embodiments, the mediator is a solution or suspension.

[0126] The terms "non-fixed combination" or "component kit" refer to combinations of therapeutic agents disclosed herein administered simultaneously, in parallel, or sequentially to a patient as separate entities, without a specific time limit, wherein such administration provides a therapeutically effective level of two compounds within the body of the subject in need. The latter also applies to cocktail therapies, such as the administration of three or more active ingredients.

[0127] Example The invention is illustrated in more detail by the following embodiments, which should not be construed as limiting.

[0128] Example 1: Cell proliferation assay: Place 15 mL of cell culture medium in a T75 flask (Corning, 430639) and place the flask in a humidified 37°C / 5% CO2 incubator (ThermoFisher, 371) for 15 minutes to allow the culture medium to equilibrate to the appropriate pH and temperature.

[0129] Remove the frozen vials of cell stock from liquid nitrogen and thaw rapidly by gently agitating them in a 37°C water bath for 1–2 minutes. Then, clean them with 70% ethanol in a Class II biosafety cabinet before opening. Transfer dropwise the vial contents to 10 mL of cell culture medium in a sterile 15 mL conical tube (BD-Falcon, 352097). Centrifuge the cells at 200 xg for 5 minutes (Eppendorf, 5810R). Aspirate the supernatant and resuspend the cell pellet in 1 mL of fresh cell culture medium, then transfer it to a T75 flask containing cell culture medium. Maintain the cells by adding fresh medium or changing the medium. Change the medium every 2–3 days. Harvest the cells from the flask and count them. Dilute the cells to the set density with medium and seed 135 μL of the cell suspension into each well of a 96-well cell culture plate (Corning, 3599).

[0130] Compound 1 benzenesulfonate (10 μM and 30 μM), dabrafenib (1 μM), cisplatin (5 μM), gemcitabine (0.002 μM), lenalidomide (5 μM), enzalutamide (1 μM), sorafenib (6 μM), oxaliplatin (2 μM), tamoxifen (5 μM), carboplatin (2 μM), and ibrutinib (5 μM) were prepared. A 10X intermediate plate was prepared. The compounds were diluted with culture medium. Based on the plate plot, 15 μl of the compound-medium solution was added from each well of the 10X intermediate plate to the cells in a 96-well assay plate. The final DMSO concentration was 0.1%. Compound 1 was tested in triplicate. The plates were incubated at 37°C for 5 days without changing the culture medium during the treatment.

[0131] After days 0, 1, 2, 3, 4, and 5, remove the plate from the incubator and equilibrate at room temperature for 15 minutes. Equilibrate CellTiter Glo reagent (Promega, G7571) to room temperature before the experiment. Using a multichannel pipette, slowly transfer 50 μL of culture medium into each well without touching the bottom of the pipette tip. Add 100 μL of CellTiter-Glo reagent (1:1 with culture medium) to each test well. Incubate the plate at room temperature for 30 minutes, then read the values ​​using EnVision (Perkin Elmer). Cell viability is calculated using the following formula: Y=(Lum 测试 - Lum 空白 ) / (Lum DMSO - Lum 空白 ) Blank: Culture medium Example 2: Cell proliferation assay of KMS-26 cell line (multiple myeloma) The KMS-26 cell line was used in the proliferation assay described in Example 1, using compound 1 (10 μM and 30 μM) and lenalidomide (5 μM). Figure 1 ).

[0132] Example 3: Cell proliferation assay of JJN-3 cell line (multiple myeloma) The JJN-3 cell line was used in the proliferation assay described in Example 1, using compound 1 (10 μM and 30 μM) and lenalidomide (5 μM). Figure 2 ).

[0133] Example 4: Cell proliferation assay of OPM-2 cell line (multiple myeloma) The OPM-2 cell line was used in the proliferation assay described in Example 1, using compound 1 (10 μM and 30 μM) and lenalidomide (5 μM). Figure 3 ).

[0134] Example 5: Cell proliferation assay of MCF7 cell line (breast cancer) The MCF7 cell line was used in the proliferation assay described in Example 1, using compound 1 (10 μM and 30 μM) and tamoxifen (5 μM). Figure 4 ).

[0135] Example 6: Cell proliferation assay of MDA-MB-231 cell line (TNB breast cancer) The MDA-MB-231 cell line was used in the proliferation assay described in Example 1, using compound 1 (10 μM and 30 μM) and gemcitabine (0.002 μM). Figure 5 ).

[0136] Example 7: Cell proliferation assay of HMC-1-8 cell line (breast cancer) The HMC-1-8 cell line was used in the proliferation assay described in Example 1, using compound 1 (10 μM and 30 μM) and sorafenib (6 μM). Figure 6 ).

[0137] Example 8: Cell proliferation assay of SK-MEL-28 cell line (melanoma) The SK-MEL-28 cell line was used in the proliferation assay described in Example 1, using compound 1 (10 μM and 30 μM) and dabrafenib (1 μM). Figure 7 ).

[0138] Example 9: Cell proliferation assay of A101D cell line (melanoma) The A101D cell line was used in the proliferation assay described in Example 1, using compound 1 (10 μM and 30 μM) and dabrafenib (1 μM). Figure 8 ).

[0139] Example 10: Cell proliferation assay of Hs 294T cell line (melanoma) The Hs 294T cell line was used in the proliferation assay described in Example 1, using compound 1 (10 μM and 30 μM) and dabrafenib (1 μM). Figure 9 ).

[0140] Example 11: Cell proliferation assay of MDA-MB-435S cell line (melanoma) The MDA-MB-435S cell line was used in the proliferation assay described in Example 1, using compound 1 (10 μM and 30 μM) and dabrafenib (1 μM). Figure 10 ).

[0141] Example 12: Cell proliferation assay of HOS cell line (osteosarcoma) The HOS cell line was used in the proliferation assay described in Example 1, using compound 1 (10 μM and 30 μM) and cisplatin (5 μM). Figure 11 ).

[0142] Example 13: Cell proliferation assay of Saos-2 cell line (osteosarcoma) The Saos-2 cell line was used in the proliferation assay described in Example 1, using compound 1 (10 μM and 30 μM) and cisplatin (5 μM). Figure 12 ).

[0143] Example 14: Cell proliferation assay of NCI-H2081 cell line (SCLC lung cancer) The NCI-H208 cell line was used in the proliferation assay described in Example 1, using compound 1 (10 μM and 30 μM) and cisplatin (5 μM). Figure 13 ).

[0144] Example 15: Cell proliferation assay of ACHN cell line (renal carcinoma) The ACHN cell line was used in the proliferation assay described in Example 1, using compound 1 (10 μM and 30 μM) and sorafenib (6 μM). Figure 14 ).

[0145] Example 16: Cell proliferation assay of G-402 cell line (renal carcinoma) The G-402 cell line was used in the proliferation assay described in Example 1, using compound 1 (10 μM and 30 μM) and sorafenib (6 μM). Figure 15 ).

[0146] Example 17: Cell proliferation assay of T24 cell line (bladder cancer) The T24 cell line was used in the proliferation assay described in Example 1, using compound 1 (10 μM and 30 μM) and gemcitabine (0.002 μM). Figure 16 ).

[0147] Example 18: Cell proliferation assay of OAW28 cell line (ovarian cancer) The OAW28 cell line was used in the proliferation assay described in Example 1, using compound 1 (10 μM and 30 μM) and carboplatin (2 μM). Figure 17 ).

[0148] Example 19: Cell proliferation assay of LNCaP cell line (prostate cancer) The LNCaP cell line was used in the proliferation assay described in Example 1, using compound 1 (10 μM and 30 μM) and enzalutamide (1 μM). Figure 18 ).

[0149] Example 20: Cell proliferation assay of Caco-2 cell line (colorectal cancer) The Caco-2 cell line was used in the proliferation assay described in Example 1, using compound 1 (10 μM and 30 μM) and oxaliplatin (2 μM). Figure 19 ).

[0150] Example 21: Cell proliferation assay of SU-DHL-1 cell line (lymphoma) The SU-DHL-1 cell line was used in the proliferation assay described in Example 1, using compound 1 (10 μM and 30 μM) and ibrutinib (5 μM). Figure 20 ).

Claims

1. A method for treating cancer in a subject of need, the method comprising administering to the subject 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione: (Compound 1), or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, wherein compound 1 is in the form of a salt.

3. The method according to claim 1, wherein compound 1 is in the form of a benzenesulfonate.

4. The method according to any one of claims 1 to 3, wherein the cancer is bladder cancer, breast cancer, bile duct cancer, colorectal cancer, kidney cancer, liver cancer, lung cancer, lymphoma, myeloma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, or skin cancer.

5. The method according to claim 4, wherein the breast cancer is ER-positive breast cancer, ER-positive metastatic breast cancer, or triple-negative breast cancer (TNB).

6. The method according to claim 4, wherein the myeloma is multiple myeloma (MM).

7. The method according to claim 4, wherein the skin cancer is melanoma.

8. The method according to claim 4, wherein the lung cancer is small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC).

9. The method according to any one of claims 1 to 8, further comprising administering an additional therapeutic agent.

10. The method of claim 9, wherein the additional therapeutic agent is a targeted agent, chemotherapy, immunotherapy (IO), radiotherapy, gene therapy, or cell therapy, or any combination thereof.

11. The method of claim 9, wherein the additional therapeutic agent is a targeted agent selected from the group consisting of apalutamide, dabrafenib, enzalutamide, fulvestrant, ibrutinib, lenalidomide, palbociclib, pomalidomide, sorafenib, tamoxifen, and thalidomide.

12. The method of claim 9, wherein the additional therapeutic agent is a chemotherapeutic agent selected from the group consisting of: 5-fluorouracil, bleomycin, capecitabine, carboplatin, cisplatin, cyclophosphamide, dacarbazine, docetaxel, doxorubicin, epirubicin, etoposide, etoposide, leucovorin, gemcitabine, ifosfamide, methotrexate, nitrogen mustard, oxaliplatin, prednisolone, procarbazine, vinorelbine, and vinorelbine.

13. The method of claim 9, wherein the additional therapeutic agent is a CTLA-4 blocker, a PD-1 blocker, or a PD-L1 blocker.

14. The method of claim 13, wherein the CTLA-4 blocker is ipilimumab or trimemumab.

15. The method of claim 13, wherein the PD-1 blocker is nivolumab or pembrolizumab.

16. The method of claim 13, wherein the PD-L1 blocker is atezolizumab, avelumab, cimiprimab, or durvalumab.

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