TAM receptor inhibitors

Abstract

Compounds of formula (I) [Case 1] JPEG2025528215000063.jpg64170 is disclosed. The variables R1-R4, X1-X6, and Het are defined herein. Pharmaceutical compositions containing such compounds and methods of using the compounds to treat TAM-associated disorders are also disclosed.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 399,404, filed August 19, 2022, the contents and disclosure of which are incorporated herein by reference in their entirety. [Background technology]

[0002] TAM receptors include TYRO3, AXL, and MERTK, a well-studied family of receptor tyrosine kinases associated with immune system, kidney, cardiovascular, and cancer diseases. See Graham et al., Nature Reviews 14, 769 (2014) and Paplino et al., Cancers 8, 97 (2016).

[0003] In cancer patients, TAM receptors (e.g., AXL and MERTK) have dual regulatory roles. They control not only tumor cell development and progression, but also the anti-tumor responses of various immune cells. See ibid. Such responses include tumor-associated macrophages (e.g., M1 and M2 phenotypes) activated by the TAM receptor MERTK. See Genard, Frontiers in Immunology 8, 828 (2017). The M2 phenotype plays a central role in tumor progression, metastasis, and post-treatment recurrence, while the M1 phenotype is responsible for the anti-tumor immune response. See ibid.

[0004] It has been reported that (i) overexpression of AXL reduces M1 phenotype macrophages, (ii) overexpression of MERTK reduces M1 phenotype macrophages and increases M2 phenotype macrophages, (iii) selective inhibition of AXL causes drug resistance due to upregulation of MERTK, and (iv) inhibition of both AXL and MERTK enhances antitumor efficacy and antitumor immune responses. See Linger et al., Oncogene, 32, 3420-3431 (2013) and McDaniel et al., Molecular Cancer Therapeutics, 17(11), 2297-2308 (2018).

[0005] Currently, no TAM inhibitors are on the market for the treatment of cancer. A very limited number of compounds are being studied in the preclinical stage. Their efficacy remains unclear.

[0006] There is a need to develop inhibitors of AXL, MERTK, or both, for the treatment of TAM-associated disorders, including cancer, immune system diseases, kidney diseases, and cardiovascular diseases. Summary of the Invention

[0007] The present invention is based on the unexpected discovery that certain heteroaryl compounds effectively inhibit AXL, MERTK, or both, and are suitable for treating cancer, immune system diseases, kidney diseases, and cardiovascular diseases.

[0008] In one aspect, the present invention relates to compounds of formula (I): [ka] In this formula, each of R1 and R2 is independently H, deuterium (D), halo, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 heterocycloalkyl, aryl, heteroaryl or deleted, R3 is H, deuterium, halo, C 1-6 Alkyl, C 3-6 Cycloalkyl, C1-6 Heterocycloalkyl, aryl, heteroaryl or NR 3a R 3b and R 3a and R 3b Each of these independently represents H, deuterium, or C. 1-6 is alkyl or aryl, R4 is H, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 is heterocycloalkyl, X1 is C, CH, CD or S; X2 is C or N; X3 is O, CH, S or NH; at least one of X1, X2 and X3 is O, S, N or NH; X4 is N, CH or CH(CN); X5 is O or NH; X6 is N or CH; Het is [ka] is selected from the group consisting of Two [ka] is a single bond and the other is a double bond, and C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heterocycloalkyl, aryl, heteroaryl and Het each represent deuterium, hydroxyl, halo, nitro, cyano, amino, C 1-6 Acylamino, C 1-6 Alkylamino, C 1-6 Alkyl, C 1-6 Aminoalkyl, C 1-6 Alkoxyl, C 1-6 Alkyl carbonyl, C 3-10 Cycloalkyl, C 1-6It is optionally substituted with one or more of the chemical groups consisting of heterocycloalkyl, aralkyl, aryl, and heteroaryl. The substituents and subsequent occurrences may be further substituted with the above chemical groups.

[0009] Preferably, the compound has the following characteristics: (i) R1 is H or phenyl; (ii) R2 is H, C 1-6 being alkyl or heteroaryl; (iii) R3 is H, methyl, phenyl, pyridinyl, methylamino, or phenylamino; (iv) R4 is H; (v) each of X1 and X2 is C; (vi) Between X1 and X2 [ka] is a double bond, (vii) X3 is O or NH; (viii) X4 is N; (ix) X5 is O; (x) X6 is CH; and (xi) Het is [ka] and optionally substituted with one or more of methyl, ethoxy, phenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methyl-4-fluorophenyl, 2-fluoropyridin-3-yl, and butylenecarbonyl; has one or more of the following.

[0010] A subset of compounds of formula (I) includes compounds of formula (II): [ka] Each of R1, R2, X3 and Het is defined above.

[0011] Some preferred compounds of formula (II) have the following characteristics: R1 is phenyl; R2 is H or heteroaryl; X3 is O or NH; Het is [ka] each of phenyl and heteroaryl is amino, C 1-6 Acylamino, C 1-6 Alkylamino, C 1-6 Alkyl and C 1-6 and Het is optionally substituted with one or more chemical groups consisting of C 1-6 Optionally substituted with one or more of alkyl and phenyl, wherein phenyl is hydroxyl, halo, amino, C 1-6 Alkyl or C 1-6 and optionally substituted with alkoxy.

[0012] Table 1 below lists 178 exemplary compounds of the present invention, ie, compounds 1-178, along with their structures and mass spectrometry (m / z) data. [Table 1] JPEG2025528215000010.jpg252112JPEG2025528215000011.jpg252116JPEG2025528215000012.jpg252112JPEG2025528215000013.jpg252113JPEG2025528215000014.jpg245119JPEG2025528215000015.jpg252111JPEG2025528215000016.jpg252115JPEG2025528215000017.jpg244116JPEG2025528215000018.jpg247117JPEG2025528215000019.jpg252112JPEG2025528215000020.jpg252116JPEG2025528215000021.jpg252113JPEG2025528215000022.jpg252109JPEG2025528215000023.jpg247118JPEG2025528215000024.jpg252108JPEG2025528215000025.jpg246115JPEG2025528215000026.jpg246115JPEG2025528215000027.jpg252113JPEG2025528215000028.jpg248118JPEG2025528215000029.jpg248116JPEG2025528215000030.jpg252111JPEG2025528215000031.jpg252109JPEG2025528215000032.jpg245115JPEG2025528215000033.jpg127156

[0013] Another subset of compounds is N-(4-{[5-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy}phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, N-(4- N-(4-{[5-(3-aminophenyl)-6-(1-methyl-1H-pyrazol-4-yl)furo[2,3-d]pyrimidin-4-yl]oxy}phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridin e-3-carboxamide), N-(4-{[5-(4-aminophenyl)-6-(1-methyl-1H-pyrazol-4-yl)furo[2,3-d]pyrimidin-4-yl]oxy}phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide oxo-1,2-dihydropyridine-3-carboxamide), N-{4-[(5-{3-[(dimethylamino)methyl]phenyl}-6-(1-methyl-1H-pyrazol-4-yl)furo[2,3-d]pyrimidin-4-yl)oxy]phenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxamide (N-{4-[(5-{3-[(dimethylamino)methyl]phenyl}-6-(1-methyl-1H-pyrazol-4-yl)furo[2,3-d]pyrimidin-4-yl)oxy]phenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxamide), 1-(4-fluorophenyl)-N-[4-({5-[3-(methylamino)phenyl]-6-(1-methyl-1H-pyrazol-4-yl)furo[2,3-d]pyrimidin-4-yl}oxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide (1-(4-fluorophenyl)-N-[4-({5-[3-( methylamino)phenyl]-6-(1-methyl-1H-pyrazol-4-yl)furo[2,3-d]pyrimidin-4-yl}oxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide), N-(4-{[5-(3-aminophenyl)-6-(1-methyl-1H-pyrazol-4-yl)furo[2,3-d]pyrimidin-4-yl]oxy}phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide N-(4-{[5-(3-aminophenyl)-6-(1-methyl-1H-pyrazol-4-yl)furo[2,3-d]pyrimidin-4-yl]oxy}phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide), N-(4-{[5-(3-aminophenyl)-6-(1-methyl-1H-pyrazol-4-yl)furo[2,3-d]pyrimidin-4-yl]oxy}phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide N-(4-{[5-(3-amino-phenyl)-6-(1-methyl-1H-pyrazol-4-yl)furo[2,3-d]pyrimidin-4-yl]oxy}phenyl)-1-(4-fluoro-phenyl)-4-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide), N-{4-[(5-{3-[(dimethylamino)-methyl]phenyl}-7H-pyrrolo[2,N-{4-[(5-{3-[(dimethylamino)-methyl]phenyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]phenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, 1-(3,4-difluorophenyl)- N-{4-[(5-{3-[(dimethylamino)methyl]-phenyl}-6-(1-methyl-1H-pyrazol-4-yl)furo[2,3-d]pyrimidin-4-yl)oxy]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxamide (1-(3,4-difluorophenyl)-N-{4-[(5-{3-[(dimethylamino)methyl]-phenyl}-6-(1-methyl-1H-pyrazol-4-yl)furo[2,3-d]pyrimidin-4-yl)oxy]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxamide l)oxy]phenyl}-2-oxo-1,2-di-hydropyridine-3-carboxamide), N-(4-{[5-(3-aminophenyl)-6-(1-methyl-1H-pyrazol-4-yl)furo[2,3-d]pyrimidin-4-yl]oxy}phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-carboxamide -4-yl)furo[2,3-d]pyrimidin-4-yl]oxy}phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide) and N-{4-[(5-{3-[(dimethylamino)methyl]phenyl}-6-(1-methyl-1H-pyrazol-4-yl)furo[2,3-d]pyrimidin-4-yl)oxy]phenyl}-2-(4-fluorophenyl)-1-methyl-3-oxo-2,Contains 3-dihydro-1H-pyrazole-4-carboxamide (N-{4-[(5-{3-[(dimethylamino)methyl]phenyl}-6-(1-methyl-1H-pyrazol-4-yl)furo[2,3-d]pyrimidin-4-yl)oxy]phenyl}-2-(4-fluorophenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide).

[0014] Also within the scope of the present invention is a method of treating a TAM-associated disorder comprising administering to a subject in need thereof an effective amount of any of the compounds described above.

[0015] Additionally, within the scope of the present invention is a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier thereof.

[0016] The term "halo" herein refers to a fluoro, chloro, bromo, or iodo radical. A particular halogen is the fluoro radical (F). The term "amino" refers to a radical derived from an amine that is unsubstituted or mono- / di-substituted with alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. The term "aminoalkyl" refers to NH2-alkyl, i.e., an alkyl substituted with at least one amino group. The term "alkylamino" refers to alkyl-NH-. Examples of aminoalkyl include aminomethyl and 2-aminoethyl. The term "acylamino" refers to -C(O)-NH-.

[0017] The term "alkyl" refers to an alkyl group having 1 to 20 carbon atoms (e.g., C 1-6) and a straight- or branched-chain hydrocarbon group containing a monovalent radical center derived by the removal of a hydrogen atom from a carbon atom of a parent alkane. Exemplary alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, and n-hexyl. The term "alkylcarbonyl" refers to alkyl-C(O)-. The term "haloalkyl" refers to alkyl substituted with one or more halo atoms. Examples include fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl (e.g., 1-fluoroethyl and 2-fluoroethyl), difluoroethyl (e.g., 1,1-, 1,2-, and 2,2-difluoroethyl), and trifluoroethyl (e.g., 2,2,2-trifluoroethyl).

[0018] The term "alkoxy" refers to an -O-alkyl group. Examples are methoxy, ethoxy, propoxy, and isopropoxy. Alkoxy also includes haloalkoxy, i.e., alkoxy substituted with one or more halogens, such as -O-CH2Cl and -O-CHClCH2Cl.

[0019] The term "alkylcarbonyl" refers to a -C(O)-alkyl group.

[0020] The term "cycloalkyl" refers to a non-aromatic, saturated or unsaturated, mono-, bi-, tri-, or tetra-cyclic hydrocarbon group containing 3 to 12 carbons (e.g., C 3-6 and C 3-10) Examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The term "heterocycloalkyl" refers to a non-aromatic, saturated or unsaturated, 3- to 8-membered monocyclic, 8- to 12-membered bicyclic, or 11- to 14-membered tricyclic ring system containing one or more heteroatoms (e.g., O, N, P, and S). Examples include aziridinyl, azetidinyl, pyrrolidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydro-2-H-thiopyran-1,1-dioxidyl, piperazinyl, piperidinyl, morpholinyl, imidazolidinyl, azepanyl, dihydrothiadiazolyl, dioxanyl, and quinuclidinyl. Both "cycloalkyl" and "heterocycloalkyl" also include fused, bridged, and spiro ring systems.

[0021] The term "alkenyl" refers to an alkyl group having 2 to 20 carbon atoms (e.g., C 2-4 , C 2-6 and C 2-10 ) and one or more carbon-carbon double bonds. Examples are ethenyl (also known as vinyl), 1-methylethenyl, 1-methyl-1-propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 1-propenyl, 2-propenyl, 2-butenyl, and 2-pentenyl. The term "alkenylene" refers to an alkyl group having 2 to 20 carbon atoms (e.g., C 2-4 , C 2-6 and C 2-10 ) and a straight or branched divalent unsaturated aliphatic chain having one or more carbon-carbon double bonds.

[0022] The term "alkynyl" refers to an alkynyl group having 2 to 20 carbon atoms (e.g., C 2-4 , C 2-6 and C 2-10 ) and one or more carbon-carbon triple bonds. Examples are ethynyl, 2-propynyl, 2-butynyl, 3-methylbutynyl, and 1-pentynyl. The term "alkynylene" refers to an alkyl group having 2 to 20 carbon atoms (e.g., C 2-4 , C2-6 and C 2-10 ) and a straight or branched divalent unsaturated aliphatic chain having one or more carbon-carbon triple bonds.

[0023] The term "aryl" refers to a monocyclic, 6-carbon, bicyclic, or 10-carbon, or tricyclic, aromatic ring system, where each ring can have one or more (e.g., 1 to 10, 1 to 5, and 1 to 3) substituents. Examples include phenyl, biphenyl, 1- or 2-naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, and indanyl. The term "aralkyl" refers to an alkyl substituted with an aryl group.

[0024] The term "heteroaryl" refers to an aromatic 5- to 8-membered monocyclic, 8- to 12-membered bicyclic, or 11- to 14-membered tricyclic ring system having one or more heteroatoms (e.g., O, N, P, and S). Examples include pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiophenyl, benzofuranyl, pyrazolyl, triazolyl, oxazolyl, thiadiazolyl, tetrazolyl, oxazolyl, isoxazolyl, carbazolyl, furyl, imidazolyl, thienyl, thiazolyl, and benzothiazolyl.

[0025] As used herein, alkyl, alkoxyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, and heteroaryl include both substituted and unsubstituted moieties unless otherwise specified. Examples of substituents include hydroxyl (OH), halo (e.g., F and Cl), amino (NH), cyano (CN), nitro (NO), alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, acylamino, alkylamino, aminoalkyl, haloalkyl (e.g., trifluoromethyl), heterocycloalkyl, alkoxycarbonyl, amido, carboxy (COOH), alkanesulfonyl, alkylcarbonyl, alkenylcarbonyl, carbamido, carbamyl, carboxyl, thioureido, thiocyanato, sulfonamido, aryl, arylamino, aralkyl, and heteroaryl. All substituents may be further substituted.

[0026] The term "compound," when referring to a compound of the present invention, also includes salts, solvates, and prodrugs thereof. Pharmaceutically acceptable salts include those listed in Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2nd Revised Edition, P.H. Stahl and C.G. Wermuth (Eds.), Wiley-VCH, New York (2011). In addition to pharmaceutically acceptable salts, other salts are contemplated herein. They may serve as intermediates in the purification of compounds or the preparation of other pharmaceutically acceptable salts, or may be useful in identifying, characterizing, or purifying compounds of the present invention. A solvate refers to a complex formed between an active compound and a pharmaceutically acceptable solvent. Examples of pharmaceutically acceptable solvents include water, ethanol, isopropanol, ethyl acetate, acetic acid, and ethanolamine. A prodrug refers to a compound that is metabolized to a pharmaceutically active drug after administration. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives.

[0027] The compounds of the present invention may contain one or more non-aromatic double bonds or asymmetric centers. Each of them occurs as a racemate or racemic mixture, a single R enantiomer, a single S enantiomer, an individual diastereomer, a diastereomeric mixture, a cis isomer, or a trans isomer. Such isomeric forms of the compounds are within the scope of the present invention. They may exist as a mixture or may be isolated using chiral synthesis or chiral separation techniques.

[0028] The invention also features the use of one or more of the compounds described above to treat a disorder associated with a TAM (eg, AXL, MERTK, or both).

[0029] The term "TAM" refers to a family of receptor tyrosine kinases that includes TYRO3, AXL, and MERTK.

[0030] The term "AXL" refers to the Axl receptor tyrosine kinase, an enzyme encoded by the AXL gene and expressed in tumor cells and tumor vasculature as well as normal tissues, including bone marrow stroma and myeloid cells.

[0031] The term "MERTK" refers to Mer receptor tyrosine kinase, an enzyme encoded by the MERTK gene.

[0032] The terms "treat" or "treatment" refer to the administration of one or more compounds to a subject for the purpose of providing a therapeutic effect, e.g., slowing, interrupting, inhibiting, controlling, or halting the progression of an existing disorder and / or its symptoms, but not necessarily indicating the complete disappearance of all symptoms. An "effective amount" refers to the amount of compound required to provide a therapeutic effect. Effective doses will vary depending on the type of condition being treated, the route of administration, excipient usage, and the possibility of co-administration with other therapeutic treatments, as will be recognized by those skilled in the art.

[0033] The disorders include cancer, kidney disease, immune system disease, and cardiovascular system disease. The cancer is selected from the group consisting of hepatocellular carcinoma, bladder cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, anal cancer, Merkel cell carcinoma, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, melanoma, ovarian cancer, prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myeloid leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, hairy cell leukemia, Burkitt's lymphoma, glioblastoma, melanoma, and rhabdomyosarcoma. Preferably, the cancer is breast cancer, lung cancer, acute myeloid leukemia, or colon cancer.

[0034] The term "subject" refers to an animal, including a human or non-human, such as a mammal. Humans are the preferred subject.

[0035] The compound of the present invention can be administered alone or in the form of a pharmaceutical composition with a pharmaceutically acceptable carrier, diluent or excipient. Such pharmaceutical compositions and the process for their preparation are known in the art (see, for example, Remington: The Science and Practice of Pharmacy, A. Adejare, Editor, 23rd Edition, Academic Press, 2020).

[0036] To practice the methods of the present invention, compositions or kits containing one or more of the above-described compounds may be administered alone or in combination with at least one other pharmacologically active substance, either simultaneously, in parallel, sequentially, consecutively, alternatingly, or separately. Simultaneous administration, also referred to as combined administration, includes substantially simultaneous administration. Concurrent administration includes administering active agents within the same general period, e.g., on the same day(s), but not necessarily at the same time. Alternating administration includes administering one agent for a period, e.g., over several days or a week, followed by administering the other agent for a subsequent period, e.g., over several days or a week, and repeating the pattern for one or more cycles. Sequential or consecutive administration includes administering one agent using one or more doses during a first period (e.g., over several days or a week), followed by administering the other agent using one or more doses during a second and / or additional period (e.g., over several days or a week). Overlapping schedules may also be employed, which involve administering active agents on different days throughout the treatment period, not necessarily in a regular order. Variations on these general guidelines may also be employed, depending, for example, on the agents used and the subject's condition.

[0037] The elements of the combination of the present invention may be administered by methods conventional to those skilled in the art, for example, by oral, enteral, parenteral, nasal, vaginal, rectal or topical routes of administration (whether dependent or independent), and may be formulated either alone or together in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, excipients and / or vehicles appropriate for each route of administration.

[0038] As used herein, the term "parenteral" refers to subcutaneous, intracutaneous, intravenous, intraperitoneal, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, or intracranial injection and any suitable infusion technique.

[0039] The composition for oral administration can be any orally acceptable dosage form, including capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.For tablets, commonly used carriers include lactose and cornstarch.Lubricants such as magnesium stearate are also usually added.For oral administration in capsule form, useful diluents include lactose and dried cornstarch.When aqueous suspensions or emulsions are orally administered, the active ingredient can be suspended or dissolved in an oil phase combined with an emulsifier or suspending agent.If desired, certain sweeteners, flavors or colorants can be added.

[0040] Nasal aerosol or inhalation compositions can be prepared according to techniques known in the art of pharmaceutical formulation. For example, such compositions can be prepared as a solution in saline, employing benzyl alcohol or other suitable preservatives, absorption enhancers which enhance bioavailability, fluorocarbons and / or other solubilizing or dispersing agents.

[0041] Compositions having one or more of the compounds described above may also be administered in the form of suppositories for rectal administration.

[0042] A carrier in a pharmaceutical composition must be "acceptable" in the sense of being compatible with (and preferably capable of stabilizing) the active ingredient(s) of the composition and not harmful to the subject being treated. One or more solubilizing agents may be utilized as pharmaceutical excipients for delivery of the active compound(s). Examples include colloidal silicon oxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow #10.

[0043] The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. DETAILED DESCRIPTION OF THE INVENTION

[0044] The present invention is based on the surprising discovery that compounds of formula (I), reproduced below, are effective in inhibiting AXL / MERTK activity and treating AXL / MERTK-related disorders, including cancer. In vivo studies demonstrate their effectiveness in treating cancer. [ka]

[0045] The variables R1 to R4, X1 to X6 and Het are defined above.

[0046] Compounds of formula (I) can be prepared by synthetic methods known in the art. See, for example, R. Larock, Comprehensive Organic Transformations (3 rd Ed., John Wiley and Sons 2018), P.G. M. Buts and T.W. Greene, Greene's Protective Groups in Organic Synthesis (4 th Ed., John Wiley and Sons 2007), L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (John Wiley and Sons 1994) and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (2 nd ed., John Wiley and Sons 2009) and its subsequent editions.

[0047] The resulting compounds may be purified according to conventional methods such as crystallization, distillation / vacuum distillation, flash chromatography on silica and preparative liquid chromatography.

[0048] The efficacy of the compounds of the present invention may be initially determined using in vitro methods to identify their AXL and MERTK activity, all of which are described in the Examples below. Selected compounds may be further tested to verify their in vivo efficacy, pharmacokinetic profile, and toxicity, for example, by administering them to animals. Based on the results, an appropriate dosage range and administration route may be determined.

[0049] The compounds of the present invention are preferably formulated into pharmaceutical compositions containing a pharmaceutical carrier, and the pharmaceutical compositions are then administered to a subject in need thereof to inhibit TAM (e.g., AXL and MERTK) and thereby treat a TAM-associated disorder, such as cancer.

[0050] Without further elaboration, it is believed that one skilled in the art can, based on the preceding description, utilize the present invention to its fullest extent. The following examples are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

[0051] All publications cited herein are hereby incorporated by reference in their entirety.

[0052] Examples illustrating the preparation and efficacy evaluation of compounds of the present invention are set forth below. [Example]

[0053] Examples 1 to 178: Synthesis of Compounds 1 to 178 Compounds 1-178 of the present invention were prepared according to the procedures provided below, taking the synthesis of compound 11 as an example. The synthetic steps are shown in Scheme 1 below. Unless otherwise noted, all reagents are commercially available from various suppliers, such as MilliporeSigma (St. Louis, MO) and Fisher Chemical Co. (Waltham, MA). [ka]

[0054] 1-Methyl-4-[(trimethylsilyl)ethynyl]-1H-pyrazole (B). To a solution of 4-iodo-1-methyl-1H-pyrazole (5 g, 24.04 mmol) in dry N,N-dimethylformamide (DMF, 25 mL) was added trimethylsilylacetylene (5.13 mL, 36.06 mmol), diisopropylamine (DIPA, 4.4 mL, 31.25 mmol), CuI (275 mg, 1.44 mmol), triphenylphosphine (1.26 g, 4.81 mmol), and palladium(II) acetate (Pd(OAc)2, 324 mg, 1.44 mmol). The reaction mixture was then heated to 60 °C and stirred for 1.5 h. It was cooled to room temperature, diluted with water, and extracted three times with ether. The combined ether layers were dried over MgSO, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (10-15% ethyl acetate in hexane) to give compound B (2.9 g, 68%) as a brown liquid. 1 H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 7.48 (s, 1H), 3.86 (s, 3H), 0.20 (s, 9H). LRMS (ESI) m / z: 179.2 [M+H] +

[0055] 4-Ethynyl-1-methyl-1H-pyrazole (C). To a solution of compound B (2.9 g, 16.26 mmol) in tetrahydrofuran (THF, 40 mL) at 0 °C, tetra-n-butylammonium fluoride (TBAF, 18 mL, 17.89 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, diluted with water, and extracted three times with ether. The combined ether layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (20% ethyl acetate in hexane) to give compound C (1.3 g, 76%) as a yellow liquid. 1 H NMR (300 MHz, CDCl3) δ 7.58 (s, 1H), 7.51 (s, 1H), 3.87 (s, 3H), 2.99 (s, 1H) LRMS (ESI) m / z: 107.2 [M+H] +

[0056] 6-Chloro-5-iodo-4,5-dihydropyrimidin-4-ol (E). To a solution of 6-chloropyrimidin-4-ol (5 g, 38.31 mmol) in dichloromethane (DCM, 106 mL) was added N-iodosuccinimide (NIS, 9.48 g, 42.14 mmol) and trifluoroacetic acid (TFA, 21.3 mL, 69 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 12 hours and concentrated under reduced pressure. The resulting crude product was washed with water and ether, followed by filtration to give compound E (8.4 g, 85%) as a pink solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 8.16 (s, 1H). LRMS (ESI) m / z: 256.1 [M+H] +

[0057] 4-Chloro-6-(1-methyl-1H-pyrazol-4-yl)furo[2,3-d]pyrimidine (F). To a solution of compound E (6.9 g, 26.91 mmol) in THF (90 mL) was added compound C (2.85 g, 26.91 mmol), Pd(PPh3)4 (1.55 g, 1.35 mmol), CuI (256 mg, 1.35 mmol), and triethylamine (11 mL, 80.7 mmol). The reaction mixture was stirred at 70 °C for 12 h, cooled to room temperature, concentrated under reduced pressure, dissolved in ethyl acetate, and washed with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (15-20% ethyl acetate in hexanes) to give compound F as a white solid (1.9 g, 30%). 1 H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 7.92 (s, 1H), 7.87 (s, 1H), 6.75 (s, 1H), 4.00 (s, 3H). LRMS (ESI) m / z: 235.1 [M+H] +

[0058] 5-Bromo-4-chloro-6-(1-methyl-1H-pyrazol-4-yl)furo[2,3-d]pyrimidine (G). To a solution of compound F (1.9 g, 8.1 mmol) in DMF (20 mL) was added N-bromosuccinimide (NBS, 1.72 g, 9.72 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, warmed to room temperature, and stirred for 2 h. The mixture was then slowly diluted with water and stirred for 30 min to precipitate a white solid, which was collected by filtration to give compound G (1.85 g, 73%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 4.03 (s, 3H). LRMS (ESI) m / z: 313.0 [M+H] +

[0059] 4-{[5-Bromo-6-(1-methyl-1H-pyrazol-4-yl)furo[2,3-d]pyrimidin-4-yl]oxy}aniline (H). To a solution of sodium hydride (232 mg, 5.82 mmol) in DMF (10 mL) was added a solution of 4-aminophenol (577 mg, 5.29 mmol) in THF (10 mL) at 0° C. for 5 min, followed by a solution of compound G (1.65 g, 5.29 mmol) in THF (7.6 mL) and DMF (7.6 mL) at 0° C. The reaction mixture was stirred at room temperature for 12 h before being quenched with water (10 mL). The resulting crude product was taken and stirred in water (50 mL) for 30 minutes to precipitate a solid which was collected by filtration to give compound H as a brown solid (1.85 g, 90.7%). 1 H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 7.05 (d, J = 8.8 Hz, 2H), 6.76 (d, J = 8.8 Hz, 2H), 4.01 (s, 3H), 3.71 (s, 2H). LRMS (ESI) m / z: 386.1 [M+H] +

[0060] N-(4-{[5-bromo-6-(1-methyl-1H-pyrazol-4-yl)furo[2,3-d]pyrimidin-4-yl]oxy}phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (I). To a solution of 1-(4-fluoro-phenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (1.45 g, 6.21 mmol) in DMF (84 mL) at 0 ° C., 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate (TBTU, 2.49 g, 7.77 mmol), N,N-diisopropylethylamine (DIPEA, 3.24 mL, 18.64 mmol), and compound H (2 g, 5.18 mmol) were added. The reaction mixture was stirred at 0 ° C. for 2 hours, warmed to room temperature, stirred for 10 hours, diluted with water (200 mL), and stirred for 20 minutes. The resulting precipitate was collected by filtration to give compound I as a white solid (3.1 g, 100%). 1 H NMR (400 MHz, CDCl3) δ 11.91 (s, 1H), 8.76 (dd, J = 7.2, 2.4 Hz, 1H), 8.45 (s, 1H), 8.20 (s, 1H), 8.13 (s, 1H), 7.85 (d, J = 8.8 Hz, 2H), 7.61 (dd, J = 6.6, 2.4 Hz, 1H), 7.45-7.37 (m, 2H), 7.31-7.21 (m, 3H), 6.61 (dd, J = 7.2, 6.6 Hz, 1H), 4.02 (s, 3H). LRMS (ESI) m / z: 601.1 [M+H] +

[0061] N-(4-{[5-(3-aminophenyl)-6-(1-methyl-1H-pyrazol-4-yl)furo[2,3-d]pyrimidin-4-yl]oxy}phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (11). To a solution of compound I (3.11 g, 5.17 mmol) in DMF (51.7 mL) and THF (51.7 mL) was added (3-aminophenyl)boronic acid (1.06 g, 7.76 mmol), Pd(dppf)Cl (1.14 g, 1.55 mmol), and 2 M NaCO 3(aq) (10.2 mL, 20.69 mmol) was added. The resulting mixture was stirred at 110° C. under argon for 16 h. Subsequently, it was cooled to room temperature, concentrated under reduced pressure, and purified by flash column chromatography (2-3% methanol in dichloromethane) to give compound 11 as a white solid (2.74 g, 86.4%). 1H NMR (400 MHz, DMSO-d6) δ 11.97 (s, 1H), 8.58 (dd, J = 7.6, 2.4 Hz, 1H), 8.45 (s, 1H), 8.11 (dd, J = 7.0, 2.4 Hz, 1H), 8.05 (d, J = 0.8 Hz, 1H), 7.73 (d, J = 9.0 Hz, 2H), 7.61 (dd, J = 8.8, 4.8 Hz, 2H), 7.52 (d, J = 0.8 Hz, 1H), 7.42 (dd, J = 8.8, 8.4 Hz, 2H), 7.20 (d, J = 9.0 Hz, 2H), 7.13 (dd, J = 7.8, 7.6 Hz, 1H), 6.81 (dd, J = 2.2, 1.6 Hz, 1H), 6.74 (ddd, J = 7.6, 1.6, 1.0 Hz, 1H), 6.72 (dd, J = 7.6, 7.0 Hz, 1H), 6.61 (ddd, J = 7.8, 2.2, 1.0 Hz, 1H), 5.21 (s, 2H), 3.87 (s, 3H). LRMS (ESI) m / z: 614.3 [M+H] +

[0062] HRMS(ESI)m / z:C 34 H 24 For F1N7Na1O4, the calculated value is 636.1772 [M+Na] + While it was 636.1771.

[0063] Compounds 1-10 and 12-178 were prepared following similar procedures as described above with appropriate reagents either commercially available or prepared according to procedures known in the art. 1 H-NMR data is provided below, see Table 2. [Table 2] JPEG2025528215000037.jpg252153JPEG2025528215000038.jpg252158JPEG2025528215000039.jpg252153JPEG2025528215000040.j pg252153JPEG2025528215000041.jpg252153JPEG2025528215000042.jpg252156JPEG2025528215000043.jpg252156JPEG2025528215 000044.jpg252158JPEG2025528215000045.jpg252152JPEG2025528215000046.jpg252153JPEG2025528215000047.jpg252153JPEG20 25528215000048.jpg252157JPEG2025528215000049.jpg252153JPEG2025528215000050.jpg252152JPEG2025528215000051.jpg54170

[0064] AXL and MERTK inhibitory activity in vitro activity The resulting exemplary compounds of formula (I) were evaluated for in vitro efficacy in inhibiting AXL and MERTK proteins.

[0065] Purified kinases (AXL or MERTK) were incubated with compounds or DMSO (control) in assay buffer (25 mM Tris, pH 7.4, 10 mM MgCl, 4 mM MnCl, 2 mM DTT, 0.01% BSA, 0.02% Triton X-100, 0.01% Brij 35, and 0.5 mM NaVO for MERTK; 40 mM Tris, pH 7.4, 20 mM MgCl, 2 mM DTT, 0.01% BSA, and 0.5 mM NaVO for AXL) for 15 min. The substrates and ATP (12 μM for MERTK and 50 μM for AXL) prepared above were added. The mixtures were incubated at 30°C for 3 h. Kinase activity was determined by calculating luminescence using the Kinase Glo Assay Kit for MERTK and the ADP-Glo ​​Kinase Assay Kit for AXL according to the manufacturer's instructions (Promega, Madison, Wis.).

[0066] The results are shown in Table 3 below. [Table 3] JPEG2025528215000053.jpg252134JPEG2025528215000054.jpg184169

[0067] In Table 2 above, "+++" indicates IC 50 "++" indicates IC values ​​less than 20 nM 50 The IC value is between 20 nM and 100 nM, and "+" indicates IC 50 Indicates values ​​greater than 100 nM but less than 50,000 nM.

[0068] In vitro enzyme assay A study was conducted to compare exemplary compounds of Formula (I) in inhibiting TAM activity, including MERTK, AXL, and TYRO3. An enzyme assay was used in this study. Purified kinases (i.e., MERTK, AXL, or TYRO3) were incubated with compound or DMSO (control) in assay buffer (25 mM Tris, pH 7.4, 10 mM MgCl, 4 mM MnCl, 2 mM DTT, 0.01% BSA, 0.02% Triton X-100, 0.01% Brij 35, and 0.5 mM NaVO for MERTK). The mixtures were incubated for approximately 15 minutes in 40 mM Tris, pH 7.4, 20 mM MgCl2, 2 mM DTT, 0.01% BSA, and 0.5 mM Na3VO4 for AXL; and 25 mM Tris, pH 7.4, 10 mM MgCl2, 4 mM MnCl2, 2 mM DTT, 0.01% BSA, and 0.5 mM Na3VO4 for TYRO3. The resulting substrate and ATP (12 μM for MERTK, 50 μM for AXL and TYRO3) were added. The mixtures were incubated at 30°C for 3 hours. Kinase Glo Assay Kit for MERTK and ADP-Glo ​​Kinase Assay Kit for AXL and TYRO3 were used according to the manufacturer's instructions (Promega) to calculate luminescence and determine kinase activity. Percent inhibition and half-maximal inhibitory concentration (IC) were measured. 50 ) values ​​were calculated. A high percentage of inhibition and a low IC 50 The values ​​indicate high potency of the test compound.

[0069] Each of the eight compounds of the present invention (i.e., compounds 3, 4, 7, 11, 37, 46, 114, and 123) was tested against MERTK, AXL, and TYRO3, and the results are shown in Table 4 below. [Table 4]

[0070] In vitro Ba / F3-MER TK cell assay Compounds 11, 37, 114 and 123 were evaluated for their in vivo efficacy in inhibiting MERTK using the Ba / F3-MERTK cell assay.

[0071] Cells were seeded at the appropriate density in 96-well plates and treated with compounds for 72 hours. At the end of the treatment, MTS reaction medium was prepared in 96-well microtiter plates using phenol red-free DMEM, MTS (tetrazolium compound [3-(4,5-dimethylthiozol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] Promega, Madison, WI), and PMS (phenazine methosulfate, Sigma, St. Louis, MO) in a ratio of 8:2:0.1. The MTS reaction medium was dispensed (100 μL / well) onto the cells, which were then incubated at 37°C in a humidified 5% CO atmosphere for 1.5 hours. The absorbance was recorded at 490 nm.

[0072] The results show that these four exemplary compounds are all potent inhibitors, each with IC values ​​ranging from 4.2 nM to 138.7 nM. 50 It is shown that the value is

[0073] immunomodulatory activity Compound 11 was evaluated for its immunomodulatory activity in the MC38 mouse colon tumor model. Female C57BL / 6J mice aged 8–10 weeks were used. Before injection into the animals, the mouse colon tumor MC38 cells were detected as free of Mycoplasma species. 10 ... 5 MC38 cells were subcutaneously implanted into the left flank of mice (n = 5-6 per group) using a 25-5 / 8-gauge needle. Compound 11 was dissolved in a mixture of 10% DMA: 40% PEG400: 50% (1% CMC) (v / v / v). Approximately 150 mm 3Tumors were included, and treatment was initiated after randomization. Tumor growth was measured with electronic calipers, and volume was calculated as L x W x W / 2. After tumor cell inoculation, tumor size and animal weight were measured twice a week. All experiments were performed according to protocols approved by the National Health Research Institutes' Institutional Animal Care and Use Committee.

[0074] One group of mice was orally administered either vehicle alone or Compound 11 at 50 mg / kg twice daily for 5 days. Ten days after treatment, tumor cells and spleen cells from the mice were harvested to examine the effect of this compound on immune cells, namely tumor-associated macrophages and T cells. Briefly, vehicle control and Compound 11 tumors and spleens were harvested and dissociated into single cells. Single cell suspensions were preincubated with mouse Fc receptor blockers before staining with appropriate antibody conjugates for Cd45, Cd3, Cd4, Cd8, F4 / 80, Cd11b, Cd86, AXL, and MERTK, and analyzed by flow cytometry to identify Cd4 (Cd3 + Cd4 + ), Cd8(Cd3 + Cd8 + ), macrophages (Cd11b + F4 / 80 + ), tumor-associated macrophages (M2, Cd11b + F4 / 80 + Cd206 + ), classical macrophages (M1, Cd11b + F4 / 80 + / Cd86 + The accumulation of immune cells, including a population of tumor-associated macrophages (Cd206), was quantified. For intracellular staining of tumor-associated macrophage marker Cd206 expression, cells were fixed using the Cytofix / Cytoperm™ kit (BD Biosciences, Franklin Lakes, NJ) after surface marker staining and stained with an anti-mouse Cd206 antibody conjugate. A live / dead fixable dye was used to exclude nonviable cells from the analysis.

[0075] The results showed that (i) at 10 days after treatment, the tumor size in mice treated with compound 11 was 200 mm 3 from 350mm 3 In contrast, tumor size in vehicle-treated mice increased slightly to 200 mm 3 to 1000mm 3 (ii) in tumor cells, the level of macrophages decreased from 18% to 13% and the level of their M2 phenotype decreased from 10% to 5%; (iii) in spleen cells, the total T cells, CD4 + T cells, CD8 + T cell levels increased from 30% to 43%, 5% to 10%, and 18% to 28%, respectively; and (iv) in spleen cells, CD8 + T cells and CD4 + AXL expression in T cells also decreased from 13% to 5% and from 1.8% to 0.7%, respectively, and CD8 + T cells and CD4 + The expression of MERTK in T cells also showed a decrease from 32% to 20% and from 7% to 3%, respectively.

[0076] In vivo activity against colon tumors Compound 11 was evaluated for its in vivo efficacy in the treatment of colon tumors. 8-10 week old female C57BL / 6J mice were used. Mouse colon tumor MC38 cells were detected as free of Mycoplasma species before injection into the animals. 10 cells were cultured in 100 μL of culture medium per mouse. 5 MC38 cells were subcutaneously implanted into the left flank of mice (n=8 per group) using a 25-5 / 8-gauge needle. Compound 11 was dissolved in 10% DMA: 40% PEG400: 50% (1% CMC) (v / v / v). Approximately 50 mm 3 of tumors were included and treatment was initiated after randomization.

[0077] One group of MC-38 murine colon tumor-bearing mice was orally administered compound 11 at 50 mg / kg twice daily for 5 days. Control animals were orally administered vehicle alone. Tumor growth was measured with electronic calipers, and the volume was calculated as L x W x W / 2. After tumor cell inoculation, tumor size and animal weight were measured twice weekly. After treatment, changes in tumor volume and body weight were measured.

[0078] The results showed that on the 17th day after treatment, the tumor volume in the group treated with compound 11 was 0-300 mm 3 In contrast, the tumor volume in the control group ranged from 0 to 2000 mm 3 It grew into.

[0079] In vivo activity against breast cancer Compound 11 was further evaluated for its in vivo efficacy in the treatment of breast cancer. The MDA-MB-231TNBC cell line was used. Before injection into animals, cancer cells were detected as free of mycoplasma species. Five million MDA-MB-231 cells in culture medium and Matrigel (1:1, v / v) were subcutaneously injected into the left flank of NOD / SCID mice (n=8 per group). Approximately 150 mm 3 Treatment was initiated after randomization, with tumors included. Compounds were formulated using 10% DMA:40% PEG400:50% (1% CMC) (v / v / v).

[0080] Three groups of mice were used: (1) a control group, (2) a group treated with compound 11 at 25 mg / kg, and (3) a group treated with compound 11 at 50 mg / kg. Each group was orally dosed twice daily for 5 days. Control animals were orally dosed with vehicle alone. Tumor growth was measured with an electronic caliper, and the volume was calculated as L x W x W / 2. After tumor cell inoculation, tumor size and animal weight were measured twice a week.

[0081] The results showed that on the 35th day after treatment, the tumor volume in groups (1) to (3) was 150 mm 3to 600mm respectively 3 , 300mm 3 and 220mm 3 It was shown that the Other Embodiments

[0082] All of the features disclosed herein may be combined in any combination. Each feature disclosed herein may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only one example of a generic series of equivalent or similar features.

[0083] From the foregoing description, those skilled in the art can readily grasp the essential characteristics of the present invention and can make various changes and modifications to the present invention to adapt it to various uses and conditions without departing from its spirit and scope. For example, compounds structurally similar to the compounds of the present invention may also be made and screened for their effectiveness in treating conditions associated with SOS1. Accordingly, other embodiments are within the scope of the claims.

Claims

1. A compound of formula (I) 【Chemical 1】 R １ and R ２ each independently represents H, deuterium, halo, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ heterocycloalkyl, aryl, heteroaryl or deleted, R ３ is H, halo, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Heterocycloalkyl, aryl, heteroaryl or -NR ３ａ R ３ｂ and R ３ａ and R ３ｂ each independently represents H, C １－６ is alkyl or aryl, R ４ is H, C １－６ Alkyl, C ３－６ Cycloalkyl or C １－６ is heterocycloalkyl, X １ is C, CH, CD or S, X ２ is C or N, X ３ is O, CH, S or NH, X １ , X ２ and X ３ at least one of is O, S, N, or NH; X ４ is N, CH or CH(CN), X ５ is O or NH, X ６ is N or CH, Het is 【Chemistry 2】 is selected from the group consisting of Two 【Chemistry 3】 is a single bond and the other is a double bond, and C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Heterocycloalkyl, aryl, heteroaryl and Het each represent deuterium, hydroxyl, halo, nitro, cyano, amino, C １－６ Acylamino, C ３－６ Alkylamino, C １－６ Alkyl, C １－６ Aminoalkyl, C １－６ Alkoxyl, C １－６ Alkylcarbonyl, C ３－１０ Cycloalkyl, C １－６ optionally substituted with one or more chemical groups selected from the group consisting of heterocycloalkyl, aralkyl, aryl, and heteroaryl; compound.

2. X １ and X ２ Each of the is C, and X ３ is O or NH, and X ４ is N and X １ and X ２ The above between 【Chemistry 4】 The compound of claim 1 , wherein is a double bond.

3. R １ is H or phenyl.

4. R ２ is H, C １－６ 4. The compound of any one of claims 1 to 3, which is alkyl or heteroaryl.

5. R ３ is H, methyl, phenyl, pyridinyl, methylamino or phenylamino, R ４ The compound of any one of claims 1 to 4, wherein is H.

6. X ５ is O and X ６ 6. The compound of claim 1, wherein is CH.

7. Het is 【Chemistry 5】 and optionally substituted with one or more of methyl, ethoxy, phenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methyl-4-fluorophenyl, 2-fluoropyridin-3-yl, and butylenecarbonyl.

8. Formula (II) 【Chemistry 6】 8. The compound according to any one of claims 1 to 7, which is a compound of the formula:

9. X ３ is O or NH.

10. Het is 【Chemistry 7】 and each of them is C １－６ Optionally substituted with one or more of alkyl and phenyl, wherein phenyl is hydroxyl, halo, amino, C １－６ Alkyl or C １－６ 10. The compound of claim 8 or 9, optionally substituted with alkoxy.

11. R １ is phenyl, and R ２ is H or heteroaryl, and each of phenyl and heteroaryl is selected from amino, C １－６ Acylamino, C １－６ Alkylamino, C １－６ Alkyl and C １－６ 11. The compound of any one of claims 8 to 10, optionally substituted with one or more chemical groups consisting of aminoalkyl.

12. The compound of claim 1, which is one of compounds 1 to 174.

13. 13. The compound of claim 12, which is one of compounds 3, 11, 30, 37, 46, 63, 71, 82, 95, 121 and 123.

14. 10. A method of treating a disorder, comprising administering to a subject in need thereof an effective amount of the compound of claim 1, wherein the disorder is associated with TAM.

15. 10. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier thereof.

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