Tlr7 agonists and pharmaceutical combinations thereof for the treatment of lung cancer

Abstract

The present application relates to a compound of Formula I or a pharmaceutically acceptable salt thereof, as a Toll-like Receptor 7 (TLR7) agonist, for use in the treatment of lung cancer, a pharmaceutical combination of a TLR7 agonist and a tyrosine kinase inhibitor for use in the treatment of lung cancer, and the use of a compound of Formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical combination in the treatment of lung cancer.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit and priority of Chinese Patent Application No. 201810560770.X, filed with the State Intellectual Property Office of the People's Republic of China on May 25, 2018, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This application relates to Toll-like Receptor 7 (TLR7) agonists and combinations thereof. Specifically, this application relates to TLR7 agonists for the treatment of lung cancer, the use of TLR7 agonists in the treatment of lung cancer, and combinations thereof with tyrosine kinase inhibitors, and the use of such combinations in the treatment of lung cancer. Background Technology

[0004] Tyrosine kinases are a group of enzymes that catalyze the phosphorylation of tyrosine residues in proteins. They play a crucial role in intracellular signal transduction, participating in the regulation, signal transduction, and development of normal cells, and are also closely related to the proliferation, differentiation, migration, and apoptosis of tumor cells. Many receptor tyrosine kinases are associated with tumorigenesis and can be classified according to their extracellular domain structures, such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), and fibroblast growth factor receptor (FGFR).

[0005] Toll-like receptors are expressed on a variety of immune cells. They recognize highly conserved structural motifs: pathogen-associated microbial patterns (PAMPs) expressed by microbial pathogens or damage-associated molecular patterns (DAMPs) released by necrotic cells. Stimulation of Toll-like receptors via the corresponding PAMPs or DAMPs triggers a signaling cascade that activates transcription factors such as AP-1, NF-κB, and interferon regulators (pulse response functions). This leads to a variety of cellular responses, including the production of interferons, pro-inflammatory cytokines, and effector cytokines, thereby generating an immune response. To date, 13 Toll-like receptors have been identified in mammals. Toll-like receptors 1, 2, 4, 5, and 6 are primarily expressed on the cell surface, while Toll-like receptors 3, 7, 8, and 9 are expressed in endosomes. Different Toll-like receptors recognize different pathogen-derived ligands. For Toll-like receptor 7 (TLR7), it is primarily expressed by plasmacytoid dendritic cells (pDCs) and ligand recognition induces the secretion of interferon-α (IFN-α). Several TLR7 agonists have been reported, such as imiquimod, resiquimod, and GS-9620. WO2016023511 and WO2017076346 (the entire contents of which are incorporated herein by reference) also disclose a new class of TLR7 agonists, which exhibit good biological activity and selectivity.

[0006] The role of TLR7 in oncology has been studied. Imiquimod is an FDA-approved TLR7 agonist used to treat genital warts, actinic keratosis, and superficial basal cell carcinoma. Imiquimod can promote the body's immune response and can also be used as an adjuvant to enhance the effects of radiotherapy. However, TLR7 agonists are not suitable for all types of tumors.

[0007] Although there are many treatment options for patients with proliferative diseases (such as cancer), there is still a need for more effective treatments for clinical use, especially combinations of more than one drug. Invention Overview

[0009] On the one hand, this application provides a Formula I compound or a pharmaceutically acceptable salt thereof for treating lung cancer, or a pharmaceutical composition comprising a Formula I compound or a pharmaceutically acceptable salt thereof for treating lung cancer.

[0010] On the other hand, this application also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating lung cancer. This application also provides a method of treating lung cancer, comprising administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to an individual in need. This application also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for treating lung cancer.

[0011] Secondly, this application provides a drug combination comprising a TLR7 agonist and anlotinib.

[0012] On the other hand, this application also provides the use of the said pharmaceutical combination in the preparation of a medicament for treating lung cancer. This application also provides a method of treating lung cancer, comprising administering an effective amount of the pharmaceutical combination of this application to an individual in need. This application also provides the said pharmaceutical combination for treating lung cancer. This application also provides the use of the said pharmaceutical combination for treating lung cancer. The pharmaceutical combination includes a TLR7 agonist and anlotinib. Invention Details

[0014] On one hand, this application provides a compound of formula I or a pharmaceutically acceptable salt thereof for treating lung cancer, or a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof for treating lung cancer, wherein the compound of formula I is as follows:

[0015]

[0016] in,

[0017] L1 and L2 are each independently selected from -O-, -CH2-, -S-, -NH-, -NHC(=O)-, -C(=O)-, -C(=O)NH-, -S(=O)-, -S(=O)2-, -NHS(=O)2- or -S(=O)2NH-, wherein -CH2-, -NH-, -NHC(=O)-, -C(=O)NH-, -NHS(=O)2- or -S(=O)2NH- are optionally replaced by one or more R4;

[0018] R1 is selected from hydrogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cycloalkyl group, 3-10 membered heterocyclic alkyl group, 3-10 membered aryl group and 3-10 membered heteroaryl group, wherein the C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 The cyclic hydrocarbon group, 3-10 membered heterocyclic hydrocarbon group, 3-10 membered aryl group and 3-10 membered heteroaryl group may be substituted by one or more R4 groups;

[0019] R2 is selected from hydrogen, halogen, cyano, hydroxyl, mercapto, amino, -COOH, -CONH2, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10Cycloalkyl, 3-10 membered heterocyclic alkyl, 3-10 membered aryl and 3-10 membered heteroaryl, wherein the hydroxyl, mercapto, amino, -COOH, -CONH2, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 The cyclic hydrocarbon group, 3-10 membered heterocyclic hydrocarbon group, 3-10 membered aryl group and 3-10 membered heteroaryl group may be substituted by one or more R4 groups;

[0020] B is selected from C. 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic hydrocarbon groups, 3-10 membered aryl groups, and 3-10 membered heteroaryl groups;

[0021] L3 is selected from the key, C 0-6 alkylene, imino, -O-, -S-, -S(=O)- or -S(=O)2-, wherein C 0-6 The alkylene and imino groups may optionally be substituted with one or more R4 groups;

[0022] R3 is selected from hydrogen, amino, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cycloalkyl group, 3-10 membered heterocyclic alkyl group, 3-10 membered aryl group and 3-10 membered heteroaryl group, wherein the amino group, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 The cyclic hydrocarbon group, 3-10 membered heterocyclic hydrocarbon group, 3-10 membered aryl group, and 3-10 membered heteroaryl group may be optionally substituted by one or more R4 groups, or

[0023] R3 and L3 together with adjacent atoms on ring B form saturated or unsaturated 5-8 membered rings, which may optionally be replaced by one or more R4s.

[0024] n is 0, 1, 2, 3, 4 or 5;

[0025] R4 is selected from halogen, cyano, -R, -OR, =O, -SR, -NR2, =NR, -C (halogen)3, -CR (halogen)2, -CR2 (halogen), -OCN, -SCN, -N=C=O, -NCS, -NO, -NO2, -NRC(=O)R, -NRC(=O)OR, -NRC(=O)NRR, -C(=O)NRR, -C(=O)OR, -OC(=O)NRR, -OC(=O)OR, -C(=O)R, -S(=O)2OR, -S(=O)2R, -OS( =O)2OR, -S(=O)2NRR, -S(=O)R, -NRS(=O)2R, -NRS(=O)2NRR, -NRS(=O)2OR, -OP(=O)(OR)2, -P(=O)(OR)2, -C(=O)R, -C(=S)R, -C(=O)OR, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NRR, -C(=S)NRR, -C(=NR)NRR or -NRC(=NR)NRR; each R is independently selected from H, C 1-8 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, 3-8 membered aryl, 3-8 membered heteroaryl, 3-8 membered arylalkyl and 3-8 membered heteroarylalkyl;

[0026] Furthermore, when L1 is -CH2- or -NH-, R3 is not H;

[0027] Or its pharmaceutically acceptable salt.

[0028] In some embodiments of this application, the compound of formula I or a pharmaceutically acceptable salt thereof may have the structure shown below.

[0029] In some embodiments of the compound of formula I, L1 and L2 are independently selected from -O-, -CH2-, -S-, -NH-, -C(=O)-, -S(=O)-, or -S(=O)2-, wherein -CH2- and -NH- are optionally substituted with one or more R4 groups. In some embodiments of the compound of formula I, L1 and L2 are independently selected from -O-, -CH2-, -S-, or -NH-, wherein -CH2- and -NH- are optionally substituted with one or more R4 groups. In some embodiments of the compound of formula I, L1 and L2 are independently selected from -O- or -CH2-, wherein -CH2- is optionally substituted with one or more R4 groups.

[0030] In some embodiments of the compound of formula I, R1 is selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6Cycloalkyl, 3-6 membered heterocyclic alkyl, 3-6 membered aryl and 3-6 membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 The cyclic hydrocarbon group, 3-6 membered heterocyclic hydrocarbon group, 3-6 membered aryl group, and 3-6 membered heteroaryl group are optionally substituted with one or more R4 groups. In some embodiments of the compound of formula I, R1 is selected from C4. 1-6 Alkyl, wherein the C 1-6 The alkyl group may optionally be substituted with one or more R4 groups.

[0031] In some embodiments of the compound of formula I, R2 is selected from hydrogen, halogen, cyano, hydroxyl, mercapto, amino, -COOH, -CONH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-6 membered heterocyclic hydrocarbon groups, 3-6 membered aryl groups, and 3-6 membered heteroaryl groups, wherein the hydroxyl group, mercapto group, amino group, -COOH group, -CONH2 group, C group, etc. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 The cyclic hydrocarbon group, 3-6 membered heterocyclic hydrocarbon group, 3-6 membered aryl group, and 3-6 membered heteroaryl group are optionally substituted with one or more R4 groups. In some embodiments of the compound of formula I, R2 is selected from hydrogen, halogen, cyano, hydroxyl, amino, -CONH2, and C. 1-6 Alkyl groups, wherein the hydroxyl, amino, -CONH2, and C 1-6 The alkyl group may optionally be substituted with one or more R4 groups. In some embodiments of the compound of formula I, R2 is selected from hydrogen, cyano, and -CONH2, wherein the -CONH2 may optionally be substituted with one or more R4 groups.

[0032] In some embodiments of the compound of Formula I, B is selected from 3-10 aryl and 3-10 heteroaryl groups. In some embodiments of the compound of Formula I, B is selected from 5-7 aryl and 5-7 heteroaryl groups. In some embodiments of the compound of Formula I, B is selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, thiopheneyl, thiazolyl, furanyl, oxazolyl, thiadiazolyl, isoxazolyl, oxadiazolyl, pyrroleyl, imidazolyl, pyrazolyl, isothiazolyl, and triazolyl. In some embodiments of the compound of Formula I, B is selected from phenyl, pyridinyl, and thiazolyl groups.

[0033] In some embodiments of the compound of formula I, L3 is selected from the bond and C. 0-6 alkylene, wherein the C 0-6 The alkylene group may optionally be substituted with one or more R4 groups.

[0034] In some embodiments of the compound of formula I, R3 is selected from hydrogen, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclic alkyl group, 3-8 membered aryl group and 3-8 membered heteroaryl group, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 The cyclic hydrocarbon group, 3-8 membered heterocyclic hydrocarbon group, 3-8 membered aryl group, and 3-8 membered heteroaryl group are optionally substituted with one or more R4 groups; or R3 and L3 together with adjacent atoms on the B ring form a saturated or unsaturated 5-8 membered ring, which is optionally substituted with one or more R4 groups. In some embodiments of the compound of formula I, R3 is selected from hydrogen, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl group, 3-8 membered heterocyclic alkyl group, 3-8 membered aryl group and 3-8 membered heteroaryl group, wherein the amino group, C 1-6 Alkyl, C 3-8 The cyclic hydrocarbon group, 3-8 membered heterocyclic hydrocarbon group, 3-8 membered aryl group, and 3-8 membered heteroaryl group are optionally substituted with one or more R4 groups; or R3 and L3 together with adjacent atoms on the B ring form a saturated or unsaturated 5-8 membered ring, which is optionally substituted with one or more R4 groups. In some embodiments of the compound of formula I, R3 is selected from hydrogen, amino, C 1-6 Alkyl, piperazinyl, morpholinyl, tetrahydropyrrolyl, piperidinyl, aziridine, diazacyclobutyl, diazacycloheptyl, and 2-oxa-5-azabicyclo[2.2.1]heptyl, wherein the amino group, C 1-6 Alkyl, piperazine, morpholino, tetrahydropyrrolyl, piperidinyl, aziridine, diazacyclobutyl, diazacycloheptyl, and 2-oxa-5-azabicyclo[2.2.1]heptyl are optionally substituted with one or more R4s; or R3 and L3 together with adjacent atoms on ring B form a saturated or unsaturated 6-membered ring, which is optionally substituted with one or more R4s.

[0035] In some embodiments of the compound of formula I, R4 is selected from halogen, cyano, -R, -OR, =O, -SR, -NR2, =NR, -C(halogen)3, -CR(halogen)2, -CR2(halogen), -OCN, -SCN, -N=C=O, -NCS, -NO, -NO2, -NRC(=O)R, -C(=O)NRR, -C(=O)OR, -OC(=O)NRR, -C(=O)R, -S(=O)2OR, -S(=O)2R, -OS(=O)2OR, -S(=O)2NRR, -S(=O)R, -NRS(=O)2R, -C(=O)R, -C(=O)OR or -C(=O)NRR. In some embodiments of the compound of formula I, R4 is selected from halogen, cyano, -R, -OR, =O, -NR2, =NR, -C (halogen)3, -CR (halogen)2, or -CR2 (halogen). In some embodiments of the compound of formula I, R4 is selected from halogen, -R, -OR, or =O. In the above embodiments, each R is independently selected from H, C, ... 1-8 Alkyl, C 3-8 Cyclic hydrocarbon groups, 3-8 membered heterocyclic hydrocarbon groups, 3-8 membered aryl groups, 3-8 membered heteroaryl groups, 3-8 membered arylalkyl groups and 3-8 membered heteroarylalkyl groups.

[0036] In some embodiments of this application, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from one or more compounds or pharmaceutically acceptable salts thereof:

[0037] 2-Butoxy-7-(3-(((4-methylpiperazin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0038] 2-Butoxy-7-(3-(morpholinomethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0039] 7-(3-(aminomethyl)benzyl)-2-butoxy-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0040] 2-Butoxy-7-(3-(pyrrolidine-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0041] 2-Butoxy-7-(4-((3,3-difluoropyrrolidone-1-yl)methyl)benzyl-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0042] 2-Butoxy-7-(4-((3-fluoropyrrolidone-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0043] 1-(4-((4-amino-2-butoxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)benzyl)pyrrolidin-3-ol;

[0044] 2-Butoxy-7-(4-(piperidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0045] 2-Butoxy-7-(4-(morpholinomethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0046] 2-Butoxy-7-(4-((4-methylpiperazin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0047] 2-Butoxy-7-(4-((dimethylamino)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0048] 2-Butoxy-7-(4-((diethylamino)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0049] 2-Butoxy-7-(4-((dipropylamino)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0050] 7-(4-(azacyclobutane-1-ylmethyl)benzyl)-2-butoxy-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0051] 2-Butoxy-7-(4-((3-methoxyazacyclobutane-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0052] 2-Butoxy-7-(4-((4-methyl-1,4-diazacycloheptane-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0053] 2-Butoxy-7-(4-((2,6-dimethylmorpholino)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0054] 7-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-ylmethyl)benzyl)-2-butoxy-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0055] 2-Butoxy-7-(4-((4-methoxypiperidin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0056] 2-Butoxy-7-(4-((4-isopropylpiperazin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0057] 2-Butoxy-7-(4-(pyrrolidine-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0058] 2-Butoxy-7-((6-(pyrrolidine-1-ylmethyl)pyridin-3-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0059] 2-Butoxy-7-(3-(2-(pyrrolidine-1-yl)ethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0060] 2-Butoxy-7-(4-(1-(pyrrolidine-1-yl)ethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0061] 2-Butoxy-7-(4-(1-methylpiperidin-4-yl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0062] 2-Butoxy-7-(4-(1-methylpyrrolidine-2-yl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0063] 1-(4-((4-amino-2-butoxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)phenyl)-4-methylpiperazin-2-one;

[0064] 7-Benzyl-2-(2-methoxyethoxy)-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0065] 2-(2-methoxyethoxy)-7-((6-methylpyridin-3-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0066] 7-((5-chloropyridin-2-yl)methyl)-2-(2-methoxyethoxy)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0067] 2-(2-methoxyethoxy-)-7-((6-(pyrrolidine-1-ylmethyl)pyridin-3-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0068] 1-(4-((4-amino-2-(2-methoxyethoxy)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)phenyl)-4-methylpiperazin-2-one;

[0069] 2-Butoxy-7-((5-(pyrrolidine-1-ylmethyl)pyridin-2-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0070] 4-Amino-2-butoxy-7-((6-(pyrrolidine-1-ylmethyl)pyridin-3-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidine-6-carboxylonitrile;

[0071] 4-Amino-2-butoxy-7-(4-(pyrrolidine-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-6-carboxynitrile;

[0072] 4-Amino-2-butoxy-7-(4-(morpholinomethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-6-carboxynitrile;

[0073] 4-Amino-2-butoxy-7-(4-((4-methylpiperazin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-6-carboxynitrile;

[0074] 4-Amino-2-butoxy-7-(4-(pyrrolidine-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-6-carboxamide;

[0075] 2-Butoxy-7-((1,2,3,4-tetrahydroisoquinoline-7-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0076] 2-Butoxy-7-((2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0077] 2-Butoxy-7-((2-ethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0078] 2-Butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinoline-7-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0079] 2-Butoxy-7-((1,2,3,4-tetrahydroisoquinoline-6-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0080] 2-Butoxy-7-((2-methyl-1,2,3,4-tetrahydroisoquinoline-6-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine;

[0081] 2-Butoxy-7-((2-ethyl-1,2,3,4-tetrahydroisoquinoline-6-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine; or

[0082] 2-Butoxy-7-((2-(pyrrolidine-1-ylmethyl)thiazolyl)methyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine.

[0083] In some embodiments of this application, the compound of formula I or a pharmaceutically acceptable salt thereof is 2-butoxy-7-(4-(pyrrolidine-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine or a pharmaceutically acceptable salt thereof.

[0084] On the other hand, this application also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating lung cancer. This application also provides a method of treating lung cancer, comprising administering to an individual in need an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof. This application also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof, for treating lung cancer. In some embodiments of this application, in said use and method, the compound of formula I or a pharmaceutically acceptable salt thereof may form a pharmaceutical combination with anlotinib or a pharmaceutically acceptable salt thereof.

[0085] Secondly, this application provides a drug combination comprising a TLR7 agonist and anlotinib.

[0086] In some embodiments of this application, a pharmaceutical combination comprising a TLR7 agonist and 1 mg / kg / day of anlotinib or a pharmaceutically acceptable salt thereof is provided; specifically, the pharmaceutical combination comprises 20 mg / kg of a TLR7 agonist and 1 mg / kg / day of anlotinib or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments of this application, the TLR7 agonist in the drug combination described herein is selected from imiquimod, GSK-2245035, resiquimod, vesatolimod (GS-9620), telratolimod, TMX-202, DSP-0509, RG-7854, Loxoribine, or a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the compound of formula I or a pharmaceutically acceptable salt thereof has the structure as described above or is selected from one or more of the compounds described above.

[0088] In some embodiments of this application, the TLR7 agonist in the drug combination may be one or more TLR7 agonists. As used herein, the term "multiple" may mean more than one, for example, two, three, four, five or more. For example, in some embodiments of this application, the TLR7 agonist is selected from GSK-2245035, vesatolimod, or 2-butoxy-7-(4-(pyrrolidine-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine, 2-butoxy-7-((2-(pyrrolidine-1-ylmethyl)thiazolyl)methyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine, or any combination of pharmaceutically acceptable salts thereof.

[0089] In some embodiments of this application, the pharmaceutical combination is a fixed combination. In some embodiments, the fixed combination is in the form of a solid pharmaceutical composition; in some embodiments, the solid pharmaceutical composition is selected from tablets or capsules.

[0090] In some embodiments of this application, the drug combination is a non-fixed combination. In some embodiments, the TLR7 agonist and anlotinib in the non-fixed combination are each in the form of a solid pharmaceutical composition; in some embodiments, the solid pharmaceutical composition is selected from tablets or capsules.

[0091] In some embodiments of this application, the TLR7 agonist in the drug combination is selected from GSK-2245035, vesatolimod, 2-butoxy-7-(4-(pyrrolidine-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine or 2-butoxy-7-((2-(pyrrolidine-1-ylmethyl)thiazolyl-5-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments of this application, the pharmaceutical combination comprises 2-butoxy-7-(4-(pyrrolidone-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine or 2-butoxy-7-((2-(pyrrolidone-1-ylmethyl)thiazolyl-5-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine or a pharmaceutically acceptable salt thereof and anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments of this application, the pharmaceutical combination comprises 2-butoxy-7-(4-(pyrrolidone-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine or a pharmaceutically acceptable salt thereof and anlotinib dihydrochloride.

[0093] In some embodiments of this application, the pharmaceutical combination described herein comprises 0.0001 mg / kg / d to 20 mg / kg / d of 2-butoxy-7-(4-(pyrrolidone-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine or a pharmaceutically acceptable salt thereof and 1 mg / kg / d of anlotinib dihydrochloride. In some embodiments of this application, the pharmaceutical combination described herein comprises 0.001 mg / kg / d to 10 mg / kg / d of 2-butoxy-7-(4-(pyrrolidone-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine or a pharmaceutically acceptable salt thereof and 1 mg / kg / d of anlotinib dihydrochloride. In some embodiments of this application, the pharmaceutical combination described herein comprises 0.0001 mg / kg / day to 20 mg / kg / day of 2-butoxy-7-(4-(pyrrolidone-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine or a pharmaceutically acceptable salt thereof, and anlotinib dihydrochloride at a dose of 6 mg, 8 mg, 10 mg, or 12 mg once daily. In some embodiments of this application, the pharmaceutical combination described herein comprises 20 mg / kg / day of 2-butoxy-7-(4-(pyrrolidone-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine or a pharmaceutically acceptable salt thereof, administered three times a week at a dose of 0.0001 mg / kg / time to 20 mg / kg / time, and anlotinib dihydrochloride, administered continuously for 11 days. In some embodiments of this application, the drug combination described herein comprises 2-butoxy-7-(4-(pyrrolidine-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine or a pharmaceutically acceptable salt thereof, administered three times a week at a dose of 0.001 mg / kg / time to 10 mg / kg / time, and anlotinib dihydrochloride, administered continuously for 11 days at a dose of 1 mg / kg / day.In some embodiments of this application, the drug combination described herein comprises 2-butoxy-7-(4-(pyrrolidone-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine or a pharmaceutically acceptable salt thereof, administered three times a week at a dose of 0.0001 mg / kg / time to 20 mg / kg / time, and anlotinib dihydrochloride, administered once daily for 11 consecutive days. In some embodiments of this application, the drug combination described herein comprises 2-butoxy-7-(4-(pyrrolidine-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine administered three times a week at a dose of 20 mg / kg / time and anlotinib dihydrochloride administered continuously for 11 days at a dose of 1 mg / kg / day.

[0094] On the other hand, this application also provides the use of the pharmaceutical combination of this application in the preparation of a medicament for treating lung cancer. This application also provides a method of treating lung cancer, comprising administering an effective amount of the pharmaceutical combination of this application to an individual in need. This application also provides the use of the pharmaceutical combination of this application for treating lung cancer. The pharmaceutical combination includes a TLR7 agonist and anlotinib. In some embodiments of this application, the TLR7 agonist is selected from imiquimod, GSK-2245035, resiquimod, vesatolimod (GS-9620), telratolimod, TMX-202, DSP-0509, RG-7854, Loxoribine, or a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the compound of formula I or a pharmaceutically acceptable salt thereof has the structure as described above or is selected from one or more of the compounds described above. In some embodiments of this application, the TLR7 agonist is selected from GSK-2245035, vesatolimod, or 2-butoxy-7-(4-(pyrrolidine-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine or 2-butoxy-7-((2-(pyrrolidine-1-ylmethyl)thiazolyl-5-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine or a pharmaceutically acceptable salt thereof, or any combination thereof. In some embodiments of this application, the TLR7 agonist is selected from 2-butoxy-7-(4-(pyrrolidine-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine or 2-butoxy-7-((2-(pyrrolidine-1-ylmethyl)thiazolyl-5-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine or a pharmaceutically acceptable salt thereof. In some embodiments of this application, the TLR7 agonist is 2-butoxy-7-(4-(pyrrolidine-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine.

[0095] In some embodiments of this application, the use of a TLR7 agonist and anlotinib in the preparation of a combination medicament for the treatment of lung cancer is provided, wherein the TLR7 agonist and anlotinib are prepared separately into pharmaceutical compositions.

[0096] In some embodiments of this application, a kit for treating lung cancer is also provided, comprising (a) a first pharmaceutical composition containing a TLR7 agonist as an active ingredient; and (b) a second pharmaceutical composition containing anlotinib as an active ingredient.

[0097] In some embodiments of this application, the lung cancer includes small cell lung cancer and non-small cell lung cancer.

[0098] Definitions and Explanations

[0099] Unless otherwise stated, the following terms as used in this application have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When a trade name appears in this application, it is intended to refer to the corresponding product or its active ingredient.

[0100] As used in this application, the chemical name of the anlotinib is 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinoline-7-yl]oxy]methyl]cyclopropylamine, which has the following structural formula:

[0101]

[0102] As used in this application, the names, structural formulas, and chemical names of the TLR7 agonists of the aforementioned portion are shown in the table below.

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109] The terms "substitution" or "substituted" refer to the replacement of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced; oxo substitution does not occur on the aromatic group.

[0110] The terms “optional” or “optionally” mean that the event or condition subsequently described may or may not occur, including both the occurrence and non-occurrence of said event or condition. For example, the ethyl group “optionally” being halogenated means that the ethyl group can be unsubstituted (CH2CH3), monosubstituted (e.g., CH2CH2F), polysubstituted (e.g., CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized is introduced.

[0111] C in this articlem-n This means that the part has an integer number of carbon atoms within a given range. For example, "C 1-6 "" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.

[0112] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by two Rs, each R has an independent option.

[0113] When the number of a linking group is 0, such as -(CH2)0-, it indicates that the linking group is a covalent bond.

[0114] When a substituent is cross-bonded to two atoms on a ring, it can bond to any atom on that ring. For example, structural units. This indicates that it can be substituted at any position on the cyclohexyl group or cyclohexadiene.

[0115] The terms “halogen,” “halogenated,” or “halogen” refer to fluorine, chlorine, bromine, and iodine.

[0116] The term "hydroxyl group" refers to the -OH group.

[0117] The term "cyano" refers to the -CN group.

[0118] The term "thiol" refers to the -SH group.

[0119] The term "amino" refers to the -NH2 group.

[0120] The term "alkyl" refers to a compound with the general formula C10. n H 2n+1 The alkyl group is a hydrocarbon group. This alkyl group can be straight-chain or branched. For example, the term "C1-6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, monoalkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups has the same definition as above.

[0121] The term "alkoxy" refers to -O-alkyl.

[0122] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one double bond. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butadienyl.

[0123] The term "alkynyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one triple bond. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH), and 1,3-butyrynyl (-C≡CC≡CH).

[0124] The term "cycloalkyl" refers to a fully saturated carbon ring that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 10-membered ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, and adamantyl.

[0125] The term "cyclic hydrocarbon group" refers to a saturated or unsaturated non-aromatic cyclic hydrocarbon group composed of carbon and hydrogen atoms, preferably containing one or two rings. The cyclic hydrocarbon group can be a monocyclic, fused polycyclic, bridged, or spirocyclic structure. Non-limiting examples of cyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclic [2.2.1]heptyl, and spiro[3.3]heptyl.

[0126] The term "heterocyclic group" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated) and can exist as a monocyclic, fused polycyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3- to 7-membered ring containing one to three heteroatoms independently selected from sulfur, oxygen, and / or nitrogen (preferably one or two heteroatoms). Non-limiting examples of heterocyclic groups include, but are not limited to, ethylene oxide, tetrahydrofuranyl, dihydrofuranyl, pyrrolyl, N-methylpyrrolyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, and tetrahydrothiopheneyl.

[0127] The term "heterocyclic alkyl" refers to a fully saturated cyclic group that may exist as a monocyclic, fused polycyclic, bridged, or spirocyclic group. Unless otherwise indicated, the heterocycle is typically a 3- to 7-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, and / or nitrogen. Examples of 3-membered heterocyclic alkyl groups include, but are not limited to, ethylene oxide, cyclothioethylene, and cycloazoethylene; non-limiting examples of 4-membered heterocyclic alkyl groups include, but are not limited to, acridine, oxadiazolyl, and thiobutyl; examples of 5-membered heterocyclic alkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, imidazolyl, and tetrahydropyrazolyl; examples of 6-membered heterocyclic alkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, piperazine, 1,4-thiaoxane, 1,4-dioxane, thiomorpholinyl, 1,3-dithiaalkyl, and 1,4-dithiaalkyl; and examples of 7-membered heterocyclic alkyl groups include, but are not limited to, azirheptanyl, oxeheptyl, and thioheptyl. Monocyclic heterocyclic alkyl groups having 5 or 6 ring atoms are preferred.

[0128] The term "heterocyclic hydrocarbon group" refers to a non-aromatic monocyclic, fused polycyclic, bridged, or spirocyclic system group, in which some ring atoms are selected from N, O, and S(O). n The ring consists of heteroatoms (where n is 0, 1, or 2), with the remaining ring atoms being carbon. Such a ring can be saturated or unsaturated (e.g., having one or more double bonds), but does not have a fully conjugated π-electron system. Examples of 3-membered heterocyclic hydrocarbon groups include, but are not limited to, ethylene oxide, cyclothioethane, and cycloazoethane; examples of 4-membered heterocyclic hydrocarbon groups include, but are not limited to, acridine, oxadiazolyl, and thiobutyryl; examples of 5-membered heterocyclic hydrocarbon groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolyl, isoxazolyl, oxazolyl, isothiazolyl, 1,1-dioxoisothiazolyl, thiazolyl, imidazolyl, tetrahydropyrazolyl, pyrrolinyl, dihydrofuranyl, and dihydrothiophenyl; and 6-membered heterocyclic hydrocarbon groups... Examples include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, piperazine, 1,4-thiaoxane, 1,4-dioxane, thiomorpholinyl, 1,2-, 1,4-dithiaranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyranyl, tetrahydropyranyl and dihydrothiaranyl, and examples of 7-membered heterocyclic hydrocarbon groups include, but are not limited to, azirheptanyl, oxaheptanyl, thioheptanyl, oxaazabicyclo[2.2.1]heptyl and azispir[3.3]heptyl, etc.

[0129] The term "aryl" refers to an aromatic ring group consisting of a fully conjugated monocyclic or fused polycyclic aromatic ring with a complete carbon-based π-electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, and 1,2,3,4-tetrahydronaphthalene.

[0130] The term "heteroaryl" refers to a monocyclic or fused polycyclic system containing at least one ring atom selected from N, O, and S, with the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryls have a single 4- to 8-membered ring, particularly a 5- to 8-membered ring, or multiple fused rings comprising 6 to 14, particularly 6 to 10 ring atoms. Non-limiting examples of heteroaryls include, but are not limited to, pyrroleyl, furanyl, thiopheneyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothiopheneyl, indoleyl, and isoindoleyl.

[0131] The term "treatment" generally refers to achieving a desired pharmacological and / or physiological effect. This effect can be preventative, based on the complete or partial prevention of the disease or its symptoms; and / or therapeutic, based on the partial or complete stabilization or cure of the disease and / or side effects resulting from the disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including: (a) prevention of disease or symptoms occurring in a patient who is susceptible to the disease or its symptoms but has not yet been diagnosed with the disease; (b) suppression of the symptoms of the disease, i.e., prevention of its progression; or (c) relief of the symptoms of the disease, i.e., causing the disease or its symptoms to regress.

[0132] The term "effective amount" means (i) the amount of the compound of this application used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the present disclosure.

[0133] As used in this application, the Formula I compound or a pharmaceutically acceptable salt thereof may be administered by any applicable route and method, such as oral or parenteral (e.g., intravenous) administration. Therapeuticly effective amounts of the Formula I compound or a pharmaceutically acceptable salt thereof include, but are not limited to, from about 0.0001 mg / kg weight / day to 20 mg / kg weight / day, for example, from 0.001 mg / kg weight / day to 10 mg / kg weight / day. The dosage and frequency of administration of the Formula I compound are determined by the individual patient's needs, such as once or twice daily, or more times daily. Administration may be intermittent, for example, wherein an individual receives a daily dose of the Formula I compound for a period of several days, followed by a period of several or more days during which the patient does not receive a daily dose of the Formula I compound.

[0134] Anlotinib can be administered via a variety of routes, including but not limited to oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, local, subcutaneous, intra-fat, intra-articular, intraperitoneal, and intrathecal administration. In some specific embodiments, anlotinib is administered orally. The dosage of anlotinib can be determined based on the severity of the disease, the response to the disease, any treatment-related toxicities, the patient's age, and health status. For example, the daily dose of anlotinib can range from 2 mg to 20 mg, and in some embodiments, the daily dose of a compound of formula I or a pharmaceutically acceptable salt thereof can be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16 mg. Anlotinib can be administered once or multiple times daily. In some embodiments, anlotinib is administered once daily as an oral solid dosage form.

[0135] The dosing regimen for anlotinib can be determined based on a comprehensive assessment of the drug's activity, toxicity, and patient tolerability. Preferably, anlotinib is administered in an intermittent dosing pattern. This intermittent dosing includes a dosing period and a withdrawal period, during which anlotinib can be administered once or multiple times daily. For example, the ratio of the dosing period to the withdrawal period in days is 2:0.5–5, preferably 2:0.5–3, more preferably 2:0.5–2, and even more preferably 2:0.5–1. In some embodiments, the drug is administered for 2 weeks and then withdrawn for 2 weeks. In some embodiments, the drug is administered for 2 weeks and then withdrawn for 1 week. In some embodiments, the drug is administered for 5 days and then withdrawn for 2 days. For example, anlotinib can be administered orally once daily at doses of 6 mg, 8 mg, 10 mg, or 12 mg for 2 weeks followed by a 1-week withdrawal period.

[0136] As used in this application, the TLR7 agonist and anlotinib include their non-salt forms (e.g., free acids or free bases) as well as their pharmaceutically acceptable salts, both of which are included within the scope of protection of this application. For example, a pharmaceutically acceptable salt of the TLR7 agonist may be a hydrochloride salt, and a pharmaceutically acceptable salt of anlotinib may be a hydrochloride salt or a dihydrochloride salt.

[0137] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0138] The term "pharmaceutically acceptable salt" includes salts formed by a base ion and a free acid or salts formed by an acid ion and a free base, such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, succinate, methanesulfonate, benzenesulfonate, or p-toluenesulfonate, preferably hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, methanesulfonate, p-toluenesulfonate, sodium salt, potassium salt, ammonium salt, or amino acid salt. In this application, when forming a pharmaceutically acceptable salt, the molar ratio of the free acid to the base ion is about 1:0.5 to 1:5, preferably 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, or 1:8. In this application, when a pharmaceutically acceptable salt is formed, the molar ratio of the free base to the anion is about 1:0.5 to 1:5, preferably 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7 or 1:8.

[0139] As used in this application, compounds in the pharmaceutical composition of this application, if having, for example, at least one basic center, can form acid addition salts. If desired, corresponding acid addition salts having additionally present basic centers can also be formed. Compounds having at least one acidic group (e.g., COOH) can also form salts with a base. If the compound, for example, contains both a carboxyl group and an amino group, it can also form corresponding internal salts.

[0140] The compounds of this application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds containing asymmetric carbon atoms of this application can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0141] The term "individual" refers to a mammal. In some embodiments, the individual is a mouse. In some embodiments, the individual is a human.

[0142] The term “about” should be understood as encompassing within three standard deviations of the mean or within a specific range of standard tolerances. In some implementations, “about” should be understood as a variation not exceeding 0.5. “About” modifies all values ​​listed thereafter. For example, “about 1, 2, 3” means “about 1”, “about 2”, and “about 3”.

[0143] The term "drug combination" refers to the simultaneous, parallel, or sequential use of two or more active ingredients. Drug combinations allow the active ingredients to exhibit a synergistic (cooperative) effect. In some embodiments, this effect is a synergistic effect. Drug combinations can be fixed or non-fixed combinations.

[0144] The term "fixed combination" refers to the simultaneous administration of an active ingredient (such as a TLR7 agonist or anlotinib) to an individual at a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition, or formulation. In other words, the active ingredient is present in the same pharmaceutical formulation, and in some embodiments, for example, in the same tablet, capsule, or pouch.

[0145] The term "non-fixed combination" refers to the simultaneous, concurrent, or sequential administration of two or more active ingredients as independent entities (e.g., pharmaceutical compositions, pharmaceutical formulations) to an individual without a specific time limit, wherein the administered active ingredients to the individual reach a therapeutically effective level. Examples of non-fixed combinations include cocktail therapy, such as administering three or more active ingredients. In a non-fixed combination, the individual active ingredients can be packaged, marketed, or administered as completely independent pharmaceutical compositions. The term "non-fixed combination" also includes the combined use of "fixed combinations" between each other, or of a "fixed combination" with any one or more independent entities of active ingredients.

[0146] The term "pharmaceutical composition" refers to one or more compounds of this application, or pharmaceutically acceptable salts thereof, or combinations thereof, or mixtures thereof consisting of salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of this application or combinations thereof to an individual.

[0147] The term "synergistic effect" refers to the simple additive effect of two active components (such as a TLR7 agonist and anlotinib) (e.g., inhibiting lung cancer cell growth or alleviating lung cancer symptoms) being greater than the effect of either component administered alone.

[0148] Application method

[0149] The following content is not intended to limit the administration of the drug combination of this application.

[0150] The active components in the pharmaceutical combination of this application can be formulated separately, or some or all of them can be formulated together. In one embodiment, the pharmaceutical combination of this application can be formulated into a pharmaceutical composition suitable for single or multiple administration.

[0151] The active components in the pharmaceutical combination of this application can be administered individually, or some or all of them can be administered together. The active components in the pharmaceutical combination of this application can be administered substantially separately, or some or all of them can be administered substantially simultaneously.

[0152] The active components of the pharmaceutical combination of this application may be administered independently, or in combination, via various suitable routes, including, but not limited to, oral or parenteral administration (via intravenous, intramuscular, local, or subcutaneous routes). In some embodiments, the active components of the pharmaceutical combination of this application may be administered orally or by injection, such as intravenous or intraperitoneal injection, either independently or in combination.

[0153] The active components in the pharmaceutical combination of this application may be individually, or together in part or in whole, suitable dosage forms, including, but not limited to, tablets, lozenges, pills, capsules (e.g., hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), powders, emulsions, suspensions, solutions, dispersants, and sustained-release formulations for oral or non-oral administration.

[0154] The active components in the pharmaceutical combination of this application may be formulated independently, or in part or in whole, with a pharmaceutically acceptable carrier and / or excipient.

[0155] The drug combination of this application may also include additional therapeutic agents. In one embodiment, the additional therapeutic agent may be a cancer therapeutic agent known in the art, preferably a lung cancer therapeutic agent.

[0156] Technical effect

[0157] The inventors of this application have surprisingly discovered that compounds of formula I, or pharmaceutically acceptable salts thereof, as TLR7 agonists, exhibit good anti-lung cancer activity. Furthermore, the combination of a TLR7 agonist and anlotinib also demonstrates good anti-lung cancer activity. Example

[0158] For clarity, the invention is further illustrated by examples, but these examples are not intended to limit the scope of this application. All reagents used in this application are commercially available and can be used without further purification.

[0159] The preparation method of the compound of formula I in this application and its in vitro receptor binding activity against Toll-like receptor 7 can be found in WO2016023511 and WO2017076346.

[0160] Example 1: Antitumor experiment on LLC mouse lung cancer model

[0161] In Example 1, the TLR7 agonist is selected from... The anlotinib is selected from anlotinib dihydrochloride.

[0162] Subcutaneous xenografts of LLC (Lewis Lung Cancer) mouse lung cancer (concentration 2×10⁻⁶) 6 (0.2 mL / mouse) was aseptically inoculated into the right axilla of C57BL / 6 mice (hair was shaved at the inoculation site before inoculation), and passaged using the grafting method. The C57BL / 6 mice were female, weighing 16-18 g, and housed in SPF-grade environments. The diameter of the C57BL / 6 xenograft was measured with calipers, and passaged when the tumor grew to 100-300 mm. 3 The animals were then randomly divided into 5 groups:

[0163] i. Control group (blank control group);

[0164] ii. Single-drug group: Anlotinib 5 mg / kg / d (positive control group), solvent was physiological saline;

[0165] iii. Monotherapy group: TLR7 agonist 20 mg / kg three times a week, solvent is ethanol + Tween 80 (v:v = 1:1);

[0166] iv. Single-drug group: Anlotinib 1 mg / kg / day, solvent: normal saline;

[0167] v. Combination therapy group: TLR7 agonist 20 mg / kg three times a week + anlotinib 1 mg / kg / day.

[0168] The control group and the single-drug group were administered the drug at a volume of 10 mL / kg. In the combination therapy group, when two drugs were administered simultaneously, the volume of each drug was 10 mL / kg. Initially, body weight and tumor diameter were measured every three days, and the animals' performance was observed daily.

[0169] Mice were divided into groups on day 0, with 12 mice in the control group and 6 mice in each of the other groups. Drug administration began on day 1 via gavage (ig). Administration was discontinued on day 12. Tumor volume was measured on days 0, 3, 6, 9, 12, and 15 during the experiment. The experiment ended on day 15, and tumors were harvested and weighed.

[0170] Use the following formulas to calculate tumor volume and tumor inhibition rate:

[0171] Tumor volume (TV) = (length × width) 2 ) / 2.

[0172] Tumor inhibition rate (TGI) = (1 - tumor weight in treatment group / tumor weight in control group) * 100%.

[0173] The results are shown in Table 1, which indicate that TLR7 agonists can inhibit the growth of tumor LLC, and that their combination with anlotinib can also inhibit the growth of tumor LLC, showing a synergistic effect.

[0174] Table 1. Efficacy of TLR7 agonists and anlotinib in the treatment of subcutaneous xenografts of LLC lung cancer in mice.

[0175]

Claims

Use of 1,2-butoxy-7-(4-(pyrrolidone-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in the preparation of a medicament for the treatment of lung cancer:

2. The use according to claim 1, wherein the 2-butoxy-7-(4-(pyrrolidine-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine or a pharmaceutically acceptable salt thereof is administered in combination with anlotinib or a pharmaceutically acceptable salt thereof.

3. The use according to claim 2, comprising 0.0001 mg / kg / d to 20 mg / kg / d of 2-butoxy-7-(4-(pyrrolidine-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine or a pharmaceutically acceptable salt thereof and 1 mg / kg / d of anlotinib dihydrochloride.

4. The use according to claim 2, comprising 0.001 mg / kg / d to 10 mg / kg / d of 2-butoxy-7-(4-(pyrrolidine-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine or a pharmaceutically acceptable salt thereof and anlotinib dihydrochloride at a dose of 6 mg, 8 mg, 10 mg or 12 mg once daily.

5. The use according to any one of claims 1-4, wherein the lung cancer is small cell lung cancer or non-small cell lung cancer.

6. A combination of drugs comprising 2-butoxy-7-(4-(pyrrolidone-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine or a pharmaceutically acceptable salt thereof and anlotinib or a pharmaceutically acceptable salt thereof:

7. The drug combination according to claim 6, wherein the drug combination is selected from fixed combinations or non-fixed combinations.

8. The pharmaceutical composition according to claim 6, wherein the 2-butoxy-7-(4-(pyrrolidine-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine or a pharmaceutically acceptable salt thereof and anlotinib or a pharmaceutically acceptable salt thereof are respectively prepared into pharmaceutical compositions.

9. The pharmaceutical combination according to claim 6, comprising 0.0001 mg / kg / d to 20 mg / kg / d of 2-butoxy-7-(4-(pyrrolidone-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine or a pharmaceutically acceptable salt thereof and 1 mg / kg / d of anlotinib dihydrochloride.

10. The pharmaceutical combination according to claim 6, comprising 0.001 mg / kg / d to 10 mg / kg / d of 2-butoxy-7-(4-(pyrrolidone-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine or a pharmaceutically acceptable salt thereof and anlotinib dihydrochloride at a dose of 6 mg, 8 mg, 10 mg or 12 mg once daily.

11. Use of the pharmaceutical combination of any one of claims 6-10 in the preparation of a medicament for treating lung cancer, wherein the lung cancer is small cell lung cancer or non-small cell lung cancer.

Images