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CN117769421A - Combination therapy for treating cancer using PRMT5 inhibitors - Google Patents

Combination therapy for treating cancer using PRMT5 inhibitors Download PDF

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Publication number
CN117769421A
CN117769421A CN202280037172.9A CN202280037172A CN117769421A CN 117769421 A CN117769421 A CN 117769421A CN 202280037172 A CN202280037172 A CN 202280037172A CN 117769421 A CN117769421 A CN 117769421A
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alkyl
inhibitor
hydrogen
alkoxy
cancer
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Inventor
L·D·恩格斯托姆
P·奥尔森
J·G·克里斯滕森
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Mirati Therapeutics Inc
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Mirati Therapeutics Inc
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Priority claimed from PCT/US2022/023394 external-priority patent/WO2022216648A1/en
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Abstract

The present disclosure relates to methods of treating cancer. The present disclosure further relates to compounds useful as PRMT5 inhibitors, particularly with KRAS G12C Inhibition ofThe combination of agents treats cancer in a subject.

Description

Combination therapy for treating cancer using PRMT5 inhibitors
Background
Cross Reference to Related Applications
The present application claims priority from U.S. provisional application No. 63/172,639 filed on 8 of 4 months of 2021 and U.S. provisional application No. 63/252,998 filed on 6 of 10 months of 2021, the disclosures of each of which are hereby incorporated by reference in their entireties.
Technical Field
The present disclosure relates to methods of treating cancer. The present disclosure further relates to the use of compounds that are inhibitors of the protein arginine N-methyltransferase 5 (PRMT 5), particularly glycine to cysteine (G12C) (KRAS) which are homologs of the compound with Kirsten rat sarcoma virus oncogene (KRAS) G12C ) A combination of inhibitors to treat cancer in a subject.
Description of the Related Art
PRMT5 is a type II arginine methyltransferase that catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to the guanidino-functional ω -nitrogen of a protein L-arginine residue (ω -monomethylation) and a second methyl group to another ω -nitrogen, yielding symmetrical dimethylarginine (sDMA). PRMT5 forms a complex with the methylbody protein 50 (MEP 50) that is necessary for substrate recognition and targeting and is also necessary for PRMT 5-catalyzed histone 2A and histone 4 methyltransferase activity (see, e.g., ho et al (2013) PLoS ONE 8 (2): e 57008).
Homozygous deletions of p16/CDKN2a are common in cancer, and these mutations typically involve co-deletions of adjacent genes, including the gene encoding methylthioadenosine phosphorylase (MTAP). It is estimated that approximately 15% of all human cancers have homozygous deletions of the MTAP gene (see, e.g., firestone & schram (2017) j.am.chem soc.139 (39): 13754-13760).
Cells lacking MTAP activity have elevated levels of MTAP substrate Methylthioadenosine (MTA), a potent inhibitor of PRMT 5. Inhibition of PRMT5 activity results in reduced methylation activity and increased sensitivity of cell proliferation to PRMT5 depletion or loss of activity. Thus, loss of MTAP activity reduces the methylation activity of PRMT5, making cells selectively dependent on PRMT5 activity.
Although PRMT5 is important for cell viability and its prevalence in cancer, effective therapies to inhibit PRMT5 have been elusive. Thus, there remains a need to develop new PRMT5 inhibitor therapies to treat a wide range of cancers.
Disclosure of Invention
One aspect of the present disclosure provides a method for treating cancer in a subject. Such methods comprise administering to a subject a therapeutically effective amount of KRAS G12C An inhibitor and a therapeutically effective amount of a PRMT5 inhibitor.
Also provided herein is a method for treating cancer in a subject in need thereof. Such methods include determining that the cancer is associated with a homozygous deletion of MTAP (e.g., MTAP-associated cancer). The methods optionally further comprise determining cancer and KRAS G12C Mutation-related. Such methods further comprise administering to the subject a therapeutically effective amount of KRAS G12C An inhibitor and a therapeutically effective amount of a PRMT5 inhibitor.
These and other features and advantages of the present invention will be more fully understood from the following detailed description and appended claims. It should be noted that the scope of the claims is defined by the recitations therein and not by the specific discussion of features and advantages set forth in the present description.
Drawings
The accompanying drawings are included to provide a further understanding of the methods of the present disclosure, and are incorporated in and constitute a part of this specification. The drawings illustrate one or more embodiments of the present disclosure and, together with the description, serve to explain the principles and operations of the disclosure.
FIG. 1 shows KRAS grown in immunodeficient mice by the method of example 1 G12C And CDKN2A/MTAP DEL Results in lung tumor xenograft LU99 model. The PRMT5 inhibitor used in the method is MRTX9768 administered at 100mg/kg twice daily (BID), and KRAS G12C The inhibitor was MRTX849 administered at 30mg/kg once daily (QD). Mean tumor volume ± standard error of the mean was plotted on the study day shown.
FIG. 2 shows example 2KRAS grown in immunodeficient mice G12C And CDKN2A/MTAP DEL Results in lung tumor xenograft LU99 model. The PRMT5 inhibitor used in the method is MRTX7477 administered at 200mg/kg BID, and KRAS G12C The inhibitor was MRTX849 administered at 30mg/kg QD. Mean tumor volume ± standard error of the mean was plotted on the study day shown.
FIG. 3 shows the results of the method of example 3 in a LU99 PRMT5-041 lung tumor xenograft model. The PRMT5 inhibitor used in the method is MRTX1719 administered at 50mg/kg QD, and KRAS G12C The inhibitor was MRTX849 administered at 30mg/kg QD. Mean tumor volume ± standard error of the mean was plotted on the study day shown.
Fig. 4 shows the results of the method of example 4 in a SW1573 PRMT5-044 lung tumor xenograft model. The PRMT5 inhibitor used in the method is MRTX1719 administered at 50mg/kg QD, and KRAS G12C The inhibitor was MRTX849 administered at 100mg/kg QD. Mean tumor volume ± standard error of the mean was plotted on the study day shown.
Detailed Description
Before describing the disclosed processes and materials, it is to be understood that aspects described herein are not limited to particular embodiments and, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to be limiting unless specifically defined herein.
In view of this disclosure, one of ordinary skill in the art can configure the methods and compositions described herein to meet desired needs. The present disclosure provides improvements for treating cancer in a subject. As used herein, the term "subject" or "patient" is used interchangeably to refer to any animal, including mammals, and most preferably humans.
The methods provided herein can be used to treat a variety of cancers, including tumors, such as lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, and the like. More particularly, cancers that may be treated by the compositions and methods of the present invention include, but are not limited to, tumor types such as: astrocyte, breast, cervix, colorectal, endometrial, esophageal, gastric, head and neck, hepatocytes, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas. More specifically, these compounds may be used for the treatment of: and (3) heart: sarcomas (hemangiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchogenic carcinoma (squamous cell type, undifferentiated small cell type, undifferentiated large cell type, adenocarcinoma), alveolar (bronchi) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondrimatous hamartoma, mesothelioma; gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagon tumor, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); urogenital tract: kidney (adenocarcinoma, wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urinary tract (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gall bladder cancer, ampulla cancer, bile duct cancer; bone: osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondral tumor (osteochondral exochoma), benign chondrioma, chondroblastoma, chondromucoid fibroma, osteoid osteoma and giant cell tumor; the nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, amoebonite), meninges (meningioma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma); gynaecology: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-cancerous cervical dysplasia), ovary (ovarian carcinoma (serous cystic adenocarcinoma, mucinous cystic adenocarcinoma, unclassified carcinoma), follicular cell-follicular cytoma, selaginella cell carcinoma, anaplastic cytoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), blood system (blood (myelogenous leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, kaposi's sarcoma, nevus dysplasia, moles, hemangioma, skin fibroma, keloids, psoriasis, and adrenal gland blastoma).
In certain embodiments of the methods of the present disclosure, the cancer is an MTAP-associated cancer. For example, in certain embodiments, the cancer comprises a homozygous deletion of the MTAP gene (MTAP DEL ). The subject may be identified or diagnosed as having an MTAP-associated cancer, where the MTAP is determined, for example, using a suitable assay or kit DEL . Alternatively, the subject is suspected of having an MTAP-associated cancer or the subject has a clinical record indicating that the subject has an MTAP-associated cancer.
In certain embodiments of the methods of the present disclosure, the cancer comprises KRAS G12C Mutation of the gene. The subject may be identified or diagnosed as having KRAS G12C Cancer, wherein KRAS is determined using a suitable assay or kit G12C Mutation. Alternatively, the subject is suspected of having KRAS G12C Cancer or a subject having a KRAS indication G12C Clinical record of cancer.
In certain embodiments of the methods of the present disclosure, the cancer may further comprise a cyclin-dependent kinase inhibitor 2A (CDKN 2A) gene homozygous deletion (CDKN 2A) DEL ). Subjects may be identified or diagnosed as having CDKN2A DEL Wherein the deletion is determined using a suitable assay or kit. Alternatively, the subject is suspected of having CDKN2A DEL Cancer, or a subject with a composition indicative of a subject suffering from CDKN2A DEL Clinical record of cancer.
In some embodiments of any of the methods or uses described herein, an assay is used to determine whether a patient has MTAP using a sample from a subject (e.g., a biological sample or a biopsy sample, such as a paraffin embedded biopsy sample) DEL And/or KRAS G12C And/or CDKN2A DEL . Such assays include, but are not limited to, next generation sequencing, immunohistochemistry, fluorescence microscopy, split-isolation FISFI analysis, southern blotting. Western blotting, FACS analysis, northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well known in the art, assays are typically performed using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or antigen binding fragment thereof.
In certain embodiments, the cancer in the methods of the present disclosure is selected from lung cancer, pancreatic cancer, colon cancer, head and neck cancer, bladder cancer, esophageal cancer, lymphoma, gastric cancer, skin cancer, breast cancer, and brain cancer.
In certain embodiments, the cancer in the methods of the present disclosure is selected from lung cancer, pancreatic cancer, colon cancer, head and neck cancer, esophageal cancer, and melanoma.
In certain embodiments, the cancer in the methods of the present disclosure is selected from lung cancer (e.g., mesothelioma or non-small cell lung cancer (NSCLC), including adenocarcinoma and squamous cell), pancreatic cancer, colon cancer, head and neck cancer such as squamous cell carcinoma (HNSCC), bladder cancer, esophageal cancer, lymphoma (e.g., diffuse large B-cell lymphoma), gastric cancer, melanoma, breast cancer, and brain cancer (e.g., glioblastoma multiforme and glioma).
In certain embodiments, the cancer in the methods of the present disclosure is selected from lung cancer (e.g., mesothelioma or NSCLC, including adenocarcinoma and squamous cell carcinoma), pancreatic cancer, colon cancer, head and neck cancer (e.g., squamous cell carcinoma (HNSCC)), esophageal cancer, and melanoma.
In certain embodiments, the cancer in the methods of the present disclosure is selected from mesothelioma, NSCLC (e.g., adenocarcinoma and squamous cell carcinoma), pancreatic cancer, HNSCC, and colon cancer.
In one embodiment of the methods of the present disclosure, the cancer is lung cancer. For example, lung cancer may be NSCLC (e.g., adenocarcinoma and squamous cell carcinoma) or mesothelioma. In certain embodiments, the cancer is NSCLC.
In one embodiment of the methods of the present disclosure, the cancer is pancreatic cancer.
In one embodiment of the methods of the present disclosure, the cancer is colon cancer.
As described above, KRAS is administered in the methods of the present disclosure G12C An inhibitor. As used herein, "KRAS G12C The term "inhibitor" means an agent capable of negatively regulating or inhibiting KRAS G12C All or part of the enzymatically active compounds of (a). KRAS of the present disclosure G12C Inhibitors and KRAS G12C Interactions and/or irreversible binding (e.g., by formation of a covalent adduct with the thiol side chain of the cysteine residue at position 12), thereby inhibiting KRAS G12C Is a complex of a polypeptide and a polypeptide.
In certain embodiments, KRAS G12C The inhibitor is selected from adaglazecloth (also referred to as MRTX849, mirati Therapeutics, inc., san Diego, california), sotorragon (also referred to as AMG510, amgen Inc., thonsand Oaks, california), JNJ-74699157 (also referred to as ARS-3248,Janssen Research)&Development, LLC, raritan, new Jersey), GDC-6036 (Roche, basel, switzerland), LY3499446 (Eli Lilly and Company, indianapolis, indiana), JDQ443 (Novartis Pharmaceuticals, basel, switzerland), D-1553 (InventisBio Inc., shanggai, china) and combinations thereof.
In one embodiment of the methods of the present disclosure, KRAS G12C The inhibitor is adaglazeb or sotorubib. In one embodiment, KRAS G12C The inhibitor is SotolaAnd (5) a piece of sibcloth.
In one embodiment, KRAS G12C The inhibitor is adaglazeb. Adaglazecloth has the following structure:
in certain embodiments, KRAS of the present disclosure G12C The inhibitor is KRAS disclosed in the following International patent publication No G12C Any of the inhibitors: WO 2017/201161 A1 published 11/23 in 2017, WO 2019/099524 A1 published 5/23 in 2019, WO 2019/2173307 A1 published 11/14 in 2019, WO 2020/047192 A1 published 3/5 in 2020, WO 2020/101736 A1 published 22 in 2020 or WO 2020/146613 A1 published 16 in 2020, which are all incorporated by reference in their entirety.
As noted above, PRMT5 inhibitors are also administered in the methods of the present disclosure. As used herein, "PRMT5 inhibitor" refers to a compound of the present disclosure described herein. These compounds are capable of negatively modulating or inhibiting all or part of the enzymatic activity of PRMT5, particularly in the presence of bound MTA in vitro or in vivo or in cells expressing elevated levels of MTA. In certain embodiments, the PRMT5 inhibitor is an MTA synergistic PRMT5 inhibitor.
In certain embodiments, the PRMT5 inhibitor of the present disclosure is any one of the PRMT5 inhibitors disclosed in international patent publication No. WO 2021/050915 A1, published at month 18 of 2021, which is incorporated by reference in its entirety.
In certain other embodiments, the PRMT5 inhibitor of the present disclosure is any one of the PRMT5 inhibitors disclosed in U.S. provisional application No. 63/200,521, filed on day 2021, month 3, and 11, which provisional application is incorporated by reference in its entirety.
For example, the PRMT5 inhibitor in the methods of the present disclosure described herein is a compound of formula IIA, IIB, or IIC (example 1):
or a pharmaceutically acceptable salt thereof, wherein:
a is CR 9 Or N;
d is (C (R) 9 ) 2 ) 1-2 -NH 2 、Or D is +.>Wherein methylene is bonded to E, wherein E is C;
E is C, CR 9 Or N;
each L is independently a bond or C 1 -C 3 An alkylene group;
w is CR 9 Or N;
each X is independently a bond, O, S, -NR 4 -or-NR 4 C(O)-；
Each Z is independently a bond, -SO-, -SO 2 -, -CH (OH) -or-C (O) -;
each R 2 Independently hydroxy, halogen, cyano, cyanomethyl, - (NR) 4 ) 2 Hydroxyalkyl, alkoxy, -SO 2 C 1 -C 3 Alkyl, -X-aryl C 1 -C 3 Alkyl, heteroalkyl, C 2 -C 4 Alkynyl, -X-haloalkyl, -X-C 1 -C 5 Alkyl, -Z-C 1 -C 5 Alkyl, heterocyclyl, -X-L-cycloalkyl, -Z-cycloalkyl, -X-aryl, -Z-aryl or-X-heteroaryl, wherein said heterocyclyl, said cycloalkyl, said aryl and said heteroaryl are optionally substituted with one or more R 5 Substitution;
each R 4 Independently hydrogen or C 1 -C 3 An alkyl group;
each R 5 Independently and separatelyIs cyano, oxo, halogen, C 1 -C 3 Alkyl, hydroxyalkyl, hydroxy, alkoxy-C 1 -C 3 Alkyl, -X-haloalkyl, -Z-cycloalkyl, -X-aryl C 1 -C 3 Alkyl, cyano-substituted-X-aryl C 1 -C 3 Alkyl, optionally via C 1 -C 3 Alkyl-or oxo-substituted-X-L-cycloalkyl, optionally with one or more C' s 1 -C 3 Alkyl-or oxo-substituted-X-L-heteroaryl, optionally substituted with one or more C' s 1 -C 3 Alkyl or oxo-substituted-X-L-heterocyclyl or-X-aryl;
R 6 is hydrogen, halogen or C 1 -C 3 Alkyl, haloalkyl, hydroxy, alkoxy, C 1 -C 3 Alkyl-alkoxy, N (R) 9 ) 2 、NR 9 C(O)R 9 、C(O)R 9 Oxetane and THF;
R 7 for H or C optionally substituted by one or more halogens 1 -C 3 An alkyl group;
R 8 is H or C 1 -C 3 An alkyl group; and is also provided with
Each R 9 Independently H or C 1 -C 3 Alkyl, halogen or haloalkyl.
Example 2 provides PRMT5 inhibitors in the methods of the present disclosure as compounds of formula IIA:
example 3 provides PRMT5 inhibitors in the methods of the present disclosure as compounds of formula IIB:
example 4 provides PRMT5 inhibitors in the methods of the present disclosure as compounds of formula IIC:
embodiment 5 provides the method of any one of embodiments 1-4, wherein W is CR 9 。
Embodiment 6 provides the method of any one of embodiments 1-4, wherein A is CR 9 。
Embodiment 7 provides the method of any one of embodiments 1-4, wherein E is N.
Embodiment 8 provides the method of any one of embodiments 1-7, wherein W is CR 9 A is CR 9 And E is N.
Embodiment 9 provides the method of any one of embodiments 1-8, wherein R 2 Selected from: benzothiophene, naphthalene, quinoline, chromane, isochroman, dihydrobenzodioxin, indolizine, tetrahydroindolizine, dihydroisobenzofuran, benzene, isoquinolinone, benzodioxanone, thienopyridine, tetrahydroindolinone, indolizine, indolizinone, imidazopyridone, thienopyrimidine, thiophene, pyrrolopyrimidinone, thiazolopyridone, dihydropyrrolizine, isobenzoquinone, and tetrahydroisoquinoline.
Embodiment 10 provides the method of any one of embodiments 1-8, wherein each R 5 Independently cyano, oxo, halogen, C1-C3 alkyl, hydroxy, hydroxyalkyl, alkoxy-C1-C3 alkyl, optionally C1-C3 alkyl-or oxo-substituted-X-L-heterocyclyl, optionally C1-C3 alkyl-or oxo-substituted-X-L-cycloalkyl.
Embodiment 11 provides the method of any one of embodiments 1-8, wherein R 6 Selected from hydrogen, hydroxy, chloro, -NHC (O) CH 3 、-C(O)CF 2 H、-NH 2 、-CF 2 、-CH 3 、-O-CH 2 CH 3 、-CH 2 -CH 2 -O-CH 3 Oxetane and THF.
Embodiment 12 provides the method of any one of embodiments 1-11, wherein one of L, X and Z is a bond.
Embodiment 13 provides the method of embodiment 12, wherein L, X and Z are both bonds.
An aspect of the present disclosure provides a method wherein the PRMT5 inhibitor is a compound of formula (IIIC) (example 14):
or a pharmaceutically acceptable salt thereof, wherein
A is CR 9 Or N;
d is-CH 2 -NH 2 、
W is CR 9 Or N, wherein R 9 Is H or C 1 -C 3 An alkyl group;
G. q, J and U are independently selected from C (H), C (R) 5 ) And N, provided that only one or both of G, Q, J and U can be N;
each R 5 Independently hydroxy, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 3 -C 6 Cycloalkoxy radicals C 3 -C 6 Cycloalkyl, C 3 -C 6 Heterocycloalkyl or C 1 -C 3 Alkoxy C 1 -C 3 An alkyl group;
R 6 is hydrogen, halogen or C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, hydroxy, C 1 -C 6 Alkoxy, C 1 -C 3 Alkoxy C 1 -C 3 Alkyl, C 3 -C 6 Heterocyclylalkyl, -C (O) -C 1 -C 3 Haloalkyl, -N (R) 9 ) 2 or-NR 15 (CO)R 16 ，
Wherein each R is 9 Independently H or C 1 -C 3 Alkyl, R 15 Is hydrogen or methyl, andand R is 16 Is C 1 -C 3 An alkyl group; and is also provided with
R 7 Is C 1 -C 3 Alkyl or C 1 -C 3 A haloalkyl group.
Embodiment 15 provides the method of embodiment 14, wherein a is CH.
Embodiment 16 provides the method of embodiment 14 or 15, wherein W is N.
Embodiment 17 provides the method of embodiment 14 or 15, wherein W is CH.
Embodiment 18 provides the method of any one of embodiments 14 to 17, wherein D is-CH 2 -NH 2 。
Example 19 provides a method of the present disclosure, wherein the PRMT5 inhibitor is a compound according to the formula of example 14:
embodiment 20 provides the method of any one of embodiments 14-19, wherein R 6 Is hydrogen, halogen or C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, hydroxy, C 1 -C 6 Alkoxy, C 1 -C 3 Alkoxy C 1 -C 3 Alkyl, C 3 -C 6 Heterocyclylalkyl, -C (O) -C 1 -C 3 Haloalkyl, -N (R) 9 ) 2 or-NR 15 (CO)R 16 。
Embodiment 21 provides the method of any one of embodiments 14-19, wherein R 6 Is hydrogen, halogen or C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, hydroxy, C 1 -C 3 Alkoxy, C 1 -C 3 Alkoxy C 1 -C 3 Alkyl, C 3 -C 6 Heterocyclylalkyl, -C (O) -C 1 -C 3 Haloalkyl, -N (R) 9 ) 2 or-NR 15 (CO)R 16 。
Examples22 provides a method according to any one of embodiments 14 to 19, wherein R 6 Is hydrogen, chlorine, fluorine, methyl, ethyl, difluoromethyl, hydroxy, methoxy, ethoxy, (methoxy) methyl, (ethoxy) methyl, (methoxy) ethyl, (ethoxy) ethyl, oxetanyl, tetrahydrofuranyl, -C (O) -difluoromethyl, -NH 2 or-NH (CO) CH 3 。
Embodiment 23 provides the method of any one of embodiments 14-19, wherein R 6 Is halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, hydroxy, C 1 -C 6 Alkoxy, C 1 -C 3 Alkoxy C 1 -C 3 Alkyl, C 3 -C 6 Heterocyclylalkyl, -C (O) -C 1 -C 3 Haloalkyl, -N (R) 9 ) 2 or-NR 15 (CO)R 16 。
Embodiment 24 provides the method of any one of embodiments 14-19, wherein R 6 Is halogen, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, hydroxy, C 1 -C 3 Alkoxy, C 1 -C 3 Alkoxy C 1 -C 3 Alkyl, C 3 -C 6 Heterocyclylalkyl, -C (O) -C 1 -C 3 Haloalkyl, -N (R) 9 ) 2 or-NR 15 (CO)R 16 。
Embodiment 25 provides the method of any one of embodiments 14-19, wherein R 6 Is chloro, fluoro, methyl, ethyl, difluoromethyl, hydroxy, methoxy, ethoxy, (methoxy) methyl, (ethoxy) methyl, (methoxy) ethyl, (ethoxy) ethyl, oxetanyl, tetrahydrofuranyl, -C (O) -difluoromethyl, -NH 2 or-NH (CO) CH 3 。
Embodiment 26 provides the method of any one of embodiments 23-25, wherein each G, Q, J and U is independently C (H).
Embodiment 27 provides the method of any one of embodiments 23 to 25, wherein G, Q, J and U are independently selected from C (H) and C (R 5 )。
Embodiment 28 provides the method of any one of embodiments 23-25, wherein G, Q, J and U are independently selected from C (H) and N.
Embodiment 29 provides the method of any one of embodiments 14-19, wherein
R 6 Is hydrogen;
G. at least one of Q, J and U is C (R 5 ) And the remainder of G, Q, J and U are independently selected from C (H), C (R) 5 ) And N, wherein each R 5 Independently hydroxy, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 3 -C 6 Cycloalkoxy radicals C 3 -C 6 Cycloalkyl, C 3 -C 6 Heterocycloalkyl or C 1 -C 3 Alkoxy C 1 -C 3 An alkyl group.
Embodiment 30 provides the method of embodiment 29, wherein one or both of G, Q, J and U is N.
Embodiment 31 provides the method of any one of embodiments 14-19, wherein
R 6 Is hydrogen;
G. at least one of Q, J and U is C (R 5 ) And the remainder of G, Q, J and U are independently selected from C (H) and C (R) 5 ) Wherein each R is 5 Independently hydroxy, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 3 -C 6 Cycloalkoxy radicals C 3 -C 6 Cycloalkyl, C 3 -C 6 Heterocycloalkyl or C 1 -C 3 Alkoxy C 1 -C 3 An alkyl group.
Embodiment 32 provides the method of embodiment 31, wherein at least one of G, Q, J and U is C (R 5 ) And the remainder G, Q, J and U are independently C (H); for example, only one of G, Q, J and U is C (R 5 )。
Embodiment 33 provides the method of embodiment 31, wherein two of G, Q, J and U are C (R 5 ) And the remainder G, Q, J and U are independently C (H).
Example 34 provides the method of example 31, wherein three of G, Q, J and U are C (R 5 ) And the remainder G, Q, J and U are C (H).
Embodiment 35 provides the method of any one of embodiments 14 to 19, wherein G, Q, J and U together with the thiophene to which they are attached form:
example 36 provides the method of example 35, wherein G, Q, J and U together with the thiophene ring to which they are attached form benzo [ b ] thiophene.
Embodiment 37 provides the method of any one of embodiments 14-36, wherein R 5 Hydroxyl, halogen, C if present 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkoxy, C 3 -C 6 Cycloalkoxy radicals C 3 -C 6 Cycloalkyl, C 3 -C 6 Heterocycloalkyl or C 1 -C 3 Alkoxy C 1 -C 3 An alkyl group.
Embodiment 38 provides the method of any one of embodiments 14-36, wherein R 5 Hydroxyl, halogen, C if present 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkoxy, C 3 -C 6 Heterocycloalkyl or C 1 -C 3 Alkoxy C 1 -C 3 An alkyl group.
Embodiment 39 provides the method of any one of embodiments 14-36, wherein R 5 Hydroxyl, chloro, fluoro, methyl, ethyl, methoxy, ethoxy, 2-difluoroethoxy, oxetanyl, tetrahydrofuranyl, (methoxy) methyl, (ethoxy) methyl, (methoxy) ethyl or (ethoxy) ethyl, if present.
Embodiment 40 is directed to the method of any one of embodiments 14 to 39, wherein R 7 Is methyl.
Embodiment 41 is directed to the method of any one of embodiments 14 to 39, wherein R 7 Is ethyl.
Embodiment 42 provides the method of any one of embodiments 14-39, wherein R 7 Is propyl (e.g., isopropyl).
Embodiment 43 provides the method of any one of embodiments 14-39, wherein R 7 Is difluoromethyl or trifluoromethyl.
Example 44 provides the method of example 14, wherein the PRMT5 inhibitor has the formula:
wherein the method comprises the steps of
G. Q, J and U together with the thiophene to which they are attached form:
wherein each R is 5 Independently hydroxy, halogen, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkoxy, C 3 -C 6 Heterocycloalkyl or C 1 -C 3 Alkoxy C 1 -C 3 An alkyl group; and is also provided with
R 6 Is hydrogen, halogen or C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, hydroxy, C 1 -C 3 Alkoxy, C 1 -C 3 Alkoxy C 1 -C 3 Alkyl, C 3 -C 6 Heterocyclylalkyl, -C (O) -C 1 -C 3 Haloalkyl, -N (R) 9 ) 2 or-NR 15 (CO)R 16 。
Example 45 provides the method of example 14, wherein the PRMT5 inhibitor has the formula:
wherein the method comprises the steps of
G. Q, J and U together with the thiophene to which they are attached form:
wherein each R is 5 Independently hydroxy, halogen, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkoxy, C 3 -C 6 Heterocycloalkyl or C 1 -C 3 Alkoxy C 1 -C 3 An alkyl group; and is also provided with
R 6 Is halogen, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, hydroxy, C 1 -C 3 Alkoxy, C 1 -C 3 Alkoxy C 1 -C 3 Alkyl, C 3 -C 6 Heterocyclylalkyl, -C (O) -C 1 -C 3 Haloalkyl, -N (R) 9 ) 2 or-NR 15 (CO)R 16 。
Example 46 provides the method of example 14, wherein the PRMT5 inhibitor has the formula:
wherein the method comprises the steps of
G. Q, J and U together with the thiophene to which they are attached form:
Wherein each R is 5 Independently hydroxy, halogen, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkoxy, C 3 -C 6 Heterocycloalkyl or C 1 -C 3 Alkoxy C 1 -C 3 An alkyl group.
Example 47 provides a method of the present disclosure, wherein the PRMT5 inhibitor is a compound of formula (IIIB):
or a pharmaceutically acceptable salt thereof, wherein
A is CR 9 Or N;
d is-CH 2 -NH 2 、
W is CR 9 Or N, wherein R 9 Is H or C 1 -C 3 An alkyl group;
R 51 is hydrogen, fluorine, chlorine or methyl, or R 51 And R is 52 Together with the atoms to which they are attached form C 4 -C 6 Heterocycloalkyl (e.g., hydrofuran);
R 52 is fluorine, chlorine or methyl, or R 52 And R is 53 Together with the atoms to which they are attached form a phenyl group;
R 53 hydrogen, fluorine, chlorine or methyl;
R 54 is hydrogen, halogen or C 1 -C 3 Alkyl or C 1 -C 3 An alkoxy group;
L 5 is-O-or-CH 2 -；
R 6 Is hydrogen, halogen or C 1 -C 6 Alkyl, hydroxy, C 1 -C 6 Alkoxy, C 1 -C 3 Alkoxy C 1 -C 3 Alkyl, C 3 -C 6 Heterocyclylalkyl, -C (O) -C 1 -C 3 Haloalkyl or-NR 15 (CO)R 16 Wherein R is 15 Is hydrogen or methyl, and R 16 Is C 1 -C 3 An alkyl group;
R 7 is C 1 -C 3 Alkyl or C 1 -C 3 A haloalkyl group.
Embodiment 48 provides the method of embodiment 47, wherein:
a is-CH or-CCH 3 ；
D is-CH 2 -NH 2 ；
W is-CH, -CCH 3 Or N;
R 51 、R 52 、R 53 and R is 54 Each independently selected from hydrogen, fluorine, chlorine or methyl;
L 5 is-O-;
R 6 hydrogen, fluorine, chlorine or methyl; and is also provided with
R 7 Is C 1 -C 2 Alkyl or C 1 -C 2 A haloalkyl group.
Embodiment 49 provides the method of embodiment 47 or embodiment 48, wherein:
a and W are-CH;
d is-CH 2 -NH 2 ；
R 51 、R 52 And R is 53 Each independently selected from hydrogen, fluorine, chlorine and methyl;
R 54 is hydrogen;
L 5 is-O-;
R 6 is hydrogen; and is also provided with
R 7 Is methyl group。
Embodiment 50 provides the method of any one of aspects 47-49, wherein:
a and W are-CH;
d is-CH 2 -NH 2 ；
R 51 And R is 52 Each independently selected from fluorine, chlorine and methyl;
R 53 and R is 54 Is hydrogen;
L 5 is-O-;
R 6 is hydrogen; and is also provided with
R 7 Is methyl.
Embodiment 51 provides the method of embodiment 47, wherein a is CH.
Embodiment 52 provides the method of embodiment 47 or 48, wherein W is N.
Embodiment 53 provides the method of embodiment 47 or 48, wherein W is CH.
Embodiment 54 provides the method of any one of embodiments 47 to 50, wherein D is-CH 2 -NH 2 。
Embodiment 55 provides the method of any one of embodiments 47-51, wherein R 54 Is hydrogen or methyl.
Embodiment 56 provides the method of any one of embodiments 47-51, wherein R 54 Is hydrogen.
Embodiment 57 provides the method of any one of embodiments 47-51, wherein R 54 Is methyl.
Example 58 provides the method of example 47, wherein the PRMT5 inhibitor has the formula:
such as for example +.>
Embodiment 59 provides a method according to any one of embodiments 47-55The method of, wherein L 5 is-CH 2 -。
Embodiment 60 provides the method of any one of embodiments 47-55, wherein L 5 is-O-.
Embodiment 61 provides the method of any one of embodiments 47-57, wherein R 6 Is hydrogen, halogen or C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, hydroxy, C 1 -C 3 Alkoxy, C 1 -C 3 Alkoxy C 1 -C 3 Alkyl, C 3 -C 6 Heterocyclylalkyl, -C (O) -C 1 -C 3 Haloalkyl, -N (R) 9 ) 2 or-NR 15 (CO)R 16 The method comprises the steps of carrying out a first treatment on the surface of the For example, wherein R 6 Is hydrogen, chlorine, fluorine, methyl, ethyl, difluoromethyl, hydroxy, methoxy, ethoxy, (methoxy) methyl, (ethoxy) methyl, (methoxy) ethyl, (ethoxy) ethyl, oxetanyl, tetrahydrofuranyl, -C (O) -difluoromethyl, -NH 2 or-NH (CO) CH 3 。
Embodiment 62 provides the method of any one of embodiments 47-57, wherein R 6 Is hydrogen, halogen or C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group; for example, R 6 Is hydrogen, halogen or C 1 -C 3 Alkyl or C 1 -C 3 An alkoxy group.
Embodiment 63 provides the method of any one of embodiments 47 to 57, wherein R 6 Is hydrogen, chlorine, fluorine, methyl, ethyl, methoxy or ethoxy.
Embodiment 64 provides the method of any one of embodiments 47 to 57, wherein R 6 Is halogen, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, hydroxy, C 1 -C 3 Alkoxy, C 1 -C 3 Alkoxy C 1 -C 3 Alkyl, C 3 -C 6 Heterocyclylalkyl, -C (O) -C 1 -C 3 Haloalkyl, -N (R) 9 ) 2 or-NR 15 (CO)R 16 The method comprises the steps of carrying out a first treatment on the surface of the For example, wherein R 6 Is chloro, fluoro, methyl, ethyl, difluoromethyl, hydroxy, methoxy, ethoxy, (methoxy) methyl, (ethoxy) methyl, (methoxy) ethyl, (ethoxy) ethyl, oxetanyl, tetrahydrofuranyl, -C (O) -difluoromethyl, -NH 2 or-NH (CO) CH 3 。
Embodiment 65 provides the method of any one of embodiments 47 to 57, wherein R 6 Is halogen, C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group; for example, R 6 Is halogen, C 1 -C 3 Alkyl or C 1 -C 3 An alkoxy group.
Embodiment 66 provides the method of any one of embodiments 47 to 57, wherein R 6 Is chloro, fluoro, methyl, ethyl, methoxy or ethoxy.
Embodiment 67 is passed through the method of any one of embodiments 47-63, wherein R 7 Is methyl.
Embodiment 68 is passed through the method of any one of embodiments 47-63, wherein R 7 Is ethyl.
Embodiment 69 provides the method of any one of embodiments 47 to 63, wherein R 7 Is propyl (e.g., isopropyl).
Embodiment 70 provides the method of any one of embodiments 47-63, wherein R 7 Is difluoromethyl or trifluoromethyl.
Embodiment 71 provides the method of any one of embodiments 47-67, wherein R 53 Is hydrogen or methoxy; or wherein R is 53 Is hydrogen.
Example 72 provides the method of example 47, wherein the PRMT5 inhibitor has the formula:
embodiment 73 provides the method of any one of embodiments 47-69, wherein R 52 Is fluorine, and R 51 Is hydrogen, fluorine, chlorine or methyl。
Embodiment 74 provides the method of any one of embodiments 47-69, wherein R 52 Is fluorine, and R 51 Is chlorine.
Embodiment 75 provides the method of any one of embodiments 47 to 69, wherein R 52 Is fluorine, and R 51 Is methyl or hydrogen (e.g. R 52 Is fluorine and R 51 Is methyl; or R is 52 Is fluorine and R 51 Hydrogen).
Embodiment 76 provides the method of any one of embodiments 47 to 69, wherein R 51 And R is 52 Together with the atoms to which they are attached form a hydrofuranyl group (e.g.,)。
embodiment 77 provides the method of any one of embodiments 47-76, wherein the PRMT5 inhibitor is
Embodiment 78 provides the method of any one of embodiments 47 to 77, wherein the PRMT5 inhibitor is
An aspect of the present disclosure provides a method wherein the PRMT5 inhibitor is a compound of formula (IIIA) (example 79):
or a pharmaceutically acceptable salt thereof, wherein
A is CR 9 Or N;
d is-CH 2 -NH 2 、
W is CR 9 Or N, wherein R 9 Is H or C 1 -C 3 An alkyl group;
R 2 is that
Wherein R is 56 Is hydrogen, fluorine, chlorine or methyl,
G. q, J and U are independently selected from C (H), C (R) 5 ) And N, provided that only one or both of G, Q, J and U can be N;
each R 5 Independently hydroxy, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 3 -C 6 Cycloalkoxy radicals C 3 -C 6 Cycloalkyl, C 3 -C 6 Heterocycloalkyl or C 1 -C 3 Alkoxy C 1 -C 3 An alkyl group;
R 6 is hydrogen, halogen or C 1 -C 6 Alkyl, hydroxy, C 1 -C 6 Alkoxy, C 1 -C 3 Alkoxy C 1 -C 3 Alkyl, C 3 -C 6 Heterocyclylalkyl, -C (O) -C 1 -C 3 Haloalkyl or-NR 15 (CO)R 16 Wherein R is 15 Is hydrogen or methyl, and R 16 Is C 1 -C 3 An alkyl group; and is also provided with
R 7 Is C 1 -C 3 Alkyl or C 1 -C 3 A haloalkyl group.
An aspect of the present disclosure provides a method wherein the PRMT5 inhibitor is a compound of formula (IIIA) (example 80):
or a pharmaceutically acceptable salt thereof, wherein
A is CR 9 Or N;
d is-CH 2 -NH 2 、
W is CR 9 Or N, wherein R 9 Is H or C 1 -C 3 An alkyl group;
R 2 Is that
Wherein R is 56 Is hydrogen, halogen or C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy or C 1 -C 6 Haloalkoxy groups;
R 6 is hydrogen, halogen or C 1 -C 6 Alkyl, hydroxy, C 1 -C 6 Alkoxy, C 1 -C 3 Alkoxy C 1 -C 3 Alkyl, C 3 -C 6 Heterocyclylalkyl, -C (O) -C 1 -C 3 Haloalkyl or-NR 15 (CO)R 16 Wherein R is 15 Is hydrogen or methyl, and R 16 Is C 1 -C 3 An alkyl group; and is also provided with
R 7 Is C 1 -C 3 Alkyl or C 1 -C 3 A haloalkyl group.
Embodiment 81 provides the method of embodiment 79 or 80, wherein a is CH.
Embodiment 82 provides the method of embodiment 79 or 80, wherein W is N.
Embodiment 83 provides the method of embodiment 79 or 80, wherein W is CH.
Embodiment 84 provides the method of any one of embodiments 79 or 80, wherein D is-CH 2 -NH 2 。
Embodiment 85 provides the method of embodiment 79 or 80, having the formula:
embodiment 86 provides the method of embodiments 79 or 81 to 85, wherein R 2 Is that
Embodiment 87 provides the method of embodiment 86, wherein G, Q, J and U are independently selected from C (H) and C (R) 5 )。
Embodiment 88 provides the method of embodiment 86, wherein G, Q, J and U are independently C (H).
Embodiment 89 provides the method of embodiment 86, wherein at least one of G, Q, J and U is C (R 5 ) And the remainder G, Q, J and U are independently C (H); for example, only one of G, Q, J and U is C (R 5 )。
Embodiment 90 provides the method of embodiment 86, wherein U is N, and G, Q and J are independently selected from C (H) and C (R 5 )。
Embodiment 91 provides the method of embodiment 86, wherein G is N, and Q, J and U are independently selected from C (H) and C (R 5 )。
Embodiment 92 provides the method of any one of embodiments 79 or 81 to 91, wherein R 5 Hydroxyl, halogen, C if present 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkoxy, C 3 -C 6 Cycloalkoxy radicals C 3 -C 6 Cycloalkyl, C 3 -C 6 Heterocycloalkyl or C 1 -C 3 Alkoxy C 1 -C 3 An alkyl group.
Embodiment 93 provides the method of any one of embodiments 79 or 81-91, whereinR 5 Hydroxyl, halogen, C if present 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkoxy, C 3 -C 6 Heterocycloalkyl or C 1 -C 3 Alkoxy C 1 -C 3 An alkyl group.
Embodiment 94 provides the method of any one of embodiments 79 or 81 to 91, wherein R 5 Hydroxyl, chloro, fluoro, methyl, ethyl, methoxy, ethoxy, 2-difluoroethoxy, oxetanyl, tetrahydrofuranyl, (methoxy) methyl, (ethoxy) methyl, (methoxy) ethyl or (ethoxy) ethyl, if present.
Embodiment 95 provides the method of any one of embodiments 79 or 81 to 91, wherein R 5 Halogen, C if present 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group; for example, R 6 Is halogen, C 1 -C 3 Alkyl or C 1 -C 3 An alkoxy group.
Embodiment 96 provides the method of any one of embodiments 79 or 81 to 91, wherein R 5 Chlorine, fluorine, methyl, ethyl, methoxy or ethoxy if present.
Embodiment 97 provides the method of any of embodiments 79 or 81-91, wherein R 56 Is fluorine, chlorine or methyl.
Embodiment 98 provides the method of embodiments 80-85, wherein R 2 Is that
Embodiment 99 provides the method of any one of embodiments 80-85 or 98, wherein R 56 Is hydrogen, fluorine, chlorine or methyl.
Embodiment 100 provides the method of any one of embodiments 79 to 99, wherein R 6 Is hydrogen, halogen or C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, hydroxy, C 1 -C 3 Alkoxy, C 1 -C 3 Alkoxy C 1 -C 3 Alkyl, C 3 -C 6 Heterocyclylalkyl, -C (O) -C 1 -C 3 Haloalkyl, -N (R) 9 ) 2 or-NR 15 (CO)R 16 The method comprises the steps of carrying out a first treatment on the surface of the For example, wherein R 6 Is hydrogen, chlorine, fluorine, methyl, ethyl, difluoromethyl, hydroxy, methoxy, ethoxy, (methoxy) methyl, (ethoxy) methyl, (methoxy) ethyl, (ethoxy) ethyl, oxetanyl, tetrahydrofuranyl, -C (O) -difluoromethyl, -NH 2 or-NH (CO) CH 3 。
Embodiment 101 provides the method of any one of embodiments 79 to 99, wherein R 6 Is hydrogen, halogen or C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group; for example, R 6 Is hydrogen, halogen or C 1 -C 3 Alkyl or C 1 -C 3 An alkoxy group.
Embodiment 102 provides the method of any one of embodiments 79 to 99, wherein R 6 Is hydrogen, chlorine, fluorine, methyl, ethyl, methoxy or ethoxy.
Embodiment 103 provides the method of any one of embodiments 79 to 99, wherein R 6 Is halogen, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, hydroxy, C 1 -C 3 Alkoxy, C 1 -C 3 Alkoxy C 1 -C 3 Alkyl, C 3 -C 6 Heterocyclylalkyl, -C (O) -C 1 -C 3 Haloalkyl, -N (R) 9 ) 2 or-NR 15 (CO)R 16 The method comprises the steps of carrying out a first treatment on the surface of the For example, wherein R 6 Is chloro, fluoro, methyl, ethyl, difluoromethyl, hydroxy, methoxy, ethoxy, (methoxy) methyl, (ethoxy) methyl, (methoxy) ethyl, (ethoxy) ethyl, oxetanyl, tetrahydrofuranyl, -C (O) -difluoromethyl, -NH 2 or-NH (CO) CH 3 。
Embodiment 104 provides the method of any one of embodiments 79 to 99, wherein R 6 Is halogen, C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group; for example, R 6 Is halogen, C 1 -C 3 Alkyl or C 1 -C 3 An alkoxy group.
Embodiment 105 provides the method of any one of embodiments 79 to 99, wherein R 6 Is chloro, fluoro, methyl, ethyl, methoxy or ethoxy.
Embodiment 106 is passed through the method of any one of embodiments 79 to 105, wherein R 7 Is methyl.
Embodiment 107 is passed through the method of any one of embodiments 79 to 105, wherein R 7 Is ethyl.
Embodiment 108 provides the method of any one of embodiments 79 to 105, wherein R 7 Is propyl (e.g., isopropyl).
Embodiment 109 provides the method of any one of embodiments 79 to 105, wherein R 7 Is difluoromethyl or trifluoromethyl.
In certain embodiments of the presently disclosed methods described herein, the PRMT5 inhibitor is:
in certain embodiments of the presently disclosed methods described herein, the PRMT5 inhibitor is:
in certain embodiments of the presently disclosed methods described herein, the PRMT5 inhibitor is:
in certain embodiments of the presently disclosed methods described herein, the PRMT5 inhibitor is:
PRMT5 inhibitors of the present disclosure and/or KRAS of the present disclosure G12C The inhibitors may be provided as pharmaceutical compositions comprising a therapeutically effective amount of such inhibitors and a pharmaceutically acceptable carrier, excipient and/or diluent. PRMT5 inhibitors of the present disclosure and/or KRAS of the present disclosure G12C Inhibitors may be formulated by any method well known in the art and may be prepared for administration by any route including, but not limited to, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal or intrarectal. In certain embodiments, the PRMT5 inhibitor of the present disclosure and/or the KRAS of the present disclosure G12C Inhibitors are administered intravenously in a hospital setting. In certain other embodiments, administration may be preferably by the oral route.
The nature of the carrier will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" refers to a non-toxic material that is compatible with a biological system (such as a cell, cell culture, tissue or organism) and does not interfere with the effectiveness of the biological activity of the active ingredient. Thus, in addition to inhibitors, the pharmaceutical compositions of the present disclosure may contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The preparation of pharmaceutically acceptable formulations is described, for example, in Remington's Pharmaceutical Sciences,18 th Edition, ed.a. gennaro, mack Publishing co., easton, pa.,1990.
PRMT5 inhibitors and KRAS of the present disclosure G12C The inhibitor is administered in a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" or "effective amount" refers to the amount of an active agent that causes a biological or medical response that is sought by a researcher, doctor or other clinician in a tissue, system, subject or person. In generalIn other words, a therapeutically effective amount is sufficient to deliver a biological or medical response to a subject without causing serious toxic effects. The dosage of the active agent may be in the range of about 0.01 to 300mg/kg per day, such as 0.1 to 100mg/kg per day, more typically 0.5 to about 25mg/kg of recipient body weight per day. In a suitable carrier, a typical topical dosage range is 0.01 to 3% wt/wt.
In certain embodiments of the methods of the present disclosure, a therapeutically effective amount of a PRMT5 inhibitor is in the range of about 0.01 to 300mg/kg per day. For example, in certain embodiments, a therapeutically effective amount of the PRMT5 inhibitor is in the range of about 0.1 to 100mg/kg per day, or 25 to 100mg/kg per day, or 50 to 100mg/kg per day.
In certain embodiments, the therapeutically effective amount of the PRMT5 inhibitor is less than 1%, e.g., less than 10%, or less than 25%, or less than 50%, of a clinically determined therapeutic amount (e.g., such as the amount required for the PRMT5 inhibitor to be administered alone).
In certain embodiments of the methods of the present disclosure, KRAS G12C The therapeutically effective amount of the inhibitor is in the range of about 0.01 to 300mg/kg per day. For example, in certain embodiments, KRAS G12C The therapeutically effective amount of the inhibitor is in the range of about 0.1 to 100mg/kg per day, or 0.1 to 50mg/kg per day, or 10 to 100mg/kg per day, or 10 to 50mg/kg per day.
In certain embodiments, KRAS G12C The therapeutically effective amount of the inhibitor is less than the clinically determined therapeutic amount (e.g., such as KRAS G12C The amount of inhibitor required when administered alone), for example, less than 10%, or less than 25%, or less than 50%.
PRMT5 inhibitors and KRAS of the present disclosure are defined G12C When the inhibitors are used, combination therapy is intended to include the administration of each agent in a sequential manner in a regimen that will provide the beneficial effects of the pharmaceutical combination (e.g., PRMT5 inhibitors and KRAS of the present disclosure G12C Inhibitors may be formulated as separate compositions for sequential administration), and are also intended to include co-administration of such agents in a substantially simultaneous manner, such as in a single dosage form having a fixed proportion of such active agents or in multiple or separate dosage forms for each agent. The book is provided withThe disclosure is not limited to the order of administration: the PRMT5 inhibitors of the present disclosure may be administered with KRAS of the present disclosure G12C The inhibitors are administered before or after (i.e., sequentially) or at the same time (i.e., simultaneously).
The methods of the present disclosure may be used as a first line therapy. Thus, in certain embodiments of the methods of the present disclosure, the subject has not previously received another first-line therapy.
The methods of the present disclosure may also be used as a first line maintenance or second line treatment. Thus, in certain embodiments of the methods of the present disclosure, the subject has previously completed another first line therapy. For example, in certain embodiments, the methods of the present disclosure may delay progression and recurrence of cancer in a subject who has previously completed another first-line chemotherapy. For example, in certain embodiments, the subject has previously completed platinum and/or taxane-based chemotherapy (e.g., carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, etc.). In certain embodiments of the methods of the present disclosure, the subject has previously completed another first-line chemotherapy and is partially responsive to such chemotherapy.
Definition of the definition
For simplicity, chemical moieties are primarily defined and referred to throughout as monovalent chemical moieties (e.g., alkyl, aryl, etc.). However, such terms may also be used to express the corresponding multivalent moiety under appropriate structural circumstances as will be apparent to those skilled in the art. For example, although the "alkyl" moiety generally refers to a monovalent group (e.g., CH 3 -CH 2 (-), but in some cases the divalent linking moiety may be an "alkyl" group, in which case the skilled artisan will understand that alkyl is a divalent group (e.g. -CH 2 -CH 2 (-) corresponds to the term "alkylene". (similarly, where a divalent moiety is desired and expressed as "aryl", those skilled in the art will understand that the term "aryl" refers to the corresponding divalent moiety, i.e., arylene.) all atoms are understood to have their normal valences for bond formation (i.e., 4 carbon, 3 n, 2 o, and 2, 4 or 6S, depending on the oxidation state of S).
The term "amino" refers to-NH 2 。
The term "acetyl" refers to "-C (O) CH 3 。
As used herein, the term "acyl" refers to an alkylcarbonyl or arylcarbonyl substituent wherein the alkyl and aryl moieties are as defined herein.
As used herein, the term "alkyl" refers to saturated straight and branched chain aliphatic groups having 1 to 12 carbon atoms. Thus, "alkyl" encompasses C 1 、C 2 、C 3 、C 4 、C 5 、C 6 、C 7 、C 8 、C 9 、C 10 、C 11 And C 12 A group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.
As used herein, the term "alkenyl" refers to an unsaturated, straight or branched chain aliphatic group having one or more carbon-carbon double bonds, having 2 to 12 carbon atoms. Thus, "alkenyl" encompasses C 2 、C 3 、C 4 、C 5 、C 6 、C 7 、C 8 、C 9 、C 10 、C 11 And C 12 A group. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.
As used herein, the term "alkynyl" refers to an unsaturated, straight or branched chain aliphatic group having 2 to 12 carbon atoms with one or more carbon-carbon triple bonds. Thus, "alkynyl" encompasses C 2 、C 3 、C 4 、C 5 、C 6 、C 7 、C 8 、C 9 、C 10 、C 11 And C 12 A group. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
An "alkylene", "alkenylene" or "alkynylene" group is an alkyl, alkenyl or alkynyl group as defined above located between and used to connect two other chemical groups. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene. Exemplary alkenylene groups include, but are not limited to, ethenylene, propenylene, and butenylene. Exemplary alkynylene groups include, but are not limited to, ethynylene, propynylene, and butynylene.
The term "alkoxy" refers to-OC 1 -C 6 An alkyl group.
As used herein, the term "cycloalkyl" is a saturated and partially unsaturated cyclic hydrocarbon group having 3 to 12 carbons. Thus, "cycloalkyl" includes C 3 、C 4 、C 5 、C 6 、C 7 、C 8 、C 9 、C 10 、C 11 And C 12 Cyclic hydrocarbon groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and cyclooctyl.
The term "heteroalkyl" refers to an alkyl group as defined above wherein one or more carbon atoms in the chain are independently replaced by an alkyl group via O, S or NR x Alternatively, wherein R x Is hydrogen or C 1 -C 3 An alkyl group. Examples of heteroalkyl groups include methoxymethyl, methoxyethyl, and methoxypropyl.
An "aryl" group is a C comprising one to three aromatic rings 6 -C 14 An aromatic moiety. Thus, "aryl" includes C 6 、C 10 、C 13 And C 14 Cyclic hydrocarbon groups. Exemplary aryl groups are C 6 -C 10 An aryl group. Specific aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and fluorenyl. "aryl" groups also include fused polycyclic (e.g., bicyclic) ring systems in which one or more of the fused rings is non-aromatic, provided that at least one ring is aromatic, such as indenyl.
An "aralkyl" or "arylalkyl" group includes an aryl group covalently attached to an alkyl group, wherein the moiety is attached to another group via an alkyl moiety. Exemplary aralkyl groups are- (C) 1 -C 6 ) Alkyl (C) 6 -C 10 ) Aryl groups including, but not limited to, benzyl, phenethyl, and naphthylmethyl. For example, aryl C 1 -C 3 Alkyl is covalently linked to C 1 -C 3 Aryl groups of alkyl groups.
"heterocyclyl" or "heterocyclic" groups are monocyclic or bicyclic (fused or spiro) ring structures having 3 to 12 atoms (3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 atoms), for example 4 to 8 atoms, wherein one or more ring atoms are independently-C (O) -, N, NR 4 O or S, and the remaining ring atoms are quaternary or carbonyl carbons. Examples of heterocyclic groups include, but are not limited to, epoxy, oxiranyl, oxetanyl, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, thietanyl, dithianyl, trithianyl, azetidinyl, oxathianyl, dioxolanyl, oxazolidinyl, oxazolidone, decahydroquinolinyl, piperidonyl, 4-piperidonyl, thiomorpholinyl, dimethyl-morpholinyl, and morpholinyl. Specifically excluded from the scope of this term are compounds having adjacent ring O and/or S atoms.
As used herein, "L-heterocyclyl" refers to a heterocyclyl group covalently linked to another group through an alkylene linker.
As used herein, the term "heteroaryl" refers to a group having 5 to 14 ring atoms, preferably 5, 6, 10, 13 or 14 ring atoms; having 6, 10 or 14 pi electrons in a circular array; and has 1 to 3 heteroatoms each independently N, O or S in addition to carbon atoms. Heteroaryl groups also include fused polycyclic (e.g., bicyclic) ring systems in which one or more of the fused rings is non-aromatic, provided that at least one ring is aromatic and at least one ring contains N, O or S ring atoms. Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzo [ d ] oxazol-2 (3H) -one, 2H-benzo [ b ] [1,4] oxazin-3 (4H) -one, benzothienyl (benzothiofuranyl), benzothienyl (benzothiophenyl), benzoxazolyl, benzothiazolyl, benzotriazole, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4 aH-carbazolyl, carbolinyl, chromanyl, benzopyranyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, octahydroisoquinolyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl oxazolidinyl, oxazolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazoles, pyridoimidazoles, pyridothiazoles, pyridinyl (pyridinyl), pyridinyl (pyridyl), pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolinyl, quinoxalinyl, quinazolinyl, quinolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2, 5-thiadiazinyl, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1,3, 4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2, 3-triazolyl, 1,2, 5-triazolyl, 1,3, 4-triazolyl and xanthenyl.
An "L-heteroarylalkyl" or "L-heteroarylalkyl" group comprises a heteroaryl group covalently linked to another group via an alkylene linker. Examples of heteroalkyl groups include C 1 -C 6 An alkyl group and a heteroaryl group having 5, 6, 9 or 10 ring atoms. Examples of heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethylquinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethylisoquinolinyl methyl, isoindolylmethyl, cinnolinyl methyl, and benzothienyl ethyl. Specifically excluded from the scope of this termIs a compound having adjacent ring O and/or S atoms.
An "arylene", "heteroarylene" or "heteroarylene" group is a divalent aryl, heteroaryl or heterocyclyl group, respectively, as defined above, located between and used to connect two other chemical groups.
As used herein, when a moiety (e.g., cycloalkyl, aryl, heteroaryl, heterocyclyl, urea, etc.) is described as "optionally substituted" without explicitly indicating a substituent means that the group optionally has 1 to 4, preferably 1 to 3, more preferably 1 or 2 non-hydrogen substituents.
The term "halogen" or "halo" as used herein refers to chlorine, bromine, fluorine or iodine.
The term "haloalkyl" refers to an alkyl chain in which one or more hydrogens have been replaced with a halogen. Exemplary haloalkyl groups are trifluoromethyl, difluoromethyl, fluorochloromethyl, chloromethyl and fluoromethyl.
The term "hydroxyalkyl" refers to-alkylene-OH.
Examples
The methods of the present disclosure are further illustrated by the following examples, which should not be construed as limiting the scope or spirit of the disclosure to the specific procedures and compounds described therein.
Study design:
the PRMT5 inhibitors of the present disclosure demonstrate selective activity in MTAP-deleted cancers by binding to PRMT5 upon binding to the intracellular metabolite MTA and further inhibiting PRMT 5. As described above, MTAP is an enzyme in the methionine rescue pathway, and its absence in cancer cells results in accumulation of MTA in these cells. PRMT5 is an essential enzyme necessary for cell viability, and thus the PRMT5 inhibitors of the present disclosure represent a novel approach to selectively treat MTAP-deleted cancers.
Single mutations may not lead to cancer—most often, multiple mutations are responsible for cancer progression. The present inventors have found that the treatment of certain cancers with PRMT5 inhibitors is improved by the use of combination therapies. In particular, the inventors have surprisingly found that, in combination with a single Compared with any inhibitor alone, PRMT5 inhibitor and KRAS G12C Combination therapies of inhibitors provide greater antitumor activity.
Study procedure:
5X10 in 50% matrigel 6 The nu 99 lung cancer cells were implanted into immunodeficient female nu/nu mice. The tumors were measured using calipers until the tumors reached approximately 150-200mm 3 . Animals received A) vehicle (0.5% methylcellulose (4000 cps)/0.2% Tween80 in water), B) PRMT5 inhibitor, C) KRAS at random G12C Inhibitors, or D) PRMT5 inhibitors and KRAS G12C Inhibitors, these substances were all administered orally (PO) for 21 days. Tumor volumes were measured twice weekly (n=5/treatment group). The mean tumor volume and standard error of the mean were calculated and plotted in GraphPad on each study day.
Example 1
This example was performed according to the study procedure described above. The PRMT5 inhibitor was MRTX9768 administered at 100mg/kg twice daily (BID). MRTX9768 is 2- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -3-fluoro-1-naphthacenecarbonitrile, as disclosed in example 16-1 on page 304 of International patent publication No. WO 2021/050915A1 published at 18, 3, 2021, which is incorporated herein by reference in its entirety.
KRAS used in this example G12C The inhibitor was MRTX849 administered at 30mg/kg once daily (QD). MRTX849 (adaglazeb) is 2- ((S) -4- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidin-4-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile, disclosed in FIG. 1A of Hallin et al 2020,Cancer Discov.10 (1): 54-71.
The results are provided in fig. 1 and table 1. At the KRAS G12C And CDKN2A/MTAP DEL The combination of MRTX9768 and MRTX849 produced greater anti-tumor activity in the lung tumor xenograft LU99 model than either inhibitor alone.
Table 1.
Example 2
This example was performed essentially according to the study procedure described above. The PRMT5 inhibitor was MRTX7477 administered at 200mg/kg BID. MRTX7477 is 2- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -1-naphthacenecarbonitrile, which is disclosed in example 4-147 on page 226 of International patent publication No. WO 2021/050915A1 published 18, 3 months 2021, which is incorporated by reference in its entirety. KRAS used in this example G12C The inhibitor was the same as in example 1, namely MRTX849 administered at 30mg/kg QD.
The results are provided in fig. 2 and table 2. At the KRAS G12C And CDKN2A/MTAP DEL The combination of MRTX7477 and MRTX849 produced greater anti-tumor activity in the lung tumor xenograft LU99 model than either inhibitor alone.
Table 2.
Example 3
Compounds of the present disclosure were evaluated in LU99 PRMT5-041 tumor xenograft models, and the results are provided in fig. 3 and table 3. This example was performed essentially according to the study procedure described above, except that mice bearing LU99 PRMT5-041 xenograft tumors were used. The PRMT5 inhibitor was MRTX1719 administered at 50mg/kg QD. MRTX1719 is (2M) -2- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile, which is disclosed in example 16-8 on page 307 of International patent publication No. WO 2021/050915 A1 published at month 18 of 2021, which is incorporated herein by reference in its entirety. KRAS used in this example G12C The inhibitor was the same as in example 1, namely MRTX849 administered at 30mg/kg QD.
Table 3.
Example 4
Compounds of the present disclosure were evaluated in SW1573PRMT5-044 tumor xenograft model and the results are provided in fig. 4 and table 4. This example was performed essentially according to the study procedure described above, except that mice bearing SW1573PRMT5-044 xenograft tumors were used. The PRMT5 inhibitor was MRTX1719 administered at 50mg/kg QD. KRAS used in this example G12C The inhibitor was the same as in example 1, namely MRTX849 administered at 100mg/kg QD.
Table 4.
It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference for all purposes.

Claims (34)

1. A method for treating cancer in a subject, the method comprising:
administering to the subject a therapeutically effective amount of the Kirsten rat sarcoma virus oncogene homolog glycine to cysteine (KRAS) G12C ) An inhibitor and a therapeutically effective amount of a protein arginine N-methyltransferase 5 (PRMT 5) inhibitor.
2. The method of claim 1, wherein the cancer comprises a homozygous deletion of the methylthioadenosine phosphorylase (MTAP) gene.
3. The method of claim 1 or 2, wherein the cancer comprises KRAS G12C Mutation of the gene.
4. The method of claim 2 or 3, wherein the cancer further comprises a cyclin-dependent kinase inhibitor 2A (CDKN 2A) gene homozygous deletion.
5. The method of any one of claims 1 to 4, wherein the cancer is lung cancer, pancreatic cancer, colon cancer, head and neck cancer, esophageal cancer, or melanoma.
6. The method of any one of claims 1 to 4, wherein the cancer is lung cancer, such as non-small cell lung cancer (NSCLC).
7. The method of any one of claims 1 to 4, wherein the cancer is pancreatic or colon cancer.
8. The method of any one of claims 1 to 7, wherein the KRAS G12C The inhibitor is selected from the group consisting of adaglazeb, sotolzeb, JNJ-74699157, GDC-6036, LY3499446, JDQ443, D-1553, and combinations thereof.
9. The method of any one of claims 1 to 7, wherein the KRAS G12C The inhibitor is adaglazeb.
10. The method of any one of claims 1 to 7, wherein the KRAS G12C The inhibitor is sotoracicada.
11. The method of any one of claims 1 to 10, wherein the PRMT5 inhibitor is a Methylthioadenosine (MTA) synergistic PRMT5 inhibitor.
12. The method of any one of claims 1 to 11, wherein the PRMT5 inhibitor is a compound of formula IIA, IIB, or IIC:
or a pharmaceutically acceptable salt thereof, wherein:
A is CR 9 Or N;
d is (C (R) 9 ) 2 ) 1-2 -NH 2 、Or D isWherein methylene is bonded to E, wherein E is C;
e is C, CR 9 Or N;
each L is independently a bond or C 1 -C 3 An alkylene group;
w is CR 9 Or N;
each X is independently a bond, O, S, -NR 4 -or-NR 4 C(O)-；
Each Z is independently a bond, -SO-, -SO 2 -, -CH (OH) -or-C (O) -;
each R 2 Independently hydroxy, halogen, cyano, cyanomethyl, - (NR) 4 ) 2 Hydroxyalkyl, alkoxy, -SO 2 C 1 -C 3 Alkyl, -X-aryl C 1 -C 3 Alkyl, heteroalkyl, C 2 -C 4 Alkynyl, -X-haloalkyl, -X-C 1 -C 5 Alkyl, -Z-C 1 -C 5 Alkyl, heterocyclyl, -X-L-cycloalkyl, -Z-cycloalkyl, -X-aryl, -Z-aryl or-X-heteroaryl, wherein said heterocyclyl, said cycloalkyl, said aryl and said heteroaryl are optionally substituted with one or more R 5 Substitution;
each R 4 Independently hydrogen or C 1 -C 3 An alkyl group;
each R 5 Independently cyano, oxo, halogen, C 1 -C 3 Alkyl, hydroxyalkyl, hydroxy, alkoxy-C 1 -C 3 Alkyl, -X-haloalkyl, -Z-cycloalkyl, -X-aryl C 1 -C 3 Alkyl, cyano-substituted-X-aryl C 1 -C 3 Alkyl, optionally via C 1 -C 3 Alkyl-or oxo-substituted-X-L-cycloalkyl, optionally with one or more C' s 1 -C 3 Alkyl-or oxo-substituted-X-L-heteroaryl, optionally substituted with one or more C' s 1 -C 3 Alkyl or oxo-substituted-X-L-heterocyclyl or-X-aryl;
R 6 is hydrogen, halogen or C 1 -C 3 Alkyl, haloalkyl, hydroxy, alkoxy, C 1 -C 3 Alkyl-alkoxy, N (R) 9 ) 2 、NR 9 C(O)R 9 、C(O)R 9 Oxetane and THF;
R 7 for H or C optionally substituted by one or more halogens 1 -C 3 An alkyl group;
R 8 is H or C 1 -C 3 An alkyl group; and is also provided with
Each R 9 Independently H or C 1 -C 3 Alkyl, halogen or haloalkyl.
13. The method of any one of claims 1 to 11, wherein the PRMT5 inhibitor is a compound of formula IIIA:
or a pharmaceutically acceptable salt thereof, wherein
A is CR 9 Or N;
d is-CH 2 -NH 2 、
W is CR 9 Or N, wherein R 9 Is H or C 1 -C 3 An alkyl group;
R 2 is that
Wherein R is 56 Is hydrogen, fluorine, chlorine or methyl,
G. q, J and U are independently selected from C (H), C (R) 5 ) And N, provided that only one or both of G, Q, J and U can be N;
each R 5 Independently hydroxy, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 3 -C 6 Cycloalkoxy radicals C 3 -C 6 Cycloalkyl, C 3 -C 6 Heterocycloalkyl or C 1 -C 3 Alkoxy C 1 -C 3 An alkyl group;
R 6 is hydrogen, halogen or C 1 -C 6 Alkyl, hydroxy, C 1 -C 6 Alkoxy, C 1 -C 3 Alkoxy C 1 -C 3 Alkyl, C 3 -C 6 Heterocyclylalkyl, -C (O) -C 1 -C 3 Haloalkyl or-NR 15 (CO)R 16 Wherein R is 15 Is hydrogen or methyl, and R 16 Is C 1 -C 3 An alkyl group; and is also provided with
R 7 Is C 1 -C 3 Alkyl or C 1 -C 3 A haloalkyl group.
14. The method of claim 13, wherein the PRMT5 inhibitor is:
or a pharmaceutically acceptable salt thereof.
15. The method of any one of claims 1 to 11, wherein the PRMT5 inhibitor is a compound of formula IIIB:
or a pharmaceutically acceptable salt thereof, wherein
A is CR 9 Or N;
d is-CH 2 -NH 2 、
W is CR 9 Or N, wherein R 9 Is H or C 1 -C 3 An alkyl group;
R 51 is hydrogen, fluorine, chlorine or methyl, or R 51 And R is 52 Together with the atoms to which they are attached form C 4 -C 6 Heterocycloalkyl (e.g., hydrofuran);
R 52 is fluorine, chlorine or methyl, or R 52 And R is 53 Together with the atoms to which they are attached form a phenyl group;
R 53 hydrogen, fluorine, chlorine or methyl;
R 54 is hydrogen, halogen or C 1 -C 3 Alkyl or C 1 -C 3 An alkoxy group;
L 5 is-O-or-CH 2 –；
R 6 Is hydrogen, halogen or C 1 -C 6 Alkyl, hydroxy, C 1 -C 6 Alkoxy, C 1 -C 3 Alkoxy C 1 -C 3 Alkyl, C 3 -C 6 Heterocyclylalkyl, -C (O) -C 1 -C 3 Haloalkyl or-NR 15 (CO)R 16 Wherein R is 15 Is hydrogen or methyl, and R 16 Is C 1 -C 3 An alkyl group;
R 7 is C 1 -C 3 Alkyl or C 1 -C 3 A haloalkyl group.
16. The method according to claim 15, wherein:
a is-CH or-CCH 3 ；
D is-CH 2 -NH 2 ；
W is-CH, -CCH 3 Or N;
R 51 、R 52 、R 53 and R is 54 Each independently selected from hydrogen, fluorine, chlorine or methyl;
L 5 is-O-;
R 6 hydrogen, fluorine, chlorine or methyl; and is also provided with
R 7 Is C 1 -C 2 Alkyl or C 1 -C 2 A haloalkyl group.
17. The method of claim 15 or claim 16, wherein:
a and W are-CH;
d is-CH 2 -NH 2 ；
R 51 、R 52 And R is 53 Each independently selected from hydrogen, fluorine, chlorine and methyl;
R 54 is hydrogen;
L 5 is-O-;
R 6 is hydrogen; and is also provided with
R 7 Is methyl.
18. The method of any one of claims 15 to 17, wherein:
a and W are-CH;
d is-CH 2 -NH 2 ；
R 51 And R is 52 Each independently selected from fluorine, chlorine and methyl;
R 53 and R is 54 Is hydrogen;
L 5 is-O-;
R 6 is hydrogen; and is also provided with
R 7 Is methyl.
19. The method of claim 15, wherein the PRMT5 inhibitor is:
or a pharmaceutically acceptable salt thereof.
20. The method of claim 15, wherein the PRMT5 inhibitor is:(MRTX 1719) or a pharmaceutically acceptable salt thereof.
21. The method of any one of claims 1 to 7, wherein the PRMT5 inhibitor is MRTX1719 or a pharmaceutically acceptable salt thereof, and the KRAS G12C The inhibitor is adaglazeb.
22. The method of any one of claims 1 to 7, wherein the PRMT5 inhibitor is MRTX1719 or a pharmaceutically acceptable salt thereof, and the KRAS G12C The inhibitor is sotoracicada.
23. The method of any one of claims 1 to 11, wherein the PRMT5 inhibitor is a compound of formula IIIC:
Or a pharmaceutically acceptable salt thereof, wherein
A is CR 9 Or N;
d is-CH 2 -NH 2 、
W is CR 9 Or N, wherein R 9 Is H or C 1 -C 3 An alkyl group;
G. q, J and U are independently selected from C (H), C (R) 5 ) And N, provided that only one or both of G, Q, J and U can be N;
each R 5 Independently hydroxy, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 3 -C 6 Cycloalkoxy radicals C 3 -C 6 Cycloalkyl, C 3 -C 6 Heterocycloalkyl or C 1 -C 3 Alkoxy C 1 -C 3 An alkyl group;
R 6 is hydrogen, halogen or C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, hydroxy, C 1 -C 6 Alkoxy, C 1 -C 3 Alkoxy C 1 -C 3 Alkyl, C 3 -C 6 Heterocyclylalkyl, -C (O) -C 1 -C 3 Haloalkyl, -N (R) 9 ) 2 or-NR 15 (CO)R 16 ，
Wherein each R is 9 Independently H or C 1 -C 3 Alkyl, R 15 Is hydrogen or methyl, and R 16 Is C 1 -C 3 An alkyl group; and is also provided with
R 7 Is C 1 -C 3 Alkyl or C 1 -C 3 A haloalkyl group.
24. The method of claim 23, wherein the PRMT5 inhibitor is:
or a pharmaceutically acceptable salt thereof.
25. The method of any one of claims 1 to 24, wherein the therapeutically effective amount of the PRMT5 inhibitor is in the range of about 0.01 to 300mg/kg per day.
26. The method of any one of claims 1 to 24, wherein the therapeutically effective amount of the PRMT5 inhibitor is in the range of about 0.1 to 100mg/kg per day.
27. The method of any one of claims 1 to 26, wherein the therapeutically effective amount of the PRMT5 inhibitor is less than 1%, e.g., less than 10%, or less than 25%, or less than 50% of a clinically determined therapeutic amount.
28. The method of any one of claims 1 to 27, wherein the KRAS G12C The therapeutically effective amount of the inhibitor is in the range of about 0.01 to 300mg/kg per day.
29. The method of any one of claims 1 to 27, wherein the KRAS G12C The therapeutically effective amount of the inhibitor is in the range of about 0.1 to 100mg/kg per day.
30. The method of any one of claims 1 to 29, wherein the KRAS G12C The therapeutically effective amount of the inhibitor is less than 1%, e.g., less than 10%, or less than 25%, or less than 50% of the clinically determined therapeutic amount.
31. The method of any one of claims 1 to 30, wherein the KRAS G12C The inhibitor and the PRMT5 inhibitor are administered sequentially.
32. The method of any one of claims 1 to 30, wherein the KRAS G12C The inhibitor and the PRMT5 inhibitor are administered simultaneously.
33. The method of any one of claims 1 to 32, wherein the subject has previously received or completed first line chemotherapy.
34. The method of claim 33, wherein the first-line chemotherapy is platinum and/or taxane-based chemotherapy.
CN202280037172.9A 2021-04-08 2022-04-05 Combination therapy for treating cancer using PRMT5 inhibitors Pending CN117769421A (en)

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