EP4626892A1 - Antagonistes des récepteurs a2a et a2b de l'adénosine, compositions pharmaceutiques et leur utilisation - Google Patents

Antagonistes des récepteurs a2a et a2b de l'adénosine, compositions pharmaceutiques et leur utilisation

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Publication number
EP4626892A1
EP4626892A1 EP23898613.7A EP23898613A EP4626892A1 EP 4626892 A1 EP4626892 A1 EP 4626892A1 EP 23898613 A EP23898613 A EP 23898613A EP 4626892 A1 EP4626892 A1 EP 4626892A1
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EP
European Patent Office
Prior art keywords
cancer
alkyl
compound
pharmaceutically acceptable
mmol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23898613.7A
Other languages
German (de)
English (en)
Inventor
Umar Faruk Mansoor
Elisabeth T. HENNESSY
Amjad Ali
Jared N. Cumming
Duane E. Demong
William P. Kaplan
Rebecca Elizabeth JOHNSON
Matthew A. Larsen
Qiaolin Deng
Christopher W. Plummer
Aaron C. Sather
Derun Li
Jesus Moreno
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Sharp and Dohme LLC
Original Assignee
Merck Sharp and Dohme LLC
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Filing date
Publication date
Application filed by Merck Sharp and Dohme LLC filed Critical Merck Sharp and Dohme LLC
Publication of EP4626892A1 publication Critical patent/EP4626892A1/fr
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the invention relates to novel compounds that inhibit at least one of the A2a and A2b adenosine receptors, and pharmaceutically acceptable salts thereof, and compositions comprising such compound(s) and salts, methods for the synthesis of such compounds, and their use in the treatment of a variety of diseases, conditions, or disorders that are mediated, at least in part, by the adenosine A2a receptor and/or the adenosine A2b receptor.
  • diseases, conditions, and disorders include but are not limited to cancer and immune-related disorders.
  • the invention further relates to combination therapies, including but not limited to a combination comprising a compound of the invention and a PD-1 antagonist.
  • Adenosine is a purine nucleoside compound comprised of adenine and ribofuranose, a ribose sugar molecule.
  • Adenosine occurs naturally in mammals and plays important roles in various biochemical processes, including energy transfer (as adenosine triphosphate and adenosine monophosphate) and signal transduction (as cyclic adenosine monophosphate).
  • Adenosine plays a causative role in processes associated with vasodilation, including cardiac vasodilation. It also acts as a neuromodulator (e.g., it is thought to be involved in promoting sleep).
  • adenosine is used as a therapeutic antiarrhythmic agent to treat supraventricular tachycardia and other indications.
  • the adenosine receptors are a class of purinergic G protein-coupled receptors with adenosine as the endogenous ligand.
  • A2a antagonists are believed to exhibit antidepressant properties and to stimulate cognitive functions.
  • A2a receptors are present in high density in the basal ganglia, known to be important in the control of movement.
  • A2a receptor antagonists are believed to be useful in the treatment of depression and to improve motor impairment due to neurodegenerative diseases such as Parkinson’s disease, senile dementia (as in Alzheimer's disease), and in various psychoses of organic origin.
  • A2a receptors and A2b receptors expressed on a variety of immune cells and endothelial cells, has been established as having an important role in protecting tissues during inflammatory responses. In this way (and others), tumors have been shown to evade host responses by inhibiting immune function and promoting tolerance. (See. e.g., Fishman, P., et al., Handb. Exp. Pharmacol. (2009) 193:399-441). Moreover, A2a and A2b cell surface adenosine receptors have been found to be upregulated in various tumor cells.
  • antagonists of the A2a and/or A2b adenosine receptors represent a new class of promising oncology 7 therapeutics.
  • activation of A2a adenosine receptor results in the inhibition of the immune response to tumors by a variety of cell types, including but not limited to the inhibition of natural killer cell cytotoxicity, the inhibition of tumor-specific CD4+/CD8+ activity, promoting the generation of LAG-3 and Foxp3+ regulatory T-cells, and mediating the inhibition of regulatory 7 T-cells.
  • Adenosine A2a receptor inhibition has also been shown to increase the efficacy of PD-1 inhibitors through enhanced anti -tumor T cell responses.
  • a cancer immunotherapeutic regimen that includes an antagonist of the A2a and/or A2b receptors, alone or together with one or more other therapeutic agents designed to mitigate immune suppression, may result in enhanced tumor immunotherapy.
  • a cancer immunotherapeutic regimen that includes an antagonist of the A2a and/or A2b receptors, alone or together with one or more other therapeutic agents designed to mitigate immune suppression.
  • Cancer cells release ATP into the tumor microenvironment when treated with chemotherapy and radiation therapy, which is subsequently converted to adenosine.
  • the adenosine can then bind to A2a receptors and blunt the anti-tumor immune response through mechanisms such as those described above.
  • the administration of A2a receptor antagonists during chemotherapy or radiation therapy has been proposed to lead to the expansion of the tumor-specific T-cells while simultaneously preventing the induction of tumor-specific regulatory T-cells. (Y oung, A., et al., Cancer Discovery (2014) 4:879-888).
  • A2a receptor antagonists may be useful in combination with checkpoint blockers.
  • the combination of a PD-1 inhibitor and an adenosine A2a receptor inhibitor is thought to mitigate the ability of tumors to inhibit the activity of tumor-specific effector T-cells.
  • the A2b receptor is a G protein-coupled receptor found in various cell types. A2b receptors require higher concentrations of adenosine for activation than the other adenosine receptor subtypes, including A2a. (Fredholm, BB., et al., Biochem. Pharmacol. (2001) 61 :443- 448). Conditions which activate A2b have been seen, for example, in tumors where hypoxia is observed. The A2b receptor may thus play an important role in pathophysiological conditions associated with massive adenosine release.
  • A2b receptor-mediated inhibition While the pathway(s) associated with A2b receptor- mediated inhibition are not well understood, it is believed that the inhibition of A2b receptors (alone or together with A2a receptors) may block pro-tumorigenic functions of adenosine in the tumor microenvironment, including suppression of T-cell function and angiogenesis, and thus expand the types of cancers treatable by the inhibition of these receptors.
  • Angiogenesis plays an important role in tumor grow th.
  • the angiogenesis process is highly regulated by a variety of factors and is triggered by adenosine under particular circumstances that are associated with hypoxia.
  • the A2b receptor is expressed in human microvascular endothelial cells, where it plays an important role in the regulation of the expression of angiogenic factors such as the vascular endothelial grow th factor (VEGF).
  • VEGF vascular endothelial grow th factor
  • hypoxia has been observed to cause an upregulation of the A2b receptors, suggesting that inhibition of A2b receptors may limit tumor growth by limiting the oxygen supply to the tumor cells.
  • the invention provides compounds (hereinafter referred to as compounds of the invention) which have been found to be inhibitors of the adenosine A2a receptor and/or the adenosine A2b receptor.
  • the compounds of the invention have a structure in accordance with the structural Formula (I): or a pharmaceutically acceptable salt thereof, wherein ring A, R 1 , and R 2 are as defined below.
  • the invention provides pharmaceutical compositions comprising at least one compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. Such compositions according to the invention may optionally further include one or more additional therapeutic agents as described herein.
  • the invention provides a method for treating or preventing a disease, condition, or disorder that is mediated, at least in part, by the adenosine A2a receptor and/or the adenosine A2b receptor in a subject (e g., an animal or human) in need thereof, said method comprising administering to the subject a therapeutically effective amount of at least one compound of the invention, or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional therapeutic agents.
  • any variable not explicitly defined in the embodiment is as defined in Formula (I). In each of the embodiments described herein, each variable is selected independently of the other unless otherwise noted.
  • the invention provides compounds having a structural Formula (I): or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 is H, F, or Cl
  • each R 2 is, independently, H, F, Cl, (C 1 -C 6 )alkyl, or -O(C 1 -C 6 )alkyl, wherein each R 2 is not H simultaneously
  • ring A is a moiety selected from
  • R 3 is selected from:
  • R 4 , R 5 , and R 6 each is (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl:
  • R 3A is H or -OH
  • R 3B is independently selected from the group consisting of halogen, -OH, -CF 3 , -CN, -N(R 3F ) 2 , (C 1 -C 6 )alkyl, and (C 3 -C 10 )cycloalkyl, wherein each of the (C 1 -C 6 )alkyl and the (C 3 -C 10 )cycloalkyl is optionally substituted with 1 to 7 moieties independently selected from the group consisting of -OH, -N(R 3F ) 2 , (C 3 -C 10 )cycloalkyl. and halogen;
  • R 3C is independently selected from the group consisting of halogen, - OH, -CN, (C 1 -C 6 )alkyl, (C 3 -C 10 )cycloalkyl, -O(C 1 -C 6 )alkyl, -CO(C 1 -C 6 )alkyl -CO(C 3 - C 6 )cycloalkyl, and -CO(C 3 -C 6 )cyclohaloalkyl.
  • the (C 1 -C 6 )alkyl being optionally substituted with 1 to 4 moieties independently selected from the group consisting of -OH and halogen;
  • R 3D is independently selected from the group consisting of -OH, -
  • R 3E is independently selected from the group consisting of -OH, halogen, -CN, -CF 3 , morpholin-4-yl, (C 1 -C 4 )alkylsulfonyl-, -CO(C 1 -C 6 )alkyl, oxetanyl, (C 1 -C 6 )alkyl, -O(C 1 -C 6 )alkyl.
  • (C 3 -C 10 )cycloalkyl (C 3 -C 10 )cycloalkyl. (C 3 -C 10 )cyclohaloalkyl, tetrahydrofuranyl, pyrimidinyl. and wherein each of the (C 1 -C 6 )alkyl, the -O(C 1 -C 6 )alkyl, and the (C 3 -C 10 )cycloalkyl is optionally substituted with 1 to 4 moieties independently selected from the group consisting of -OH, (C 1 - C 4 )alkyl, -N(R 3F ) 2 , and halogen;
  • R 3F at each occurrence, is independently, H, (C 1 -C 4 )alkyl, or (C 1 -C 4 )haloalkyl;
  • R 3J at each occurrence, is independently. -OH. (C 1 -C 6 )alkyl. (C 1 -C 6 )haloalkyl, (C 1 - C 6 )hydroxyalkyl. or (C 3 -C 6 )cycloalkyl;
  • R 3K is (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl or (C 3 -C 10 )cycloalkyl; m, n, and p, at each occurrence, are independently a number from 0 to 2; q is 0 or 1; r is a number from 0 to 3; s, at each occurrence, is independently a number from 0 to 4; and B is a nitrogen or a carbon atom.
  • R 4 is (C 1 -C 6 )alkyl, and m is 0 or 1.
  • the invention provides a compound of any of the immediately preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is CH 3 .
  • the invention provides a compound of any of the immediately preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 3 is - (CHR 3A ) q (CH 2 ) n (C 6 -C 10 )aryl, wherein the aryl is optionally substituted with 1 to 3 R 3B groups, and wherein
  • R 3B is independently selected from the group consisting of halogen, -OH, -CF 3 , -CN, -N(R 3F ) 2 , (C 1 -C 6 )alkyl, and (C 3 -C 10 )cycloalkyl, wherein each of the (C 1 -C 6 )alkyl and the (C 3 -C 10 )cycloalkyl is optionally substituted with 1 to 7 moieties independently selected from the group consisting of -OH, -N(R 3F ) 2 , (C 3 -C 10 )cycloalkyl, and halogen.
  • R 3B is not substituted. In some embodiments. R 3B is optionally substituted with 1 to 7 moieties selected from the above list. In some embodiments, R 3B is optionally substituted w ith 1 to 6 moieties selected from the above list. In some embodiments, R 3B is optionally substituted with 1 to 5 moieties selected from the above list. In some embodiments, R 3B is optionally substituted with 1 to 4 moieties selected from the above list. In some embodiments, R 3B is optionally substituted with 1 to 3 moieties selected from the above list. In some embodiments, R 3B is optionally substituted with 1 or 2 moieties selected from the above list.
  • R 3B is optionally substituted with 1 moiety selected from the above list. In other embodiments, R 3B is substituted with 1 moiety selected from the above list. In other embodiments, R 3B is substituted with 2, 3, 4, 5, 6, or 7 moieties selected from the above list.
  • the invention provides a compound of any of the first four embodiments, or a pharmaceutically acceptable salt thereof, wherein R 3 is a 4- to 7 -membered heterocycloalkyl having 1 to 3 heteroatoms independently selected from N. O, and S. optionally substituted with 1 to 4 R 3C groups, and wherein
  • R 3C is independently selected from the group consisting of halogen, - OH, -CN, (C 1 -C 6 )alkyl, (C 3 -C 10 )cycloalkyl, -O(C 1 -C 6 )alkyl, -CO(C 1 -C 6 )alkyl -CO(C 3 - C 6 )cycloalkyl, and -CO(C 3 -C 6 )cyclohaloalkyl.
  • R 3D is independently selected from the group consisting of -OH, -
  • R 3E at each oc p consisting of -OH, halogen, -CN, -CF 3 , morpholin-4-yl, (C 1 -C 4 )alkylsulfonyl-. -CO(C 1 -C 6 )alkyl, oxetanyl, (C 1 -C 6 )alkyl, - 1
  • (C 3 -C 10 )cycloalkyl (C 3 -C 10 )cycloalkyl. (C 3 -C 10 )cyclohaloalkyl, tetrahydrofuranyl, pyrimidinyl. and wherein each of the (C 1 -C 6 )alkyl, the -O(C 1 -C 6 )alkyl, and the (C 3 -C 10 )cycloalkyl is optionally substituted with 1 to 4 moieties independently selected from the group consisting of -OH, (C 1 - C 4 )alkyl, -N(R 3F ) 2 , and halogen.
  • the invention provides a compound of the first embodiment having Formula (I.1),
  • the invention provides a compound of the immediately preceding embodiment, or a pharmaceutically acceptable salt thereof, wherein R 4 is -CH 3 , and m is 1. [0030] In another embodiment, the invention provides a compound of the immediately preceding embodiment, or a pharmaceutically acceptable salt thereof, wherein R 3 is pyridinyl, piperidinyl, phenyl, imidazolyl, triazolyl, pyrrolidinyl, thiazolyl, pyrrolidinonyl, pyrazolyl, pyridazinyl, cyclobutyl, oxazolyl, pyrazinyl, oxadiazolyl, or (C 1 -C 6 )alkyl, each optionally substituted with 1 to 4 moieties selected from the group consisting of -OH methyl ethyl, isopropyl, cyclopropyl, F, morpholin-4-y
  • the invention provides a compound of the immediately preceding embodiment, or a pharmaceutically acceptable salt thereof, wherein R 3 is oxazolyl, pyridinyl, pyrazinyl, oxadiazolyl, or phenyl.
  • the invention provides a compound of the immediately preceding embodiment, or a pharmaceutically acceptable salt thereof, wherein the pyridinyl, pyrazinyl x di z l l r henyl is independently substituted at 1 or 2 ring carbon atoms with - CH 3 or
  • the invention provides a compound of the immediately preceding embodiment, wherein ring A is .
  • the invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of , and .
  • the invention provides a compound selected from the group consisting of
  • the compounds of the invention comprise those compounds identified herein as examples in the tables below and the pharmaceutically acceptable salts thereof.
  • the invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of the invention or a pharmaceutically acceptable salt thereof. Such compositions according to the invention may optionally further include one or more additional therapeutic agents as described herein.
  • the disease, condition, or disorder is a cancer.
  • Any cancer for which a PD-1 antagonist and/or an A2a and/or A2b inhibitor are thought to be useful by those of ordinary skill in the art are contemplated as cancers treatable by this embodiment, either as a monotherapy or in combination with other therapeutic agents discussed below.
  • Cancers that express high levels of A2a receptors or A2b receptors are among those cancers contemplated as treatable by the compounds of the invention. Examples of cancers that express high levels of A2a and/or A2b receptors may be discerned by those of ordinary skill in the art by reference to the Cancer Genome Atlas (TCGA) database.
  • TCGA Cancer Genome Atlas
  • Non-limiting examples of cancers that express high levels of A2a receptors include cancers of the kidney, breast, lung, and liver.
  • Non-limiting examples of cancers that express high levels of the A2b receptor include lung, colorectal, head & neck cancer, and cervical cancer.
  • Another embodiment provides a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment, wherein said cancer is a cancer that expresses a high level of A2b receptor.
  • a related embodiment provides a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment, wherein said cancer is selected from lung cancer, colorectal cancer, head & neck cancer, and cervical cancer.
  • cancers which may be treatable by administration of a compound of the invention (alone or in combination with one or more additional agents described below) include cancers of the prostate (including but not limited to metastatic castration resistant prostate cancer), colon, rectum, pancreas, cervix, stomach, endometrium, brain, liver, bladder, ovary, testis, head, neck, skin (including melanoma and basal carcinoma), mesothelial lining, white blood cell (including lymphoma and leukemia) esophagus, breast, muscle, connective tissue, lung (including but not limited to small cell lung cancer, non-small cell lung cancer, and lung adenocarcinoma), adrenal gland, thyroid, kidney, or bone.
  • prostate including but not limited to metastatic castration resistant prostate cancer
  • colon including rectum, pancreas, cervix, stomach, endometrium, brain, liver, bladder, ovary, testis, head, neck, skin (including melanoma and basal carcinoma), mes
  • Additional cancers treatable by a compound of the invention include glioblastoma, mesothelioma, renal cell carcinoma, gastric carcinoma, sarcoma, choriocarcinoma, cutaneous basocellular carcinoma, and testicular seminoma, and Kaposi's sarcoma.
  • the disease, condition, or disorder is a central nervous system or a neurological disorder.
  • diseases, conditions, or disorders include movement disorders such as tremors, bradykinesias. gait disorders, dystonias, dyskinesias, tardive dyskinesias, other extrapyramidal syndromes, Parkinson's disease, and disorders associated with Parkinson's disease.
  • the compounds of the invention also have the potential, or are believed to have the potential, for use in preventing or reducing the effect of drugs that cause or worsen such movement disorders.
  • the disease, condition, or disorder is an infective disorder.
  • diseases, conditions or disorders include an acute or chronic viral infection, a bacterial infection, a fungal infection, or a parasitic infection.
  • the viral infection is human immunodeficiency virus.
  • the viral infection is cytomegalovirus.
  • Other diseases, conditions, and disorders that have the potential to be treated or prevented, in whole or in part, by the inhibition of the A2a and/or A2b adenosine receptor(s) are also candidate indications for the compounds of the invention and salts thereof.
  • Non-limiting examples of other diseases, conditions, or disorders in which a compound of the invention, or a pharmaceutically acceptable salt thereof, may be useful include the treatment of hypersensitivity reaction to a tumor antigen and the amelioration of one or more complications related to bone marrow transplant or to a peripheral blood stem cell transplant.
  • the invention provides a method for treating a subject receiving a bone marrow transplant or a peripheral blood stem cell transplant by administering to said subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, sufficient to increase the delayed-type hypersensitivity reaction to tumor antigen, to delay the time-to- relapse of post-transplant malignancy, to increase relapse-free survival time post-transplant, and/or to increase long-term post-transplant survival.
  • Combination Therapy [0050]
  • the invention provides methods for the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, (or a pharmaceutically acceptable composition comprising a compound of the invention or pharmaceutically acceptable salt thereof) in combination with one or more additional agents.
  • Such additional agents may have some adenosine A2a and/or A2b receptor activity, or, alternatively, they may function through distinct mechanisms of action.
  • the compounds of the invention may be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions for which the compounds of the invention or the other drugs described herein may have utility, where the combination of the drugs together are safer or more effective than either drug alone.
  • the combination therapy may have an additive or synergistic effect.
  • Such other drug(s) may be administered in an amount commonly used therefor, contemporaneously or sequentially, with a compound of the invention or a pharmaceutically acceptable salt thereof.
  • the weight ratio of the compound of the invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the invention is used in combination with another agent, the weight ratio of the compound of the invention to the other agent may generally range from about 1000:1 to about 1 : 1000, and in particular embodiments from about 200: 1 to about 1 :200. Combinations of a compound of the invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should generally be used.
  • the administration of an A2a receptor antagonist, an A2b receptor antagonist, and/or an A2a/A2b receptor dual antagonist according to the invention may enhance the efficacy of immunotherapies such as PD-1 antagonists.
  • the additional therapeutic agent comprises an anti-PD-1 antibody.
  • the additional therapeutic agent is an anti-PD-Ll antibody.
  • PD-1 is recognized as having an important role in immune regulation and the maintenance of peripheral tolerance. PD-1 is moderately expressed on naive T-cells, B- cells and NKT-cells and up-regulated by T-cell and B-cell receptor signaling on lymphocytes, monocytes and myeloid cells (Sharpe et al., Nature Immunology (2007); 8:239-245).
  • cancers in accordance with this embodiment include melanoma (including unresectable or metastatic melanoma), head & neck cancer (including recurrent or metastatic head and neck squamous cell cancer (HNSCC)), classical Hodgkin lymphoma (cHL), urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large-B-cell lymphoma, microsatellite instability -high (MSI-H) cancer, non-small cell lung cancer, hepatocellular carcinoma, clear cell kidney cancer, colorectal cancer, breast cancer, squamous cell lung cancer, basal carcinoma, sarcoma, bladder cancer, endometrial cancer, pancreatic cancer, liver cancer, gastrointestinal cancer, multiple myeloma, renal cancer, mesothelioma, ovarian cancer, anal cancer, biliary tract cancer, esophageal cancer, and salivary- cancer.
  • HNSCC head & neck cancer
  • cHL classical Hodg
  • a method of treating urothelial carcinoma comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist.
  • the PD-1 antagonist is pembrolizumab.
  • the PD-1 antagonist is nivolumab.
  • the PD-1 antagonist is atezolizumab.
  • the PD-1 antagonist is selected from the group consisting of: pembrolizumab. nivolumab, atezolizumab, durvalumab, avelumab, and dostarlimab.
  • a method of treating microsatellite instability- high (MSI-H) cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist.
  • the PD-1 antagonist is pembrolizumab.
  • the PD-1 antagonist is nivolumab.
  • the PD-1 antagonist is atezolizumab.
  • the PD-1 antagonist is selected from the group consisting of: pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, and dostarlimab.
  • the additional therapeutic agent comprises radiation.
  • radiation includes localized radiation therapy and total body radiation therapy.
  • the vaccine includes one or more immunogenic peptides and/or dendritic cells.
  • the invention provides a method of treating an infection by administering a compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, wherein a symptom of the infection observed after administering both the compound of the invention (or a pharmaceutically acceptable salt thereol) and the additional therapeutic agent is improved over the same symptom of infection observed after administering either alone.
  • the symptom of infection observed can be reduction in viral load, increase in CD4+ T cell count, decrease in opportunistic infections, increased survival time, eradication of chronic infection, or a combination thereof.
  • a compound in treatment means that an amount of the compound, generally presented as a component of a formulation that comprises other excipients, is administered in aliquots of an amount, and at time intervals, which provides and maintains at least a therapeutic serum level of at least one pharmaceutically active form of the compound over the time interval between dose administrations.
  • compositions for example, “at least one pharmaceutical excipient” means that one member of the specified group is present in the composition, and more than one may additionally be present.
  • Components of a composition are typically aliquots of isolated pure material added to the composition, where the purity level of the isolated material added into the composition is the normally accepted purity level for a reagent of the type.
  • “Sequentially” refers to a series administration of therapeutic agents that awaits a period of efficacy to transpire between administering each additional agent; this is to say that after administration of one component, the next component is administered after an effective time period after the first component; the effective time period is the amount of time given for realization of a benefit from the administration of the first component.
  • Effective amount or “therapeutically effective amount” is meant to describe the provision of an amount of at least one compound of the invention or of a composition comprising at least one compound of the invention which is effective in treating or inhibiting a disease or condition described herein, and thus produce the desired therapeutic, ameliorative, inhibitory or preventative effect.
  • the term ‘‘patient’ ’ refers to a mammal (e.g., rat, mouse, dog, cat, rabbit) capable of being treated with the compounds of the invention, most preferably a human.
  • the term “patient” may also include non-human animals including livestock animals and domestic animals including, but not limited to, cattle, horses, sheep, swine, goats, rabbits, cats, dogs, and other mammals in need of treatment.
  • a patient is an adult patient. In other embodiments, a patient is a pediatric patient.
  • the amount of an agent that is effective to alleviate any particular disease symptom may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the drug to elicit a desired response in the subject. Whether a disease symptom has been alleviated can be assessed by any clinical measurement typically used by physicians or other skilled healthcare providers to assess the severity or progression status of that symptom.
  • the term further includes a postponement of development of the symptoms associated with a disorder and/or a reduction in the severity of the symptoms of such disorder.
  • the terms further include ameliorating existing uncontrolled or unwanted symptoms, preventing additional symptoms, and ameliorating or preventing the underlying causes of such symptoms.
  • the terms denote that a beneficial result has been conferred on a vertebrate subject with a disorder, disease, or symptom, or with the potential to develop such a disorder, disease, or symptom.
  • Prodrug means compounds that are rapidly transformed, for example, by hydrolysis in blood, in vivo to the parent compound, e.g., conversion of a prodrug of a compound of the invention to a compound of the invention, or to a salt thereof.
  • a thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference; the scope of this invention includes prodrugs of the novel compounds of this invention.
  • substituted means that one or more of the moieties enumerated as substituents (or, where a list of substituents are not specifically enumerated, the substituents specified elsewhere in this application) for the particular type of substrate to which said substituent is appended, provided that such substitution does not exceed the normal valence rules for the atom in the bonding configuration presented in the substrate, and that the substitution ultimately provides a stable compound, which is to say that such substitution does not provide compounds with mutually reactive substituents located geminal or vicinal to each other; and wherein the substitution provides a compound sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture.
  • substituted shall be deemed to include multiple degrees of substitution by a named substituent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties. singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.
  • optional substitution by a moiety means that if substituents are present, one or more of the enumerated (or default) moieties listed as optional substituents for the specified substrate can be present on the substrate in a bonding position normally occupied by the default substituent, for example, a hydrogen atom on an alkyl chain can be substituted by one of the optional substituents, in accordance with the definition of “substituted” presented herein.
  • Haloalkyl means an alkyl as defined above wherein one or more hydrogen atoms on the alky l (up to and including each available hydrogen group) is replaced by a halogen atom.
  • halo or “halogen’ as used herein is intended to include chloro (Cl), fluoro (F), bromo (Br) and iodo (I). Chloro (Cl) and fluoro (F) halogens are generally preferred.
  • Aryl means an aromatic monocyclic or multicyclic ring system comprising 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms, wherein at least one of the rings is aromatic.
  • the aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different and are as defined herein.
  • suitable aryl groups include phenyl and naphthyl.
  • “Monocyclic aryl’” means phenyl.
  • heteroaryl may also include a heteroaryl as defined above fused to an ary l as defined above.
  • suitable heteroaryls include pyridyl, pyrazinyl, furanyl.
  • thienyl (which alternatively may be referred to as thiophenyl), pyrimidinyl, pyridone (including N-substituted pyndones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4- thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1,2- a]pyridinyl, imidazo [2.1-b] thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl.
  • heteroaryl also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
  • monocyclic heteroaryl refers to monocyclic versions of heteroaryl as described above and includes 4- to 7- membered monocyclic heteroaryl groups comprising from 1 to 4 ring heteroatoms, said ring heteroatoms being independently selected from the group consisting of N, O, and S, and oxides thereof.
  • the point of attachment to the parent moiety is to any available ring carbon or ring heteroatom.
  • Non-limiting examples of monocyclic heteroaryl moieties include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridazinyl, pyridinyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl. furazanyl, pyrrolyl, pyrazolyl, triazolyl, thiadiazolyl (e.g.. 1 ,2,4-thiadiazolyl), imidazolyl, and triazinyl (e.g., 1,2,4-triazinyl), and oxides thereof.
  • pyridyl pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridazinyl, pyridinyl, thiazolyl, isothiazolyl, oxazolyl, ox
  • Cycloalkyl means a non-aromatic fully saturated monocyclic or multicyclic ring system comprising 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms.
  • the cycloalkyl can be optionally substituted with one or more substituents, which may be the same or different, as described herein.
  • Monocyclic cycloalkyl refers to monocyclic versions of the cycloalkyl moieties described herein.
  • suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • Non-limiting examples of multicyclic cycloalkyls include [1.1.1] -bicyclopentane, 1 -decalinyl, norbomyl, adamantyl and the like.
  • “Heterocycloalkyl” (or “heterocyclyl”) means a non-aromatic saturated monocyclic bicyclic (including spirocyclic) or bridged carbocyclic ring or multicyclic ring system comprising 3 to 10 ring atoms, preferably 5 to 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination.
  • heterocycloalkyl groups contain 4, 5 or 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), -N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention.
  • the heterocyclyl can be optionally substituted by one or more substituents, which may be the same or different, as described herein.
  • the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • oxo An example of such a moiety is pyrrolidinone (or pyrrolidone):
  • the term “monocyclic heterocycloalkyl” refers to monocyclic versions of the heterocycloalkyl moieties described herein and include a 4- to 7-membered monocyclic heterocycloalkyl groups comprising from 1 to 4 ring heteroatoms, said ring heteroatoms being independently selected from the group consisting ofN, N-oxide, O, S, S-oxide, S(O), and S(O) 2 .
  • the point of attachment to the parent moiety is to any available ring carbon or ring heteroatom.
  • Non-limiting examples of monocyclic heterocycloalkyl groups include piperidyl, oxetanyl. pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, beta lactam, gamma lactam, delta lactam, beta lactone, gamma lactone, delta lactone, and pyrrolidinone, and oxides thereof.
  • Non-limiting examples of lower alkyl-substituted oxetanyl include the moiety:
  • hetero atom containing ring systems of this invention there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, and there are no N or S groups on carbon adjacent to another heteroatom. For example, there is no -OH attached directly to carbons marked 2 and 5.
  • the wavy line as used herein, indicates a point of attachment to the rest of the compound.
  • Lines drawn into the ring systems, such as, for example: indicate that the indicated line (bond) may be attached to any of the substitutable ring atoms.
  • Examples of pharmaceutically acceptable basic salts include, but are not limited to, ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts, zinc salts, salts with organic bases (for example, organic amines) such as benzathines, diethylamine, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenedi amine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-bnty 1 amines, piperazine, phenylcyclohexyl-amine, choline, tromethamine, and salts with amino acids such as arginine, lysine and the like.
  • organic bases for example, organic amines
  • organic bases for example, organic amines
  • the invention also embraces isotopically-labeled compounds of the invention which are structurally identical to those recited herein, but for the fact that a statistically significant percentage of one or more atoms in that form of the compound are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number of the most abundant isotope usually found in nature, thus altering the naturally occurring abundance of that isotope present in a compound of the invention.
  • compositions comprising compounds of the invention
  • the compounds of the invention will be combined with one or more pharmaceutically acceptable excipients.
  • excipients impart to the composition properties which make it easier to handle or process, for example, lubricants or pressing aids in powdered medicaments intended to be tableted, or adapt the formulation to a desired route of administration, for example, excipients which provide a formulation for oral administration, for example, via absorption from the gastrointestinal tract, transdermal or transmucosal administration, for example, via adhesive skin “patch”’ or buccal administration, or injection, for example, intramuscular or intravenous, routes of administration.
  • a carrier typically, formulations may comprise up to about 95 percent active ingredient, although formulations with greater amounts may be prepared.
  • solid form preparations which are intended to be converted, shortly before use, to a suspension or a solution, for example, for oral or parenteral administration.
  • solid forms include, but are not limited to, freeze dried formulations and liquid formulations adsorbed into a solid absorbent medium.
  • transdermal compositions can also take the form of creams, lotions, aerosols and/or emulsions and can be provided in a unit dosage form which includes a transdermal patch of any know in the art, for example, a patch which incorporates either a matrix comprising the pharmaceutically active compound or a reservoir which comprises a solid or liquid form of the pharmaceutically active compound.
  • the pharmaceutical preparation is in a unit dosage form.
  • the preparations subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g.. an effective amount to achieve the desired purpose.
  • an appropriate dosage level for a compound (or compounds) of the invention will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses.
  • a suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0. 1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day.
  • the compounds of the invention can be prepared readily according to the following schemes and specific examples, or modifications thereof, using readily available starting materials, reagents, and conventional synthetic procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in detail.
  • the general procedures for making the compounds claimed in this invention can be readily understood and appreciated by one skilled in the art from viewing the following Schemes and descriptions.
  • R 1 can be a dimethoxybenzyl protecting group or a hydrogen.
  • R 5 can be a methyl or a hydrogen and R 2 , R 3 , R 4 can either be halogens or a methoxy.
  • Piperidine G.1 can be reacted with carboxylic acids G.2 using a number of different amide coupling conditions to form intermediates of type G.3.
  • intermediates of type G.3 can be treated with (i) TFA in the absence of solvent or in DCM. stirring at room temperature or heating at 50 °C, or with (ii) DDQ to provide products of type G1.4.
  • Products of type G1.4 can be purified by silica gel chromatography or preparative reverse-phase HPLC.
  • diethyl ether used in the experiments described below- was Fisher ACS certified material and stabilized with BHT.
  • degassed refers to a solvent from which oxygen has been removed, generally by bubbling an inert gas such as nitrogen or argon through the solution for 10 to 15 minutes with an outlet needle to normalize pressure.
  • concentrated means evaporating the solvent from a solution or mixture using a rotary evaporator or vacuum pump.
  • evaporated means evaporating using a rotary evaporator or vacuum pump.
  • proton nuclear magnetic resonance ( 1 H NMR) spectra and proton-decoupled carbon nuclear magnetic resonance spectra were recorded on 400, 500, or 600 MHz Broker or Varian NMR spectrometers at ambient temperature. All chemical shifts (5) were reported in parts per million (ppm).
  • Proton resonances were referenced to residual protium in the NMR solvent, which can include, but is not limited to, CDCl 3 , DMSO- d 6 , and MeOD-d 4 .
  • Carbon resonances are referenced to the carbon resonances of the NMR solvent.
  • reaction mixture was stirred at -20 °C for an additional 45 minutes and then a slurry of ethyl 6-chloropyridazine-3-carboxylate (0.5 g, 2.68 mmol) in Me-THF/toluene (5 rnL) was added slowly in 5 minutes.
  • the reaction was stirred at -20 °C for 10 minutes and then warmed to 0 °C and stirred for an additional 45 minutes.
  • the reaction mixture was slowly poured into crushed ice containing IN HC1.
  • methylmagnesium bromide (809 ⁇ L, 2.427 mmol) was added and after 5 minutes the vial was allowed to warm to room temperature.
  • the reaction mixture was quenched by the addition of saturated aqueous ammonium chloride and the aqueous layer was extracted 3x with EtOAc. The combined organic layers were concentrated and not purified further.
  • the crude residue was directly purified by reverse phase HPLC purification using the following methods: Method A – TFA Modifier [0230] C18 reverse-phase Prep-HPLC (gradient elution, MeCN/H 2 O/0.1% TFA). Electrospray (ESI) Mass-triggered fraction collection was employed using positive ion polarity scanning to monitor for the target mass. Method B – Basic Modifier [0231] C18 reverse-phase Prep-HPLC (gradient elution, MeCN/H 2 O/basic modifier – 0.1% NH 4 OH). Electrospray (ESI) Mass-triggered fraction collection was employed using positive ion polarity scanning to monitor for the target mass.
  • Example 161 and 162 ((2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-2-methylpiperidin-1-yl)(3-aminocyclobutyl)methanone , 0.135 mmol) in MeCN (1 mL) was added 1-methyl-1H-imidazole (29.9 mg, 0.364 mmol), N- (2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,6S)-6-methylpiperidin-3-yl)- [1,2,4]triazolo[
  • Example 172 ((2S,5R)-5-(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl)(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)methanone acid (31 mg, 0.170 mmol) (Intermediate 66) and a stir bar was suspended in DCM (1000 ⁇ L), at which point, 7,9-difluoro-2-((3R,6S)-6-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5- amine (31.8 mg, 0.1 mmol) (Intermediate 20), DIPEA (52.4 ⁇ L, 0.300 mmol), and 1- propanephosphonic anhydride (119 ⁇ L, 0.200 mmol) were sequentially added.
  • DIPEA 52.4 ⁇ L, 0.300 m
  • reaction mixture was stirred vigorously at room temperature.
  • the reaction turned into a complete homogeneous solution after the addition of the coupling reagent.
  • LCMS analysis indicated the reaction was complete after 30 minutes.
  • the reaction was quenched with hydrochloric acid (500 ⁇ l, 0.500 mmol) and after stirring vigorously for 5 minutes, was poured into a phase separator.
  • the aqueous layer was extracted with DCM (10 mL) and passed through a phase separator again.
  • the combined organic layers were dried with Mg 2 SO 4 , filtered, and concentrated under reduced pressure.
  • Example compounds of the invention in the following Table 11 were prepared in a manner similar to Example 172, from the appropriate starting piperidine and carboxylic acid intermediates. In most cases, there was no final deprotection step necessary since the DMB group had previously been removed in a similar manner to Intermediate 20. Boc-protecting groups were removed by treatment with TFA/DCM at room temperature for 1 hour. The final compounds were purified by preparative reverse phase HPLC. TABLE 11 S compture Observe
  • Example 235 (2S)-1-[(2S,5R)-5-(5-amino-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin- 2-yl)-2-methylpiperidin-1-yl]-2-hydroxypropan-1-one [0237] To a 4 mL vial was added N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,6S)-6- methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (40 mg, 0.083 mmol) (Intermediate 10), DIPEA (0.058 ml, 0.333 mmol), (S)-2-hydroxypropanoic acid (11.25 mg, 0.125 mmol) and DCM (0.5 mL).
  • DIPEA 0.058 ml, 0.333 mmol
  • S -2-hydroxypropanoic
  • Example compounds of the invention in the following Table 12 were prepared in a manner similar to the synthesis of Example 235, from the appropriate starting piperidine and carboxylic acid intermediates.
  • DDQ was used to hydrolyze the DMB-protecting group.
  • Example compounds of the invention in the following Table 15 were prepared in a manner similar to the synthesis of Example 287, from the appropriate starting amine core and alkylating reagents. In some cases, the dimethoxybenzyl protecting was removed by treating with TFA in the manner of Example 282.
  • Example compounds of the invention in the following Table 16 were prepared in a manner similar to the synthesis of Example 297, from the appropriate starting amine core and alkylating reagents.
  • the crude mixture was purified by silica gel chromatography (24g Gold Column) eluting with 0-75% 3:1 EtOAc/EtOH:Hexanes to afford the desired product. This was taken up in DCM (7791 ⁇ L) and water (779 ⁇ L), and the reaction mixture was cooled to 0 oC. After stirring for 5 minutes, DDQ (292 mg, 1.286 mmol) was added, and the reaction stirred vigorously in the melting ice bath, allowing it to slowly warm to room temperature. The starting material looked fully consumed and cleanly converted to the desired product after 3 hours. The reaction mixture was poured into a separatory funnel containing 25 mL of DCM and saturated aqueous NaHCO 3 .
  • Example compounds of the invention in the following Table 17 were prepared in a manner similar to the synthesis of Example 300, from the appropriate starting amine core and alkylating reagents.
  • TABLE 17 Example Structure methylpiperidin-1-yl](cis-3-hydroxycyclobutyl)methanone methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (300 mg, 0.640 mmol) (Intermediate 15), DIPEA (0.45 mL, 2.56 mmol), and DCM (3 mL). To the mixture was added 1-propanephosphonic anhydride (0.762 mL, 1.281 mmol) (50% solution in MeCN).
  • Example 307 and 308 [(2S,5R)-5-(5-amino-7,9-difluoro[1,2,4]triazolo[1,5-c]quinazolin-2-yl)- 2-methylpiperidin-1-yl][3-(2-hydroxypropan-2-yl)cyclopentyl]methanone , , , , .
  • Example compounds of the invention in the following Table 19 were prepared in a manner similar to the synthesis of Example 307, from the appropriate starting piperidine and carboxylic acid. In some cases, the dimethoxybenzyl protecting was removed by treating with TFA in the manner of Example 305.
  • Example 318 [(2S,5R)-5-(5-amino-7,9-difluoro[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl][6-(2-aminopropan-2-yl)pyridin-3-yl]methanone p y g, . . p p 150 °C to dry the solid. After drying for 16 hours, the vial was cooled to room temperature under a flush of N 2 , at which point, THF (5000 ⁇ L) was added. The yellow suspension stirred vigorously at room temperature under N 2 for an hour, and was then cooled to -78 °C.
  • the reaction was quenched with 2 mL of conc. NH 4 OH and stirred vigorously for 15 minutes.
  • the solids were filtered and washed with DCM (5 mL x3) and the filtrate was poured into a separatory funnel containing 10 mL of water.
  • the layers were separated, and the aqueous layer was extracted with DCM (10 mL x3).
  • the combined organic layers were dried with Mg 2 SO 4 , filtered, combined and concentrated under reduced pressure.
  • the crude mixture was redissolved in 1 mL of DCM and trifluoroacetic acid (963 ⁇ L, 12.50 mmol), and placed on a pre-heated block to stir vigorously at 50 °C.
  • Example compounds of the invention in the following Table 20 were prepared in a manner similar to the synthesis of Example 318, from the appropriate starting amine core and alkylating reagents. TABLE 20 S nestture Observed Example m/z [M + xamp e 3 0: [( S,5 )-5-(5-am no-7,9- uoro[ , , ]tr azoo[ ,5-c]qunazo n- -y)- - methylpiperidin-1-yl] ⁇ 4-[(1R)-1-amino-2,2,2-trifluoroethyl]phenyl ⁇ methanone 4- ((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)- 2-methylpiperidine-1-carbonyl)phenyl)-2
  • Example 331 [(2S,5R)-5-(5-amino-7,9-difluoro[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl][2-(oxetan-3-yl)-2H-1,2,3-triazol-4-yl]methanone [ , , ] r azoo[ , -c]qu micho n- -y - -me y pper n- -y - , , -r azo - -y me anone (100 mg, 0.177 mmol) (Intermediate 72), triphenylphosphine (140 mg, 0.532 mmol), THF (3 mL
  • Peak 1 was taken up in TFA (1.5 mL). The mixture was stirred and heated at 50 °C for 2 hours. The solvents were evaporated, and to the residue was added DCM (4 mL) and saturated aqueous sodium bicarbonate. The organic layer was collected with a phase separator, and the solvents were evaporated.
  • reaction mixture was quenched with saturated aqueous NaHCO 3 and extracted 3x with DCM.
  • the combined organic layers were concentrated and purified on a 24 g SiO2 column eluting with 10-100% hexanes:EtOAc to afford pure material as a solid ((2S,5R)-5-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)(6-morpholinopyridin-3- yl)methanone (37 mg, 0.073 mmol).
  • Example compounds of the invention in the following Table 24 were prepared in a manner similar to Example 335, from the appropriate starting amines and intermediate 72-75.
  • DMB-deprotection was carried out by treatment with TFA similar in a manner for Example 331.
  • Example 355 [(2S,5R)-5-(5-amino-7,9-difluoro[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl][5-(2-hydroxypropan-2-yl)-4-methylpyridin-2-yl]methanone q y yp p y ypy y g, 0.709 mmol) (Intermediate 82) and dissolved in THF (3545 ⁇ L). The reaction mixture was cooled to 0 °C and to this mixture was added methylmagnesium bromide (945 ⁇ L, 2.84 mmol).
  • reaction mixture was stirred at 0 °C for 10 minutes and then allowed to warm to room temperature for 10 more minutes.
  • the reaction mixture was then quenched by the addition of saturated aqueous ammonium chloride, and the aqueous layer was extracted 3x with EtOAc.
  • the combined organic fractions were concentrated and purified on a 24 g SiO2 column eluting with 10-100% hexanes:EtOAc (3:1 EtOAc:EtOH).
  • Example compounds of the invention in the following Table 26 were prepared in a manner similar to the synthesis of Example 357, from the appropriate starting intermediates.
  • Example 364 [(2S,5R)-5-(5-amino-7,9-difluoro[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl][5-(1-hydroxycyclobutyl)pyridin-2-yl]methanone yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine; 4-((tert-butyldiphenylsilyl)oxy)dihydrofuran- 3(2H)-one (300 mg, 0.640 mmol) (Intermediate 15), triethylamine (714 ⁇ L, 5.12 mmol), 1-(6- chloropyridin-3-yl)cyclobutan-1-ol; 5016032-0031 (353 mg, 1.921 mmol) and DMSO (6403 ⁇ L) was purged with CO three times at room temperature.
  • the resulting reaction mixture was stirred under CO (15 psi) at 100 oC for 16 hours.
  • the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (200 mL).
  • the organic layer was washed with water (50 mL x3), brine, dried over Na 2 SO 4 , filtered and concentrated.
  • the resulting residue was purified by silica gel chromatography (40 g prepacked) eluting with 0-100% hexanes/ethyl acetate.
  • the isolated material was taken up in DCM (7909 ⁇ L) and water (791 ⁇ L).
  • Example 365 [(2S,5R)-5-(5-amino-7,9-difluoro[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl][6-(2-hydroxypropan-2-yl)pyridazin-4-yl]methanone [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidine-1-carbonyl)pyridazin-3-yl)ethan-1-one (140 mg, 0.227 mmol) (Intermediate 43) and methylmagnesium bromide (0.151 mL, 0.454 mmol) in THF (2 mL) was stirred at -80 oC for 1 hour to give a yellow mixture.
  • reaction mixture was warmed to room temperature and stirred for an additional 1 hour. LCMS analysis showed that the reaction was complete, and the desired product was formed.
  • the reaction mixture was quenched with NH 4 Cl (10 mL) and extracted with EtOAc (10 mL x3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The resulting crude was taken up in DCM (1 mL) and TFA (1 mL) and was stirred at room temperature for 16 hours to give a purple mixture. LCMS analysis showed that the reaction was complete, and the desired product was formed.
  • the assay plate was incubated at room temperature for 60 minutes with agitation. Using a FilterMate Harvester® (Perkin Elmer), the contents of the assay plate w ere filtered through a UniFilter-96® PEI coated plate (Perkin Elmer Cat. No. 6005274 or 6005277). Filtering w as achieved by aspirating the contents of the assay plate for 5 seconds, then washing and aspirating the contents three times with ice-cooled wash buffer (50 mM Tris-HCl pH 7.4, 150 mM NaCl) and allowing the vacuum manifold to dry the plate for 30 seconds. The filter plate was incubated for at least 1 hour at 55°C and allowed to dry. The bottom of the filter plate w as sealed with backing tape.
  • ice-cooled wash buffer 50 mM Tris-HCl pH 7.4, 150 mM NaCl
  • the reported affinity of the compounds of the invention for the human A2b adenosine receptor was determined experimentally using a radioligand filtration binding assay. This assay measures the amount of binding of a tritiated proprietary A2b receptor antagonist, in the presence and absence of a compound of the invention, to membranes made from HEK293 cells recombinantly expressing the human A2b adenosine receptor (Perkin Elmer, Cat. No. ES-013- C).
  • compounds of the invention to be tested were first solubilized in 100% DMSO and further diluted in 100% DMSO to generate, typically, a 10-point titration at half-log intervals such that the final assay concentrations did not exceed 10 mM of compound or 1% DMSO.
  • 148 pL (135 pg/mL) membranes and 2 pL test compounds were transferred to individual wells of a 96-well polypropylene assay plate and incubated for 15 to 30 minutes at room temperature with agitation.
  • Tritiated radioligand was diluted to a concentration of 14 nM in assay buffer (phosphate buffered saline without Magnesium and Calcium, pH 7.4; GE Healthcare Life Sciences, Cat.
  • Filtering was achieved by aspirating the contents of the assay plate for 5 seconds, then washing and aspirating the contents three times with ice-cooled wash buffer (assay buffer supplemented with 0.0025% Brij58) and allowing the vacuum manifold to dry the plate for 30 seconds.
  • the filter plate was incubated for at least 1 hour at 55°C and allowed to dry.
  • the bottom of the filter plate was then sealed with backing tape.
  • 40 pL Ultima GoldTM Perkin Elmer, Cat. No. 6013329
  • TopSeal-A PLUS® clear plate seal Perkin Elmer, Cat. No. 6050185).
  • x denotes not determined.

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Abstract

Dans ses nombreux modes de réalisation, l'invention propose certains composés amino triazolo quinazoline substitués de formule structurale (I), et des sels pharmaceutiquement acceptables de ceux-ci, le cycle A, R1 et R2 étant tels que définis dans la description. L'invention propose également des compositions pharmaceutiques comprenant un ou plusieurs de ces composés, seuls ou en combinaison avec un ou plusieurs autres agents thérapeutiquement actifs. L'invention propose également des procédés de préparation des composés et leur utilisation en tant qu'antagonistes des récepteurs A2a et/ou A2b, seuls ou en combinaison avec d'autres agents thérapeutiques, dans le traitement d'une variété de maladies, d'états ou de troubles qui sont médiés, au moins en partie, par le récepteur A2a de l'adénosine et/ou le récepteur A2b de l'adénosine.
EP23898613.7A 2022-11-29 2023-11-27 Antagonistes des récepteurs a2a et a2b de l'adénosine, compositions pharmaceutiques et leur utilisation Pending EP4626892A1 (fr)

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CN118812539B (zh) * 2024-06-19 2025-11-28 苏州大学 一种5-氨基三唑并嘧啶衍生物及其制备方法

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WO2017008205A1 (fr) * 2015-07-10 2017-01-19 Merck Sharp & Dohme Corp. Composés d'aminoquinazoline substitués a titre d'antagonistes du récepteur a2a
JP2022511778A (ja) * 2018-11-30 2022-02-01 メルク・シャープ・アンド・ドーム・コーポレーション アデノシン受容体拮抗薬としての７－、８－及び１０－置換されたアミノトリアゾロキナゾリン誘導体、医薬組成物及びそれらの使用
TW202039496A (zh) * 2018-11-30 2020-11-01 美商默沙東藥廠 做為腺苷受體拮抗劑之9-經取代胺基三唑喹唑啉衍生物、醫藥組合物及其用途

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