WO2024118460A1 - Adenosine a2a and a2b receptor antagonists, pharmaceutical compositions and use thereof - Google Patents
Adenosine a2a and a2b receptor antagonists, pharmaceutical compositions and use thereof Download PDFInfo
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- WO2024118460A1 WO2024118460A1 PCT/US2023/081075 US2023081075W WO2024118460A1 WO 2024118460 A1 WO2024118460 A1 WO 2024118460A1 US 2023081075 W US2023081075 W US 2023081075W WO 2024118460 A1 WO2024118460 A1 WO 2024118460A1
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- cancer
- alkyl
- compound
- pharmaceutically acceptable
- mmol
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Classifications
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- 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
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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.
- Modulation of A3 has been proposed for the management and treatment of asthma and chronic obstructive pulmonary diseases, glaucoma, cancer, stroke, and other indications. Modulation of the A2a and A2b receptors are also believed to be of potential therapeutic use.
- 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.
- A2b receptors are expressed primarily on myeloid cells.
- the engagement of A2b receptors on myeloid derived suppressor cells (MDSCs) results in their expansion in vitro (Ryzhov, S. et al., J. Immunol. 2011, 187:6120-6129).
- MDSCs suppress T-cell proliferation and anti-tumor immune responses.
- Selective inhibitors of A2b receptors and A2b receptor knockouts have been shown to inhibit tumor growth in mouse models by increasing MDSCs in the tumor microenvironment (lannone, R., et al., Neoplasia Vol. 13 No. 12, (2013) pp. 1400-1409; Ryzhov, S., et al., Neoplasia (2008) 10; 987-995).
- A2b receptor inhibition has become an attractive biological target for the treatment of a variety of cancers involving myeloid cells.
- cancers that express A2b receptors can be readily obtained through analysis of the publicly available TCGA database.
- Such cancers include lung, colorectal, head and neck, and cervical cancer, among others, and are discussed in further detail below.
- 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.
- the invention provides a compound of the immediately preceding embodiment, or a pharmaceutically acceptable salt thereof, wherein R 1 is F.
- the invention provides a compound of any of the immediately preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein ring A is
- 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.
- the invention provides a compound of any of the first four embodiments or a pharmaceutically acceptable salt thereof, wherein R 3 is (C 1 -C 6 )alkyl, or (C 3 -C 10 )cycloalkyl. each optionally substituted with 1 to 4 R 3D groups, and wherein
- R 3D is independently selected from the group consisting of -OH, -
- the invention provides a compound of any of the first four embodiments, or a pharmaceutically acceptable salt thereof, wherein R 3 is a 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4
- 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 invention provides a method for the manufacture of a medicament or a composition which may be useful for treating diseases, conditions, or disorders that are mediated, at least in part, by the adenosine A2a receptor and/or the adenosine A2b receptor, the method comprising combining a compound of the invention with one or more pharmaceutically acceptable carriers.
- 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 in need thereof 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.
- a subject e.g., an animal or human
- 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.
- one 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 A2a 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 kidney (or renal) cancer, breast cancer, lung cancer, and liver 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.
- the disease, condition, or disorder is an immune-related disease, condition, or disorder.
- immune-related diseases, conditions, or disorders include multiple sclerosis and bacterial infections. (See. e.g., Safarzadeh. E. et al., Inflamm Res 2016 65(7):511-20; and Antonioli, L., et al, Immunol Lett 80165-2478(18)30172- X 2018).
- 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 pharmaceutical composition may in specific embodiments contain such other drugs and the compound of the invention or its pharmaceutically acceptable salt in separate doses or in unit dosage form.
- the combination therapy may also include therapies in which the compound of the invention or its pharmaceutically acceptable salt and one or more other drugs are administered sequentially, on different or overlapping schedules.
- the compounds of the invention and the other active ingredients may be used in lower doses than when each is used singly.
- the pharmaceutical compositions comprising the compounds of the invention include those that contain one or more other active ingredients, in addition to 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).
- PD-1 expression on tumor infiltrating lymphocytes was found to mark dysfunctional T-cells in breast cancer and melanoma (Ghebeh et al, BMC Cancer. 2008 8:5714- 15 (2008); and Ahmadzadeh et al., Blood 114: 1537-1544 (2009)) and to correlate with poor prognosis in renal cancer (Thompson et al, Clinical Cancer Research 15: 1757-1761(2007)).
- PD-L1 expressing tumor cells interact with PD-1 expressing T- cells to attenuate T-cell activation and to evade immune surveillance, thereby contributing to an impaired immune response against the tumor.
- PD-1 antagonist means any chemical compound or biological molecule that blocks binding of PD-L1 expressed on a cancer cell to PD-1 expressed on an immune cell (T-cell, B-cell or NKT cell) and, in some embodiments, also blocks binding of PD-L2 expressed on a cancer cell to the immune-cell expressed PD-1.
- Alternative names or synonyms for PD-1 and its ligands include: PDCD1, PD1, CD279 and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc and CD273 for PD-L2.
- the PD-1 antagonist blocks binding of human PD-L1 to human PD-1, and preferably blocks binding of both human PD-L1 and PD-L2 to human PD-1.
- Human PD-1 amino acid sequences can be found in NCBI Locus No.: NP 005009.
- Human PD- L1 and PD-L2 amino acid sequences can be found in NCBI Locus No.: NP_054862 and NP_079515, respectively.
- PD-1 antagonists useful in any of the treatment methods, medicaments and uses of the invention include a monoclonal antibody (mAb), or an antigen binding fragment thereof, which specifically binds to PD-1 or PD-L1 and preferably specifically binds to human PD-1 or human PD-L1.
- the mAb may be a human antibody, a humanized antibody or a chimeric antibody, and may include a human constant region.
- the human constant region is selected from the group consisting of IgGl, IgG2, IgG3 and IgG4 constant regions, and in particular embodiments, the human constant region is an IgGl or IgG4 constant region.
- the antigen binding fragment is selected from the group consisting of Fab. Fab'- SH, F(ab')2, scFv, and Fv fragments.
- PD-1 antagonists include, but are not limited to, pembrolizumab (KEYTRUDA®, Merck and Co., Inc., Rahway, NJ, USA).
- pembrolizumab (formerly known as MK-3475, SCH 900475 and lambrolizumab and sometimes referred to as “pembro” is a humanized IgG4 mAh with the structure described in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013).
- PD-1 antagonists include nivolumab (OPDIVO®, Bristol-Myers Squibb Company, Princeton, NJ, USA), atezolizumab (MPDL3280A; TECENTRIQ®, Genentech, San Francisco, CA, USA), durvalumab (IMFINZI®, Astra Zeneca Pharmaceuticals, LP, Wilmington, DE), avelumab (BAVENCIO®, Merck KGaA, Darmstadt, Germany and Pfizer, Inc., New York, NY), and dostarlimab (JEMPERLITM, GlaxoSmithKline LLC, Philadelphia, PA).
- OPDIVO® Bristol-Myers Squibb Company, Princeton, NJ, USA
- atezolizumab MPDL3280A; TECENTRIQ®, Genentech, San Francisco, CA, USA
- durvalumab IMFINZI®, Astra Zeneca Pharmaceuticals, LP, Wilmington, DE
- avelumab BAVENCIO®, Merck
- mAbs monoclonal antibodies that bind to human PD-1. and useful in the treatment methods, medicaments and uses of the invention, are described in US7488802, US7521051, US8008449, US8354509, US8168757, W02004/004771, W02004/072286, W02004/056875, and US2011/0271358.
- Specific anti-human PD-L1 mAbs useful as the PD-1 antagonist in the treatment method, medicaments and uses of the invention include MPDL3280A, BMS-936559, MEDI4736, MSB0010718C and an antibody which comprises the heavy chain and light chain variable regions of SEQ ID NO:24 and SEQ ID NO:21, respectively, of W02013/019906.
- PD-1 antagonists useful in any of the treatment methods, medicaments and uses of the invention include an immunoadhesin that specifically binds to PD-1 or PD- LI, and preferably specifically binds to human PD-1 or human PD-L1, e.g., a fusion protein containing the extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region such as an Fc region of an immunoglobulin molecule.
- immunoadhesin molecules that specifically bind to PD-1 are described in W02010/027827 and WO2011/066342.
- Specific fusion proteins useful as the PD-1 antagonist in the treatment methods, medicaments and uses of the invention include AMP-224 (also known as B7-DCIg), which is a PD-L2-FC fusion protein that binds to human PD-1
- one embodiment provides a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with a PD-1 antagonist to a subject in need thereof.
- the compounds of the invention, or a pharmaceutically acceptable salt thereof, and PD-1 antagonist are administered concurrently or sequentially.
- 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 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, wherein said cancer is selected from unresectable or metastatic melanoma, 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, and hepatocellular carcinoma.
- the agent is a PD-1 antagonist.
- the agent is pembrolizumab.
- the agent is nivolumab.
- the agent is atezolizumab.
- Pembrolizumab is approved by the U.S. FDA for the treatment of patients with unresectable or metastatic melanoma, for the adjuvant treatment of melanoma, and for the treatment of certain patients with 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) or mismatch repair deficient cancer, MSI-H or mismatch repair deficient colorectal cancer, non- small cell lung cancer, esophageal cancer, Merkel cell carcinoma, renal cell carcinoma, endometrial carcinoma, cutaneous squamous cell carcinoma, triple negative breast cancer, hepatocellular carcinoma, and tumor mutational burden-high (TMB-H) cancer as described in the Prescribing Information for KEYTRUDATM (Merck & Co., Inc., Rah
- a method of treating 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 pembrolizumab, wherein said cancer is selected from unresectable or metastatic melanoma, 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, and hepatocellular carcinoma.
- HNSCC unresectable or metastatic melanoma
- cHL classical Hodgkin lymphoma
- MSI-H microsatellite instability-high
- a method of treating 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, wherein said cancer is selected from melanoma, HNSCC, cHL, urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large-B-cell lymphoma, MSI-H or mismatch repair deficient cancer, MSI-H or mismatch repair deficient colorectal cancer, non-small cell lung cancer, esophageal cancer, Merkel cell carcinoma, renal cell carcinoma, endometrial carcinoma, cutaneous squamous cell carcinoma, triple negative breast cancer, hepatocellular carcinoma, and TMB-H cancer.
- a PD-1 antagonist wherein said cancer is selected from melanoma, HNSCC, cHL, urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large-B-cell lymphoma, MSI-H or mismatch repair deficient cancer,
- the PD-1 antagonist is pembrolizumab.
- the agent is nivolumab.
- the agent is atezolizumab.
- the agent is durvalumab.
- the agent is avelumab.
- the agent is dostarlimab.
- a method of treating 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, wherein said cancer is selected from melanoma, non-small cell lung cancer, head and neck squamous cell cancer (HNSCC), Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, microsatellite instability-high cancer, gastric cancer, Merkel cell carcinoma, hepatocellular carcinoma, esophageal cancer and cervical cancer.
- the PD-1 antagonist is pembrolizumab.
- the PD-1 antagonist is nivolumab. In another such embodiment, the PD-1 antagonist is atezolizumab. In another such embodiment, the PD-1 antagonist is durvalumab. In another such embodiment, the PD-1 antagonist is avelumab. In another such embodiment, the agent is dostarlimab.
- a method of treating 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, wherein said cancer is selected from melanoma, non-small cell lung cancer, small cell lung cancer, head and neck cancer, bladder cancer, breast cancer, gastrointestinal cancer, multiple myeloma, hepatocellular cancer, lymphoma, renal cancer, mesothelioma, ovarian cancer, esophageal cancer, anal cancer, biliary tract cancer, colorectal cancer, cervical cancer, thyroid cancer, and salivary cancer.
- the PD-1 antagonist is pembrolizumab.
- the PD-1 antagonist is nivolumab. In another such embodiment, the PD-1 antagonist is atezolizumab. In another such embodiment, the PD-1 antagonist is durvalumab. In another such embodiment, the PD-1 antagonist is avelumab. In another such embodiment, the agent is dostarlimab.
- a method of treating unresectable or metastatic melanoma 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 recurrent or metastatic head and neck squamous cell 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.
- a method of treating classical Hodgkin lymphoma 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 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 gastric 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, dun alumab, avelumab. and dostarlimab.
- a method of treating cervical 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.
- a method of treating primary mediastinal large-B- cell lymphoma 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, dun alumab. 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.
- a method of treating non-small cell lung 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.
- a method of treating hepatocellular 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.
- the additional therapeutic agent is at least one immunomodulator other than an A2a or A2b receptor inhibitor.
- immunomodulators include CD40L, B7, B7RP1, anti-CD40, anti-CD38, anti-ICOS, 4-IBB ligand, dendritic cell cancer vaccine, IL2, IL12, ELC/CCL19, SLC/CCL21, MCP-1, IL-4, IL-18, TNF, IL-15, MDC. IFN-a/-13, M-CSF, IL-3, GM-CSF, IL-13, anti-IL-10 and indolamine 2,3- dioxygenase 1 (IDO1) inhibitors.
- IDO1 indolamine 2,3- dioxygenase 1
- the additional therapeutic agent comprises radiation.
- radiation includes localized radiation therapy and total body radiation therapy.
- the additional therapeutic agent is at least one chemotherapeutic agent.
- chemotherapeutic agents contemplated for use in combination with the compounds of the invention include: pemetrexed, alkylating agents (e.g., nitrogen mustards such as chlorambucil, cyclophosphamide, isofamide, mechlorethamine, melphalan, and uracil mustard; aziridines such as thiotepa; methanesulphonate esters such as busulfan; nucleoside analogs (e.g., gemcitabine); nitroso ureas such as carmustine, lomustine, and streptozocin; topoisomerase 1 inhibitors (e.g., irinotecan); platinum complexes such as cisplatin, carboplatin and oxaliplatin; bioreductive alkylators such as mitomycin, procarbazine, dacarbazine and altretamine); an chemotherapeutic agent.
- the additional therapeutic agent is at least one signal transduction inhibitor (STI).
- signal transduction inhibitors include BCR/ABL kinase inhibitors, epidermal growth factor (EGF) receptor inhibitors, HER-2/neu receptor inhibitors, and famesyl transferase inhibitors (FTIs).
- the additional therapeutic agent is at least one anti -infective agent.
- anti-infective agents include cytokines, non-limiting examples of which include granulocyte-macrophage colony stimulating factor (GM-CSF) and an Ht3 - ligand.
- the invention provides a method for treating or preventing a viral infection (e.g., a chronic viral infection) including, but not limited to, hepatitis C virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus, coxsackievirus, and human immunodeficiency virus (HIV).
- a viral infection e.g., a chronic viral infection
- HCV hepatitis C virus
- HPV human papilloma virus
- CMV cytomegalovirus
- EBV Epstein-Barr virus
- varicella zoster virus coxsackievirus
- coxsackievirus e.g., a chronic viral infection
- HCV hepatitis C virus
- HPV human papilloma virus
- CMV cytomegalovirus
- EBV Epstein-Barr virus
- varicella zoster virus co
- the vaccine is an anti-viral vaccine, including, for example, an anti-HTV vaccine.
- Other antiviral agents contemplated for use include an anti-HIV, anti-HPV, anti HCV, anti HSV agents and the like.
- the vaccine is effective against tuberculosis or malaria.
- the vaccine is a tumor vaccine (e.g., a vaccine effective against melanoma); the tumor vaccine may comprise genetically modified tumor cells or a genetically modified cell line, including genetically modified tumor cells or a genetically modified cell line that has been transfected to express granulocyte-macrophage stimulating factor (GM-CSF).
- GM-CSF granulocyte-macrophage stimulating factor
- 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.
- variable appears more than once in any moiety or in any compound of the invention (e.g., aryl, heterocycle, -N(R) 2 )
- the selection of moieties defining that variable for each occurrence is independent of its definition at every other occurrence unless specified otherwise in the local variable definition.
- A2a receptor antagonist 7 (equivalently, A2a antagonist) and/or "A2b receptor antagonist” (equivalently, A2b antagonist) means a compound exhibiting a potency (IC 50 ) of less than about 1 pM with respect to the A2a and/or A2b receptors, respectively, when assayed in accordance with the procedures described herein.
- Compounds of the invention exhibit at least 10-fold selectivity for antagonizing the A2a receptor and/or the A2b receptor over any other adenosine receptor (e.g., Al or A3).
- 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.
- “effective amount” means, for example, providing the amount of at least one compound of the invention that results in a therapeutic response in a patient afflicted with the disease, condition, or disorder, including a response suitable to manage, alleviate, ameliorate, or treat the condition or alleviate, ameliorate, reduce, or eradicate one or more symptoms attributed to the condition and/or long-term stabilization of the condition, for example, as may be determined by the analysis of pharmacodynamic markers or clinical evaluation of patients afflicted with the condition.
- 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.
- a patient “in need of treatment” is an individual diagnosed with, suspected of having, or predisposed to a disease or disorder in which a compound of the invention is intended to treat.
- “Treat” or “treatment” means to administer an agent, such as a composition containing any of the compounds described herein, internally or externally to a subject or patient having one or more disease symptoms, or being suspected of having a disease, for which the agent has therapeutic activity.
- the agent is administered in an amount effective to alleviate one or more disease symptoms in the treated subject or population, whether by inducing the regression of or inhibiting, delaying, or slowing the progression of such symptom(s) by any clinically measurable degree.
- 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.
- any of the various cyclic ring and ring system variables or substituents described herein may be attached to the rest of the compound at any ring atom (i.e., any carbon atom or any heteroatom) provided that a stable compound results.
- 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.
- Alkyl means an aliphatic hydrocarbon group, which may be straight or branched, comprising 1 to 10 carbon atoms.
- (C 1 -C 6 )alkyl means an aliphatic hydrocarbon group, which may be straight or branched, comprising 1 to 6 carbon atoms.
- Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl, are attached to a linear alkyd chain.
- Non- limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, and t-butyl.
- 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 means an aromatic monocyclic or multicyclic ring system comprising 5 to 14 ring atoms, preferably 5 to 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen, or sulfur, alone or in combination. Preferred heteroaryls contain 5 to 6 ring atoms.
- the “heteroaryl” can be optionally substituted by one or more substituents, which may be the same or different, as defined herein.
- the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen, or sulfur atom respectively, is present as a ring atom.
- 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 line as a bond generally indicates a mixture of, or either of, the possible isomers, e.g., containing (R)- and (S)- stereochemistry.
- the possible isomers e.g., containing (R)- and (S)- stereochemistry.
- 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.
- Oxo is defined as an oxygen atom that is double bonded to a ring carbon in a cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, or other ring described herein, e.g.,
- One or more compounds of the invention may also exist as, or optionally be converted to, a solvate.
- Preparation of solvates is generally known.
- M. Caira et al., J. Pharmaceutical Sci., 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water.
- Similar preparations of solvates, and hemisolvate, including hydrates (where the solvent is water or aqueous based) and the like are described by E. C. van Tonder et al., AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham et al.. Chem.
- a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (for example, an organic solvent, an aqueous solvent, water, or mixtures of two or more thereof) at a higher than ambient temperature, and cooling the solution, with or without an antisolvent present, at a rate sufficient to form crystals which are then isolated by standard methods.
- the desired solvent for example, an organic solvent, an aqueous solvent, water, or mixtures of two or more thereof
- Analytical techniques such as, for example I.R. spectroscopy, show the presence of the solvent (including water) in the crystals as a solvate (or hydrate in the case where water is incorporated into the crystalline form).
- purified refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof.
- purified refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan, and in sufficient purity to be characterized by standard analytical techniques described herein or well known to the skilled artisan.
- This invention also includes the compounds of the invention in isolated and purified form obtained by routine techniques. Polymorphic forms of the compounds of the invention, and of the salts, solvates and prodrugs thereof, are intended to be included in the invention. Certain compounds of the invention may exist in different isomeric forms (e.g., enantiomers, diastereoisomers, atropisomers). The inventive compounds include all isomeric forms thereof, both in pure form and admixtures of two or more, including racemic mixtures.
- the above depiction consists of the following pairs of isomers: (i) Trans- isomers ((2R,7aS)-2-methylhexahydro-lH-pyrrolizin-7a-yl)methanamine (Compound ABC-1) and ((2S,7aR)-2-methylhexahydro-lH-pyrrolizin-7a-yl)methanamine (Compound ABC-2); and (ii) Cis-isomers ((2R,7aR)-2-methylhexahydro-lH-pyrrolizin-7a-yl)methanamine (Compound ABC-3) and ((2S,7aS)-2-methylhexahydro-lH-pyrrolizin-7a-yl)methanamine (Compound ABC- 4).
- All stereoisomers of the compounds of the invention include salts and solvates of the inventive compounds and their prodrugs, such as those which may exist due to asymmetric carbons present in a compound of the invention and including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention.
- Individual stereoisomers of the compounds of the invention may be isolated in a pure form, for example, substantially free of other isomers, or may be isolated as an admixture of two or more stereoisomers or as a racemate.
- the chiral centers of the invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
- the use of the terms “salt”, “solvate” “prodrug” and the like, is intended to equally apply to salts, solvates and prodrugs of isolated enantiomers, stereoisomer pairs or groups, rotamers, tautomers, or racemates of the inventive compounds.
- diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by known methods, for example, by chiral chromatography and/or fractional crystallization, simple structural representation of the compound contemplates all diastereomers of the compound.
- enantiomers may also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individually isolated diastereomers to the corresponding purified enantiomers.
- an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride
- salts of the inventive compounds whether acidic salts formed with inorganic and/or organic acids, basic salts formed with inorganic and/or organic bases, salts formed which include zwitterionic character, for example, where a compound contains both a basic moiety, for example, but not limited to, a nitrogen atom, for example, an amine, pyridine or imidazole, and an acidic moiety, for example, but not limited to a carboxylic acid, are included in the scope of the inventive compounds described herein.
- the formation of pharmaceutically useful salts from basic (or acidic) pharmaceutical compounds are discussed, for example, by S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P.
- the invention contemplates all available salts, including salts which are generally recognized as safe for use in preparing pharmaceutical formulations and those which may be formed presently within the ordinary skill in the art and are later classified as being “generally recognized as safe’’ for use in the preparation of pharmaceutical formulations, termed herein as “pharmaceutically acceptable salts ’.
- Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, acetates, including trifluoroacetate salts, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, buty rates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates
- 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
- Basic nitrogen- containing groups may be converted to an ammonium ion or quartemized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), arylalkyl halides (e.g. benzy l and phenethyl bromides), and others.
- lower alkyl halides e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
- dialkyl sulfates e.g., dimethyl, diethyl, dibut
- a functional group in a compound termed “protected” means that the group is in modified form to preclude undesired side reactions at the protected site when the protected compound is subjected to particular reaction conditions aimed at modifying another region of the molecule.
- Suitable protecting groups are known, for example, as by reference to standard textbooks, for example, T. W. Greene et al., Protective Groups in organic Synthesis (1991), Wiley, New York.
- the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
- the invention is meant to include all suitable isotopic variations of the compounds of the invention.
- different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H).
- Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
- Isotopically enriched compounds of the invention can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically enriched reagents and/or intermediates.
- 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.
- isotopes that can be preferentially incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, iodine, fluorine and chlorine, for example, but not limited to: 2 H, 3 H, 1 1 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, and 36 C1, 123 I and 125 I. It will be appreciated that other isotopes also may be incorporated by known means.
- Certain isotopically labeled compounds of the invention are recognized as being particularly useful in compound and/or substrate tissue distribution assays using a variety of known techniques. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detection. Further, substitution of a naturally abundant isotope with a heavier isotope, for example, substitution of protium with deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
- Isotopically labeled compounds of the invention can generally be prepared by following procedures analogous to those disclosed in the reaction Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent, or by well-known reactions of an appropriately prepared precursor to the compound of the invention which is specifically prepared for such a “labeling” reaction. Such compounds are included also in the invention.
- composition is intended to encompass a product comprising the specified ingredients in the specified amounts, and any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
- composition encompasses both the bulk composition and individual dosage units comprised of one, or more than one (e.g., two), pharmaceutically active agents such as, for example, a compound of the invention (optionally together with an additional agent as described herein), along with any pharmaceutically inactive excipients.
- excipients are any constituent that adapts the composition to a particular route of administration or aids the processing of a composition into a dosage form without itself exerting an active pharmaceutical effect.
- the bulk composition and each individual dosage unit can contain fixed amounts of the aforesaid one, or more than one, pharmaceutically active agents.
- the bulk composition is material that has not yet been formed into individual dosage units.
- compositions of the invention may comprise more than one compound of the invention (or a pharmaceutically acceptable salt thereof), for example, the combination of two or three compounds of the invention, each present in such a composition by adding to the formulation the desired amount of the compound in a pharmaceutically acceptably pure form. It will be appreciated also that in formulating compositions of the invention, a composition may comprise, in addition to one or more of compounds of the invention, one or more other agents which also have pharmacological activity, as described herein.
- formulations of the invention may be employed in bulk form, it will be appreciated that for most applications the inventive formulations will be incorporated into a dosage form suitable for administration to a patient, each dosage form comprising an amount of the selected formulation which contains an effective amount of one or more compounds of the invention.
- suitable dosage forms include, but are not limited to, dosage forms adapted for: (i) oral administration, e.g., a liquid, gel, powder, solid or semi-solid pharmaceutical composition which is loaded into a capsule or pressed into a tablet and may comprise additionally one or more coatings which modify its release properties, for example, coatings which impart delayed release or formulations which have extended release properties; (ii) a dosage form adapted for intramuscular administration (IM), for example, an injectable solution or suspension, and which may be adapted to form a depot having extended release properties;
- IM intramuscular administration
- a dosage form adapted for intravenous administration for example, a solution or suspension, for example, as an IV solution or a concentrate to be injected into a saline IV bag;
- a dosage form adapted for administration through tissues of the oral cavity for example, a rapidly dissolving tablet, a lozenge, a solution, a gel, a sachets or a needle array suitable for providing intramucosal administration
- a dosage form adapted for administration via the mucosa of the nasal or upper respiratory cavity for example a solution, suspension or emulsion formulation for dispersion in the nose or airway
- a dosage form adapted for transdermal administration for example, a patch, cream or gel
- a dosage form adapted for intradermal administration for example, a microneedle array
- a dosage form adapted for deliveryvia rectal or vaginal mucosa for example, a suppository.
- 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.
- compositions can be solid, semi-solid or liquid.
- Solid form preparations can be adapted to a variety of modes of administration, examples of which include, but are not limited to, powders, dispersible granules, mini-tablets, beads, which can be used, for example, for tableting, encapsulation, or direct administration.
- Liquid form preparations include, but are not limited to, solutions, suspensions, and emulsions which for example, but not exclusively, can be employed in the preparation of formulations intended for parenteral injection, for intranasal administration, or for administration to some other mucosal membrane.
- Formulations prepared for administration to various mucosal membranes may also include additional components adapting them for such administration, for example, viscosity modifiers.
- Aerosol preparations for example, suitable for administration via inhalation or via nasal mucosa, may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable propellant, for example, an inert compressed gas, e.g., nitrogen.
- a pharmaceutically acceptable propellant for example, an inert compressed gas, e.g., nitrogen.
- 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.
- the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill in the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
- antagonism of adenosine A2a and/or A2b receptors is accomplished by administering to a patient in need of such therapy an effective amount of one or more compounds of the invention, or a pharmaceutically acceptable salt thereof.
- the compound to be administered is in the form of a pharmaceutical composition
- a pharmaceutical composition comprising the compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier (described herein).
- pharmaceutically formulations of the invention may comprise more than one compound of the invention, or a salt thereof, for example, the combination of two or three compounds of the invention, or, additionally or alternatively, another active agent such as those described herein, each present by adding to the formulation the desired amount of the compound or a salt thereof (or agent, where applicable) which has been isolated in a pharmaceutically acceptably pure form.
- administration of a compound of the invention to effect antagonism of A2a and/or A2b receptors is preferably accomplished by incorporating the compound into a pharmaceutical formulation incorporated into a dosage form, for example, one of the above-described dosage forms comprising an effective amount of at least one compound of the invention (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1 compound of the invention), or a pharmaceutically acceptable salt thereof.
- a pharmaceutical formulation incorporated into a dosage form
- a dosage form for example, one of the above-described dosage forms comprising an effective amount of at least one compound of the invention (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1 compound of the invention), or a pharmaceutically acceptable salt thereof.
- the amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition, and size of the patient as well as severity of the symptoms being treated.
- Compounds of the invention can be administered at a total daily dosage of up to 1,000 mg, which can be administered in one daily dose or can be divided into multiple doses per 24-hour period, for example, two to four doses per day.
- 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.
- compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
- the compounds may be administered on a regimen of 1 to 4 times per day or may be administered once or twice per day.
- treatment protocols utilizing at least one compound of the invention can be varied according to the needs of the patient.
- compounds of the invention used in the methods of the invention can be administered in variations of the protocols described above.
- compounds of the invention can be administered discontinuously rather than continuously during a treatment cycle.
- the dosage form administered will contain an amount of at least one compound of the invention, or a salt thereof, which will provide a therapeutically effective serum level of the compound in some form for a suitable period such as at least 2 hours, more preferably at least four hours or longer.
- dosages of a pharmaceutical composition providing a therapeutically effective serum level of a compound of the invention can be spaced in time to provide serum level meeting or exceeding the minimum therapeutically effective serum level on a continuous basis throughout the period during which treatment is administered.
- the dosage form administered may also be in a form providing an extended-release period for the pharmaceutically active compound which will provide a therapeutic serum level for a longer period, necessitating less frequent dosage intervals.
- composition of the invention can incorporate additional pharmaceutically active components or be administered simultaneously, contemporaneously, or sequentially with other pharmaceutically active agents as may be additionally needed or desired while providing treatment.
- dosage form administered may also be in a form providing an extended-release period for the pharmaceutically active compound which will provide a therapeutic serum level for a longer period, necessitating less frequent dosage intervals.
- 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.
- silica gel chromatography was carried out on an ISCO®, Analogix®, or Biotage® automated chromatography system using a commercially available cartridge as the column. Columns were usually filled with silica gel as the stationary phase. Reverse phase preparative HPLC conditions can be found at the end of the experimental section. Aqueous solutions were concentrated on a Genevac® evaporator or w ere ly ophilized.
- 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 concentrated, and the residue was taken up in EtOH (20 mL) and refluxed for another 5 hours.
- LCMS analysis showed that the reaction was complete, and the desired product was formed.
- the reaction mixture was purified by silica gel chromatography (ISCO®; 40 g SepaFlash® C18 Flash Column) eluting with 100% H 2 O gradient @ 30 mL/min) to afford ethyl 6-oxo-1,6-dihydro-1,2,4-triazine-3-carboxylate (1g. 5.91 mmol) as a solid.
- 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.
- reaction mixture was allowed to stir for 16 hours at room temperature.
- LCMS analysis indicated reaction completion, so the mixture was quenched by the addition of saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate.
- the biphasic mixture was allowed to stir for 1 hour.
- 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.
- Example compounds of the invention in the following Table 6 were prepared in a manner similar to the synthesis of Example 1, from the appropriate starting piperidine and carboxylic acid intermediates. In some cases, an additional work-up step was incorporated where the residue was treated with 1 M KOH (3 mL) and DCM (3 mL). The organic layer was collected with a phase separator, and the solvents were evaporated. The residue was purified by silica gel chromatography with 0-100% EtOAc in hexanes as eluent.
- Example 128 [(2S,5R)-5-(5-amino-7,9-difluoro[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl](cis-3-hydroxy-3-methylcyclobutyl)methanone methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (2.69 g, 5.74 mmol) (Intermediate 15), (1S,3S)-3-hydroxy-3-methylcyclobutane-1-carboxylic acid (0.859 g, 6.60 mmol), DIPEA (2.01 ml, 11.48 mmol), and DCM (15 mL).
- Example compounds of the invention in the following Table 8 were prepared in a manner similar to the synthesis of Example 150, from the appropriate starting piperidine and carboxylic acid intermediates.
- 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.
- Triethylamine (42.5 ⁇ L, 0.305 mmol) was added and the resulting reaction mixture stirred at room temperature for 2 hours. LCMS analysis indicated >70% conversion to the desired product. The reaction mixture was concentrated, then TFA (235 ⁇ L, 3.05 mmol) was added and the mixture stirred for an additional 2 hours at 60 oC.
- 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 13 were prepared in a manner similar to the synthesis of Example 235, from the appropriate starting piperidine and carboxylic acid intermediates. No final deprotection step was necessary since the DMB group had previously been removed in a similar manner to Intermediate 20. The final compounds were purified by reverse phase HPLC purification.
- Example compounds of the invention in the following Table 14 were prepared in a manner similar to the synthesis of Example 282, from the appropriate starting piperidine and carboxylic acid intermediates.
- 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.
- the reaction was quenched with saturated aqueous NH 4 Cl (5 mL) and treated with EtOAc (15 mL) and water (10 mL). The resulting suspension was filtered. The filtrate was extracted with EtOAc (15 mL x2). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated.
- 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 A2a receptor affinity binding assay measured the amount of binding of a tritiated ligand with high affinity for the A2a adenosine receptor to membranes made from HEK293 or CHO cells recombinantly expressing the human A2a adenosine receptor, in the presence of varying concentrations of a compound of the invention.
- the tested compounds of the invention were 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.
- 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
In its many embodiments, the invention provides certain substituted amino triazolo quinazoline compounds of the structural Formula (I), and pharmaceutically acceptable salts thereof, wherein, ring A, R1 and R2 are as defined herein. Also provided are pharmaceutical compositions comprising one or more such compounds, alone or in combination with one or more other therapeutically active agents. Methods for the preparation of the compounds and their use as antagonists of A2a and/or A2b receptors, either alone or in combination with other therapeutic agents, 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, are also provided.
Description
ADENOSINE A2A AND A2B RECEPTOR ANTAGONISTS, PHARMACEUTICAL
COMPOSITIONS AND USE THEREOF
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63/428,579, filed November 29, 2022, the disclosure of which is incorporated herein by its entirety.
FIELD OF THE INVENTION
[0002] 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. Such 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.
BACKGROUND OF THE INVENTION
[0003] 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). In addition to its involvement in these biochemical processes, adenosine is used as a therapeutic antiarrhythmic agent to treat supraventricular tachycardia and other indications. [0004] The adenosine receptors are a class of purinergic G protein-coupled receptors with adenosine as the endogenous ligand. There are four ty pes of adenosine receptors in humans, namely, A1, A2a, A2b, and A3. Modulation of A1 has been proposed for the management and treatment of neurological disorders, asthma, and heart and renal failure, among others.
Modulation of A3 has been proposed for the management and treatment of asthma and chronic
obstructive pulmonary diseases, glaucoma, cancer, stroke, and other indications. Modulation of the A2a and A2b receptors are also believed to be of potential therapeutic use.
[0005] In the central nervous system, 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. Hence. 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.
[0006] In the immune system, adenosine signaling through 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. Thus, antagonists of the A2a and/or A2b adenosine receptors represent a new class of promising oncology7 therapeutics. For example, 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 regulatory7 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. As each of these immunosuppressive pathways has been identified as a mechanism by which tumors evade host 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. (See, e.g.. P. Beavis, et al., Cancer Immunol. Res. DOI: 10.1158/2326-6066. CIR-14-0211, February 11, 2015; Willingham, SB., et al.. Cancer Immunol. Res., 6(10), 1136- 49; and Leone RD, et al., Cancer Immunol. Immunother., Aug 2018, Vol. 67, Issue 8, 1271- 1284).
[0007] Cancer cells release ATP into the tumor microenvironment when treated with chemotherapy and radiation therapy, which is subsequently converted to adenosine. (See Martins, L, et al.. Cell Cycle, vol. 8, issue 22, pp. 3723 to 3728.) 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).
[0008] The combination of an A2a receptor antagonist with anti-tumor vaccines is believed to provide at least an additive therapeutic effect in view of their different mechanisms of action. Further, A2a receptor antagonists may be useful in combination with checkpoint blockers. By way of example, 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. (See, e.g., Willingham, SB., et al.. Cancer Immunol. Res. (2018); 6(10), 1136-49; Leone, RD., et al., Cancer Immunol. Immunother., Aug 2018, Vol. 67, Issue 8, pp. 1271-1284; Fishman, P., et al., Handb. Exp. Pharmacol. (2009) 193:399-441; and Sitkovsky, MV., et al., (2014) Cancer Immunol. Res 2:598-605.)
[0009] 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. 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.
[0010] A2b receptors are expressed primarily on myeloid cells. The engagement of A2b receptors on myeloid derived suppressor cells (MDSCs) results in their expansion in vitro (Ryzhov, S. et al., J. Immunol. 2011, 187:6120-6129). MDSCs suppress T-cell proliferation and anti-tumor immune responses. Selective inhibitors of A2b receptors and A2b receptor knockouts have been shown to inhibit tumor growth in mouse models by increasing MDSCs in the tumor microenvironment (lannone, R., et al., Neoplasia Vol. 13 No. 12, (2013) pp. 1400-1409; Ryzhov, S., et al., Neoplasia (2008) 10; 987-995). Thus, A2b receptor inhibition has become an attractive biological target for the treatment of a variety of cancers involving myeloid cells. Examples of cancers that express A2b receptors can be readily obtained through analysis of the publicly
available TCGA database. Such cancers include lung, colorectal, head and neck, and cervical cancer, among others, and are discussed in further detail below.
[0011] 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). In certain tumor types, 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. Furthermore, experiments involving adenylate cyclase activation indicate that A2b receptors are the sole adenosine receptor subtype in certain tumor cells, suggesting that A2b receptor antagonists may exhibit effects on particular tumor types. (See, e.g., Feoktistov, I., et al., (2003) Circ. Res. 92:485-492; and P. Fishman, P., et al., Handb. Exp. Pharmacol. (2009) 193:399-441).
[0012] In view of their promising and varied therapeutic potential, there remains a need in the art for potent and selective inhibitors of the A2a and/or A2b adenosine receptors, for use alone or in combination with other therapeutic agents. The present invention addresses this and other needs.
SUMMARY OF THE INVENTION
[0013] In one aspect, 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, R1, and R2 are as defined below. [0014] In another aspect, 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. [0015] In another aspect, 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. These and other aspects and embodiments of the invention are described more fully below.
DETAILED DESCRIPTION OF THE INVENTION
[0016] The present disclosure may be understood more readily by reference to the following detailed description of the various embodiments of the disclosure and the examples included herein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure pertains.
Embodiments
[0017] For each of the following embodiments, 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.
[0018] In one aspect (first embodiment), the invention provides compounds having a structural Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R1 is H, F, or Cl; each R2 is, independently, H, F, Cl, (C1-C6)alkyl, or -O(C1-C6)alkyl, wherein each R2 is not H simultaneously; ring A is a moiety selected from
R3 is selected from:
(1) -(CHR3A)q(CH2)n(C6-C10)ary l, wherein the aryl is optionally substituted with 1 to 3 R3B groups;
(2) a 4- to 7 -membered heterocycloalkyl having 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 R3C groups;
(3) (C1-C6)alkyl or (C3-C10)cycloalkyl, each optionally substituted with 1 to 3 R3D groups;
(4) a 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O. and S, optionally substituted with 1 to 4 R3E groups;
R4, R5, and R6, each is (C1-C6)alkyl or (C1-C6)haloalkyl:
R3A is H or -OH;
R3B, at each occurrence, is independently selected from the group consisting of halogen, -OH, -CF3, -CN, -N(R3F)2, (C1-C6)alkyl, and (C3-C10)cycloalkyl,
wherein each of the (C1-C6)alkyl and the (C3-C10)cycloalkyl is optionally substituted with 1 to 7 moieties independently selected from the group consisting of -OH, -N(R3F)2, (C3-C10)cycloalkyl. and halogen;
R3C, at each occurrence, is independently selected from the group consisting of halogen, - OH, -CN, (C1-C6)alkyl, (C3-C10)cycloalkyl, -O(C1-C6)alkyl, -CO(C1-C6)alkyl -CO(C3- C6)cycloalkyl, and -CO(C3-C6)cyclohaloalkyl. the (C1-C6)alkyl being optionally substituted with 1 to 4 moieties independently selected from the group consisting of -OH and halogen;
R3D, at each occurrence, is independently selected from the group consisting of -OH, -
CF3, -CN, -N(R3F)2
(C1-C6)alkyl, (C1-C6)haloalkyl, -O(C1-C6)alkyl, -O(C1- C4)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C4)alkylsulfonyl, halogen, and oxadiazolyl, the oxadiazolyl being optionally substituted with (C1-C4)alkyl;
R3E , at each occurrence, is independently selected from the group consisting of -OH, halogen, -CN, -CF3,
morpholin-4-yl, (C1-C4)alkylsulfonyl-, -CO(C1-C6)alkyl, oxetanyl, (C1-C6)alkyl, -O(C1-C6)alkyl.
(C3-C10)cycloalkyl. (C3-C10)cyclohaloalkyl, tetrahydrofuranyl, pyrimidinyl. and
wherein each of the (C1-C6)alkyl, the -O(C1-C6)alkyl, and the (C3-C10)cycloalkyl is optionally substituted with 1 to 4 moieties independently selected from the group consisting of -OH, (C1- C4)alkyl, -N(R3F)2, and halogen;
R3F, at each occurrence, is independently, H, (C1-C4)alkyl, or (C1-C4)haloalkyl;
R3J at each occurrence, is independently. -OH. (C1-C6)alkyl. (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl. or (C3-C6)cycloalkyl;
R3K is (C1-C4)alkyl, (C1-C4)haloalkyl or (C3-C10)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.
[0019] In another embodiment, the invention provides a compound of the immediately preceding embodiment, or a pharmaceutically acceptable salt thereof, wherein R1 is F.
[0020] In another embodiment, the invention provides a compound of any of the immediately preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein ring A is
[0021] In another embodiment, the invention provides a compound of any of the immediately preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R4 is CH3. [0022] In another embodiment, the invention provides a compound of any of the immediately preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R3 is - (CHR3A)q(CH2)n(C6-C10)aryl, wherein the aryl is optionally substituted with 1 to 3 R3B groups, and wherein
R3B, at each occurrence, is independently selected from the group consisting of
halogen, -OH, -CF3, -CN, -N(R3F)2,
(C1-C6)alkyl, and (C3-C10)cycloalkyl, wherein each of the (C1-C6)alkyl and the (C3-C10)cycloalkyl is optionally substituted with 1 to 7 moieties independently selected from the group consisting of -OH, -N(R3F)2, (C3-C10)cycloalkyl, and halogen.
[0023] In some embodiments, R3B is not substituted. In some embodiments. R3B is optionally substituted with 1 to 7 moieties selected from the above list. In some embodiments, R3B is optionally substituted w ith 1 to 6 moieties selected from the above list. In some embodiments, R3B is optionally substituted with 1 to 5 moieties selected from the above list. In some embodiments, R3B is optionally substituted with 1 to 4 moieties selected from the above list. In some embodiments, R3B is optionally substituted with 1 to 3 moieties selected from the above list. In some embodiments, R3B is optionally substituted with 1 or 2 moieties selected from the above list. In some embodiments, R3B is optionally substituted with 1 moiety selected from the above list. In other embodiments, R3B is substituted with 1 moiety selected from the above list. In other embodiments, R3B is substituted with 2, 3, 4, 5, 6, or 7 moieties selected from the above list.
[0024] In another embodiment, the invention provides a compound of any of the first four embodiments, or a pharmaceutically acceptable salt thereof, wherein R3 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 R3C groups, and wherein
R3C, at each occurrence, is independently selected from the group consisting of halogen, - OH, -CN, (C1-C6)alkyl, (C3-C10)cycloalkyl, -O(C1-C6)alkyl, -CO(C1-C6)alkyl -CO(C3- C6)cycloalkyl, and -CO(C3-C6)cyclohaloalkyl. the (C1-C6)alkyl being optionally substituted with 1 to 4 moieties independently selected from the group consisting of -OH, and halogen; [0025] In another embodiment, the invention provides a compound of any of the first four embodiments or a pharmaceutically acceptable salt thereof, wherein R3 is (C1-C6)alkyl, or (C3-C10)cycloalkyl. each optionally substituted with 1 to 4 R3D groups, and wherein
R3D, at each occurrence, is independently selected from the group consisting of -OH, -
CF3, -CN, -N(R3F)2, (C1-C6)alkyl, (C1-C6)haloalkyl, -O(C1-C6)alkyl, -O(C1-
C4)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C4)alkylsulfonyl, halogen, and oxadiazolyl, the oxadiazolyl being optionally substituted with (C1-C4)alkyl.
[0026] In another embodiment, the invention provides a compound of any of the first four embodiments, or a pharmaceutically acceptable salt thereof, wherein R3 is a 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4
R3E , at each oc p consisting of -OH,
halogen, -CN, -CF3, morpholin-4-yl, (C1-C4)alkylsulfonyl-. -CO(C1-C6)alkyl, oxetanyl, (C1-C6)alkyl, - 1
(C3-C10)cycloalkyl. (C3-C10)cyclohaloalkyl, tetrahydrofuranyl, pyrimidinyl. and wherein each of the (C1-C6)alkyl, the -O(C1-C6)alkyl, and the (C3-C10)cycloalkyl is optionally substituted with 1 to 4 moieties independently selected from the group consisting of -OH, (C1- C4)alkyl, -N(R3F)2, and halogen.
[0028] In another embodiment, the invention provides a compound of the first embodiment having Formula (I.1),
(I.1) or a pharmaceutically acceptable salt thereof. [0029] In another embodiment, the invention provides a compound of the immediately preceding embodiment, or a pharmaceutically acceptable salt thereof, wherein R4 is -CH3, 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 R3 is pyridinyl, piperidinyl, phenyl, imidazolyl, triazolyl, pyrrolidinyl, thiazolyl, pyrrolidinonyl, pyrazolyl, pyridazinyl, cyclobutyl, oxazolyl, pyrazinyl, oxadiazolyl, or (C1-C6)alkyl, each optionally substituted with 1 to 4 moieties selected from the group consisting of -OH methyl ethyl, isopropyl, cyclopropyl, F, morpholin-4-yl
, and cyclobutyl, the cyclobutyl being optionall OH or -CH3. [0031] In another embodiment, the invention provides a compound of the immediately preceding embodiment, or a pharmaceutically acceptable salt thereof, wherein R3 is oxazolyl, pyridinyl, pyrazinyl, oxadiazolyl, or phenyl. [0032] In another embodiment, 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 - CH3 or
[0033] In another embodiment, the invention provides a compound of the immediately preceding embodiment, wherein ring A is
. [0034] In another embodiment, the invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of
, and . [0035] In another embodiment, the invention provides a compound selected from the group consisting of
, an . [0036] In another embodiment, the compounds of the invention comprise those compounds identified herein as examples in the tables below and the pharmaceutically acceptable salts thereof. [0037] In another aspect, 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. [0038] In another aspect, the invention provides a method for the manufacture of a medicament or a composition which may be useful for treating diseases, conditions, or disorders that are mediated, at least in part, by the adenosine A2a receptor and/or the adenosine A2b receptor, the method comprising combining a compound of the invention with one or more pharmaceutically acceptable carriers. [0039] In another aspect, 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 in need thereof 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. Specific non-limiting examples of such diseases, conditions, and disorders are described herein.
Indications
Oncology
[0040] In some embodiments, 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. 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.
[0041] Thus, one 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 A2a receptor.
[0042] 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 kidney (or renal) cancer, breast cancer, lung cancer, and liver cancer.
[0043] 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.
[0044] 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.
[0045] Additional non-limiting examples of 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. 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.
CNS and Neurological Disorders
[0046] In other embodiments, the disease, condition, or disorder is a central nervous system or a neurological disorder. Non-limiting examples of such 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.
Infections
[0047] In other embodiments, the disease, condition, or disorder is an infective disorder. Non- limiting examples of such diseases, conditions or disorders include an acute or chronic viral infection, a bacterial infection, a fungal infection, or a parasitic infection. In one embodiment, the viral infection is human immunodeficiency virus. In another embodiment, the viral infection is cytomegalovirus.
Immune Disease
[0048] In other embodiments, the disease, condition, or disorder is an immune-related disease, condition, or disorder. Non-limiting examples of immune-related diseases, conditions, or disorders include multiple sclerosis and bacterial infections. (See. e.g., Safarzadeh. E. et al., Inflamm Res 2016 65(7):511-20; and Antonioli, L., et al, Immunol Lett 80165-2478(18)30172- X 2018).
Additional Indications
[0049] 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. Thus, in another embodiment, 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] In another aspect, 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. When a compound of the invention is used contemporaneously with one or more other drugs, the pharmaceutical composition may in specific embodiments contain such other drugs and the compound of the invention or its pharmaceutically acceptable salt in separate doses or in unit dosage form. However, the combination therapy may also include therapies in which the compound of the invention or its pharmaceutically acceptable salt and one or more other drugs are administered sequentially, on different or overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions comprising the compounds of the
invention include those that contain one or more other active ingredients, in addition to a compound of the invention or a pharmaceutically acceptable salt thereof.
[0051] 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.
[0052] Given the immunosuppressive role of adenosine, 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. Thus, in one embodiment, the additional therapeutic agent comprises an anti-PD-1 antibody. In another embodiment, the additional therapeutic agent is an anti-PD-Ll antibody.
[0053] As noted above, 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).
[0054] Two known ligands for PD-1, PD-L1 (B7-H1) and PD-L2 (B7-DC) are expressed in human cancers arising in various tissues. In large sample sets of, for example, ovarian, renal, colorectal, pancreatic, and liver cancers, and in melanoma, it was shown that PD-L1 expression correlated with poor prognosis and reduced overall survival irrespective of subsequent treatment. (Dong et al., Nat Med. 8(8):793-800 (2002); Yang et al, Invest Ophthamol Vis Sci. 49: 2518- 2525 (2008); Ghebeh et al, Neoplasia 8: 190-198 (2006); Hamanishi et al, Proc. Natl. Acad. Sci. USA 104: 3360-3365 (2007); Thompson et al. Cancer 5: 206-211 (2006): Nomi et al., Clin. Cancer Research 13:2151-2157 (2007); Ohigashi et ak, Clin. Cancer Research 11 : 2947-2953;
Inman et al., Cancer 109: 1499-1505 (2007); Shimauchi et al., Int. J. Cancer 121 :2585-2590 (2007); Gao et al, Clin. Cancer Research 15: 971-979 (2009); Nakanishi J., Cancer Immunol Immunother. 56: 1173- 1182 (2007); and Hino et al, Cancer 00; 1-9 (2010)).
[0055] Similarly, PD-1 expression on tumor infiltrating lymphocytes was found to mark dysfunctional T-cells in breast cancer and melanoma (Ghebeh et al, BMC Cancer. 2008 8:5714- 15 (2008); and Ahmadzadeh et al., Blood 114: 1537-1544 (2009)) and to correlate with poor
prognosis in renal cancer (Thompson et al, Clinical Cancer Research 15: 1757-1761(2007)). Thus, it has been proposed that PD-L1 expressing tumor cells interact with PD-1 expressing T- cells to attenuate T-cell activation and to evade immune surveillance, thereby contributing to an impaired immune response against the tumor.
[0056] Immune checkpoint therapies targeting the PD-1 axis have resulted in groundbreaking improvements in clinical response in multiple human cancers (Brahmer, et al, N Engl J Med
2012, 366: 2455-65; Garon et al., N Engl J Med 2015, 372: 2018-28; Hamid et al, N Engl J Med
2013, 369: 134-44; Robert et al., Lancet 2014, 384: 1109-17; Robert et al, N Engl J Med 2015, 372: 2521-32; Robert et al., N Engl J Med 2015, 372: 320-30: Topalian et al., N Engl J Med 2012, 366: 2443-54; Topalian et al., J Clin Oncol 2014, 32: 1020-30; and Wolchok et al, N Engl J Med 2013, 369: 122-33).
[0057] "PD-1 antagonist" means any chemical compound or biological molecule that blocks binding of PD-L1 expressed on a cancer cell to PD-1 expressed on an immune cell (T-cell, B-cell or NKT cell) and, in some embodiments, also blocks binding of PD-L2 expressed on a cancer cell to the immune-cell expressed PD-1. Alternative names or synonyms for PD-1 and its ligands include: PDCD1, PD1, CD279 and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc and CD273 for PD-L2.
[0058] In any of the treatment methods, medicaments and uses of the invention in which a human individual is being treated, the PD-1 antagonist blocks binding of human PD-L1 to human PD-1, and preferably blocks binding of both human PD-L1 and PD-L2 to human PD-1. Human PD-1 amino acid sequences can be found in NCBI Locus No.: NP 005009. Human PD- L1 and PD-L2 amino acid sequences can be found in NCBI Locus No.: NP_054862 and NP_079515, respectively.
[0059] PD-1 antagonists useful in any of the treatment methods, medicaments and uses of the invention include a monoclonal antibody (mAb), or an antigen binding fragment thereof, which specifically binds to PD-1 or PD-L1 and preferably specifically binds to human PD-1 or human PD-L1. The mAb may be a human antibody, a humanized antibody or a chimeric antibody, and may include a human constant region. In some embodiments the human constant region is selected from the group consisting of IgGl, IgG2, IgG3 and IgG4 constant regions, and in particular embodiments, the human constant region is an IgGl or IgG4 constant region. In some embodiments, the antigen binding fragment is selected from the group consisting of Fab. Fab'- SH, F(ab')2, scFv, and Fv fragments. Examples of PD-1 antagonists include, but are not limited to, pembrolizumab (KEYTRUDA®, Merck and Co., Inc., Rahway, NJ, USA).
[0060] “Pembrolizumab” (formerly known as MK-3475, SCH 900475 and lambrolizumab and sometimes referred to as “pembro” is a humanized IgG4 mAh with the structure described in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013). Additional examples of PD-1 antagonists include nivolumab (OPDIVO®, Bristol-Myers Squibb Company, Princeton, NJ, USA), atezolizumab (MPDL3280A; TECENTRIQ®, Genentech, San Francisco, CA, USA), durvalumab (IMFINZI®, Astra Zeneca Pharmaceuticals, LP, Wilmington, DE), avelumab (BAVENCIO®, Merck KGaA, Darmstadt, Germany and Pfizer, Inc., New York, NY), and dostarlimab (JEMPERLI™, GlaxoSmithKline LLC, Philadelphia, PA).
[0061] Examples of monoclonal antibodies (mAbs) that bind to human PD-1. and useful in the treatment methods, medicaments and uses of the invention, are described in US7488802, US7521051, US8008449, US8354509, US8168757, W02004/004771, W02004/072286, W02004/056875, and US2011/0271358.
[0062] Examples of mAbs that bind to human PD-L1, and useful in the treatment methods, medicaments and uses of the invention, are described in W02013/019906,
W02010/077634 Al and US8383796. Specific anti-human PD-L1 mAbs useful as the PD-1 antagonist in the treatment method, medicaments and uses of the invention include MPDL3280A, BMS-936559, MEDI4736, MSB0010718C and an antibody which comprises the heavy chain and light chain variable regions of SEQ ID NO:24 and SEQ ID NO:21, respectively, of W02013/019906.
[0063] Other PD-1 antagonists useful in any of the treatment methods, medicaments and uses of the invention include an immunoadhesin that specifically binds to PD-1 or PD- LI, and preferably specifically binds to human PD-1 or human PD-L1, e.g., a fusion protein containing the extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region such as an Fc region of an immunoglobulin molecule. Examples of immunoadhesin molecules that specifically bind to PD-1 are described in W02010/027827 and WO2011/066342. Specific fusion proteins useful as the PD-1 antagonist in the treatment methods, medicaments and uses of the invention include AMP-224 (also known as B7-DCIg), which is a PD-L2-FC fusion protein that binds to human PD-1
[0064] Thus, one embodiment provides a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with a PD-1 antagonist to a subject in need thereof. In such embodiments, the compounds of the invention, or a pharmaceutically acceptable salt thereof, and PD-1 antagonist are administered concurrently or sequentially.
[0065] Specific non-limiting examples of such 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.
[0066] In one embodiment, there is provided a method of treating 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, wherein said cancer is selected from unresectable or metastatic melanoma, 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, and hepatocellular carcinoma. In one such embodiment, the agent is a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.
[0067] Pembrolizumab is approved by the U.S. FDA for the treatment of patients with unresectable or metastatic melanoma, for the adjuvant treatment of melanoma, and for the treatment of certain patients with 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) or mismatch repair deficient cancer, MSI-H or mismatch repair deficient colorectal cancer, non- small cell lung cancer, esophageal cancer, Merkel cell carcinoma, renal cell carcinoma, endometrial carcinoma, cutaneous squamous cell carcinoma, triple negative breast cancer, hepatocellular carcinoma, and tumor mutational burden-high (TMB-H) cancer as described in the Prescribing Information for KEYTRUDA™ (Merck & Co., Inc., Rahway, NJ USA; initial U.S. approval 2014, updated August 2022). In another embodiment, there is provided a method of treating 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
pembrolizumab, wherein said cancer is selected from unresectable or metastatic melanoma, 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, and hepatocellular carcinoma.
[0068] In one embodiment, there is provided a method of treating 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, wherein said cancer is selected from melanoma, HNSCC, cHL, urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large-B-cell lymphoma, MSI-H or mismatch repair deficient cancer, MSI-H or mismatch repair deficient colorectal cancer, non-small cell lung cancer, esophageal cancer, Merkel cell carcinoma, renal cell carcinoma, endometrial carcinoma, cutaneous squamous cell carcinoma, triple negative breast cancer, hepatocellular carcinoma, and TMB-H cancer. In one such embodiment, the PD-1 antagonist is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In another such embodiment, the agent is durvalumab. In another such embodiment, the agent is avelumab. In another such embodiment, the agent is dostarlimab. [0069] In another embodiment, there is provided a method of treating 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, wherein said cancer is selected from melanoma, non-small cell lung cancer, head and neck squamous cell cancer (HNSCC), Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, microsatellite instability-high cancer, gastric cancer, Merkel cell carcinoma, hepatocellular carcinoma, esophageal cancer and cervical cancer. In one such embodiment, the PD-1 antagonist is pembrolizumab. In another such embodiment, the PD-1 antagonist is nivolumab. In another such embodiment, the PD-1 antagonist is atezolizumab. In another such embodiment, the PD-1 antagonist is durvalumab. In another such embodiment, the PD-1 antagonist is avelumab. In another such embodiment, the agent is dostarlimab.
[0070] In another embodiment, there is provided a method of treating 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, wherein said cancer is selected from melanoma, non-small cell lung cancer, small cell lung cancer, head and neck cancer, bladder cancer, breast cancer, gastrointestinal cancer, multiple
myeloma, hepatocellular cancer, lymphoma, renal cancer, mesothelioma, ovarian cancer, esophageal cancer, anal cancer, biliary tract cancer, colorectal cancer, cervical cancer, thyroid cancer, and salivary cancer. In one such embodiment, the PD-1 antagonist is pembrolizumab. In another such embodiment, the PD-1 antagonist is nivolumab. In another such embodiment, the PD-1 antagonist is atezolizumab. In another such embodiment, the PD-1 antagonist is durvalumab. In another such embodiment, the PD-1 antagonist is avelumab. In another such embodiment, the agent is dostarlimab.
[0071] In one embodiment, there is provided a method of treating unresectable or metastatic melanoma 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. In one such embodiment, the PD-1 antagonist is pembrolizumab. In another such embodiment, the PD-1 antagonist is nivolumab. In another such embodiment, the PD-1 antagonist is atezolizumab. In another such embodiment, the PD-1 antagonist is selected from the group consisting of: pembrolizumab. nivolumab, atezolizumab, durvalumab, avelumab, and dostarlimab.
[0072] In one embodiment, there is provided a method of treating recurrent or metastatic head and neck squamous cell cancer (HNSCC) 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. In one such embodiment, the PD-1 antagonist is pembrolizumab. In another such embodiment, the PD-1 antagonist is nivolumab. In another such embodiment, the PD-1 antagonist is atezolizumab. In another such embodiment, the PD-1 antagonist is selected from the group consisting of: pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, and dostarlimab.
[0073] In one embodiment, there is provided a method of treating classical Hodgkin lymphoma (cHL) 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. In one such embodiment, the PD-1 antagonist is pembrolizumab. In another such embodiment, the PD-1 antagonist is nivolumab. In another such embodiment, the PD-1 antagonist is atezolizumab. In another such embodiment, the PD-1 antagonist is selected from the group consisting of: pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, and dostarlimab.
[0074] In one embodiment, there is provided 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. In one such embodiment, the PD-1 antagonist is pembrolizumab. In another such embodiment, the PD-1 antagonist is nivolumab. In another such embodiment, the PD-1 antagonist is atezolizumab. In another such embodiment, the PD-1 antagonist is selected from the group consisting of: pembrolizumab. nivolumab, atezolizumab, durvalumab, avelumab, and dostarlimab.
[0075] In one embodiment, there is provided a method of treating gastric 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. In one such embodiment, the PD- 1 antagonist is pembrolizumab. In another such embodiment, the PD-1 antagonist is nivolumab. In another such embodiment, the PD-1 antagonist is atezolizumab. In another such embodiment, the PD-1 antagonist is selected from the group consisting of: pembrolizumab, nivolumab. atezolizumab, dun alumab, avelumab. and dostarlimab.
[0076] In one embodiment, there is provided a method of treating cervical 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. In one such embodiment, the PD-1 antagonist is pembrolizumab. In another such embodiment, the PD-1 antagonist is nivolumab. In another such embodiment, the PD-1 antagonist is atezolizumab. In another such embodiment, the PD-1 antagonist is selected from the group consisting of: pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, and dostarlimab.
[0077] In one embodiment, there is provided a method of treating primary mediastinal large-B- cell lymphoma 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. In one such embodiment, the PD-1 antagonist is pembrolizumab. In another such embodiment, the PD-1 antagonist is nivolumab. In another such embodiment, the PD-1 antagonist is atezolizumab. In another such embodiment, the PD-1 antagonist is selected from the group consisting of: pembrolizumab, nivolumab, atezolizumab, dun alumab. avelumab, and dostarlimab.
[0078] In one embodiment, there is provided 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. In one such embodiment, the PD-1 antagonist is pembrolizumab. In another such embodiment, the PD-1 antagonist is nivolumab. In another such embodiment, the PD-1 antagonist is atezolizumab. In another such embodiment, the PD-1 antagonist is selected from the group consisting of: pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, and dostarlimab.
[0079] In one embodiment, there is provided a method of treating non-small cell lung 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. In one such embodiment, the PD-1 antagonist is pembrolizumab. In another such embodiment, the PD-1 antagonist is nivolumab. In another such embodiment, the PD-1 antagonist is atezolizumab. In another such embodiment, the PD-1 antagonist is selected from the group consisting of: pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, and dostarlimab.
[0080] In one embodiment, there is provided a method of treating hepatocellular 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. In one such embodiment, the PD-1 antagonist is pembrolizumab. In another such embodiment, the PD-1 antagonist is nivolumab. In another such embodiment, the PD-1 antagonist is atezolizumab. In another such embodiment, the PD-1 antagonist is selected from the group consisting of: pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, and dostarlimab.
[0081] In another embodiment, the additional therapeutic agent is at least one immunomodulator other than an A2a or A2b receptor inhibitor. Non-limiting examples of immunomodulators include CD40L, B7, B7RP1, anti-CD40, anti-CD38, anti-ICOS, 4-IBB ligand, dendritic cell cancer vaccine, IL2, IL12, ELC/CCL19, SLC/CCL21, MCP-1, IL-4, IL-18, TNF, IL-15, MDC. IFN-a/-13, M-CSF, IL-3, GM-CSF, IL-13, anti-IL-10 and indolamine 2,3- dioxygenase 1 (IDO1) inhibitors.
[0082] In another embodiment, the additional therapeutic agent comprises radiation. Such radiation includes localized radiation therapy and total body radiation therapy.
[0083] In another embodiment, the additional therapeutic agent is at least one chemotherapeutic agent. Non-limiting examples of chemotherapeutic agents contemplated for use in combination with the compounds of the invention include: pemetrexed, alkylating agents (e.g., nitrogen mustards such as chlorambucil, cyclophosphamide, isofamide, mechlorethamine,
melphalan, and uracil mustard; aziridines such as thiotepa; methanesulphonate esters such as busulfan; nucleoside analogs (e.g., gemcitabine); nitroso ureas such as carmustine, lomustine, and streptozocin; topoisomerase 1 inhibitors (e.g., irinotecan); platinum complexes such as cisplatin, carboplatin and oxaliplatin; bioreductive alkylators such as mitomycin, procarbazine, dacarbazine and altretamine); anthracy cline-based therapies (e.g., doxorubicin, daunorubicin, epirubicin and idarubicin); DNA strand-breakage agents (e.g., bleomycin); topoisomerase II inhibitors (e.g., amsacrine, dactinomycin, daunorubicin, idarubicin, mitoxantrone, doxorubicin, etoposide, and teniposide); DNA minor groove binding agents (e.g., plicamydin); antimetabolites, e.g., folate antagonists such as methotrexate and trimetrexate; pyrimidine antagonists such as fluorouracil, fluorodeoxyuridine, CB3717, azacitidine, cytarabine, and floxuridine; purine antagonists such as mercaptopurine, 6-thioguanine, fludarabine, and pentostatin; asparginase; ribonucleotide reductase inhibitors such as hydroxyurea; tubulin interactive agents (e.g., vincristine, estramustine, vinblastine, docetaxol, epothilone derivatives, and paclitaxel): hormonal agents, e.g., estrogens, conjugated estrogens, and ethynyl estradiol; diethylstilbesterol; chlortrianisen; idenestrol: progestins such as hydroxyprogesterone caproate, medroxyprogesterone, and megestrol; and androgens such as testosterone, testosterone propionate, fluoxymesterone, and methyltestosterone; adrenal corticosteroids, e.g., prednisone, dexamethasone, methylprednisolone, and prednisolone; luteinizing hormone releasing agents or gonadotropin-releasing hormone antagonists, e.g., leuprolide acetate, and goserelin acetate; antihormonal antigens, e.g., tamoxifen; antiandrogen agents such as flutamide; and antiadrenal agents such as mitotane and aminoglutethimide.
[0084] In another embodiment, the additional therapeutic agent is at least one signal transduction inhibitor (STI). Non-limiting examples of signal transduction inhibitors include BCR/ABL kinase inhibitors, epidermal growth factor (EGF) receptor inhibitors, HER-2/neu receptor inhibitors, and famesyl transferase inhibitors (FTIs).
[0085] In another embodiment, the additional therapeutic agent is at least one anti -infective agent. Non-limiting examples of anti-infective agents include cytokines, non-limiting examples of which include granulocyte-macrophage colony stimulating factor (GM-CSF) and an Ht3 - ligand.
[0086] In another embodiment, the invention provides a method for treating or preventing a viral infection (e.g., a chronic viral infection) including, but not limited to, hepatitis C virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus, coxsackievirus, and human immunodeficiency virus (HIV).
[0087] In another embodiment, the invention provides a method for the treatment of an infective disorder, said method comprising administering to a subject in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with a vaccine. In some embodiments, the vaccine is an anti-viral vaccine, including, for example, an anti-HTV vaccine. Other antiviral agents contemplated for use include an anti-HIV, anti-HPV, anti HCV, anti HSV agents and the like. In other embodiments, the vaccine is effective against tuberculosis or malaria. In still other embodiments, the vaccine is a tumor vaccine (e.g., a vaccine effective against melanoma); the tumor vaccine may comprise genetically modified tumor cells or a genetically modified cell line, including genetically modified tumor cells or a genetically modified cell line that has been transfected to express granulocyte-macrophage stimulating factor (GM-CSF). In another embodiment, the vaccine includes one or more immunogenic peptides and/or dendritic cells. In another embodiment, 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. In some embodiments, 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.
Definitions
[0088] As used herein, unless otherwise specified, the following terms have the following meanings.
[0089] Unsatisfied valences in the text, schemes, examples, structural formulae, and any Tables herein are assumed to have a hydrogen atom or atoms of sufficient number to satisfy the valences.
[0090] When a variable appears more than once in any moiety or in any compound of the invention (e.g., aryl, heterocycle, -N(R)2), the selection of moieties defining that variable for each occurrence is independent of its definition at every other occurrence unless specified otherwise in the local variable definition.
[0091] As used herein, unless otherwise specified, the term "A2a receptor antagonist’7 (equivalently, A2a antagonist) and/or "A2b receptor antagonist” (equivalently, A2b antagonist) means a compound exhibiting a potency (IC50) of less than about 1 pM with respect to the A2a
and/or A2b receptors, respectively, when assayed in accordance with the procedures described herein. Compounds of the invention exhibit at least 10-fold selectivity for antagonizing the A2a receptor and/or the A2b receptor over any other adenosine receptor (e.g., Al or A3).
[0092] As described herein, unless otherwise indicated, the use of 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.
[0093] The phrase “at least one” used in reference to the number of components comprising a composition, 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.
[0094] Whether used in reference to a substituent on a compound or a component of a pharmaceutical composition the phrase “one or more”, means the same as “at least one.” [0095] “Concurrently” and "contemporaneously" both include in their meaning (1) simultaneously in time (e.g., at the same time); and (2) at different times but within the course of a common treatment schedule.
[0096] “Consecutively” means one following the other.
[0097] "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.
[0098] “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. For example, in treating a cancer as described herein with one or more of the compounds of the invention optionally in combination with one or more additional agents, “effective amount” (or “therapeutically effective amount”) means, for example, providing the amount of at least one compound of the invention that results in a
therapeutic response in a patient afflicted with the disease, condition, or disorder, including a response suitable to manage, alleviate, ameliorate, or treat the condition or alleviate, ameliorate, reduce, or eradicate one or more symptoms attributed to the condition and/or long-term stabilization of the condition, for example, as may be determined by the analysis of pharmacodynamic markers or clinical evaluation of patients afflicted with the condition.
[0099] The term ‘‘patient’ ’ (alternatively referred to as "‘subject” or “individual” herein) 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. In some embodiments, a patient is an adult patient. In other embodiments, a patient is a pediatric patient. A patient “in need of treatment” is an individual diagnosed with, suspected of having, or predisposed to a disease or disorder in which a compound of the invention is intended to treat. [0100] “Treat” or “treatment” means to administer an agent, such as a composition containing any of the compounds described herein, internally or externally to a subject or patient having one or more disease symptoms, or being suspected of having a disease, for which the agent has therapeutic activity. Typically, the agent is administered in an amount effective to alleviate one or more disease symptoms in the treated subject or population, whether by inducing the regression of or inhibiting, delaying, or slowing the progression of such symptom(s) by any clinically measurable degree. 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. Thus, 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.
[0101] “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.
[0102] The term “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. The term “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.
[0103] Unless expressly stated to the contrary in a particular context, any of the various cyclic ring and ring system variables or substituents described herein may be attached to the rest of the compound at any ring atom (i.e., any carbon atom or any heteroatom) provided that a stable compound results.
[0104] Where optional substitution by a moiety is described (e.g. “optionally substituted”) the term 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.
[0105] “Alkyl” means an aliphatic hydrocarbon group, which may be straight or branched, comprising 1 to 10 carbon atoms. “(C1-C6)alkyl” means an aliphatic hydrocarbon group, which may be straight or branched, comprising 1 to 6 carbon atoms. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl, are attached to a linear alkyd chain. Non-
limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, and t-butyl.
[0106] “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. As appreciated by those of skill in the art. "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.
[0107] “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. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. “Monocyclic aryl’" means phenyl.
[0108] “Heteroaryl” means an aromatic monocyclic or multicyclic ring system comprising 5 to 14 ring atoms, preferably 5 to 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen, or sulfur, alone or in combination. Preferred heteroaryls contain 5 to 6 ring atoms. The “heteroaryl” can be optionally substituted by one or more substituents, which may be the same or different, as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen, or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. “Heteroaryl” may also include a heteroaryl as defined above fused to an ary l as defined above. Non-limiting examples of 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. imidazolyl, thienopyridyl, quinazolinyl. thienopyrimidyl. pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like. The term “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.
[0109] “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. Non-limiting examples of 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. [0110] “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. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred 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. Thus, the term “oxide,” when it appears in a definition of a variable in a general structure described herein, refers to the corresponding N-oxide. S-oxide, or S,S-dioxide. “Heterocyclyl” also includes rings wherein =0 replaces two available hydrogens on the same carbon atom (i.e., heterocyclyl includes rings having a carbonyl group in the ring). Such =O groups may be referred to herein as
“oxo.” An example of such a moiety is pyrrolidinone (or pyrrolidone):
As used herein, 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:
[0111] It is noted that in 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.
[0112] The line
, as a bond generally indicates a mixture of, or either of, the possible isomers, e.g., containing (R)- and (S)- stereochemistry. For example: means containing both
[0113] 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.
[0114] "Oxo" is defined as an oxygen atom that is double bonded to a ring carbon in a cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, or other ring described herein, e.g.,
[0115] As well known in the art, a bond drawn from a particular atom wherein no moiety is depicted at the terminal end of the bond indicates a methyl group bound through that bond to the atom, unless staled otherwise. For example:
[0116] One or more compounds of the invention may also exist as, or optionally be converted to, a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et al., J. Pharmaceutical Sci., 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, and hemisolvate, including hydrates (where the solvent is water or aqueous based) and the like are described by E. C. van Tonder et al., AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham et al.. Chem. Commun., 603-604 (2001). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (for example, an organic solvent, an aqueous solvent, water, or mixtures of two or more thereof) at a higher than ambient temperature, and cooling the solution, with or without an antisolvent present, at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example I.R. spectroscopy, show the presence of the solvent (including water) in the crystals as a solvate (or hydrate in the case where water is incorporated into the crystalline form). [0117] The term “purified”, “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof. Thus, the term “purified”, “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan, and in sufficient purity to be characterized by standard analytical techniques described herein or well known to the skilled artisan.
[0118] This invention also includes the compounds of the invention in isolated and purified form obtained by routine techniques. Polymorphic forms of the compounds of the invention, and of the salts, solvates and prodrugs thereof, are intended to be included in the invention. Certain compounds of the invention may exist in different isomeric forms (e.g., enantiomers, diastereoisomers, atropisomers). The inventive compounds include all isomeric forms thereof, both in pure form and admixtures of two or more, including racemic mixtures.
[0119] In similar manner, unless indicated otherwise, presenting a structural representation of any tautomeric form of a compound which exhibits tautomerism is meant to include all such
tautomeric forms of the compound. Accordingly, where compounds of the invention, their salts, and solvates and prodrugs thereof, may exist in different tautomeric forms or in equilibrium among such forms, all such forms of the compound are embraced by, and included within the scope of the invention. Examples of such tautomers include, but are not limited to, ketone/enol tautomeric forms, imine-enamine tautomeric forms, and for example heteroaromatic forms such as the following moieties:
[0120] Where a reaction scheme appearing in an example employs a compound having one or more stereocenters, the stereocenters are indicated with an asterisk, as shown below:
[0121] Accordingly, the above depiction consists of the following pairs of isomers: (i) Trans- isomers ((2R,7aS)-2-methylhexahydro-lH-pyrrolizin-7a-yl)methanamine (Compound ABC-1) and ((2S,7aR)-2-methylhexahydro-lH-pyrrolizin-7a-yl)methanamine (Compound ABC-2); and (ii) Cis-isomers ((2R,7aR)-2-methylhexahydro-lH-pyrrolizin-7a-yl)methanamine (Compound ABC-3) and ((2S,7aS)-2-methylhexahydro-lH-pyrrolizin-7a-yl)methanamine (Compound ABC- 4).
[0122] All stereoisomers of the compounds of the invention (including salts and solvates of the inventive compounds and their prodrugs), such as those which may exist due to asymmetric carbons present in a compound of the invention and including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may be isolated in a pure form, for example,
substantially free of other isomers, or may be isolated as an admixture of two or more stereoisomers or as a racemate. The chiral centers of the invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt”, “solvate” “prodrug” and the like, is intended to equally apply to salts, solvates and prodrugs of isolated enantiomers, stereoisomer pairs or groups, rotamers, tautomers, or racemates of the inventive compounds.
[0123] Where diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by known methods, for example, by chiral chromatography and/or fractional crystallization, simple structural representation of the compound contemplates all diastereomers of the compound. As is known, enantiomers may also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individually isolated diastereomers to the corresponding purified enantiomers.
[0124] As the term is employed herein, salts of the inventive compounds, whether acidic salts formed with inorganic and/or organic acids, basic salts formed with inorganic and/or organic bases, salts formed which include zwitterionic character, for example, where a compound contains both a basic moiety, for example, but not limited to, a nitrogen atom, for example, an amine, pyridine or imidazole, and an acidic moiety, for example, but not limited to a carboxylic acid, are included in the scope of the inventive compounds described herein. The formation of pharmaceutically useful salts from basic (or acidic) pharmaceutical compounds are discussed, for example, by S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al.. The Practice of Medicinal Chemistry (1996), Academic Press, New York; in The Orange Book (Food & Drug Administration, Washington, D C. on their website); and P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts; Properties, Selection, and Use, (2002) Infl. Union of Pure and Applied Chemistry, pp. 330-331. These disclosures are incorporated herein by reference.
[0125] The invention contemplates all available salts, including salts which are generally recognized as safe for use in preparing pharmaceutical formulations and those which may be formed presently within the ordinary skill in the art and are later classified as being “generally recognized as safe’’ for use in the preparation of pharmaceutical formulations, termed herein as
“pharmaceutically acceptable salts ’. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, acetates, including trifluoroacetate salts, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, buty rates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates, 3 -phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates, sulfonates (such as those mentioned herein), tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) undecanoates, and the like. [0126] 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. Basic nitrogen- containing groups may be converted to an ammonium ion or quartemized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), arylalkyl halides (e.g. benzy l and phenethyl bromides), and others.
[0127] All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the scope of the invention.
[0128] A functional group in a compound termed “protected” means that the group is in modified form to preclude undesired side reactions at the protected site when the protected compound is subjected to particular reaction conditions aimed at modifying another region of the molecule. Suitable protecting groups are known, for example, as by reference to standard textbooks, for example, T. W. Greene et al., Protective Groups in organic Synthesis (1991), Wiley, New York.
[0129] In the compounds of the invention, the atoms may exhibit their natural isotopic
abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The invention is meant to include all suitable isotopic variations of the compounds of the invention. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically enriched compounds of the invention can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically enriched reagents and/or intermediates.
[0130] 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. Examples of isotopes that can be preferentially incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, iodine, fluorine and chlorine, for example, but not limited to: 2H, 3H, 1 1C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, and 36C1, 123I and 125I. It will be appreciated that other isotopes also may be incorporated by known means.
[0131] Certain isotopically labeled compounds of the invention (e.g., those labeled with 3H, 1 1C and 14C) are recognized as being particularly useful in compound and/or substrate tissue distribution assays using a variety of known techniques. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detection. Further, substitution of a naturally abundant isotope with a heavier isotope, for example, substitution of protium with deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the invention can generally be prepared by following procedures analogous to those disclosed in the reaction Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labeled
reagent for a non-isotopically labeled reagent, or by well-known reactions of an appropriately prepared precursor to the compound of the invention which is specifically prepared for such a “labeling” reaction. Such compounds are included also in the invention.
[0132] The term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, and any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
[0133] The term “pharmaceutical composition” as used herein encompasses both the bulk composition and individual dosage units comprised of one, or more than one (e.g., two), pharmaceutically active agents such as, for example, a compound of the invention (optionally together with an additional agent as described herein), along with any pharmaceutically inactive excipients. As will be appreciated by those of ordinary skill in the art, excipients are any constituent that adapts the composition to a particular route of administration or aids the processing of a composition into a dosage form without itself exerting an active pharmaceutical effect. The bulk composition and each individual dosage unit can contain fixed amounts of the aforesaid one, or more than one, pharmaceutically active agents. The bulk composition is material that has not yet been formed into individual dosage units.
[0134] It will be appreciated that pharmaceutical formulations of the invention may comprise more than one compound of the invention (or a pharmaceutically acceptable salt thereof), for example, the combination of two or three compounds of the invention, each present in such a composition by adding to the formulation the desired amount of the compound in a pharmaceutically acceptably pure form. It will be appreciated also that in formulating compositions of the invention, a composition may comprise, in addition to one or more of compounds of the invention, one or more other agents which also have pharmacological activity, as described herein.
[0135] While formulations of the invention may be employed in bulk form, it will be appreciated that for most applications the inventive formulations will be incorporated into a dosage form suitable for administration to a patient, each dosage form comprising an amount of the selected formulation which contains an effective amount of one or more compounds of the invention. Examples of suitable dosage forms include, but are not limited to, dosage forms adapted for: (i) oral administration, e.g., a liquid, gel, powder, solid or semi-solid pharmaceutical composition which is loaded into a capsule or pressed into a tablet and may comprise additionally one or more coatings which modify its release properties, for example, coatings
which impart delayed release or formulations which have extended release properties; (ii) a dosage form adapted for intramuscular administration (IM), for example, an injectable solution or suspension, and which may be adapted to form a depot having extended release properties;
(iii) a dosage form adapted for intravenous administration (IV), for example, a solution or suspension, for example, as an IV solution or a concentrate to be injected into a saline IV bag;
(iv) a dosage form adapted for administration through tissues of the oral cavity, for example, a rapidly dissolving tablet, a lozenge, a solution, a gel, a sachets or a needle array suitable for providing intramucosal administration; (v) a dosage form adapted for administration via the mucosa of the nasal or upper respiratory cavity, for example a solution, suspension or emulsion formulation for dispersion in the nose or airway; (vi) a dosage form adapted for transdermal administration, for example, a patch, cream or gel; (vii) a dosage form adapted for intradermal administration, for example, a microneedle array; and (viii) a dosage form adapted for deliveryvia rectal or vaginal mucosa, for example, a suppository.
[0136] For preparing pharmaceutical compositions comprising compounds of the invention, generally the compounds of the invention will be combined with one or more pharmaceutically acceptable excipients. These 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. These excipients are collectively termed herein “a carrier.” Typically, formulations may comprise up to about 95 percent active ingredient, although formulations with greater amounts may be prepared.
[0137] Pharmaceutical compositions can be solid, semi-solid or liquid. Solid form preparations can be adapted to a variety of modes of administration, examples of which include, but are not limited to, powders, dispersible granules, mini-tablets, beads, which can be used, for example, for tableting, encapsulation, or direct administration. Liquid form preparations include, but are not limited to, solutions, suspensions, and emulsions which for example, but not exclusively, can be employed in the preparation of formulations intended for parenteral injection, for intranasal administration, or for administration to some other mucosal membrane. Formulations prepared for administration to various mucosal membranes may also include additional components
adapting them for such administration, for example, viscosity modifiers.
[0138] Aerosol preparations, for example, suitable for administration via inhalation or via nasal mucosa, may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable propellant, for example, an inert compressed gas, e.g., nitrogen.
Also included are 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. Examples of such solid forms include, but are not limited to, freeze dried formulations and liquid formulations adsorbed into a solid absorbent medium.
[0139] The compounds of the invention may also be deliverable transdermally or transmucosally, for example, from a liquid, suppository, cream, foam, gel, or rapidly dissolving solid form. It will be appreciated that 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.
[0140] Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions mentioned above may be found in A. Gennaro (ed.), Remington; The Science and Practice of Pharmacy. 20th Edition, (2000), Lippincott Williams & Wilkins, Baltimore, MD.
[0141] Preferably, the pharmaceutical preparation is in a unit dosage form. In such 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.
[0142] The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill in the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
[0143] In accordance with the invention, antagonism of adenosine A2a and/or A2b receptors is accomplished by administering to a patient in need of such therapy an effective amount of one or more compounds of the invention, or a pharmaceutically acceptable salt thereof.
[0144] In some embodiments, it is preferred that the compound to be administered is in the form of a pharmaceutical composition comprising the compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier
(described herein). It will be appreciated that pharmaceutically formulations of the invention may comprise more than one compound of the invention, or a salt thereof, for example, the combination of two or three compounds of the invention, or, additionally or alternatively, another active agent such as those described herein, each present by adding to the formulation the desired amount of the compound or a salt thereof (or agent, where applicable) which has been isolated in a pharmaceutically acceptably pure form.
[0145] As mentioned above, administration of a compound of the invention to effect antagonism of A2a and/or A2b receptors is preferably accomplished by incorporating the compound into a pharmaceutical formulation incorporated into a dosage form, for example, one of the above-described dosage forms comprising an effective amount of at least one compound of the invention (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1 compound of the invention), or a pharmaceutically acceptable salt thereof. Methods for determining safe and effective administration of compounds which are pharmaceutically active, for example, a compound of the invention, are known to those skilled in the art, for example, as described in the standard literature, for example, as described in the “Physicians’ Desk Reference” (PDR), e.g., 1996 edition (Medical Economics Company, Montvale, NJ 07645-1742, USA), the Physician’s Desk Reference, 56th Edition, 2002 (published by Medical Economics company, Inc. Montvale, NJ 07645-1742), or the Physician’s Desk Reference, 57th Edition, 2003 (published by Thompson PDR, Montvale, NJ 07645-1742); the disclosures of which is incorporated herein by reference thereto. The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition, and size of the patient as well as severity of the symptoms being treated. Compounds of the invention can be administered at a total daily dosage of up to 1,000 mg, which can be administered in one daily dose or can be divided into multiple doses per 24-hour period, for example, two to four doses per day.
[0146] As those of ordinary' skill in the art will appreciate, 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. For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0,
75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day or may be administered once or twice per day.
[0147] Those skilled in the art will appreciate that treatment protocols utilizing at least one compound of the invention can be varied according to the needs of the patient. Thus, compounds of the invention used in the methods of the invention can be administered in variations of the protocols described above. For example, compounds of the invention can be administered discontinuously rather than continuously during a treatment cycle.
[0148] In general, in whatever form administered, the dosage form administered will contain an amount of at least one compound of the invention, or a salt thereof, which will provide a therapeutically effective serum level of the compound in some form for a suitable period such as at least 2 hours, more preferably at least four hours or longer. In general, as is known in the art, dosages of a pharmaceutical composition providing a therapeutically effective serum level of a compound of the invention can be spaced in time to provide serum level meeting or exceeding the minimum therapeutically effective serum level on a continuous basis throughout the period during which treatment is administered. As will be appreciated the dosage form administered may also be in a form providing an extended-release period for the pharmaceutically active compound which will provide a therapeutic serum level for a longer period, necessitating less frequent dosage intervals. As mentioned above, a composition of the invention can incorporate additional pharmaceutically active components or be administered simultaneously, contemporaneously, or sequentially with other pharmaceutically active agents as may be additionally needed or desired while providing treatment. As will be appreciated, the dosage form administered may also be in a form providing an extended-release period for the pharmaceutically active compound which will provide a therapeutic serum level for a longer period, necessitating less frequent dosage intervals.
Preparative Examples
[0149] 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.
[0150] One strategy for the synthesis of compounds of type G.4 is via a two-step procedure shown in the general scheme, wherein R1 can be a dimethoxybenzyl protecting group or a hydrogen. R5 can be a methyl or a hydrogen and R2, R3, R4 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. In the second step, 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.
Experimental
[0151] Abbreviations used in the experimental may include, but are not limited to, the following:
General Experimental Information:
[0152] Unless otherwise noted, all reactions were magnetically stirred and performed under an inert atmosphere such as nitrogen or argon.
[0153] Unless otherwise noted, diethyl ether used in the experiments described below- was Fisher ACS certified material and stabilized with BHT.
[0154] Unless otherwise noted, “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.
[0155] Unless otherwise noted, “concentrated” means evaporating the solvent from a solution or mixture using a rotary evaporator or vacuum pump.
[0156] Unless otherwise noted, “evaporated” means evaporating using a rotary evaporator or vacuum pump.
[0157] Unless otherwise noted, silica gel chromatography was carried out on an ISCO®, Analogix®, or Biotage® automated chromatography system using a commercially available cartridge as the column. Columns were usually filled with silica gel as the stationary phase. Reverse phase preparative HPLC conditions can be found at the end of the experimental section. Aqueous solutions were concentrated on a Genevac® evaporator or w ere ly ophilized.
[0158] Unless otherwise noted, 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, CDCl3, DMSO- d6, and MeOD-d4. Carbon resonances are referenced to the carbon resonances of the NMR solvent. Data are represented as follows: chemical shift, multiplicity (hr = broad, br s = broad singlet, s = singlet, d = doublet, dd = doublet of doublets, ddd = doublet of doublet of doublets, t = triplet, q = quartet, m = multiplet), coupling constants (J) in Hertz (Hz), integration.
[0159] Reverse phase HPLC purification was achieved using the following methods:
Method A - TFA Modifier
[0160] C18 reverse-phase Prep-HPLC (gradient elution, MeCN/H2O/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
[0161] C18 reverse-phase Prep-HPLC (gradient elution, MeCN/H2O/basic modifier - 0.1% NH4OH). Electrospray (ESI) Mass-triggered fraction collection was employed using positive ion polarity scanning to monitor for the target mass.
[0162] In cases where isomers are formed these were resolved using a CHIRAL-Prep SFC [Column: DAICEL CHIRALPAK AD-H, OJ-H or CC4: 250x21mm; gradient elution: 5-45% (0.1% ammonium hydroxide in methanol)/CO2.
[0163] A solution of 4-fluoro-3-methoxyaniline (350.0 g, 2.48 mol) in EtOAc (3.5 L) was cooled at 0-5° C. To the mixture was added telra-n -butylammonium tribromide (14.0 kg, 2.90 mol) portion wise. The mixture was warmed to 15 °C and stirred at that temperature for 1 hour. The mixture was adjusted to pH = 8 with saturated aqueous Na2CO3 The mixture was extracted with EtOAc and the combined organic layer was washed with water (1.5 L x2) and dried with anhydrous Na2SO4. The solids were removed by filtration, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-100% EtOAc in
petroleum ether as eluent to afford 2-bromo-4-fluoro-5-methoxyaniline. LCMS (C7H7BrFNO) (ES, m/z): 220, 222 [M+H]+.
[0164] To a solution of 2-bromo-4-fluoro-5-methoxyaniline (300 g. 1.36 mol) (Intermediate 1) in DMF (2.1 L) was added Zn(CN)2 (327 g, 2.78 mol) and Pd(PPh3)4 (90.0 g, 0.08 mol). The mixture was degassed under vacuum and purged with nitrogen and heated with stirring at 130 °C for 1 hour. The reaction mixture was poured into ice w ater (4 L) and extracted with EtOAc x3 (3 L, 2 L, 1 L). The combined organic layers were washed with brine x3 (2 L, 1.5 L), dried over Na2SO4, filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-100% EtOAc in petroleum ether as eluent to afford 2-amino-5- fluoro-4-methoxybenzonitrile. LCMS (C8H7FN2O) (ES, m/z): 167 [M+H]+.
[0165] To a 20 mL vial was added 2-amino-5-fluoro-4-methoxybenzonitrile (817 mg, 4.92 mmol) (Intermediate 2), DCM (6 mL), and pyridine (1 mL). To the mixture was added 1- (isocyanatomethyl)-2,4-dimethoxybenzene (1425 mg, 7.38 mmol) and the resulting mixture was heated with stirring at 40 °C for 16 hours. The solids were collected by filtration and washed with MeOH (3 mL x3), to afford 1-(2-cyano-4-fluoro-5-methoxyphenyl)-3-(2,4- dimethoxybenzyl)urea. LCMS (Cl8H18FN3O4) (ES, m/z): 382 [M+Na]+.
[0166] To a 100 mL round bottom flask was added 1-(2-cyano-4-fluoro-5-methoxyphenyl)-3- (2,4-dimethoxybenzyl)urea (1.16 g, 3.22 mmol) (Intermediate 3), triphenylphosphine (1.69 g. 6.44 mmol), triethylamine (1.80 mL, 12.9 mmol), and DCM (25 mL). The mixture was stirred and cooled at 0 °C. To the mixture was added a solution of carbon tetrabromide (2.14 g, 6.44 mmol) in DCM (5 mL) dropwise. After 30 minutes, the mixture was concentrated. The residue was purified by silica gel chromatography with 0-70% EtOAc in hexanes as eluent, to afford 2- ((((2,4-dimethoxybenzyl)imino)methylene)amino)-5-fluoro-4-methoxybenzonitrile. LCMS (C18H16FN3O3) (ES, m/z): 364 [M+Na]+.
[0167] A solution of (R)-ethyl piperidine-3 -carboxylate (200.0 g, 1270 mmol), triethylamine (257.5 g, 2540 mmol) and DMAP (15.5 g, 130 mmol) in DCM (2 L) was cooled to 0 °C. To the mixture was added di-tert-butyl dicarbonate (305.4 g, 1400 mmol) portion wise. The mixture was stirred at room temperature for 3 hours. Then the organic layer was washed with aqueous saturated sodium bicarbonate (1 L x3). The combined organic layers were dried over anhydrous MgSO4, filtered, and the solvents of the filtrate were evaporated to afford 1-(tert-butyl) 3-ethyl (R)-piperidine-L3-dicarboxylate.
[0168] A solution of (R)- 1 -tert- butyl 3-ethyl piperidine- 1.3-dicarboxylate (320.0 g. 1243 mmol) (Intermediate 5) and hydrazine hydrate (31 1.3 g, 6217 mmol) in EtOH (1.6 L) was stirred and heated at 80 °C for 16 h. The solvents were evaporated and the resulting residue was
purifiedbysilicagelchromatographyelutingwith100%DCMtoaffordtert-butyl(R)-3-(hydrazinecarbonyl)piperidine-1-carboxylate.LCMS(C11H21N3O3)(ES,m/z):244[M+H]+.Intermediate7:(R)-tert-butyl 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine-1-carboxylate [0ca
rboxylate(Intermediate6)(596mg,2.45mmol),DCM(7mL)andAcOH(0.07mL,1.2mmol).Tothemixturewas added2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5-fluoro-4-methoxybenzonitrile(Intermediate4)(836mg,2.45mmol).Theresultingreactionmixturewasstirredfor16hours.Thesolutionwasloadedontoasilicagelcolumnandpurifiedwith0-80%EtOAcinhexaneaseluenttoafford(R)-tert-butyl3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine-1-carboxylateLCMS(C29H35FN6O5)(ES,m/z):567[M+H]+. Intermediate8:(R)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine [0170] T fluoro-
8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine-1-carboxylate(1.40g,2.47mmol)(Intermediate7)andformicacid(4mL).Thesolutionwasstirredatroomtemperaturefor16hours.ThemixturewasdilutedwithDCM(50mL)andwashedwith2Maqueouspotassiumcarbonate(75mL).ThemixturewasextractedwithadditionalDCM(50mL).Thecombinedorganiclayersweredriedoversodiumsulfate,filtered,andthesolvents of thefiltratewereevaporatedtoafford(R)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine.LCMS(C24H27FN6O3)(ES,m/z):467[M+H]+.
[0171] The intermediates in the following Table 1 were synthesized in a manner similar to the synthesis of Intermediate 8 from the appropriate intermediates and starting materials.
TABLE 1
Intermediate 20: (R)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(piperidin-3-yl)- [1,2,4]triazolo[1,5-c]quinazolin-5-amine 3 n vial containin
g - , - me oxy enzy - , - uoro- - , - -me y pper n- -y - [1,2,4]triazolo[1,5-c]quinazolin-5-amine (1000 mg, 2.134 mmol) and a stir bar. The reaction mixture was stirred vigorously at 65 °C. LCMS analysis indicated clean conversion to the desired product after 1 hour. After cooling, the reaction was filtered through celite and washed with water (5 mL x5). LCMS analysis of the filtered purple solid contained minimal amounts of product, so the filtrate was basified with a solution of sodium hydroxide (2561 mg, 64.0 mmol) in water (10 mL). The reaction mixture was poured into a separatory funnel containing 50 mL of 3:1 CHCl3/IPA. The layers were separated, and the aqueous layer was extracted with 3:1 CHCl3/IPA (50 mL x2). The combined organic layers were dried with Mg2SO4, filtered, and concentrated under reduced pressure to give a solid which was used without further purification. LCMS (C15H16F2N6) (ES, m/z): 319 [M+H]+. The intermediates in the following Table 2 were synthesized in a manner similar to the synthesis of Intermediate 20 from the appropriate intermediates and starting materials. TABLE 2 Structure Observed
Intermediate 26: ((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)((R)-pyrrolidin-3-yl)methanone
[0172] To a 4 mL vial was added N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3A, 6S)-6- methylpiperidin-3-yl)- [1,2,4]triazolo[1,5-c]quinazolin-5-amine (750 mg, 1.561 mmol) (Intermediate 10), DIPEA (1.09 mL, 6.24 mmol), and DCM (5 mL). To the mixture was added 1-propanephosphonic anhydride (1.86 mL, 3.12 mmol). The mixture was stirred at room temperature for 2 hours. Analysis by LCMS showed the reaction was complete. The mixture was concentrated and the resulting residue was purified by silica gel chromatography with 0-100% EtOAc:EtOH (3: 1) as eluent. The isolated intermediate was taken up in formic acid (3 mL) and the mixture was stirred at room temperature for 4 hours. The solvents were evaporated. To the mixture was added 1 M NaOH (100 mL). The mixture was extracted with DCM (100 mL x2). The organic layer was dried over sodium sulfate, filtered, and the solvents of the filtrate were evaporated, yielding ((2S, 5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-l-yl)((R)-pyrrolidin-3-yl)methanone (589 mg, 1.020 mmol) as a solid. LCMS (C30H36PN7O4) (ES, m/z): 578 [M+H] ' .
[0173] Water (604 μL) was added to a 20 mL scintillation vial containing 2-(6-bromopyridin- 3-yl)propan-2-amine (130 mg, 0.604 mmol) and a stir bar. After stirring vigorously for 1 minute, BOC-Anhydride (154 μL, 0.665 mmol) was added, and the reaction vial was placed on a pre- heated block to vigorously stir at 50 °C. for 16 hours. After cooling, the reaction was concentrated under reduced pressure and purified by silica gel chromatography (4g Gold Column) with 0-50% 3: 1 EtOAc/EtOH: Hexanes as eluent to afford the tert-butyl (2-(6- bromopyridin-3-yl)propan-2-yl)carbamate (159 mg, 0.504 mmol) as a solid. LCMS (C13H19BrN2O2) (ES, m/z): 315 [M+H]+.
[0174] A 20 mL scintillation vial containing tert-butyl (2-(6-bromopyridin-3-yl)propan-2- yl)carbamate (159 mg, 0.504 mmol) (Intermediate 27) and a stir bar was sequentially charged with 1,1'-bis(diphenylphosphino)ferrocene (55.9 mg, 0.101 mmol) and 1.1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (41.2 mg, 0.05 mmol). The solids were suspended in DMF (2522 μL), MeOH (2522 μL), and triethylamine (703 μL, 5.04 mmol). The reaction was placed in a carbonlyation reactor. The reaction was sequentially purged and backfdled with N2 and CO, at which point it was heated to 80 °C with stirring at 90 psi for 16 hours. LCMS analysis indicated the full conversion of starting material to the desired product. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (4g Gold Column) with 0-50% 3: 1 EtOAc/EtOH: Hexanes as eluent to afford methyl 5-(2-((tert-butoxycarbonyl)amino)propan-2-yl)picolinate (141 mg, 0.479 mmol) as a solid. LCMS (C15H22N2O4) (ES. m/z): 295 [M+H]+.
[0175] THF (3.593 mL) and water (1.198 mL) were added to a 20 mL scintillation vial containing methyl 5-(2-((tert-butoxycarbonyl)amino)propan-2-yl)picolinate (141 mg, 0.479 mmol) (Intermediate 28). After stirring vigorously for 1 minute, lithium hydroxide (22.94 mg, 0.958 mmol) was added, and the reaction continued to stir at room temperature. LCMS analysis indicated the starting material was consumed after 1 hour. The reaction mixture was quenched with hydrochloric acid (1.916 mL, 1.916 mmol) and poured into a separatory funnel containing 10 mL of 3: 1 CHCl3/IPA and water. The layers were separated, and the aqueous layer was extracted with 3: 1 CHCl3/IPA (10 mL x4). The combined organic layers were dried with MgSO4 , filtered, and concentrated under reduced pressure to afford 5-(2-((tert- butoxycarbonyl)amino)propan-2-yl)picolinic acid, which w as used without further purification. LCMS (C14H20N2O4) (ES, m/z): 281 [M+H]+.
[0176] The intermediates in the following Table 3were synthesized in a manner similar to the [0177]
synthesis of Intermediate 29 from the appropriate intermediates and starting materials. TABLE 3 Structure Observed Intermediate m/z [M +
Intermediate 32: 5-((2S,5R)-5-(5-((2,4-dmet oxybenzy )am no)-7,9- difluoro[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidine-1-carbonyl)picolinonitrile
manner described for Intermediate 26. LCMS (C31H28F2N8O3) (ES, m/z): 599 [M+H]+. Intermediate 33: 4-((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro- [1,2,4]triazolo[1,5c]quinazolin-2-yl)-2-methylpiperidine-1-carbonyl)benzaldehyde
manner escr e or nterme ate 6. C S (C32 0 2N6O4) ( S, mz): 60 [ + ] . Intermediate 34: 4-((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro- [1,2,4]triazolo[1,5c]quinazolin-2-yl)-2-methylpiperidine-1-carbonyl)benzaldehyde
dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidine- 1-carbonyl)benzaldehyde (601 mg, 1.001 mmol) (Intermediate 33) and a stir bar. After stirring for 1 minute, titanium(IV) ethoxide (1.05 mL, 5.00 mmol) was added. After stirring for another minute, (S)-(-)-2-methyl-2-propanesulfinamide (146 mg, 1.201 mmol) was added. The reaction continued to stir vigorously at room temperature for 16 hours. LCMS analysis indicated the starting material was consumed.10 mL of saturated aqueous NaHCO3 were added to the reaction to crash out the titanium salts. After stirring vigorously for 10 minutes, the reaction mixture was filtered through celite and rinsed with 10 mL of EtOAc and 10 mL of water. The filtrate was poured into a separatory funnel. The layers were separated, and the aqueous layer was extracted with EtOAc (25 mL x2). The combined organic layers were dried with Mg2SO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel chromatography (12g Gold Column) with 0-50% 3:1 EtOAc/EtOH:Hexanes as eluent to afford 4-((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5c]quinazolin-2- yl)-2-methylpiperidine-1-carbonyl)benzaldehyde (476 mg, 0.676 mmol). LCMS (C36H39F2N7O4S) (ES, m/z): 704 [M+H]+. Intermediate 35: (S)-N-((R)-1-(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)-2,2,2- trifluoroethyl)-2-methylpropane-2-sulfinamide
[0181] A 20 mL scintillation vial containing a stir bar was sequentially charged with (S)-N- ((E)-4-((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-2-methylpiperidine-l-carbonyl)benzylidene)-2-methylpropane-2-sulfinamide (108 mg, 0. 153 mmol) (Intermediate 34) and tetrabutylammonium difluorotriphenylsilicate (166 mg, 0.307 mmol). The reaction was cooled to -40 °C, and after stirring for 5 minutes, trifluoromethyl)trimethylsilane (34.0 μl, 0.230 mmol) was added neat and dropwise over 1 minute. The reaction mixture continued to vigorously stir in its ice bath. LCMS analysis indicated incomplete conversion, so additional (trifluoromethyl)trimethylsilane (34.0 μl, 0.230 mmol) was added. The reaction turned blood orange almost immediately, so it was quenched with 5 mL of saturated aqueous NH4Cl. After warming to room temperature, the reaction mixture was poured into a separatory funnel containing 10 mL of EtOAc and brine. The layers were separated, and the aqueous layer was extracted with EtOAc (10 mL). The combined organic layers were dried with Mg2SO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel chromatography (12g Gold Column) with 0-100% EtOAc:Hexanes as eluent to afford (5)-N-((R)-l-(4-((2S,5R)-5-(5-((2,4- dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[L5-c]quinazolin-2-yl)-2-methylpiperidine- l-carbonyl)phenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfmamide (54.3 mg, 0.07 mmol) as an oil. LCMS (C37H40F5N7O4S) (ES, m/z): 774 [M+H]+.
[0182] Intermediate 36 was synthesized in a manner described for Intermediate 29. LCMS (C9H10BrNO3) (ES, m/z): 261 [M+H]+.
[0183] To a solution of 5-bromo-2-chloropyridine (6 g, 31.2 mmol) in THF (60 mL) was added dropwise a solution of diisopropylmagnesium; LiCl adduct in THF (28.8 mL, 37.4 mmol) at -10 °C. The resulting mixture was stirred for 1 hour at -10 °C. Then cyclobutanone (2.40 g, 34.3 mmol) was added dropwise. The mixture was then warmed and stirred at 0 °C for 2 hours. The reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with EtOAC (50 mL x4). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dry ness.
[0184] The residue was dissolved in 50% hexane/ ethylacetate, filtered through a short pad of silica gel, washed with (50% hexane/ethylacetate) and concentrated to dryness to afford product as an oil, which was used in the next step without further purification. LCMS (C7H10CINO) (ES, m/z): 184 [M+H]+.
[0185] In a dried reaction flask, ethyl 2-amino-2-thioxoacetate (5 g, 37.5 mmol) was dissolved in degassed EtOH (60 mL). The solution was stirred at room temperature for 10 minutes, tert- Butyl carbazate (4.96 g, 37.5 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. LCMS analysis showed the reaction w as complete. The mixture was filtered and the filter cake was collected to afford the desired product tert-butyl (Z)-2-(l-amino- 2-ethoxy-2-oxoethylidene)hydrazine-l-carboxylate (6 g, 20.76 mmol) as a solid. This was used for the next step without further purification. LCMS (C9H17N3O4) (ES, m/z): 232 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 9.25 (hr s, 1H), 6.24 (s, 2H), 4.14-4.24 (m, 2H), 1.43 (s, 9H), 1.24 (t, J = 7.2 Hz, 3H).
Intermediate 39: ethyl 6-oxo- 1,6-dihydro- 1,2.4-triazine-3-carboxylate
[0186] A mixture of tert-butyl (Z)-2-(1-amino-2-ethoxy-2-oxoethylidene)hydrazine-l- carboxylate (2 g, 8.65 mmol) (Intermediate 38) and ethyl 2-oxoacetate (3.60 mL, 18.16 mmol) in toluene (20 mL) was stirred at 70 °C for 4 hours to give a white mixture. The reaction mixture was concentrated, formic acid (20 mL) added, and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated, and the residue was taken up in EtOH (20 mL) and refluxed for another 5 hours. LCMS analysis showed that the reaction was complete, and the desired product was formed. The reaction mixture was purified by silica gel chromatography (ISCO®; 40 g SepaFlash® C18 Flash Column) eluting with 100% H2O gradient @ 30 mL/min) to afford ethyl 6-oxo-1,6-dihydro-1,2,4-triazine-3-carboxylate (1g. 5.91 mmol) as a solid. LCMS (C6H7N3O3) (ES, m/z): 170 [M+H]+. 'H NMR (400MHz, DMSO- d6) 5 = 14.51 (s, 1H), 7.94 (hr s, 1H), 4.38 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H) Intermediate 40: methyl 6-(prop-l-en-2-yl)pyridazine-4-carboxylate
[0187] To a stirred solution of methyl 6-chloropyridazine-4-carboxylate (350 mg, 2.028 mmol) in 1,4-dioxane (2 mL) was added K2CO3 (841 mg, 6.08 mmol), PdC12(dppf)2 (148 mg, 0.203 mmol) and 4,4,5,5-tetramethyl-2-(prop-l-en-2-yl)-1,3,2-dioxaborolane (511 mg, 3.04 mmol) at room temperature under N2. The reaction was stirred at 80 °C for 16 hours. LCMS analysis indicated the reaction was complete. This reaction was poured into water (10 mL) and extracted with EtOAc (10 mL x3). The combined organic layers were dried over Na2SO4. filtered and the filtrate was concentrated in vacuo. The mixture was purified by silica gel chromatography (ISCO; 4 g SepaFlash Silica Flash Column) eluting with 0-30% EtOAc/PE to afford methyl 6- (prop-l-en-2-yl)pyridazine-4-carboxylate (300 mg, 1.662 mmol) as a solid. LCMS (C9H10N2O2) (ES, m/z): 179 [M+H]+.
[0188] A mixture of methyl 6-(prop-l-en-2-yl)pyridazine-4-carboxylate (100 mg, 0.561 mmol)
(Intermediate 40), potassium osmate(VI) dihydrate (20.68 mg, 0.056 mmol) and sodium periodate (360 mg, 1.684 mmol) in THF (3 mL) and water (0.6 mL) was stirred at room temperature for 16 hours to give a white mixture. LCMS analysis showed that the reaction was complete, and the desired product was formed. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude was purified by silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column) eluting with 50% EtOAc/PE to afford methyl 6-acetylpyridazine-4-carboxylate (80 mg, 0.444 mmol) as an oil. LCMS (C8H8 N2O3) (ES, m/z); 181 [M+H]+.
[0189] A mixture of methyl 6-acetylpyridazine-4-carboxylate (150 mg, 0.833 mmol) (Intermediate 41) and LiOH (39.9 mg, 1.665 mmol) in MeOH (5 mL) and water (1 mL) was stirred at room temperature for 1 hour to give a red mixture. LCMS analysis showed that the reaction was complete, and the desired product was formed. The solvent was removed to give crude 6-acetylpyridazine-4-carboxylic acid (138 mg, 0.831 mmol), which was used in the next step directly without further purification. LCMS (C7H6N2O3) (ES, m/z): 167 [M+H]+.
Intermediate 43: 1-(5-((2S.5R)-5-(5-((2.4-dimethoxvbenzyl)amino)-7.9-difluoro-
[0190] A mixture of N -(2,4-dimethoxybenzyl)-7,9-difluoro-2-((3R , 6S)-6-methylpiperidin-3- yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (200 mg. 0.427 mmol) (Intermediate 15), 6- acetylpyridazine-4-carboxylic acid (138 mg, 0.831 mmol) (Intermediate 42) and HATU (325 mg, 0.854 mmol) in DMF (10 mL) was stirred at room temperature for 16 hours to give a brown mixture. LCMS analysis showed that the reaction was complete, and the desired product was formed. The solvent was removed, and the mixture was dissolved in EtOAc (20 mL) and water
(20 mL). The organic layer was re-extracted with water (20 mL x3), washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column) eluting with 100% EtOAc to afford 1-(5-((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)pyridazin-3-yl)ethan-1-one (140 mg, 0.168 mmol, 39.4) as oil. LCMS (C31H30F2N8O4) (ES, m/z): 617 [M+H]+. Intermediate 44: (E)-3-(5-bromo-2-chloropyridin-4-yl)-N-methoxy-N-methylacrylamide [01 as
added diethyl(2-(methoxy(methyl)amino)-2-oxoethyl)phosphonate (2.47 g, 10.34 mmol) at room temperature. The mixture was stirred at 0 °C for 30 minutes. Then to the mixture was added 5- bromo-2-chloroisonicotinaldehyde (1.9 g, 8.62 mmol) and the resulting solution was stirred at room temperature for an additional 30 minutes. LCMS analysis indicated the reaction was complete. The reaction mixture was quenched with NH4Cl (20 mL), extracted with EtOAc (30 mL x2). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo. The mixture was purified by silica gel chromatography (ISCO; 12 g SepaFlash Silica Flash Column) eluting with 0-35% EtOAc/PE to afford (E)-3-(5-bromo-2- chloropyridin-4-yl)-N-methoxy-N-methylacrylamide (2 g, 6.51 mmol) as a solid. LCMS (C10H10BrClN2O2) (ES, m/z): 306 [M+H]+. Intermediate 45: 3-(5-bromo-2-chloropyridin-4-yl-) N-methoxy-N-methylpropanamide [0192]
ylacrylamide (2 g, 6.55 mmol) (Intermediate 44) in EtOAc (30 mL) was added rhodium (1.35 g, 0.655 mmol) and the resulting reaction mixture heated at 40 °C for 12 hours under an H2 atmosphere at 15 psi. LCMS analysis confirmed product formation. The mixture was filtered and evaporated under reduced pressure to give 3-(5-bromo-2-chloropyridin-4-yl)-N-methoxy-N-methylpropanamide (1.8 g, 5.85 mmol) as a solid. The crude product was used directly in next step without further
purification. LCMS (C10H12BrClN202) (ES, m/z): 308 [M+HJ+.
[0193] To a solution of 3-(5-bromo-2-chloropyridin-4-yl)-N-methoxy-N-methylpropanamide (1.8 g, 5.85 mmol) in THF (20 mL) was added n-butyllithium (2.81 mL, 7.02 mmol) at -60 °C. The resulting reaction mixture was stirred for 1 hour under an N2 atmosphere. Consumption of starting material was confirmed by monitoring by TEC. The reaction mixture was quenched with NHiCI (20 mL) and extracted with EtOAc (30 mL x3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ISCO; 12 g SepaFlash Silica Flash Column) eluting with 0-30% EtOAc/PE to afford 3-chloro-5.6-dihydro-7H- cyclopenta[c]pyridin-7-one (350 mg, 1.88 mmol, 32.1) as a solid. LCMS (C8H6CINO) (ES, m/z): 168 [M+H]+. 'H NMR (500 MHz, CHLOROFORM-d) 5 8.78 (s, 1H), 7.49 (s, 1H), 3.16-3.20 (m, 2H), 2.74-2.78 (m, 2H).
[0194] To a stirred solution of 3-chloro-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one (300 mg, 1.79 mmol) (Intermediate 46) in THF (3 mL) was added methylmagnesium bromide (7.16 mL, 7.16 mmol) at -78 °C and the resulting reaction mixture stirred for 2 hours. The reaction was warmed to room temperature and stirred for an additional 16 hours. LCMS analysis showed the reaction was complete. The mixture was poured into a solution of NH4CI (15 mL) and extracted with EtOAc (15 mL x3). The combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column) eluting with of 0-50% EtOAc/ PE to afford 3-chloro-7-methyl- 6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (220 mg, 1.198 mmol) as an oil. LCMS (C9H10CINO) (ES, m/z): 184 [M+H]+. 1H NMR (CHLOROFORM-d) 5: 8.26 (s, 1H), 7.16 (s, 1H), 2.92-3.07 (m, 1H), 2.73-2.89 (m, 1H), 2.23 (t, J = 7.2 Hz, 2H), 1.60 (s, 3H).
Intermediate 48: 2-(6-chloropyridazin-3-yl)propan-2-ol
[0195] To a solution of Me-THF (2.1 mL) and toluene (2.1 mL) was added an etheral solution of 3M MeMgBr (4.47 mL, 13.40 mmol). The mixture was cooled in a crushed ice/NaCl bath to around -20 °C. A solution of t-BuOH (0.26 mL, 2.68 mmol) in toluene (2ml) was added in 10 minutes. The 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. The organic layer was extracted with ethyl acetate, washed with brine, dried and concentrated and purified by silica gel chromatography (12g Gold Column) eluting with 0-50% EtOAc/Hexanes to afford 2-(6-chloropyridazin-3-yl)propan-2-ol (263 mg, 1.524 mmol). LCMS (C7H9CIN2O) (ES, m/z); 173 [M+H]+.
[0196] Intermediate 49 was synthesized from Intermediate 48 in a manner described for to the synthesis of Intermediate 40. LCMS (C15H22N2O3) (ES, m/z); 197 [M+H]+.
[0197] Intermediate 50 was synthesized in a manner described for Intermediate 29. LCMS (C8H10N2O3) (ES, m/z): 183 [M+H]+.
The intermediates in the following Table 4 were synthesized in a manner similar to the synthesis of Intermediate 50 from the appropriate intermediates and starting materials.
TABLE 4
nerme ae : (-romo-,,-t a azo--y)(( , )--(-((,- metoxyenzy)amno)- 7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)methanone
2-carboxylic acid in a manner described for Intermediate 26. LCMS (C27H25BrF2N8O3S) (ES, m/z): 660 [M+H]+. Intermediate 68: 5-morpholino-1,3,4-oxadiazole-2-carboxylic acid [019 (250 mg,
1.131 mmol) and THF (2 mL) was added DIPEA (0.24 mL, 1.36 mmol), followed by morpholine (0.1 mL, 1.13 mmol). The resulting reaction mixture was stirred for 10 minutes. Analysis by LCMS showed full conversion to the desired product. To the mixture was added
water (0.5 mL), followed by lithium hydroxide hydrate (119 mg, 2.83 mmol). The mixture was stirred at room temperature for 16 hours. Analysis by LCMS showed hydrolysis was complete. The mixture was adjusted to pH 2 with 1 M aqueous HC1. The solvents were evaporated. The residue was taken up in MeOH (5 mL) and filtered through Celite, washing with MeOH. The filtrate was evaporated to afford 5-morpholino-l,3,4-oxadiazole-2-carboxylic acid (125 mg, 0.628 mmol) as a solid. LCMS (C7H9N3O4) (ES, m/z): 200 [M+H]+.
[0200] The intermediates in the following Table 5 were synthesized in a manner similar to the synthesis of Intermediate 68 from the appropriate intermediates and starting materials.
TABLE 5
Intermediate 72: ((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-2-methylpiperidin-1-yl)(2H-1,2,3-triazol-4-yl)methanone
. , 564 [M+H]+. Intermediate 73: ((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-2-methylpiperidin-1-yl)(6-fluoropyridin-3-yl)methanone
manner described for Intermediate 26. LCMS (C30H28F3N7O3) (ES, m/z): 592 [M+H] . Intermediate 74: ((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-2-methylpiperidin-1-yl)(6-fluoro-2-methylpyridin-3-yl)methanone
[0203] Intermediate 74 was synthesized from Intermediate 15 and 6-fluoro-2-methylnicotinic acid in a manner described for Intermediate 26. LCMS (C31H30F3N7O3) (ES, m/z): 606 [M+H]+. Intermediate 75: (5-chloropyrazin-2-yl)((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-7,9- difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)methanone
carboxylic acid in a manner described for Intermediate 26. LCMS (C29H27ClF2N8O3) (ES, m/z): 610 [M+H]+. Intermediate 76: (2-chlorothiazol-5-yl)((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-7,9- difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)methanone
carboxylic acid in a manner described for Intermediate 26. LCMS (C28H26ClF2N7O3S) (ES, m/z): 615 [M+H]+. Intermediate 77: 4-((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidine-1-carbonyl)oxazole-2-carbonitrile
methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (100 mg, 0.208 mmol) (Intermediate 10), DIPEA (0.145 mL, 0.832 mmol), and DCM (2 mL). To the mixture was added 2-cyanooxazole-5-carbonyl chloride (55.4 mg, 0.354 mmol) as a solution in DCM (1 mL).
After 30 minutes, analysis by LCMS showed full conversion to the product. The mixture was purified by silica gel chromatography with 0-100% EtOAc:EtOH (3:1) in hexanes as eluent to afford 4-((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-2-methylpiperidine-1-carbonyl)oxazole-2-carbonitrile (100.4 mg, 0.167 mmol) as a solid. LCMS (C30H29FN8O5) (ES, m/z): 601 [M+H]+. Intermediate 78: ((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-2-methylpiperidin-1-yl)(5-(hydroxymethyl)-4-methylpyridin-2-yl)methanone
methylpicolinic acid in a manner described for Intermediate 26. LCMS (C32H33F2N7O4) (ES, m/z): 618 [M+H]+. Intermediate 79: 6-((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)-4-methylnicotinaldehyde
[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)(5-(hydroxymethyl)-4- methylpyridin-2-yl)methanone (500 mg, 0.810 mmol) (Intermediate 78) was added Dess- Martin periodinane (687 mg, 1.619 mmol) and the contents were suspended in DCM (4048 µL). The reaction mixture was allowed to stir for 16 hours at room temperature. LCMS analysis indicated reaction completion, so the mixture was quenched by the addition of saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate. The biphasic mixture was allowed to stir for 1 hour. The aqueous layer was then extracted 3x with DCM and the combined organic layers were washed with brine, concentrated and carried forward without purification to afford 6- ((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)-4-methylnicotinaldehyde (498 mg, 0.809 mmol). LCMS (C32H31F2N7O4) (ES, m/z): 616 [M+H]+. Intermediate 80: ((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-2-methylpiperidin-1-yl)(5-(1-hydroxyethyl)-4-methylpyridin-2-yl)methanone
[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidine-1-carbonyl)-4-methylnicotinaldehyde (498 mg, 0.809 mmol) (Intermediate 79) was added THF (4045 µL) and the reaction mixture was cooled to 0 °C. At this point methylmagnesium bromide (809 µL, 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 product was collected as to afford ((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-7,9- difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)(5-(1-hydroxyethyl)-4- methylpyridin-2-yl)methanone (500 mg, 0.792 mmol). LCMS (C33H35F2N7O4) (ES, m/z): 632 [M+H]+. Intermediate 81: 6-((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)-4-methylnicotinaldehyde
Intermediate 79. LCMS (C33H33F2N7O4) (ES, m/z): 630 [M+H]+. Intermediate 82: 1-(6-((2S,5R)-5-(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)- 2-methylpiperidine-1-carbonyl)-4-methylpyridin-3-yl)ethan-1-one
o-
yl)ethan-1-one (450 mg, 0.715 mmol) (Intermediate 81) was added DCM (3573 µL) followed by TFA (3573 µL) and the reaction mixture was allowed to stir for 16 hours at room temperature. LCMS analysis indicated complete conversion to the desired product, so the mixture was quenched by the addition of saturated aqueous sodium bicarbonate and the aqueous layer was extracted 3x with EtOAc. The combined organic layers were concentrated and not purified further. The crude product, 1-(6-((2S,5R)-5-(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-2-methylpiperidine-1-carbonyl)-4-methylpyridin-3-yl)ethan-1-one (340 mg, 0.709 mmol), was isolated. LCMS (C24H23F2N7O2) (ES, m/z): 480 [M+H]+. Intermediate 83: methyl 2-((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)nicotinate
(methoxycarbonyl)picolinic acid in a manner described for Intermediate 26. LCMS (C32H31F2N7O5) (ES, m/z): 632 [M+H]+. Intermediate 84: methyl 2-((2S,5R)-5-(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)-2-methylpiperidine-1-carbonyl)nicotinate
[0 In
. 3 7 , . Intermediate 85: methyl 2-((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-7,9- difluoro[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-2-oxoacetate [ m
ethylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (1 g, 2.13 mmol) (Intermediate 10), triethylamine (0.387 mL, 2.77 mmol), and DCM (15 mL). Methyl 2-chloro-2-oxoacetate (0.23mL, 2.46 mmol) was added and the reaction mixture stirred at room temperature. After 5 minutes, analysis by LCMS showed full conversion. To the mixture was added water (15 mL). The aqueous layer was extracted with DCM (20 mL), and the combined organic layers were dried over sodium sulfate, filtered, and the solvents evaporated to afford methyl 2-((2S,5R)-5-(5- ((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl)-2-oxoacetate (1.184 g, 2.135 mmol). LCMS (C27H28F2N6O5) (ES, m/z): 555 [M+H]+. Intermediate 86: 2-((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-2-oxoacetohydrazide
[0215] To a 100 mL flask was added methyl 2-((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)- 7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-2-oxoacetate (1.184 g, 2.135 mmol) (Intermediate 85) and EtOH (10 mL). To the stirring mixture was added hydrazine hydrate (0.524 mL, 10.68 mmol) and the resulting reaction mixture heated at 80 °C for 2 minutes. Analysis by LCMS showed minor product formation. The mixture was stirred at room temperature for an additional 2 hours. Analysis by LCMS showed the reaction was complete. The mixture was concentrated and the resulting residue was triturated in diethyl ether to afford 2- ((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)- 2-methylpiperidin-1-yl)-2-oxoacetohydrazide (1.04 g, 1.875 mmol) as a solid. LCMS (C26H28F2N8O4) (ES, m/z): 555 [M+H]+. Intermediate 87: N'-(2-((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-2- oxoacetyl)cyclopropanecarbohydrazide
acid in a manner described for Intermediate 26. LCMS (C30H32F2N8O5) (ES, m/z): 623 [M+H]+. Intermediate 88: 6-(trifluoromethoxy)nicotinic acid [0217]
(trifluoromethyl)-1l3-benzo[d][1,2]iodaoxol-3(1H)-one (1032 mg, 1.306 mmol) in nitromethane (15 mL) was stirred at 100 °C for 5 hours. LCMS analysis showed the reaction was complete. The reaction mixture was then allowed to cool to room temperature, filtered through a pad of celite, and washed with ethyl acetate (10 ml x3). The combined organic solvent was removed under reduced pressure and the resulting residue taken up in THF (2 mL) and water (1 mL).
LiOH (32.5 mg, 1.357 mmol) was added, and the resulting reaction mixture stirred at room temperature for 2 hours. LCMS analysis showed the reaction was complete. The mixture was acidified by the addition of HCl (3 M) to pH=3 and extracted with EtOAc (10 mL x3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford crude 6-(trifluoromethoxy)nicotinic acid (100 mg, 0.483 mmol) as solid. LCMS (C7H4F3NO3) (ES, m/z): 208 [M+H]+. Intermediate 89: methyl 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)benzoate
y )-[ , , ]tr azo o[ ,5-c]qu nazo n-5-amne (300 mg, 0.6 mmo ) ( ntermed ate 5) n C (5 mL) was added 4-(methoxycarbonyl)benzoic acid (173 mg, 0.96 mmol), HATU (487 mg, 1.28 mmol) and Et3N (0.27 mL, 1.921 mmol). The reaction mixture was stirred at room temperature for 16 hours. LCMS analysis showed the starting material was consumed and desired product formation was observed. The residue was purified by silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column) eluting with of 0-50% EtOAc/ PE to afford methyl 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)benzoate (385 mg, 0.592 mmol) as a solid. LCMS (C33H32F2N6O5) (ES, m/z): 631 [M+H]+. Intermediate 90: methyl 5-(methylthio)picolinate [0219] To a s
l) in DMF (5 mL) was added sodium methanethiolate (200 mg, 2.85 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 2 hours. LCMS analysis showed the reaction was complete. The mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x3). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue
was purified by silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column) eluting with 28% EtOAc/PE to afford methyl 5-(methylthio)picolinate (470 mg, 2.052 mmol) as a solid. LCMS (C8H9NO2S) (ES, m/z): 184 [M+H]+.1H NMR (CHLOROFORM-d, 400MHz): δ 8.57 (d, J = 1.6 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.64 (dd, J = 8.4, 2.0 Hz, 1H), 4.00 (s, 3H), 2.56 (s, 3H). Intermediate 91: methyl 5-(S-methylsulfonimidoyl)picolinate [0220] l) (Interme
a e n e m was a e ace oxy o o enzene mg, .73 mmol) and ammonium carbamate (213 mg, 2.73 mmol). The resulting reaction mixture was stirred at room temperature for 3 hours. LCMS analysis showed the reaction was complete. The mixture was poured into water (10 mL) and extracted with DCM (10 mL x3). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column) eluting with 7% MeOH/DCM to afford methyl 5-(S-methylsulfonimidoyl)picolinate (160 mg, 0.568 mmol) as a solid. LCMS (C8H10N2O3S) (ES, m/z): 215 [M+H]+.1H NMR (CHLOROFORM-d, 400MHz): δ 9.30 (d, J = 1.6 Hz, 1H), 8.46 (dd, J = 8.0, 2.0 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 4.05 (s, 3H), 3.21 (s, 3H) Intermediate 92: potassium 5-(S-methylsulfonimidoyl)picolinate [0221] 0
mmol) (Intermediate 91) in THF (2 mL) was added potassium trimethylsilanolate (53.9 mg, 0.420 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. LCMS analysis showed the reaction was complete. The mixture was concentrated under reduced pressure to afford crude potassium 5-(S-methylsulfonimidoyl)picolinate (60 mg, 0.191 mmol) as a solid, which was used for next step without further purification. LCMS (C7H8N2O3S) (ES, m/z): 221 [M+H]+. Example 1: [(2S,5R)-5-(5-amino-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl][(1S,2R)-2-methylcyclopropyl]methanone
, , , , . (Intermediate 10), (1S,2R)-2-methylcyclopropane-1-carboxylic acid (10.00 mg, 0.100 mmol), 1-propanephosphonic anhydride (0.074 mL, 0.125 mmol), DIPEA (0.044 ml, 0.250 mmol), and DCM (1 mL). The mixture was sealed and stirred at room temperature for 2 hours. Analysis by LCMS showed the reaction was complete. To the mixture was added TFA (1 mL). The mixture was stirred and heated at 50 ºC for 2 hours. LCMS analysis indicated the reaction was complete. The solvents were evaporated, and the residue was purified by reverse phase HPLC (C18 column MeCN/H2O with 0.1% TFA as eluent), to afford ((2S,5R)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)((1S,2R)-2- methylcyclopropyl)methanone.2,2,2-trifluoroacetate (18.5 mg, 0.035 mmol) as a solid. LCMS (C21H25FN6O2) (ES, m/z): 413 [M+H]+.1H NMR (499 MHz, DMSO-d6) δ 7.90 (d, J = 11.0 Hz, 1H), 7.75 (bs, 2H), 7.19 (d, J = 7.9 Hz, 1H), 4.99 - 4.88 (m, 1H), 4.77 (d, J = 9.9 Hz, 1H), 4.73 – 4.64 (m, 1H), 4.41 – 4.37 (m, 1H), 3.98 (s, 3H), 3.58 – 3.49 (m, 1H), 2.97 – 2.91 (m, 2H), 2.12 – 2.03 (m, 2H), 1.94 – 1.85 (m, 1H), 1.78 – 1.74 (m, 1H), 1.70 – 1.66 (m, 1H), 1.30 – 1.16 (m, 5H), 0.98 (dd, J = 21.7, 6.2 Hz, 4H), 0.79 (dt, J = 18.6, 7.0 Hz, 3H). [0223] The example compounds of the invention in the following Table 6 were prepared in a manner similar to the synthesis of Example 1, from the appropriate starting piperidine and carboxylic acid intermediates. In some cases, an additional work-up step was incorporated where the residue was treated with 1 M KOH (3 mL) and DCM (3 mL). The organic layer was collected with a phase separator, and the solvents were evaporated. The residue was purified by silica gel chromatography with 0-100% EtOAc in hexanes as eluent. The residue was then further purified by reverse phase HPLC purification using the following methods: Method A – TFA Modifier [0224] C18 reverse-phase Prep-HPLC (gradient elution, MeCN/H2O/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 [0225] C18 reverse-phase Prep-HPLC (gradient elution, MeCN/H2O/basic modifier – 0.1% NH4OH). Electrospray (ESI) Mass-triggered fraction collection was employed using positive ion polarity scanning to monitor for the target mass. [0226] In cases where isomers are formed these were resolved using a CHIRAL-Prep SFC [Column: DAICEL CHIRALPAK AD-H, OJ-H or CC4; 250x21mm; gradient elution: 5-45% (0.1% ammonium hydroxide in methanol)/CO2; Flow rate: 70 mL/min; Column temp: 40 °C; 220 nm. TABLE 6 Structure Observe d m/z
Example 128: [(2S,5R)-5-(5-amino-7,9-difluoro[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl](cis-3-hydroxy-3-methylcyclobutyl)methanone
methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (2.69 g, 5.74 mmol) (Intermediate 15), (1S,3S)-3-hydroxy-3-methylcyclobutane-1-carboxylic acid (0.859 g, 6.60 mmol), DIPEA (2.01 ml, 11.48 mmol), and DCM (15 mL). To the mixture was added 1- propanephosphonic anhydride (5.12 mL, 8.61 mmol). The mixture was sealed and stirred at room temperature for 30 minutes. LCMS analysis showed conversion to product, but the reaction had stalled. To the mixture was added additional DIPEA (1 ml, 5.74 mmol) and 1- propanephosphonic anhydride (5.12 ml, 8.61 mmol). After 20 minutes, analysis by LCMS showed the reaction was complete. To the mixture was added water (50 mL) and the mixture was stirred for 10 minutes. The mixture was extracted with DCM (50 mL x2). The combined organic layers were dried over sodium sulfate, filtered, and the solvents were evaporated to afford ((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-2-methylpiperidin-1-yl)((1S,3R)-3-hydroxy-3-methylcyclobutyl)methanone (3.23 g, 5.56 mmol) as a solid. This was transferred to a 250 mL RBF and concentrated aqueous HCl (31.7 mL, 386 mmol) was added. The mixture was heated with stirring at 50 ºC. After 30 minutes, analysis by LCMS showed the reaction was complete. The mixture was diluted in water
(150 mL) and stirred for another 15 minutes. The mixture was filtered through Celite, cooled to 0 ºC, and basified to pH 12 by addition of 10 M aqueous KOH. To the mixture was added DCM (150 mL) and the mixture was stirred for 30 minutes. The layers were separated, and the aqueous layer was extracted with additional DCM (150 mL). The combined organic layers were dried over sodium sulfate, filtered, and to the mixture was added MeCN (30 mL). The DCM was evaporated resulting in the formation of a precipitate. These solids were collected by filtration. The solids were triturated in MeCN (20 mL) and collected by filtration. The combined filtrates were concentrated to the point where more solids precipitated, which were triturated in MeCN (10 mL) and collected by filtration again. The combined solids were stirred in MeCN for 16 hours. The solvents were evaporated to afford ((2S,5R)-5-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)((1S,3R)-3-hydroxy-3- methylcyclobutyl)methanone (1.62 g, 3.76 mmol) as a solid. LCMS (C21H24F2N6O2) (ES, m/z): 431 [M+H]+.1H NMR (499 MHz, DMSO-d6) δ 8.04 (s, 3H), 7.78 (d, J = 8.1 Hz, 2H), 7.72 – 7.63 (m, 2H), 4.98 – 4.89 (m, 2H), 4.88 – 4.79 (m, 1H), 4.76 (d, J = 7.3 Hz, 1H), 4.26 – 4.14 (m, 1H), 3.94 (d, J = 13.0 Hz, 1H), 3.38 (t, J = 12.3 Hz, 1H), 3.32 (d, J = 1.9 Hz, 1H), 3.07 – 2.96 (m, 1H), 2.96 – 2.80 (m, 4H), 2.23 (q, J = 13.9, 12.2 Hz, 3H), 2.17 – 1.98 (m, 7H), 1.83 – 1.58 (m, 4H), 1.30 (s, 3H), 1.25 (s, 5H), 1.15 (d, J = 5.2 Hz, 2H). [0228] The example compounds of the invention in the following Table 7 were prepared in a manner similar to the synthesis of Example 128, from the appropriate starting piperidine and carboxylic acid intermediates. TABLE 7 Structure Observe
118
(S or R)-3-[(2S,5R)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidine-1-
Example 150: [(2S,5R)-5-(5-amino-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl][1-(propan-2-yl)-1H-pyrazol-4-yl]methanone
0.208 mmol) was added COMU (62.4 mg, 0.146 mmol) and DMF (1040 µL) followed by DIPEA (54.5 µL, 0.312 mmol). The flask was capped, and the contents stirred at room temperature for 10 minutes. 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 (50 mg, 0.104 mmol)
(Intermediate 10) was added and the resulting reaction mixture stirred at room temperature overnight. The course of reaction was followed by LCMS analysis. Desired product formation was observed. The mixture was diluted with water and DCM. The layers were separated and the organic layer was washed several times with water. The organic layer was then concentrated and re-dissolved in TFA (802 µL, 10.40 mmol) and heated to 50 ºC for 1 hour. The reaction mixture was then quenched with saturated aqueous NaHCO3 and diluted with DCM. The layers were separated and the DCM layer was loaded directly onto a 24 g Isco Combiflash column, eluting from 0-10% MeOH in DCM to afford ((2S,5R)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)(1-isopropyl-1H-pyrazol-4- yl)methanone (18.8 mg, 0.040 mmol) as an oil. LCMS (C23H27FN8O2) (ES, m/z): 467 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.93 – 7.85 (m, 1H), 7.74 (br. s, 2H), 7.69 (s, 1H), 7.19 (d, J = 7.9 Hz, 1H), 4.76 (br. s, 2H), 4.62 – 4.46 (m, 2H), 3.97 (s, 3H), 3.03 (d, J = 45.9 Hz, 1H), 2.21 – 2.03 (m, 2H), 1.93 – 1.78 (m, 1H), 1.71 (d, J = 12.6 Hz, 1H), 1.43 (d, J = 6.6 Hz, 6H), 1.28 (br. s, 3H). The example compounds of the invention in the following Table 8 were prepared in a manner similar to the synthesis of Example 150, from the appropriate starting piperidine and carboxylic acid intermediates. In some cases, 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/H2O/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/H2O/basic modifier – 0.1% NH4OH). Electrospray (ESI) Mass-triggered fraction collection was employed using positive ion polarity scanning to monitor for the target mass. TABLE 8 Structure Observe
125
25622 (R)-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)piperidin-1-yl)(2-cyclopropyl-1H-imidazol-5-
yl)piperidin-1-yl]-3-hydroxy-3-methylbutan-1-one
[ , , ]tr azo o[ ,5-c]qu nazo n-5-am ne ( 8.5 mg, .06 mmo ) ( ntermed ate 3), 3- y roxy-3- methylbutanoic acid (12.61 mg, 0.107 mmol), DMAP (0.745 mg, 6.10 µmol) and EDC (20.46 mg, 0.107 mmol) were added to a vial in DCM (1220 µL). Triethylamine (42.5 µL, 0.305 mmol) was added and the resulting reaction mixture stirred at room temperature for 2 hours. LCMS analysis indicated >70% conversion to the desired product. The reaction mixture was concentrated, then TFA (235 µL, 3.05 mmol) was added and the mixture stirred for an additional 2 hours at 60 ºC. The crude mixture was concentrated to a pink oil and the resulting residue diluted with DMA/MeOH and the solution was purified by reverse HPLC Reverse phase (C-18), eluting with acetonitrile/water + 0.1% TFA, to afford (R)-1-(3-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-3-hydroxy-3-methylbutan-1-one, TFA (24 mg, 0.045 mmol) as a solid. LCMS (C20H25FN6O3) (ES, m/z): 417 [M+H]+.1H NMR (499 MHz, DMSO-d6) δ 7.83 (s, 2H), 7.43 (ddd, J = 8.3, 5.7, 2.7 Hz, 1H), 7.19 (dd, J = 11.0, 2.6 Hz, 1H), 4.79 (d, J = 12.6 Hz, 1H), 4.19 (dd, J = 8.9, 4.3 Hz, 1H), 4.04 (d, J = 13.3 Hz, 1H), 3.94 (s, 3H), 3.22 - 3.09 (m, 1H), 3.06 - 2.82 (m, 2H), 2.54 (dd, J = 10.7, 3.9 Hz, 2H), 2.29 - 2.11 (m, 1H), 2.03 - 1.71 (m, 2H), 1.68 - 1.43 (m, 1H), 1.23 - 1.09 (m, 6H). [0233] The example compounds of the invention in the following Table 9 were prepared in a manner similar to the synthesis of Example 159, from the appropriate starting piperidine and carboxylic acid intermediates. TABLE 9 Example Structure
128
Observed IUPAC Name m/z [M + H]+ 99
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[1,5-c]quinazolin-5-amine (50 mg, 0.104 mmol) (Intermediate 10) and chloro- N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (43.8 mg, 0.156 mmol) at room temperature under an N2 atmosphere. The mixture was stirred at room temperature for 2 hours. LCMS analysis indicated full conversion to the desired product. The mixture was evaporated under reduced pressure, extracted with DCM (15 mL x2), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by preparative TLC (SiO2, 100% EtOAc) to afford tert-butyl (3-((2S,5R)-5-(5-((2,4- dimethoxybenzyl)amino)-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidine-1-carbonyl)cyclobutyl)carbamate as an oil. This was taken up in DCM (2 mL) and TFA (2 mL, 26.0 mmol) and stirred at room temperature for 16 hours. LCMS analysis indicated the reaction was complete. The mixture was evaporated under reduced pressure and the resulting crude was purified by HPLC Reverse phase (C-18), eluting with acetonitrile/water +
0.1% TFA, to afford the desired product as a solid. LCMS (C21H26FN7O2) (ES, m/z): 428 [M+H]+. The isomers were resolved by SFC (Column: Chiralpak AD-3150×4.6mm I.D., 3 μm Mobile, Condition: 40% of iso-propanol (0.05% DEA) in CO2, Mobile phase: A: CO2 B: IPA (0.1% NH3H2O), Gradient: from 5% to 40% of B in 5.5 min and hold 40% for 3 min, then 5% of B for 1.5 min, Flow rate: 25 mL/min, Column temp: 35 °C.) to give Example 161 ((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 (4.92 mg, 0.011 mmol) (tR= 0.561 min, UV = 220 nm), 1H NMR (500MHz, METHANOL-d4) δ = 7.79 (d, J=10.8 Hz, 1H), 7.09 (dd, J=2.6, 7.6 Hz, 1H), 4.25 - 3.95 (m, 1H), 3.90 (d, J=1.7 Hz, 3H), 3.42 - 3.26 (m, 1H), 3.06 - 2.89 (m, 2H), 2.51 - 2.37 (m, 2H), 2.10 - 1.90 (m, 4H), 1.80 - 1.66 (m, 2H), 1.27 (d, J=6.9 Hz, 1H), 1.21 - 1.14 (m, 3H) and Example 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 (5.88 mg, 0.013 mmol) (tR= 0.559 min, UV = 220 nm), 1H NMR (500MHz, METHANOL-d4) δ = 7.74 (br s, 1H), 7.04 (br s, 1H), 4.90 - 4.81 (m, 1H), 4.07 (br d, J=5.2 Hz, 1H), 3.91 - 3.86 (m, 3H), 3.48 - 3.37 (m, 1H), 3.37 - 3.28 (m, 1H), 3.11 - 2.80 (m, 2H), 2.52 (td, J=3.6, 7.5 Hz, 1H), 2.47 - 2.35 (m, 1H), 2.11 - 1.91 (m, 4H), 1.81 - 1.65 (m, 2H), 1.27 - 1.17 (m, 3H). The example compounds of the invention in the following Table 10 were prepared in a manner similar to the synthesis of Examples 161 and 162, from the appropriate starting piperidine and carboxylic acid intermediates. TABLE 10 Structure Observed +
[(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-
xampe an : (( , )--(-amno-- uoro--metoxy-[,,]trazoo[,- c]quinazolin-2-yl)-2-methylpiperidin-1-yl)(3-aminocyclobutyl)methanone
dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidine-1-carbonyl)cyclobutanecarbonitrile (65 mg, 0.111 mmol) in DCM (2 mL) and water (1 mL) at 0 °C under an N2 atmosphere and the mixture was stirred at 0 °C for an additional hour. LCMS analysis showed that the desired product had formed. The reaction
mixture was quenched with Na2CO3 (1 mL) and extracted with DCM (10 mL x3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude product was purified by HPLC Reverse phase (C-18), eluting with acetonitrile/water + 0.1% TFA, to afford 3-((2S,5R)-5-(5-amino-9- fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidine-1- carbonyl)cyclobutanecarbonitrile (40 mg, 0.088 mmol) as a solid. The isomers were resolved by SFC (Column: DAICEL CHIRALPAK AD 250mmx30mm,10 ^m) using water (0.1%NH3OH) and EtOH as eluents (Mobile phase A water (0.1%NH3OH), detective wavelength: 220 nm.) followed by concentration (below 50 ºC) to give two crude products which were purified by HPLC Reverse phase (C-18), eluting with acetonitrile/water + 0.1% TFA, to afford 3-((2R,5S)-5- (5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidine-1- carbonyl)cyclobutanecarbonitrile (9.61 mg, 0.022 mmol) (Rt = 3.148 min) (Example 170) and 3-((2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidine-1-carbonyl)cyclobutanecarbonitrile (19.52 mg, 0.045 mmol) (Rt = 3.427 min) (Example 171) as solids. 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 µL), 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 µL, 0.300 mmol), and 1- propanephosphonic anhydride (119 µL, 0.200 mmol) were sequentially added. The 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 µl, 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 Mg2SO4, filtered, and concentrated under reduced
pressure. The crude reaction mixture was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water + 0.1% TFA, to afford ((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 (20.9 mg, 0.043 mmol) as a solid. LCMS (C23H24F2N8O2) (ES, m/z): 483 [M+H]+.1H NMR (600 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.78 (s, 1H), 8.18 – 7.89 (m, 3H), 7.82 (d, J = 7.1 Hz, 1H), 7.74 – 7.58 (m, 2H), 5.55 (d, J = 19.7 Hz, 2H), 4.99 (s, 1H), 4.90 (d, J = 12.3 Hz, 1H), 4.12 – 4.00 (m, 1H), 3.93 (d, J = 10.4 Hz, 1H), 3.58 (t, J = 12.8 Hz, 1H), 3.27 – 3.09 (m, 3H), 2.10 (td, J = 27.8, 25.2, 13.7 Hz, 3H), 1.99 – 1.85 (m, 2H), 1.81 (d, J = 12.8 Hz, 1H), 1.67 (d, J = 12.9 Hz, 1H), 1.51 (s, 4H), 1.47 (s, 3H), 1.33 (t, J = 7.9 Hz, 4H). The 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 Structure 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). To the mixture was added HATU (63.3 mg, 0.166 mmol). The mixture was sealed and stirred at room temperature for 2 hours. To the mixture was added TFA (0.5 ml). The mixture was heated with stirring at 50 ºC for 2 hours. The solvents were evaporated and the residue was purified by reverse phase HPLC (acetonitrile/water + 0.1% NH4OH) to afford (S)-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 (10.4 mg, 0.026 mmol) as a solid. LCMS (C19H23FN6O3) (ES, m/z): 403 [M+H]+.1H NMR (499 MHz, DMSO-d6) δ 7.90 (d, J = 10.5 Hz, 2H), 7.74 (s, 3H), 7.19 (d, J = 5.6 Hz, 2H), 4.98 (d, J = 39.6 Hz, 3H), 4.85 – 4.76 (m, 1H), 4.73 (d, J = 11.3 Hz, 1H), 4.56 – 4.38 (m, 3H), 4.21 (d, J = 13.3 Hz, 2H), 4.02 – 3.93 (m, 4H), 3.48 – 3.38 (m, 2H), 3.14 – 3.00 (m, 2H), 3.00 – 2.85 (m, 3H), 2.19 – 1.97 (m, 4H), 1.93 – 1.63 (m, 5H), 1.30 (d, J = 4.9 Hz, 2H), 1.23 (d, J = 4.3 Hz, 3H), 1.18 (d, J = 5.0 Hz, 2H). The 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. For examples 265-268, DDQ was used to hydrolyze the DMB-protecting group. TABLE 12 Structure Observed +
[0238] The example compounds of the invention in the following Table 13 were prepared in a manner similar to the synthesis of Example 235, from the appropriate starting piperidine and carboxylic acid intermediates. No final deprotection step was necessary since the DMB group had previously been removed in a similar manner to Intermediate 20. The final compounds were purified by reverse phase HPLC purification.
TABLE 13
[(2S,5R)-5-(5-amino-7,9-difluoro[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-2-methylpiperidin-1-yl](pyridin-3-
Example 282: [(2S,5R)-5-(5-am no-9- uoro-8-met oxy[1,2,4]trazoo[1,5-c]qu nazo n-2-y )-2- methylpiperidin-1-yl][(3R)-1-(propan-2-yl)pyrrolidin-3-yl]methanone
methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)((R)-pyrrolidin-3- yl)methanone (30 mg, 0.052 mmol) (Intermediate 26), sodium triacetoxyborohydride (13.21 mg, 0.062 mmol), DCE (0.5 mL), acetic acid (2.97 µL, 0.052 mmol), followed by acetone (0.011 mL, 0.156 mmol). The reaction mixture was stirred at room temperature for 30 minutes. To the
mixture was added TFA (0.5 ml). The mixture was heated at 50 ºC for 2 hours. The solvents were evaporated and the residue was purified by HPLC Reverse phase (C-18), eluting with acetonitrile/water + 0.1% TFA, to afford ((2S,5R)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)((R)-1-isopropylpyrrolidin-3- yl)methanone 2,2,2-trifluoroacetate (2.8 mg, 4.80 µmol) as a solid. LCMS (C24H32FN7O2) (ES, m/z): 470 [M+H]+. [0240] The example compounds of the invention in the following Table 14 were prepared in a manner similar to the synthesis of Example 282, from the appropriate starting piperidine and carboxylic acid intermediates. TABLE 14 Structure Observed Example m/z [M +
Example 287: [(2S,5R)-5-(5-am no-9- uoro-8-met oxy[1,2,4]trazoo[1,5-c]qu nazo n-2-y )-2- methylpiperidin-1-yl][(3R)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]methanone
methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)((R)-pyrrolidin-3- yl)methanone (40 mg, 0.069 mmol) (Intermediate 26), cesium carbonate (45.1 mg, 0.138 mmol), and DMA (0.5 mL). To the mixture was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.015 mL, 0.104 mmol). The mixture was stirred and heated at 90 ºC for 16 hours. Analysis by LCMS showed the reaction was complete. The mixture was diluted in diethyl ether (30 mL) and washed with water (30 mL x2). The organic layer was dried over magnesium sulfate, filtered, and the solvents were evaporated. The residue was purified by
HPLC Reverse phase (C-18), eluting with acetonitrile/water + 0.1% TFA, to afford ((2S,5R)-5- (5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)((R)- 1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)methanone 2,2,2-trifluoroacetate (18 mg, 0.029 mmol) as a solid. LCMS (C23H27F4N7O2) (ES, m/z): 510 [M+H]+. [0242] The 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. TABLE 15 Structure Observed Example m/z [M +
Example 297: [(2S,5R)-5-(5-amino-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl][(3R)-1-(2-hydroxy-2-methylpropyl)pyrrolidin-3-yl]methanone
met oxy-[ , , ]tr azoo[ , -c]qu nazo n- -y)- -met yp per n- -y )(( )-pyrro n- - yl)methanone (40 mg, 0.069 mmol) (Intermediate 26), THF (0.5 mL), DIPEA (0.015 mL, 0.083 mmol) and ethyl 2-bromoacetate (7.67 µL, 0.069 mmol). The vial was sealed, and the contents heated at 80 ºC for 30 minutes. The mixture was cooled to room temperature. To the mixture was added methyl magnesium bromide (0.231 mL, 0.692 mmol), dropwise over 5 minutes. The mixture was stirred for an additional 30 minutes. Analysis by LCMS showed conversion to the tertiary alcohol. The mixture was quenched with saturated aqueous NH4Cl. The mixture was diluted in water (30 mL) and extracted with DCM (30 mL x2). The organic layer was dried over sodium sulfate, filtered and the solvents were evaporated. To the residue was added TFA (0.5 mL). The mixture was stirred and heated at 50 ºC for 2 hours. The solvents were evaporated, and the residue was treated with 1 M KOH (3 mL) and then DCM (3 mL). The organic layer was collected with a phase separator. The solvents were evaporated and the residue was purified by HPLC Reverse phase (C-18), eluting with acetonitrile/water + 0.1% TFA, to afford ((2S,5R)-5- (5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)((R)- 1-(2-hydroxy-2-methylpropyl)pyrrolidin-3-yl)methanone 2,2,2-trifluoroacetate (14.2 mg, 0.023 mmol) as a solid. LCMS (C25H34FN7O3) (ES, m/z): 500 [M+H]+. [0244] The 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. TABLE 16 Structure Observed +
Example 299 and 300: [(2S,5R)5(5amino9fluoro8methoxy[1,2,4]triazolo[1,5 c]quinazolin-2-yl)-2-methylpiperidin-1-yl][3-(2-hydroxypropan-2-yl)cyclobutyl]methanone
uoro-8-metoxy--((3 ,6S)-6-metypper n-3-y)-[,,]trazoo[,5-c]qunazo n-5-amne hydrochloride (905 mg, 1.750 mmol) (Intermediate 10). The solids were dissolved in DCM (17.5 mL) and DIPEA (1.22 mL, 7.00 mmol), at which point 3-(2-hydroxypropan-2- yl)cyclobutane-1-carboxylic acid (332 mg, 2.101 mmol) and 1-propanephosphonic anhydride (1114 mg, 3.50 mmol) were sequentially added. The reaction mixture was stirred vigorously at room temperature. The reaction proceeded slowly and appeared to stall after stirring for 3 hours, so more DIPEA (1.22 mL, 7.00 mmol), 3-(2-hydroxypropan-2-yl)cyclobutane-1-carboxylic acid (332 mg, 2.101 mmol), and 1-propanephosphonic anhydride (1114 mg, 3.50 mmol) were sequentially added. The starting material was mostly consumed after about an additional hour of stirring. The reaction was quenched with 25 mL of water and stirred vigorously for 16 hours.
The reaction mixture was poured into a separatory funnel and the aqueous layer was extracted with DCM (25 mL x2). The combined organic layers were dried with Mg2SO4, filtered, and concentrated under reduced pressure. 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 µL) and water (779 µL), 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 NaHCO3. The layers were separated, and the aqueous layer was extracted with DCM (25 mL). The combined organic layers were dried with Mg2SO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel chromatography (12g Gold Column) eluting with 0-100% 3:1 EtOAc/EtOH:Hexanes [w/ 1% Et3N]) to afford 559 mg of an oil. This was then submitted to SFC for achiral separation [Column: biphenyl; 250x21mm; gradient elution: 15% (0.1% ammonium hydroxide in acetonitrile/methanol – 1:1)/CO2.] to afford the faster eluting peak 1: LCMS (C24H31FN6O3) (ES, m/z): 471 [M+H]+; 1H NMR (499 MHz, DMSO-d6) δ 7.94 – 7.85 (m, 1H), 7.72 (d, J = 11.8 Hz, 2H), 7.19 (d, J = 7.7 Hz, 1H), 4.91 – 4.81 (m, 1H), 4.77 (d, J = 8.7 Hz, 1H), 4.17 (d, J = 19.3 Hz, 1H), 4.08 – 4.01 (m, 1H), 3.98 (s, 3H), 3.77 (d, J = 12.6 Hz, 1H), 3.40 – 3.34 (m, 1H), 3.14 – 2.95 (m, 2H), 2.90 (d, J = 7.0 Hz, 1H), 2.25 – 1.96 (m, 8H), 1.70 (q, J = 16.6, 13.6 Hz, 3H), 1.25 (d, J = 5.9 Hz, 2H), 1.15 (d, J = 6.8 Hz, 2H), 1.03 (s, 3H), 0.98 (s, 3H) (Example 299) and a slower eluting peak 2: LCMS (C24H31FN6O3) (ES, m/z): 471 [M+H]+; 1H NMR (499 MHz, DMSO-d6) δ 7.89 (d, J = 10.9 Hz, 1H), 7.72 (d, J = 12.8 Hz, 2H), 7.19 (d, J = 7.7 Hz, 1H), 4.87 – 4.75 (m, 1H), 4.72 (d, J = 8.5 Hz, 1H), 4.24 – 4.13 (m, 1H), 4.05 (d, J = 7.5 Hz, 1H), 3.97 (s, 3H), 3.96 – 3.90 (m, 1H), 3.40 – 3.34 (m, 1H), 3.11 – 2.91 (m, 2H), 2.87 (d, J = 7.5 Hz, 1H), 2.19 – 1.84 (m, 8H), 1.73 – 1.61 (m, 2H), 1.25 (d, J = 6.5 Hz, 2H), 1.14 (d, J = 6.8 Hz, 2H), 0.98 (s, 3H), 0.96 (s, 3H) (Example 300). [0246] The 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). The mixture was sealed and stirred at room temperature for 30 minutes. Analysis by LCMS showed the reaction was complete. To the mixture was added water (10 mL). The mixture was stirred for 10 minutes and extracted with DCM (20 mL x2). The organic layer was dried over sodium sulfate, filtered, and the solvents of the filtrate were evaporated to afford 3-((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)cyclobutan-1-one (362 mg, 0.641 mmol) as a solid. This was taken up in MeOH (2 mL) and sodium borohydride (10.05 mg, 0.266 mmol) was added. The mixture was stirred for 30 minutes. The solvents were evaporated and to the mixture was added TFA (1 mL). The mixture was heated at 50 °C for 30 minutes. The solvents were evaporated. To the residue was added 1 M KOH (5 mL). The mixture was extracted with DCM (5 mL), and the organic layer was
collected with a phase separator. The solvents were evaporated. The residue was purified by silica gel chromatography with 0-100% EtOAc in hexanes as eluent, and the residue was lyophilized from MeCN/water to afford ((2S,5R)-5-(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-2-methylpiperidin-1-yl)((1S,3R)-3-hydroxycyclobutyl)methanone (44.6 mg, 0.107 mmol) as a solid. LCMS (C20H22F2N6O2) (ES, m/z): 417 [M+H]+.1H NMR (499 MHz, DMSO-d6) δ 8.05 (s, 4H), 7.79 (d, J = 7.9 Hz, 2H), 7.72 – 7.62 (m, 2H), 5.11 – 5.01 (m, 2H), 4.88 – 4.78 (m, 1H), 4.78 – 4.71 (m, 1H), 4.27 – 4.15 (m, 2H), 4.05 – 3.91 (m, 3H), 3.41 – 3.34 (m, 1H), 3.34 – 3.30 (m, 4H), 3.07 – 2.96 (m, 1H), 2.96 – 2.87 (m, 2H), 2.85 – 2.70 (m, 3H), 2.46 – 2.29 (m, 4H), 2.14 – 1.99 (m, 7H), 1.99 – 1.90 (m, 1H), 1.70 (d, J = 17.7 Hz, 5H), 1.28 – 1.21 (m, 4H), 1.15 (d, J = 4.9 Hz, 3H). [0248] The example compounds of the invention in the following Table 18 were prepared in a manner similar to the synthesis of Example 305, from the appropriate starting amine core and alkylating reagents. TABLE 18 Structure Observed E l M +
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
, , , , . (Intermediate 15), DIPEA (0.134 mL, 0.768 mmol), and DCM (1.5 mL). To the mixture was added 1-propanephosphonic anhydride (0.228 mL, 0.384 mmol) (50% solution in MeCN). The mixture was sealed and stirred at room temperature for 30 minutes. To the mixture was added water (10 mL). The mixture was extracted with DCM (10 mL x2), and the organic layer was dried over sodium sulfate, filtered, and the solvents were evaporated. To the residue was added THF. The mixture was chilled at 0 °C. To the mixture was added methylmagnesium bromide (0.960 mL, 2.88 mmol). The mixture was stirred for 2 hours. Analysis by LCMS showed the reaction was complete. The mixture was diluted in saturated ammonium chloride (10 mL) and water (10 mL) and extracted with DCM (20 mL x2). The organic layer was dried over sodium sulfate, filtered, and the solvents were evaporated to afford ((2S,5R)-5-(5-((2,4- dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin- 1-yl)((1S,3R)-3-(2-hydroxypropan-2-yl)cyclopentyl)methanone (104 mg, 0.167 mmol) (1:1 mixture of diastereomers). This was taken up in DCM (1.5 mL), and water (0.15 mL) and the mixture was stirred and chilled at 0 °C. To the mixture was added DDQ (56.9 mg, 0.251 mmol) as a slurry in DCM (0.5 mL). After 4 hours, analysis by LCMS showed that the reaction was complete. To the mixture was added saturated sodium bicarbonate (10 mL), and the mixture was extracted with DCM (20 mL x2). The combined organic layers were dried over sodium sulfate, filtered, and the solvents were evaporated. The residue was purified by silica gel chromatography with 0-70% EtOAc:EtOH (3:1) in hexanes as eluent. The obtained diastereomeric mixture was purified by SFC (Column: Chiralpak OJ-H 250×21mm, Condition: 15% of methanol (0.1% NH4OH) in CO2. to afford faster eluting peak 1 ((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 (24.6 mg, 0.052 mmol) LCMS (C24H30F2N6O2) (ES, m/z): 473 [M+H]+; and slower eluting peak 2 ((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
(19.9 mg, 0.042 mmol) LCMS (C24H30F2N6O2) (ES, m/z): 473 [M+H]+ as colorless solids.
[0250] The 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.
TABLE 19
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 N2, at which point, THF (5000 µL) was added. The yellow suspension stirred vigorously at room temperature under N2 for an hour, and was then cooled to -78 °C. After stirring for 5 minutes, methyllithium (484 µl, 1.500 mmol) was added dropwise over 1 minute. After an additional hour of stirring, a solution of 5-((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)picolinonitrile (150 mg, 0.25 mmol) (Intermediate 32) in THF was added. The reaction continued to stir slowly warming to room temperature. LCMS analysis indicated the starting material was consumed after 1 hour, but the major product was amide bond cleavage. The reaction was quenched with 2 mL of conc. NH4OH 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 Mg2SO4, filtered, combined and concentrated under reduced pressure. The crude mixture was redissolved in 1 mL of DCM and trifluoroacetic acid (963 µL, 12.50 mmol), and placed on a pre-heated block to stir vigorously at 50 °C. The reaction was concentrated under reduced pressure and the crude reaction mixture was purified by HPLC Reverse phase (C-18), eluting with acetonitrile/water + 0.1% TFA, to afford [(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 (7 mg, 0.012 mmol). LCMS (C24H26F2N8O) (ES, m/z): 481 [M+H]+. [0252] The 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 Structure 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)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (54.3 mg, 0.070 mmol) (Intermediate 34) and a stir bar. After stirring vigorously for 1 minute to ensure dissolution, 37 % hydrochloric acid (23.05 µL, 0.281 mmol) was added. The reaction continued to stir vigorously at room temperature. LCMS analysis indicated full conversion after stirring for 16 hours. The reaction was quenched with 2 mL of saturated aqueous NaHCO3. A small exotherm was produced, so it was added slowly. The reaction mixture also crashed out upon basifying. To have the mixture go back into solution, 5 mL of water and 3:1 CHCl3/IPA were added. After stirring vigorously for 5 minutes, the reaction mixture was passed through a phase separator. The aqueous layer was extracted with 3:1 CHCl3/IPA (10 mL), passed through
a phase separator again. The combined organic layers were dried with Mg2SO4, filtered, and concentrated under reduced pressure. The reaction mixture was re-dissolved in 0.3 mL of DCM and trifluoroacetic acid (270 µL, 3.51 mmol). The reaction was placed on a pre-heated block to stir vigorously at 50 °C. After cooling, the reaction was concentrated under reduced pressure and the crude was purified by HPLC Reverse phase (C-18), eluting with acetonitrile/water + 0.1% TFA, to afford [(2S,5R)-5-(5-amino-7,9-difluoro[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl]{4-[(1R)-1-amino-2,2,2-trifluoroethyl]phenyl}methanone (22.5 mg, 0.043 mmol). LCMS (C24H22F5N7O) (ES, m/z): 520 [M+H]+. [0254] The example compounds of the invention in the following Table 21 were prepared in a manner similar to the synthesis of Example 320, from the appropriate starting reagents. TABLE 21 Structure Observed E m l / M +
[(2S,5R)-5-(5-amino-7,9-difluoro[1,2,4]triazolo[1,5- c]uinazolin-2-l)-2-methlieridin-1-l]{5-[(1R)-1-amino-
p : , -- -a o-,- uoo ,, aoo ,-cqu ao --y -- methylpiperidin-1-yl][5-(3-hydroxy-3-methylazetidin-1-yl)-1,3,4-thiadiazol-2-yl]methanone
dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin- 1-yl)methanone (75 mg, 0.114 mmol) (Intermediate 66), 3-methylazetidin-3-ol hydrochloride (42.2 mg, 0.341 mmol), 1,4-dioxane (1 mL), and DIPEA (0.119 mL, 0.682 mmol). The mixture was stirred and heated at 100 °C for 30 minutes. The solvents were evaporated. To the residue was added TFA (2 mL). The mixture was stirred and heated at 50 °C for 2 hours. The solvents were evaporated. The residue was taken up in DCM (5 mL) and washed with saturated aqueous sodium bicarbonate (5 mL). The organic layer was evaporated. The residue was purified by silica gel chromatography with 0-10% MeOH in DCM as eluent to afford ((2S,5R)-5-(5-amino-7,9- difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)(5-(3-hydroxy-3- methylazetidin-1-yl)-1,3,4-thiadiazol-2-yl)methanone (28.4 mg, 0.055 mmol) as a solid. LCMS (C22H23F2N9O2S) (ES, m/z): 516 [M+H]+.1H NMR (499 MHz, DMSO-d6) δ 8.05 (s, 2H), 7.84 –
7.74 (m, 1H), 7.72 – 7.64 (m, 1H), 5.87 (s, 1H), 5.48 (d, J = 34.1 Hz, 2H), 4.83 (d, J = 44.9 Hz, 2H), 4.06 – 3.94 (m, 3H), 3.62 – 3.51 (m, 1H), 3.26 – 3.08 (m, 3H), 2.23 – 2.03 (m, 3H), 1.99 – 1.84 (m, 2H), 1.77 (d, J = 11.9 Hz, 1H), 1.45 (d, J = 7.5 Hz, 2H), 1.34 (d, J = 21.0 Hz, 2H). The example compounds of the invention in the following Table 22 were prepared in a manner similar to the synthesis of Example 328, from the appropriate starting amines and intermediate 28. TABLE 22 Structure Observed Exam le / [M +
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 nazo 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), and oxetan-3-ol (0.034 mL, 0.532 mmol). To the mixture was added DIAD (0.104 mL, 0.532 mmol). The mixture was stirred and heated at 60 °C for 2 hours. LCMS analysis showed the reaction was complete. The solvents were evaporated, and the residue was purified by silica gel chromatography eluting with 0-100% EtOAc:EtOH (3:1) in hexanes to afford a complex mixture. The mixture was further purified by basic alumina chromatography (same solvent system) to afford the two isomers ((2S,5R)-5-(5-((2,4-dimethoxybenzyl)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 (139 mg, 0.079 mmol) and ((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-7,9- difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)(1-(oxetan-3-yl)-1H-1,2,3- triazol-4-yl)methanone (52.2 mg, 0.029 mmol) as solids. Both were heavily contaminated with triphenylphosphine oxide, but both were taken forward as is. 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. The residue was purified by silica gel chromatography with 0-100% EtOAc:EtOH (3:1) in hexanes as eluent to afford ((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 (26.8 mg, 0.057 mmol). LCMS (C21H21F2N9O2) (ES, m/z): 470 [M+H]+.1H NMR (499 MHz, DMSO-d6) δ 8.22 (d, J = 6.1 Hz, 1H), 8.07 (s, 3H), 7.78 (d, J = 29.1 Hz, 2H), 7.68 (t, J = 9.4 Hz, 1H), 5.94 (d, J = 7.3 Hz, 1H), 5.01 (dd, J = 27.1, 7.2 Hz, 5H), 4.89 (d, J = 15.0 Hz, 1H), 4.70 (s, 2H), 3.77 (d, J = 30.6 Hz, 2H), 3.56 – 3.46 (m, 1H), 3.26 – 3.05 (m, 3H), 2.22 – 2.10 (m, 2H), 1.89 (s, 2H), 1.77 (d, J = 29.1 Hz, 2H), 1.34 (dd, J = 30.6, 6.4 Hz, 4H). [0257] The example compounds of the invention in the following Table 23 were prepared in a manner similar to the synthesis of Example 331, from the appropriate starting alcohols and intermediate 41.
TABLE 23
[(2S,5R)-5-(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-2-methylpiperidin-1-yl](2-((S or R)-
methylpiperidin-1-yl][6-(morpholin-4-yl)pyridin-3-yl]methanone
[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)(6-fluoropyridin-3-yl)methanone (100 mg, 0.169 mmol) (Intermediate 73) followed by morpholine (29.2 μL, 0.338 mmol) and finally potassium carbonate (117 mg, 0.845 mmol). DMA (423 µL) was added and the reaction mixture was heated to 100 °C for 16 hours. LCMS analysis indicated product formation so the mixture was put directly onto a SiO2 column and purified with 0-80% hexanes:EtOAc (3:1 EtOAc:EtOH). The product was collected, and any remaining DMA was removed under hi- vacuum. The desired product was collected and dissolved in DCM (2760 µL) and water (276 µL). The mixture was cooled to 0 °C and to this mixture was added DDQ (68.9 mg, 0.304 mmol) and the mixture was allowed to warm to room temperature. LCMS analysis indicated product formation and consumption of starting material after 2 hours. The reaction mixture was quenched with saturated aqueous NaHCO3 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). LCMS (C25H26F2N8O2) (ES, m/z): 509 [M+H]+.1H NMR (499 MHz, DMSO-d6) δ 8.25 (d, J = 2.0 Hz, 1H), 8.04 (s, 2H), 7.83 – 7.72 (m, 1H), 7.72 – 7.61 (m, 2H), 6.87 (d, J = 9.1 Hz, 1H), 3.73 – 3.65 (m, 4H), 3.58 – 3.47 (m, 4H), 3.26 – 3.05 (m, 2H), 2.18 – 2.04 (m, 2H), 1.96 – 1.79 (m, 1H), 1.77 – 1.63 (m, 1H), 1.30 (d, J = 6.9 Hz, 3H). The 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. For
Examples 341-354, DMB-deprotection was carried out by treatment with TFA similar in a manner for Example 331.
TABLE 24
, , , , )-2- methylpiperidin-1-yl][2-(aminomethyl)-1,3-oxazol-4-yl]methanone -
, , , carbonitrile (40 mg, 0.067 mmol) (Intermediate 77), and MeOH (2 mL). Sodium borohydride (7.56 mg, 0.200 mmol) was added, and the resulting reaction mixture heated at 100 ºC for 30 minutes. The reaction mixture was concentrated and to the resulting residue was added TFA (1 mL). The mixture was stirred and heated at 50 °C for 2 hours. The solvents were evaporated and the residue was purified by HPLC Reverse phase (C-18), eluting with acetonitrile/water + 0.1% TFA, to afford ((2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)- 2-methylpiperidin-1-yl)(2-(aminomethyl)oxazol-4-yl)methanone 2,2,2-trifluoroacetate (12 mg, 0.021 mmol) as a solid. LCMS (C21H23FN8O3) (ES, m/z): 455 [M+H]+.1H NMR (499 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.53 (s, 2H), 7.89 (d, J = 10.5 Hz, 1H), 7.73 (s, 2H), 7.19 (d, J = 7.9 Hz, 1H), 5.02 – 4.72 (m, 3H), 4.45 – 4.27 (m, 2H), 3.98 (s, 2H), 3.20 – 2.94 (m, 3H), 2.22 – 2.01 (m, 2H), 1.92 – 1.81 (m, 1H), 1.80 – 1.66 (m, 1H), 1.43 – 1.23 (m, 2H). 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 µL). The reaction mixture was cooled to 0 °C and to this mixture was added methylmagnesium bromide (945 µL, 2.84 mmol). The 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). The isolated material was further purified by HPLC Reverse phase (C-18), eluting with acetonitrile/water + 0.1% TFA, to afford ((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 (44 mg, 0.089 mmol) as a solid. LCMS (C25H27F2N7O2) (ES, m/z): 496 [M+H]+.1H NMR (499 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.53 (s, 1H), 8.16 – 7.90 (m, 3H), 7.86 – 7.78 (m, 1H), 7.74 – 7.61 (m, 2H), 7.37 (s, 1H), 5.00 – 4.92 (m, 1H), 4.88 (d, J = 10.0 Hz, 1H), 4.15 – 4.03 (m, 2H), 3.99 – 3.90 (m, 1H), 3.22 – 3.06 (m, 3H), 2.60 (s, 2H), 2.57 (s, 1H), 2.19 – 2.11 (m, 1H), 2.10 – 2.02 (m, 1H), 1.57 (s, 3H), 1.52 (s, 2H), 1.30 (dd, J = 10.9, 7.1 Hz, 3H). [0261] The example compound of the invention in the following Table 25 were prepared in a manner similar to the synthesis of Example 355, from Intermediate 83. TABLE 25 Structure Observe
, , , , , methylpiperidin-1-yl](5-cyclopropyl-1,3,4-oxadiazol-2-yl)methanone [0 9-
difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-2- oxoacetyl)cyclopropanecarbohydrazide (62 mg, 0.100 mmol) (Intermediate 87), DCM (2 mL), DIPEA (0.052 mL, 0.299 mmol), and Ts-Cl (28.5 mg, 0.149 mmol). The mixture was stirred at room temperature for 2 hours. Analysis by LCMS showed the dehydration was complete. To the mixture was added TFA (1 mL) and the resulting mixture was heated at 50 °C. After 30 minutes, analysis by LCMS showed the reaction was complete. The solvents were evaporated and the resulting residue was purified by HPLC Reverse phase (C-18), eluting with acetonitrile/water + 0.1% NH4OH, to afford ((2S,5R)-5-(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)- 2-methylpiperidin-1-yl)(5-cyclopropyl-1,3,4-oxadiazol-2-yl)methanone (22 mg, 0.048 mmol) as a solid. LCMS (C21H20F2N8O2) (ES, m/z): 455 [M+H]+.1H NMR (499 MHz, DMSO-d6) δ 8.07 (s, 4H), 7.81 (d, J = 6.4 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.72 – 7.63 (m, 2H), 4.90 (s, 2H), 4.87 – 4.76 (m, 3H), 3.68 – 3.57 (m, 2H), 3.29 – 3.20 (m, 3H), 3.20 – 3.07 (m, 3H), 2.36 – 2.29 (m,
2H), 2.22- 2.06 (m, 4H), 2.00- 1.85 (m, 3H), 1.84-1.71 (m, 3H), 1.39 (d, J= 6.8 Hz, 2H), 1.31 (d, J=7.0Hz, 2H), 1.25- 1.15 (m, 3H), 1.13-1.04 (m, 3H).
[0263] The 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.
TABLE 26
Example 362: [(2S,5R)-5-(5-amino-7,9-difluoro[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl][4-(1-hydroxycyclopropyl)phenyl]methanone
7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidine-1-carbonyl)benzoate (380 mg, 0.603 mmol) (Intermediate 89) in THF (5 mL) was added titanium(IV) isopropoxide (685 mg, 2.410 mmol) and the resulting reaction mixture stirred for 30 minutes. Ethylmagnesium bromide (0.803 ml, 2.410 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature slowly and stirred for 16 hours. LCMS analysis showed minor conversion to desired product. The mixture was re-cooled with an ice bath and excess
titanium(IV) isopropoxide (1028 mg, 3.62 mmol) was added dropwise. After stirring for 30 minutes, ethylmagnesium bromide (482 mg, 3.62 mmol) was added dropwise and the mixture was allowed to warm to room temperature slowly and stirred for another 16 hours. LCMS showed increased conversion to the desired product. The reaction was quenched with saturated aqueous NH4Cl (5 mL) and treated with EtOAc (15 mL) and water (10 mL). The resulting suspension was filtered. The filtrate was extracted with EtOAc (15 mL x2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column) eluting with 0-55% EtOAc/ PE to afford ((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)(4-(1- hydroxycyclopropyl)phenyl)methanone (25 mg, 0.039 mmol) as a solid. This was taken up in an ice-cooled solution of DCM (1 mL), water (0.2 mL) and DDQ (18.05 mg, 0.080 mmol). The reaction mixture was stirred for 1 hour at 0 ºC. LCMS analysis showed the starting material was consumed. The reaction was quenched with saturated aqueous NaSO3 (1 mL) and extracted with DCM (5 mL x3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified first by prep-HPLC (neutral) to afford the product as a solid with minor impurity which was then further purified by prep-TLC (EtOAc) to afford ((2S,5R)-5-(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1- yl)(4-(1-hydroxycyclopropyl)phenyl)methanone (2.61 mg, 4.84 µmol) as a solid. LCMS (C25H24F2N6O2) (ES, m/z): 479 [M+H]+. Example 3633-[(2S,5R)-5-(5-amino-7,9-difluoro[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidine-1-carbonyl]-1,2,4-triazin-6(1H)-one -
yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (200 mg, 0.427 mmol) (Intermediate 15) in THF (4 mL) was added trimethylaluminum (0.427 mL, 0.854 mmol) at 0 ºC over 1 minute. After stirring for 30 minutes at room temperature, ethyl 6-oxo-1,6-dihydro-1,2,4-triazine-3-carboxylate (108 mg, 0.640 mmol) (Intermediate 39) was added to the mixture at room temperature and the resulting mixture was stirred for another 16 hours at 80 ºC. LCMS analysis showed the reaction
was completed and the desired target was formed. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL x3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column) eluting with 10% MeOH/DCM. The isolated material 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 completed, and the desired product was formed. The reaction was concentrated and the residue was purified by HPLC Reverse phase (C-18), eluting with acetonitrile/water + 0.05% NH3OH + 10mM NH4HCO3, to afford 3-((2S,5R)-5-(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidine-1-carbonyl)-1,2,4-triazin-6(1H)-one (16.80 mg, 0.038 mmol) as a solid. LCMS (C19H17F2N9O2) (ES, m/z): 442 [M+H]+. 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 µL, 5.12 mmol), 1-(6- chloropyridin-3-yl)cyclobutan-1-ol; 5016032-0031 (353 mg, 1.921 mmol) and DMSO (6403 µL) 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 Na2SO4, 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 µL) and water (791 µL). The mixture was cooled to 0 °C and to this mixture was added sodium bicarbonate (183 mg, 2.175 mmol) and DDQ (296 mg, 1.305 mmol) and the mixture was allowed to warm to room temperature. After 1 hour, the reaction mixture was quenched with saturated aqueous NaHCO3 and saturated aqueous NaSO3, and extracted 3x with DCM. The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, concentrated and dissolved in DMF. The residue was purified by HPLC Reverse phase (C-18), eluting with acetonitrile/water + 0.1% NH4OH, to afford [(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 as a solid. LCMS (C25H25F2N7O2) (ES, m/z): 494 [M+H]+.1H NMR (499 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.67 (s, 1H), 8.07 (s, 1H), 7.99 (dd, J = 17.6, 7.8 Hz, 3H), 7.81 (d, J = 7.6 Hz, 1H), 7.75 – 7.60 (m, 2H), 7.58 (d, J = 8.0 Hz, 2H), 5.81 (s, 1H), 5.77 (s, 1H), 4.98 (s, 1H), 4.89 (d, J = 10.0 Hz, 1H), 4.07 (s, 1H), 3.94 (d, J = 11.0 Hz, 1H), 3.53 (t, J = 12.6 Hz, 1H), 3.24 – 3.07 (m, 3H), 2.49 – 2.38 (m, 3H), 2.38 – 2.23 (m, 3H), 2.21 – 2.03 (m, 3H), 2.02 – 1.88 (m, 2H), 1.87 – 1.57 (m, 4H), 1.31 (dd, J = 16.1, 6.7 Hz, 4H). 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. The 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 NH4Cl (10 mL) and extracted with EtOAc (10 mL x3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, 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 solvent was removed and the residue was purified by HPLC Reverse phase (C-18), eluting with acetonitrile/water + 0.1% TFA, to afford ((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 (6 mg, 0.012 mmol) as a solid. LCMS (C23H24F2N8O2) (ES, m/z): 483 [M+H]+. Biological Assays
[0268] The IC50 values reported for each of the compounds of the invention shown in the table below were measured in accordance with the methods described below.
[0269] The A2a receptor affinity binding assay measured the amount of binding of a tritiated ligand with high affinity for the A2a adenosine receptor to membranes made from HEK293 or CHO cells recombinantly expressing the human A2a adenosine receptor, in the presence of varying concentrations of a compound of the invention. In each assay, the tested compounds of the invention were 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.
Measurement of A2a Binding Affinity Using Radioligand Binding
[0270] 148 pL (5 pg/mL) membranes (Perkin Elmer, Cat. No. RBHA2aM400UA) and 2 pL compounds of the invention to be tested (test compound) were transferred to individual w ells of a 96-well polypropylene assay plate and incubated for 15 to 30 minutes at room temperature.
[3H] SCH58261 ((7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-l,2,4-triazolo[l,5- c] pyrimidine)) was diluted in assay buffer (50 mM Tris pH 7.4, 10 mM MgCh, 0.005% Tween20) to a concentration of 4 nM and 50 pL transferred to each w ell of the assay plate. To define total and non-specific binding, wells containing 1% DMSO and 1 mM ZM241385 (Tocris Bioscience, Cat. No. 1036) respectively, were also included. 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. 40 pL Ultima Gold™ (Perkin Elmer, Cat. No. 6013329) was added to each well of the filter plate and the top of the plate was sealed with TopSeal-A PLUS® clear plate seal (Perkin Elmer, Cat. No. 6050185). The plate was incubated for at least 20 minutes, and then the amount of radioactivity remaining in each w ell was determined using a TopCount® (Perkin Elmer) scintillation counter. After normalization to total and non-specific binding, the percent effect at each compound concentration was calculated. The plot of percent effect versus the log of compound concentration was analyzed electronically using a 4-parameter logistic fit based on the Levenberg-Marquardt algorithm to generate IC50 values.
Measurement of A2b Binding Affinity Using Radioligand Binding
[0271] 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).
[0272] To perform the assay, 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. No. SH30256.01) and then 50 pL of the solution was transferred to each well of the assay plate. To define total and non-specific binding, wells containing 1% DMSO and 20 mM N-ethylcarboxamidoadenosine (Tocris Bioscience, Cat. No. 1691) respectively, were also included. The wells of the assay plate were incubated at room temperature for 60 minutes with agitation, then filtered using a FilterMate Harvester® (Perkin Elmer) or similar equipment through a UniFilter-96® PEI coated plate (Perkin Elmer Cat. No. 6005274 or 6005277). 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 Gold™ (Perkin Elmer, Cat. No. 6013329) was added to each well of the filter plate and the top of the plate was sealed with TopSeal-A PLUS® clear plate seal (Perkin Elmer, Cat. No. 6050185). The plates were then incubated for at least 20 minutes, and then the amount of radioactivity remaining in each w ell was determined using a TopCount® (Perkin Elmer) scintillation counter. After normalization to total and non-specific binding, the percent effect at each compound concentration was calculated. The plot of percent effect versus the log of compound concentration was analyzed electronically using a 4-parameter logistic fit based on the Levenberg-Marquardt algorithm to generate IC50 values.
Measurement of A2A and A2B antagonism in cAMP cell-based Assay
[0273] The ability of compounds to antagonize human A2A and A2B adenosine receptors was determined using a kit to measure changes in intracellular cyclic AMP levels (LANCE cAMP 384 Kit, Perkin Elmer. Cat. No. AD0264). HEK293 cells recombinantly expressing either human A2A or A2B receptors, previously frozen in Recovery Medium (Life Technologies, Cat. No. 12648-010) were thawed and diluted into stimulation buffer (HBSS (Hy clone SH 30268.01), 5 mM HEPES (Gibco 15630-106). 200 nM rolipram (Tocris, Cat. No. 0905), and 1.5 %(V/v) ESA stabilizer (kit component). The cell suspension was centrifuged at 200 x g for 10 min and then resuspended in stimulation buffer, supplemented with a 1 : 10 000 dilution of Alexa Fluor 647 anti-cAMP antibody, to a density of 6.0 xlO’ cells/mL. A Labcyte Echo 550 acoustic dispenser was used to transfer up to 25 nL of test compound dissolved in DMSO into the wells of a dry Optiplate-384 plate (Perkin Elmer. Cat. No. 6008289). All subsequent liquid additions were performed using a multichannel pipettor. Next, 5 pL of the cell suspension was added to the wells of the Optiplate-384 and incubated for 30 min. at 37°C and 5% CO2 in a humidified environment. After this time 5 pL of either 300 nM or 600 nM adenosine (Sigma Cat. No. A9251) for A2A and A2B respectively was added and incubated for 30 minutes at 37°C and 5% CO2 in a humidified environment. At this time detection mix was prepared by combining the LANCE Eu-W8044 labeled streptavidin and Biotin-cAMP in detection buffer according to the manufacturers protocol. 10 pL of the detection mix was added to each well of the Optiplate-384 which was covered with a plate seal and incubated under ambient conditions for 2 hours prior to reading the plate using an Envision (Perkin Elmer, Waltham, MA) multimode plate reader. Data was normalized by defining minimal effect as stimulation in the presence of 0.25% (v/v) DMSO and maximal effect as stimulation in the presence of 1 pM ZM241385 (Cayman, Cat. No. 1036). Curve fitting of the percent effect data versus the log of compound concentration used a 4- parameter concentration response curve fitting algorithm to calculate IC50 values. Compound concentrations tested were 10,000. 3,333, 1.111. 370.4, 123.4, 41.2. 13.7. 4.6, 1.5 and 0.5 nM with 0.25% residual DMSO.
Claims
1. A compound having a structural Formula (I):
or a pharmaceutically acceptable salt thereof, wherein;
R1 is H, F, or Cl; each R2 is, independently, H, F, Cl, (C1-C6)alkyl, or -O(C1-C6)alkyl, wherein each R2 is not H simultaneously; ring A is a moiety selected from
R3 is selected from:
(1) -(CHR3A)q(CH2)n(C6-C10)aryl, wherein the aryl is optionally substituted with 1 to 3 R3B groups;
(2) a 4- to 7-membered heterocycloalkyl having 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 R3C groups;
(3) (C1-C6)alkyl or (C3-C10 )cycloalkyl, each optionally substituted with 1 to 3 R3D groups;
(4) a 5- tol O-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 R3E groups;
r (C1-C6)haloalkyl;
R3A is H or -OH; R3B, at each occurrence, is independently selected from the group consisting of halogen, -OH, -CF3, -CN, -N(R3F) , (C1-C6)alkyl, and (C3-C10)cycloalkyl, wherein each of the (C1-C6)alkyl a C3-C10 cycloalkyl is optionally substituted with 1 to 7
moieties independently selected from the group consisting of -OH, -N(R3F)2, (C3-C10)cycloalkyl, and halogen; R3C, at each occurrence, is independently selected from the group consisting of halogen, - OH, -CN, (C1-C6)alkyl, (C3-C10)cycloalkyl, -O(C1-C6)alkyl, -CO(C1-C6)alkyl -CO(C3- C6)cycloalkyl, and -CO(C3-C6)cyclohaloalkyl, the (C1-C6)alkyl being optionally substituted with 1 to 4 moieties independently selected from the group consisting of -OH and halogen;
R3D, at each occurrence, is independently selected from the group consisting of -OH, -
)alkyl, (C1-C6)haloalkyl, -O(C1-C6)alkyl, -O (C1- C4)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C4)alkylsulfonyl, halogen, and oxadiazolyl, the oxadiazolyl being optionally substituted with (C1-C4)alkyl;
R3E , at each occurrence, is independently selected from the group consisting of -OH, halogen,
morpholin-4-yl, (C1-C4)alkylsulfonyl-, -CO(C1-C6)alkyl, oxetanyl, (C1-C6)alkyl, -O(C1-C6)alkyl,
(C3-C10)cycloalkyl, (C3-C10)cyclohaloalkyl, tetrahydrofuranyl, pyrimidinyl,
wherein each of the (C1-C6)alkyl, the -O(C1-C6)alkyl, and the (C3-C10)cycloalkyl is optionally substituted with 1 to 4 moieties independently selected from the group consisting of -OH, (C1- C4)alkyl, -N(R3F)2, and halogen;
R3F, at each occurrence, is independently, H, (C1-C4)alkyl, or (C1-C4)haloalkyl;
R3J, at each occurrence, is independently, -OH, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, or (C3-C6)cycloalkyl;
R3K is (C1-C4)alkyl, (C1-C4)haloalkyl or (C3-C10)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 carbon atom.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
R1 is F.
3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein ring A is
4. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R4 is CH3.
5. The compound of any of claims 1- 4, or a pharmaceutically acceptable salt thereof, wherein R3 is -(CHR3A)q(CH2)n(C6-C10)aryl, wherein the aryl is optionally substituted with 1 to 3 R3B groups, wherein
R3B, at each occurrence, is independently selected from the group consisting of halogen, -OH, -CF3, -CN, -N(R3F)2 (C1-C6)alkyl, and (C3-C10)cycloalkyl,
wherein each of the (C1-C6)alkyl and the (C3-C10)cycloalkyl is optionally substituted with 1 to 7 moieties independently selected from the group consisting of -OH, -N(R3F)2, (C3-C10)cycloalkyl, and halogen.
6. The compound of any of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R3 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 R3C groups, wherein
R3C, at each occurrence, is independently selected from the group consisting of halogen, - OH, -CN, (C1-C6)alkyl, (C3-C10 )cycloalkyl, -O(C1-C6)alkyl, -CO(C1-C6)alkyl -CO(C3-
C6)cycloalkyl, and -CO(C3-C6)cyclohaloalkyl, the (C1-C6)alkyl being optionally substituted with 1 to 4 moieties independently selected from the group consisting of -OH and halogen.
7. The compound of any of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R3 is (C1-C6)alkyl, or (C3-C10)cycloalkyl, each optionally substituted with 1 to 4 R3D groups, wherein
R3D, at each occurrence, is independently selected from the group consisting of -OH, -
8. The compound of any of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R3 is a 5- tol O-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 R3E groups, wherein
R3E , at each occurrence, is independently selected from the group consisting of -OH, halogen, -CN, -CF3,
N(R3F)2, CON(R3F)2, morpholin-4-yl, (C1-C4)alkylsulfonyl-, -CO(C1-C6)alkyl, oxetanyl, (C1-C6)alkyl, -O(C1-C6)alkyl,
(C3-C10)cycloalkyl, (C3-C10)cyclohaloalkyl, tetrahydrofuranyl, pyrimidinyl, and
wherein each of the (C1-C6)alkyl, the -O(C1-C6)alkyl, and the (C3-C10)cycloalkyl is optionally substituted with 1 to 4 moieties independently selected from the group consisting of -OH, (Ci- C4)alkyl, -N(R3F)2, and halogen.
11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R4 is -CH3, and m is 1.
12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R3 is pyridinyl, piperidinyl, phenyl, imidazolyl, triazolyl, pyrrolidinyl, thiazolyl, pyrrol i di nonyl, pyrazolyl, pyridazinyl, cyclobutyl, oxazolyl, pyrazinyl, oxadiazolyl, or (C1-C6)alkyl, each optionally substituted with 1 to 4 moieties selected from the group consisting of -OH, methyl, ethyl, isopropyl, cyclopropyl, F, morpholin-4-yl, and
cyclobutyl, the cyclobutyl being optionally substituted, independently, with 1 to 2 -OH or -CH3.
13. The compound of claim 1 1, or a pharmaceutically acceptable salt thereof, wherein R3 is oxazolyl, pyridinyl, pyrazinyl, oxadiazolyl, or phenyl.
16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of
17. A pharmaceutical composition comprising a compound of any of claims 1 to 16, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
18. A method of treating cancer in a patient in need thereof, the method comprising administering an effective amount of a compound of any of claims 1 to 15, or a pharmaceutically acceptable salt thereof to the patient.
19. The method of claim 18, wherein said cancer is selected from the group consisting of melanoma, head & neck cancer, classical Hodgkin lymphoma, urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large-B-cell lymphoma, microsatellite instability- high 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, salivary cancer, and prostate cancer, and metastatic castration resistant prostate cancer.
20. The method of claim 19, wherein the cancer is selected from the group consisting of non- small cell lung cancer, colorectal cancer, pancreatic cancer, head & neck cancer, and cervical cancer.
21. The method of claim 20, wherein said compound, or pharmaceutically acceptable salt thereof, is administered in combination with an additional therapeutic agent.
TL The method of claim 21, wherein said additional therapeutic agent is a PD-1 antagonist.
23. The method of claim 22, wherein said PD-1 antagonist is selected from pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, and dostarlimab.
24. The method of claim 22, wherein said PD-1 antagonist is pembrolizumab.
26. A compound, wherein the compound is selected from the group consisting of
27. A pharmaceutical composition comprising a compound of claim 26, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
28. A method of treating cancer in a patient in need thereof, the method comprising administering an effective amount of a compound of claim 26, or a pharmaceutically acceptable salt thereof, to the patient.
29. The method of claim 28, wherein said cancer is selected from the group consisting of melanoma, head & neck cancer, classical Hodgkin lymphoma, urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large-B-cell lymphoma, microsatellite instability- high 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, salivary cancer, and prostate cancer, and metastatic castration resistant prostate cancer.
30. The method of claim 29, wherein the cancer is selected from the group consisting of non- small cell lung cancer, colorectal cancer, pancreatic cancer, head & neck cancer, and cervical cancer.
31. The method of claim 29 or claim 30, wherein said compound, or a pharmaceutically acceptable salt thereof, is administered in combination with an additional therapeutic agent.
32. The method of claim 31, wherein said additional therapeutic agent is a PD-1 antagonist.
33. The method of claim 32, wherein said PD-1 antagonist is selected from pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, and dostarlimab.
34. The method of claim 33, wherein said PD-1 antagonist is pembrolizumab.
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US20180362530A1 (en) * | 2015-07-10 | 2018-12-20 | Merck Sharp & Dohme Corp. | Substituted aminoquinazoline compounds as a2a antagonist |
WO2020112706A1 (en) * | 2018-11-30 | 2020-06-04 | Merck Sharp & Dohme Corp. | 7-, 8-, and 10-SUBSTITUTED AMINO TRIAZOLO QUINAZOLINE DERIVATIVES AS ADENOSINE RECEPTOR ANTAGONISTS, PHARMACEUTICAL COMPOSITIONS AND THEIR USE |
US20210107904A1 (en) * | 2018-11-30 | 2021-04-15 | Merck Sharp & Dohme Corp. | 9-substituted amino triazolo quinazoline derivatives as adenosine receptor antagonists, pharmaceutical compositions and their use |
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US20180362530A1 (en) * | 2015-07-10 | 2018-12-20 | Merck Sharp & Dohme Corp. | Substituted aminoquinazoline compounds as a2a antagonist |
WO2020112706A1 (en) * | 2018-11-30 | 2020-06-04 | Merck Sharp & Dohme Corp. | 7-, 8-, and 10-SUBSTITUTED AMINO TRIAZOLO QUINAZOLINE DERIVATIVES AS ADENOSINE RECEPTOR ANTAGONISTS, PHARMACEUTICAL COMPOSITIONS AND THEIR USE |
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