Patent Application
20240018115
The present invention is directed to allosteric chromenone inhibitors of phosphoinositide 3-kinase (PI3K) useful in the treatment of diseases, or disorders associated with PI3K modulation. The invention is directed toward compounds, and compositions which inhibit PI3K, methods of (or uses for) treating a disease, or disorder associated with PI3K (e.g., CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal, and spinal syndrome), PIK3CA-related overgrowth syndrome (PROS), breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer), and using, or methods of using, PI3K inhibitors in combination with one or more additional cancer therapies.
The phosphoinositide 3-kinases (PI3Ks) signaling pathway is one of the most highly mutated systems in human cancers. PI3K signaling is involved in many other disease states including allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel diseases, chronic obstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma, disorders related to diabetic complications, and inflammatory complications of the cardiovascular system such as acute coronary syndrome.
PI3Ks are members of a unique, and conserved family of intracellular lipid kinases that phosphorylate the 3′-OH group on phosphatidylinositols, or phosphoinositides. The PI3K family comprises 15 kinases with distinct substrate specificities, expression patterns, and modes of regulation (Katso et al., Annu Rev Cell Dev Biol. 2001; 17:615-75). The class I PI3Ks (p110α, p110β, p110δ, and p110γ) are typically activated by tyrosine kinases, or G-protein coupled receptors to generate PIP3, which engages downstream effectors such as those in the pathways of Akt/PDK1, mTOR, the Tec family kinases, and the Rho family GTPases. The class II, and III PI3Ks play a key role in intracellular trafficking through the synthesis of PI(3)P, and PI(3,4)P2.
The PI3K isoforms have been implicated, for example, in a variety of human cancers, and disorders. Mutations in the gene coding for PI3K isoforms, or mutations which lead to upregulation of a PI3K isoform are believed to occur in many human cancers. Mutations in the gene coding for a PI3K isoform are point mutations clustered within several hotspots in helical, and kinase domains. Because of the high rate of PI3K mutations, targeting of this pathway may provide valuable therapeutic opportunities.
Genetic alterations in genes in PI3K signaling are believed to be involved in a range of cancers such as endometrial cancer, breast cancer, esophageal squamous-cell cancer, cervical squamous-cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small-cell lung cancer, esophagogastric cancer, nerve-sheath tumor, head and neck squamous-cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft-tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, renal non-clear-cell carcinoma, renal clear-cell carcinoma, germ-cell carcinoma, thymic tumor, pheochromocytoma, miscellaneous neuroepithelial tumor, thyroid cancer, leukemia, and encapsulated glioma (Goncalves M D, Hopkins B D, Cantley L C. Phosphatidylinositol 3-Kinase, Growth Disorders, and Cancer. N Engl J Med. 2018 Nov. 22; 379(21):2052-2062).
The alpha (a) isoform of PI3K has been implicated, for example, in a variety of human cancers. Angiogenesis has been shown to selectively require the a isoform of PI3K in the control of endothelial cell migration. (Graupera et al, Nature 2008; 453; 662-6). Mutations in the gene coding for PI3Kα, or mutations which lead to upregulation of PI3Kα are believed to occur in many human cancers such as lung, stomach, endometrial, ovarian, bladder, breast, colon, brain, prostate, and skin cancers. Mutations in the gene coding for PI3Kα are point mutations clustered within several hotspots in helical, and kinase domains, such as E542K, E545K, and H1047R. Many of these mutations have been shown to be oncogenic gain-of-function mutations. Because of the high rate of PI3Kα mutations, targeting of this pathway may provide valuable therapeutic opportunities. While other PI3K isoforms such as PI3Kδ, or PI3Kγ are expressed primarily in hematopoietic cells, PI3Kα, along with PI3Kβ, is expressed constitutively.
Mutated PI3Kα has been implicated in brain metastases in HR+/HER2− metastatic breast cancers. Development of brain-penetrant PI3Kα inhibitors may provide improved therapeutic benefit over current PI3Kα inhibitors. (Fitzgerald et al., Association between PIK3CA mutation status and development of brain metastases in HR+/HER2− metastatic breast cancer. Ann Oncol 30:v110, 2019 (suppl 5)).
Due to the central role of PI3Kα in regulating organismal glucose homeostasis, PI3K inhibition in patients often gives rise to hyperglycemia and/or hyperinsulinemia (Busaidy N L, et al, Management of metabolic effects associated with anticancer agents targeting the PI3K-Akt-mTOR pathway. J Clin Oncol 2012; 30:2919-28). High levels of circulating insulin could potentially be mitogenic and/or antiapoptotic for cancer cells, and thus negate the antiproliferative effects of PI3K inhibitors (Blouin M-J, et al, Abstract 4615: the hyperinsulinemia caused by PI3K inhibitors attenuates their antineoplastic efficacy, but can be minimized by co-administration of metformin. Cancer Res 2013; 73:4615).
In the setting of cancer with mutated PI3Kα, one way to overcome the problem of compensatory production of insulin and/or glucose upon systemic PI3Kα inhibition would be to develop inhibitors with enhanced selectivity for mutant PI3Kα over wild-type PI3Kα. This would create an increased window for drug dosing to selectively inhibit the pathologic signaling of mutant PI3Kα in the cancer cells without affecting the wild-type PI3Kα in the host tissues that control systemic metabolism (Okkenhaug K, Graupera M, Vanhaesebroeck B. Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy. Cancer Discov. 2016 October; 6(10):1090-1105), thus limiting toxicities, and permitting higher doses, and more complete inhibition of the drug target (Ariella B. Hanker, et al, Challenges for the clinical development of PI3K inhibitors: Strategies to improve their impact in solid tumors. Cancer Discov. 2019 April; 9(4): 482-491).
Currently PI3Kα inhibitors are nearly equipotent to wild-type, and mutant PI3Kα. Mutant selective inhibitors have been elusive due to the PI3Kα mutations location far from the active site. As such, inhibitors which target a second, peripheral binding pocket near a known mutation (e.g., H1047R) may provide a route to selective PI3Kα inhibition. Thus, targeting a mutated, peripheral binding pocket of PI3Kα, provides a valuable therapeutic target for drug development.
As such, kinases, for example lipid kinases such as PI3Ks, are prime targets for drug development. The present invention provides new kinase inhibitors.
In one aspect, the present invention relates to compounds of Formula (I):
wherein ring A is pyrrolidine optionally substituted with a —CN; or
In one aspect, the compounds of Formula (I) may include an asymmetrical carbon atom at the position designated with an asterisk (*)
In one aspect, R7 is methyl and R8 is hydrogen and the bond at the * position is as represented as
In one aspect, the present invention relates to compounds of Formula (I):
wherein ring A is pyrrolidine optionally substituted with a —CN; or
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, or carrier.
In another aspect, the present invention provides a method of modulating PI3K (e.g., PI3Kα) activity (e.g., in vitro, or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof.
In some aspects, the present invention provides a method of treating, or preventing a disease, or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof.
In some aspects, the present invention provides a method of treating, or preventing a disease, or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof.
In some aspects, the present invention provides a method of treating a disease, or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof.
In some aspects, the present invention provides a method of treating a disease, or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof for use in therapy.
In another aspect, the present invention provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof for use in modulating PI3K (e.g., PI3Kα) activity (e.g., in vitro, or in vivo).
In another aspect, the present invention provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in selective inhibition for mutant PI3Kα over wild-type PI3Kα.
In another aspect, the present invention provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in treating, or preventing a disease, or disorder disclosed herein.
In another aspect, the present invention provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in treating a disease, or disorder disclosed herein.
In another aspect, the present invention provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for modulating PI3K (e.g., PI3Kα) activity (e.g., in vitro, or in vivo).
In another aspect, the present invention provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating, or preventing a disease, or disorder disclosed herein.
In another aspect, the present invention provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease, or disorder disclosed herein.
In another aspect, the present invention provides a method of preparing a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a method of preparing a compound, of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, comprising one, or more steps described herein.
In another aspect, the present invention provides a compound obtainable by, or obtained by, a method for preparing a compound as described herein.
In another aspect, the present invention provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described in the Examples).
Other features, and advantages of the invention will be apparent from the following detailed description, and claims.
The present invention provides methods of treating, preventing, or ameliorating a disease, or disorder, (or uses in the treatment, prevention, or amelioration of a disease, or disorder), in which PI3K plays a role by administering to a patient in need thereof a therapeutically effective amount of a PI3K inhibitor of the present invention. The methods (or uses) of the present invention can be used in the treatment of a variety of PI3K-dependent diseases, and disorders.
In some embodiments, the disease, or disorder is a cancer (e.g., breast cancer, brain cancers, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer). In some embodiments, the disease, or disorder associated with PI3K includes, but is not limited to, CLOVES syndrome, PROS, endometrial cancer, breast cancer, esophageal squamous-cell cancer, cervical squamous-cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small-cell lung cancer, esophagogastric cancer, nerve-sheath tumor, head and neck squamous-cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft-tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, renal non-clear-cell carcinoma, renal clear-cell carcinoma, germ-cell carcinoma, thymic tumor, pheochromocytoma, miscellaneous neuroepithelial tumor, thyroid cancer, leukemia, and encapsulated glioma.
The details of the invention are set forth in the accompanying description below. Although methods, and materials similar, or equivalent to those described herein can be used in the practice, or testing of the present disclosure, illustrative methods, and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description, and from the claims. In the specification, and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. 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 this invention belongs. All patents, and publications cited in this specification are incorporated herein by reference in their entireties.
The articles “a”, and “an” refer to one, or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element, or more than one element.
The term “and/or” means either “and”, or “or” unless indicated otherwise.
The term “administer”, “administering”, or “administration” refers to either directly administering a disclosed compound, or pharmaceutically acceptable salt of the disclosed compound, or a composition to a subject.
The term “alkenyl” refers to a straight, or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkenyl” group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated, or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl.
The term “alkoxy” refers to a straight, or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, i.e., —O(alkyl). Examples of alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.
The term “alkyl” refers to a straight, or branched chain saturated hydrocarbon containing 1-12 carbon atoms, preferably 1-6 carbon atoms. Examples of a C1-C6 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.
The term “alkynyl” refers to a straight, or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkynyl” group contains at least one triple bond in the chain. Examples of alkynyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl.
It is understood that for example the terms “alkenyl”, “alkoxy”, “alkyl”, “alkynyl”, “haloalkyl”, “haloalkoxy” and “cycloalkyl” can be further defined by the numbers of carbons they contain, such as for example the term “C1-C6 alkoxy” refers to an alkoxy group as defined above containing 1-6 carbon atoms.
The term “aromatic” means a planar ring having 4n+2 electrons in a conjugated system. As used herein, “conjugated system” means a system of connected p-orbitals with delocalized electrons, and the system may include lone electron pairs.
The term “aryl” unless otherwise specifically defined refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic, or bicyclic groups such as phenyl, biphenyl, or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). Furthermore, when containing two fused rings the aryl groups herein defined may have one, or more saturated, or partially unsaturated ring fused with a fully unsaturated aromatic ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoannulenyl.
The term “carrier” encompasses carriers, excipients, and diluents, and means a material, composition, or vehicle, such as a liquid, or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying, or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.
The term “cyano” means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., C≡N.
The term “cycloalkyl” means mono, or polycyclic saturated carbon rings containing 3-18 carbon atoms, preferably 3-10 carbon atoms. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl, norborenyl, bicyclo[2.2.2]octanyl, and bicyclo[2.2.2]octenyl.
The term “disorder” means, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.
The term “haloalkoxy” refers to an alkoxy group, as defined herein, which is substituted with one, or more halogen. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, and trichloromethoxy.
The term “haloalkyl” refers to an alkyl group, as defined herein, which is substituted with one, or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trichloromethyl.
The term “halogen” or “halo” refers to fluorine, chlorine, bromine, or iodine.
The term “heteroaryl” unless otherwise specifically defined means a monovalent monocyclic, or a polycyclic aromatic radical of 5 to 24 ring atoms, preferably 5 to 10 ring atoms, containing one, or more ring heteroatoms selected from N, O, S, P, or B, preferably 1, 2, 3, or 4 ring heteroatoms selected from N, O, or S, the remaining ring atoms being C. A polycyclic aromatic radical includes two, or more fused rings, and may further include two, or more spiro-fused rings, e.g., bicyclic, tricyclic, tetracyclic, and the like. Unless otherwise specifically defined, “fused” means two rings sharing two ring atoms. Unless otherwise specifically defined, “spiro-fused” means two rings sharing one ring atom. Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, S, P, or B, preferably N, O, or S. Heteroaryl as herein defined also means a tricyclic heteroaromatic group containing one, or more ring heteroatoms selected from N, O, S, P, or B, preferably N, O, or S. Heteroaryl as herein defined also means a tetracyclic heteroaromatic group containing one, or more ring heteroatoms selected from N, O, S, P, or B, preferably N, O, or S. Examples of heteroaromatic groups include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuranyl, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazinyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzooxazolyl, benzoisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, and 3H-indolyl. Furthermore, when containing two, or more fused rings, the heteroaryl groups defined herein may have one, or more saturated, or partially unsaturated ring fused with one, or more fully unsaturated aromatic ring. In heteroaryl ring systems containing more than two fused rings, a saturated, or partially unsaturated ring may further be fused with a saturated, or partially unsaturated ring described herein. Furthermore, when containing three, or more fused rings, the heteroaryl groups defined herein may have one, or more saturated, or partially unsaturated ring spiro-fused. Any saturated, or partially unsaturated ring described herein is optionally substituted with one, or more oxo. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, 8H-pyrido[3,2-b]pyrrolizinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, pyrazolo[1,5-a]pyrimidin-7(4H)-onyl, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl, benzo[c][1,2]oxaborol-1(3H)-olyl, 6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-onyl, and 6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-onyl.
The term “5-member heteroaryl” unless otherwise specifically defined means a monovalent monocyclic aromatic radical of 5 ring atoms, containing one, or more ring heteroatoms selected from N, O, S, P, or B, preferably 1, 2, 3, or 4 ring heteroatoms selected from N, O, or S, the remaining ring atoms being C. Exemplary 5-member heteroaryl groups include, but are not limited to, furyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazole, triazolyl and tetrazolyl.
The term “6-member heteroaryl” unless otherwise specifically defined means a monovalent monocyclic aromatic radical of 6 ring atoms, containing one, or more ring heteroatoms selected from N, O, S, P, or B, preferably 1, 2, 3, or 4 ring heteroatoms selected from N, O, or S, the remaining ring atoms being C. Exemplary 6-member heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl.
The term “heterocyclyl”, “heterocycle”, or “heterocycloalkyl” means mono, or polycyclic rings containing 3-24 atoms, preferably 3-10 atoms, which include carbon, and one, or more heteroatoms selected from N, O, S, P, or B, preferably 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and wherein the rings are not aromatic. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl.
The term “isomers” refers to compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomers or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
The term “modulate”, “modulation”, or “modulating” refers to a biological activity of a compound, or substrate that inhibits and/or activates PI3K.
The term “patient”, or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus. Preferably, the mammal is human.
The term “therapeutically effective amount” when used in connection with a compound refers to the amount or dose of the compound which upon single or multiple dose administration to the patient, provides the desired effect in the patient under diagnosis or treatment. An effective amount can be determined by one skilled in the art by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount for a patient, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of patient; its size, age, and general health; the specific disease or disorder involved; the degree of or involvement or the severity of the disease or disorder; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
The term “treating” with regard to a subject, includes restraining, slowing, stopping, or reversing the progression or severity of an existing symptom or disorder.
In one aspect, the present invention provides compounds of Formula (I), or pharmaceutically acceptable salts thereof:
wherein R, R1, R2, R3, R4, R5, R6, R7, and R8, are as defined in the Summary for Formula (I).
In a compound of Formula (I), or pharmaceutically acceptable salts thereof,
In a compound of Formula (I), or pharmaceutically acceptable salts thereof, R and R1 together with the nitrogen to which they are attached form an optionally substituted bicyclic ring selected from dihydrobenzimidazolone, dihydroindazolone, indolinone or quinazolinone; wherein the optionally substituted bicyclic ring is optionally substituted with one to three substituents each independently selected from oxo, —CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH or C1-C6 alkoxy; or
In a compound of Formula (I), or pharmaceutically acceptable salts thereof, R′ is hydrogen, halogen, C1-C3 alkyl, —CH(OH)—CH2OH, —CO—CH2OH or C3-C6 cycloalkyl.
In a compound of Formula (I), or pharmaceutically acceptable salts thereof,
In a compound of Formula (I), or pharmaceutically acceptable salts thereof, R8 is —H.
In a further aspect, compounds of Formula (I), wherein R8 is —H, have Formula (II), or pharmaceutically acceptable salts thereof:
wherein R, R1, R2, R3, R4, R5, R6, and R7, are as defined in the Summary for Formula (I).
In a compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R and R1 together with the nitrogen to which they are attached form an optionally substituted bicyclic ring selected from dihydrobenzimidazolone, dihydroindazolone, indolinone or quinazolinone; wherein the optionally substituted bicyclic ring is optionally substituted with one to three substituents each independently selected from oxo, —CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH or C1-C6 alkoxy.
In a compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R1 is a group of a formula:
In a compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R is —H.
In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R4 is —H or halogen. Preferably R4 is —H.
In a further aspect, compounds of Formula (I) or (II) have Formula (III), or pharmaceutically acceptable salts thereof:
wherein R1, R2, R3, R5, R6, and R7 are as defined in the Summary for Formula (I) above.
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R3 is —H, halogen, —CN, —C(CN)═CHOH, —N(H)(C1-C3 alkyl), —N(C1-C3 alkyl)2, —N(H)(CH2CH2CO2H), —C(O)—C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R3 is —H, halogen, —CN, C1-C6 alkyl, C1-C6 haloalkyl, oxetane, or isoxazole. Preferably R3 is —H, —CN, C1-C3 alkyl, or C1-C3 haloalkyl. More preferably R3 is —H, —CN, methyl, or trifluoromethyl. Most preferably R3 is —H or methyl.
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R5 is —H, halogen, C1-C3 alkyl or C1-C3 haloalkyl. Preferably R5 is —H, halogen, methyl, or trifluoromethyl.
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R6 is —H or halogen.
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R7 is —CN, C1-C3 alkyl or C1-C3 haloalkyl. Preferably R7 is —CN, methyl or trifluoromethyl. More preferably R7 is methyl.
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R1 is an optionally substituted bicyclic ring selected from isobenzofuranone, benzofuranone, isoindolinone, indolinone, quinazolinone, or benzothiazolone; wherein the optionally substituted bicyclic ring is optionally substituted with one to three substituents each independently selected from oxo, —CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH or C1-C6 alkoxy.
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R1 is a group of the formula
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R1 is a group of the formula
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, each R9 is independently —H, halogen, C1-C3 alkyl, or C3-C5 cycloalkyl, preferably each R9 is independently —H, halogen, methyl, or cyclopropyl.
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, each R9 is independently —H, halogen, C1-C3 alkyl, or C1-C3 alkoxy.
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R′ is C1-C3 haloalkyl, C1-C3 alkoxy, —NO2, —N(R11)—CO2C1-C3 alkyl, —N(R11)—SO2C1-C3 alkyl, —SO2NR11R11, —SO2N(R11)—CO—C1-C3 alkyl, —C(═N—OH)—NH2, —CN, —CO2C1-C3 alkyl, —CONR11R12, —CON(R)—(CH2)n—R13, or a group of the formula
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R′ is C1-C3 haloalkyl, C1-C3 alkoxy, —NO2, —N(R)—CO2C1-C3 alkyl, —N(R)—SO2C1-C3 alkyl, —SO2NR11R11, —SO2N(R)—CO—C1-C3 alkyl, —C(═N—OH)—NH2, —CN, —CONR11R12, —CON(R)—(CH2)n—R13, or a group of the formula
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R′ is —SO2NR11R11, —SO2N(R11)(R13), —C(O)NR11R12, —C(O)N(R)—(CH2)n—R13, —C(O)—NHSO2R16, or 1,2,4-oxadiazolin-5-one.
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R′ is selected from oxetane, pyrrolidine, tetrahydrofuran, morpholine, piperidine, piperazine, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, or triazine; each of which is optionally substituted with one to three substituents independently selected from oxo, —NR11R11, —OR11, —CN, C1-C6 haloalkyl or C1-C6 alkyl optionally substituted with phenyl.
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R′ is selected from oxetane, pyrrolidine, tetrahydrofuran, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, or triazine; each of which is optionally substituted with one to three substituents independently selected from oxo, —NR11R11, —OR11, —CN, C1-C6 haloalkyl or C1-C6 alkyl optionally substituted with phenyl
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R′ is pyrrole, furan, thiophene, pyrazole, isoxazole, oxazole, isothiazole, thiazole, imidazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, or triazine; each of which is optionally substituted with one to three substituents independently selected from oxo, —NR11R11, —OR11 or C1-C6 alkyl optionally substituted with aryl.
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R′ is hydrogen, halogen, C1-C3 alkyl, or C3-C6 cycloalkyl, preferably R′ is hydrogen, halogen, or methyl.
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R′ is hydrogen, —Cl, —F—, —Br, methyl, difluoromethyl, trifluoromethyl, methoxy, —NO2, —CN, or a group of the formula:
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R1 is a group of the formula
wherein each R9 is independently —H, halogen, C1-C3 alkyl, or C3-C5 cycloalkyl, and R′ is hydrogen, halogen, C1-C3 alkyl, or C3-C6 cycloalkyl, preferably each R9 is independently —H, halogen, methyl, or cyclopropyl and R′ is hydrogen, halogen, or C1-C3 alkyl.
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R1 is a group of the formula
wherein each R9 is independently —H, halogen, C1-C3 alkyl, or C3-C5 cycloalkyl, and R′ is hydrogen, halogen, C1-C3 alkyl, or C3-C6 cycloalkyl, preferably each R9 is independently —H, halogen, methyl, or cyclopropyl and R′ is hydrogen, halogen, or C1-C3 alkyl.
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R1 is a group of the formula:
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R1 is a group of the formula
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R2 is a group of the formula
wherein each R10 is independently —H, —CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or —CO2C1-C3 alkyl; or R2 is an optionally substituted pyrazole or an optionally substituted indazole, each of which is optionally substituted with one to three substituents each independently selected from —CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or —CO2C1-C3 alkyl. Preferably R2 is a group of the formula
wherein each R10 is independently —H, —CN, or halogen; or R2 is an optionally substituted pyrazole or an optionally substituted indazole, each of which is optionally substituted with a C1-C3 alkyl.
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R2 is a group of the formula:
wherein each R10 is independently —H, —CN, C1-C6 haloalkyl, —NR11R11, —CH2—NR11R11, —CO2C1-C3 alkyl or —CH2—CO2C1-C3 alkyl; or R2 is an optionally substituted indazole, which is optionally substituted with one to three substituents each independently selected from —CN, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R2 is a group of the formula
wherein each R10 is independently —H, —CN, or C1-C3 haloalkyl; or R2 is an optionally substituted indazole, which is optionally substituted with a C1-C3 alkyl.
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R2 is a group of the formula:
wherein R10 is selected from —H, —CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy.
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R2 is a group of the formula:
wherein R11 is selected from hydrogen, alkyl, cycloalkyl, and haloalkyl.
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R2 is pyrazole optionally substituted with alkyl or triazole optionally substituted with alkyl.
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R2 is a group of the formula:
In yet a further compound of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R2 is a group of the formula
In yet a further compound of Formula (I), the compound is selected from:
or a pharmaceutically acceptable salt of any of the foregoing; wherein the bond at the * position is as represented,
In yet a further compound of Formula (I), the compound is selected from:
or a pharmaceutically acceptable salt of any of the foregoing;
wherein the bond at the * position is as represented,
In yet a further compound of Formula (I), the compound is selected from
or a pharmaceutically acceptable salt thereof.
In yet a further compound of Formula (I), the compound is selected from:
or a pharmaceutically acceptable salt of any of the foregoing; wherein the bond at the * position is as represented,
In yet a further compound of Formula (I), the compound is selected from
or a pharmaceutically acceptable salt thereof.
In yet a further compound of Formula (I), the compound is selected from
or a pharmaceutically acceptable salt thereof.
In a further embodiment of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, the compound is an isotopic derivative of any one of the compounds described herein or a pharmaceutically acceptable salt thereof. It is understood that the isotopic derivative can be prepared using any of a variety of art-recognized techniques. For example, the isotopic derivatives can generally be prepared by carrying out the procedures disclosed in the schemes and/or in the examples described herein or a pharmaceutically acceptable salt thereof, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. In the compounds of this invention any atom not specifically designated as a particular isotope is meant to represent a stable isotope of that atom.
In a further embodiment of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, the compound is deuterated at one or more positions. Unless otherwise stated, when an atom is designated specifically as “H” or “hydrogen”, the atom is understood to have hydrogen at its natural abundance isotopic composition. Also, unless otherwise stated, when an atom is designated specifically as “D” or “deuterium”, the atom is understood to have deuterium at an abundance substantially greater than the natural abundance of deuterium, which is 0.015%.
In an embodiment of a compound of Formula (I) or pharmaceutically acceptable salt thereof, R8 is —H, -D, or C1-C6 alkyl. In an embodiment of a compound of Formula (I) or pharmaceutically acceptable salt thereof, the compound is selected from:
In an embodiment of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, R2 is 1-(trideuteriomethyl)pyrazol-4-yl. In an embodiment of a compound of Formula (I) or pharmaceutically acceptable salt thereof, the compound is:
A pharmaceutically acceptable salt of a compound of the present invention is, for example, an acid-addition salt of a compound of the invention, which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric, methane sulfonate or maleic acid. In addition, a pharmaceutically acceptable salt of a compound of the present invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. Pharmaceutically acceptable salts, and common methodology for preparing them are well known in the art (see, e.g., P. Stahl, et al. Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2nd Revised Edition (Wiley-VCH, 2011); S. M. Berge, et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977).
Further representative “pharmaceutically acceptable salts” include, e.g., water-soluble, and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.
The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below.
The following are further numbered aspects of the invention:
1. A compound of a Formula (I):
R2 is a group of the formula:
9. The compound as defined in any one of aspects 1-8, or pharmaceutically acceptable salt thereof, wherein R and R1 together with the nitrogen to which they are attached form an optionally substituted bicyclic ring selected from dihydrobenzimidazolone, dihydroindazolone, indolinone or quinazolinone; wherein the optionally substituted bicyclic ring is optionally substituted with one to three substituents each independently selected from oxo, —CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH or C1-C6 alkoxy.
10. The compound as defined in aspect 9, or pharmaceutically acceptable salt thereof, wherein R and R1 together with the nitrogen to which they are attached form an optionally substituted bicyclic ring of the formula
11. The compound as defined in any one of aspects 1-8, or pharmaceutically acceptable salt thereof, wherein R is —H.
12. The compound as defined in any one of aspects 1-11, or pharmaceutically acceptable salt thereof, wherein R4 is —H or halogen.
13. The compound as defined in any one of aspects 1-12, or pharmaceutically acceptable salt thereof, wherein R4 is —H.
14. The compound as defined in any one of aspects 1-8 or 11-13, or pharmaceutically acceptable salt thereof having the Formula
15. The compound as defined in any one of aspects 1-14, or pharmaceutically acceptable salt thereof, wherein R3 is —H, —CN, C1-C3 alkyl, or C1-C3 haloalkyl.
16. The compound as defined in any one of aspects 1-15, or pharmaceutically acceptable salt thereof, wherein R3 is —H, —CN, methyl, or trifluoromethyl.
17. The compound as defined in any one of aspects 1-16, or pharmaceutically acceptable salt thereof, wherein R3 is —H or methyl.
18. The compound as defined in any one of aspects 1-16, or pharmaceutically acceptable salt thereof, wherein R5 is —H, halogen, C1-C3 alkyl or C1-C3 haloalkyl.
19. The compound as defined in any one of aspects 1-18, or pharmaceutically acceptable salt thereof, wherein R5 is —H, halogen, methyl, or trifluoromethyl.
20. The compound as defined in any one of aspects 1-19, or pharmaceutically acceptable salt thereof, wherein Rb is —H or halogen.
21. The compound as defined in any one of aspects 1-20, or pharmaceutically acceptable salt thereof, wherein R7 is —CN, C1-C3 alkyl or C1-C3 haloalkyl.
22. The compound as defined in any one of aspects 1-21, or pharmaceutically acceptable salt thereof, wherein R7 is —CN, methyl or trifluoromethyl.
23. The compound as defined in any one of aspects 1-22, or pharmaceutically acceptable salt thereof, wherein R7 is methyl.
24. The compound as defined in any one of aspects 1-8 or 11-23, or pharmaceutically acceptable salt thereof, wherein R1 is an optionally substituted bicyclic ring selected from isobenzofuranone, benzofuranone, isoindolinone, indolinone, quinazolinone, or benzothiazolone; wherein the optionally substituted bicyclic ring is optionally substituted with one to three substituents each independently selected from oxo, —CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH or C1-C6 alkoxy.
25. The compound as defined in any one of aspects 1-8 or 11-23, or pharmaceutically acceptable salt thereof, wherein R1 is a group of the formula
26. The compound of any one of claims 1-8 or 11-23, or pharmaceutically acceptable salt thereof, wherein R1 is a group of the formula
27. The compound as defined in any one of aspects 1-8, 11-23, 25 or 26, or pharmaceutically acceptable salt thereof, wherein R9 is independently —H, halogen, C1-C3 alkyl, or C1-C3 alkoxy.
28. The compound as defined in any one of aspects 1-8, 11-23, 25, or 26, or pharmaceutically acceptable salt thereof, wherein each R9 is independently —H, halogen, C1-C3 alkyl, or C3-C5 cycloalkyl.
29. The compound as defined in any one of aspects 1-4, 7-8, 11-23, or 25-28, or pharmaceutically acceptable salt thereof, wherein R′ is C1-C3 haloalkyl, C1-C3 alkoxy, —NO2, —N(R11)—CO2C1-C3 alkyl, —N(R11)—SO2C1-C3 alkyl, —SO2NR11R11, —SO2N(R11)—CO—C1-C3 alkyl, —C(═N—OH)—NH2, —CN, —CONR11R12, —CON(R11)—(CH2)n—R13, or a group of the formula
36. The compound as defined in any one of aspects 1-8 or 11-23, or pharmaceutically acceptable salt thereof, wherein R1 is a group of the formula
37. The compound as defined in any one of aspects 1-36, or pharmaceutically acceptable salt thereof, wherein R2 is a group of the formula
38. The compound as defined in any one of aspects 1-36, or pharmaceutically acceptable salt thereof, wherein R2 is a group of the formula
39. The compound as defined in any one of aspects 1-36, or pharmaceutically acceptable salt thereof, wherein R2 is a group of the formula
40. The compound as defined in any one of aspects 1-36, or pharmaceutically acceptable salt thereof, wherein R2 is a group of the formula
47. The compound as defined as defined in any one of aspects 1-36, or pharmaceutically acceptable salt thereof, wherein R2 is a group of the formula:
48. The compound as defined as defined in any one of aspects 1-36, or pharmaceutically acceptable salt thereof, wherein R2 is a group of the formula:
49. The compound as defined in aspect 1 or 2 selected from:
or a pharmaceutically acceptable salt thereof.
50. The compound as defined in aspect 1 or 2 selected from:
or a pharmaceutically acceptable salt thereof.
51. The compound as defined in aspect 1 or 2 selected from:
or a pharmaceutically acceptable salt thereof.
52. A pharmaceutical composition comprising a compound as defined in any one of aspects 1-51, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
53. A method of treating a disease or disorder associated with modulation of phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined in any one of aspects 1-51, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in aspect 52.
54. The method as defined in aspect 53, wherein the PI3K is PI3Kα.
55. The method as defined in aspect 53 or aspect 54, wherein the PI3K associated with the disease or disorder has a H1047R mutation.
56. The method as defined in any one of aspects 53-55, wherein the disease or disorder is a cancer.
57. The method as defined in aspect 56, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.
58. The method as defined in aspect 56, wherein the cancer is breast cancer.
59. The method as defined in aspect 56, wherein the cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced or metastatic breast cancer.
60. The method as defined in in any one of aspects 53-55, wherein the disorder is CLOVES syndrome, or PROS.
61. A method of inhibiting phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined in any one of aspects 1-51, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in aspect 52.
62. A method of treating cancer or a disorder associated with modulation of phosphoinositide 3-kinase (PI3K), the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined in any one of aspects 1-51, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in aspect 52.
63. The method as defined in aspect 62, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.
64. The method as defined in aspect 62, wherein the cancer is breast cancer.
65. The method as defined in aspect 62, wherein the cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced or metastatic breast cancer.
66. The method as defined in aspect 62, wherein the disorder is CLOVES syndrome or PROS.
67. The compound as defined in any one of aspects 1-51, or pharmaceutically acceptable salt thereof, for use in therapy.
68. The compound as defined in any one of aspects 1-51, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder associated with modulating PI3K.
69. The compound or a pharmaceutically acceptable salt thereof for use as defined in aspect 68, wherein the disease or disorder associated with modulating PI3K is a cancer.
70. The compound or a pharmaceutically acceptable salt thereof for use as defined in aspect 69, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.
71. The compound or a pharmaceutically acceptable salt thereof for use as defined in aspect 69, wherein the cancer is breast cancer.
72. The compound or a pharmaceutically acceptable salt thereof for use as defined in aspect 69, wherein the cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced or metastatic breast cancer.
73. The compound or a pharmaceutically acceptable salt thereof for use as defined in aspect 68, wherein the disorder is CLOVES syndrome or PROS.
74. Use of a compound as defined in any one of aspects 1-51, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder associated with modulating PI3K.
75. The use as defined in aspect 74, wherein the disease or disorder associated with modulating PI3K is a cancer.
76. The use as defined in aspect 75, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.
77. The use as defined in aspect 75, wherein the cancer is breast cancer.
78. The use as defined in aspect 75, wherein the cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced or metastatic breast cancer.
79. The use as defined in aspect 74, wherein the disorder is CLOVES syndrome or PROS.
In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I), (II), or (III) as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The compounds of Formula (I), (II), or (III) can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds of Formula (I), (II), or (III) can also be formulated for intravenous (bolus or in-fusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.
The formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity/suspending agent, buffer, and pH modifying agent, and a mixture thereof.
According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound any one of the Formulae disclosed herein, or a pharmaceutically acceptable salt, in association with a pharmaceutically acceptable diluent or carrier.
The compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
The compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.
In some aspects, the present disclosure provides a method of modulating PI3K (e.g., PI3Kα) activity (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof.
In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in combination with an effective amount of one or more therapeutic agents.
In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in combination with an effective amount of: a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof; a SERD, or a pharmaceutically acceptable salt thereof; an aromatase inhibitor, or a pharmaceutically acceptable salt thereof; a taxane, or a pharmaceutically acceptable salt thereof; an mTOR inhibitor, or a pharmaceutically acceptable salt thereof; a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof, a platinum agent; an anthracycline, or a pharmaceutically acceptable salt thereof; an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof; an antiandrogen, or a pharmaceutically acceptable salt thereof; an anti-HER2 monoclonal antibody; an anti-HER2 antibody-drug conjugate; a KRAS inhibitor, or a pharmaceutically acceptable salt thereof; an MEK inhibitor, or a pharmaceutically acceptable salt thereof, an ERK inhibitor, or a pharmaceutically acceptable salt thereof; a topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof; a SERM, or a pharmaceutically acceptable salt thereof, or a PARP inhibitor, or a pharmaceutically acceptable salt thereof; or a combination thereof.
In some embodiments, the disease or disorder is associated with an implicated PI3K activity. In some embodiments, the disease or disorder is a disease or disorder in which PI3K activity is implicated.
In some embodiments, the disease or disorder is a cancer.
In some embodiments, the cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, aids-related cancers, aids-related lymphoma, anal cancer, astrocytoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, osteosarcoma, malignant fibrous histiocytoma, brain tumors, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, cancer of unknown primary, cardiac (heart) tumors, atypical teratoid/rhabdoid tumor, primary CNS lymphoma, cervical cancer, cholangiocarcinoma, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colorectal cancer, craniopharyngioma, cutaneous t-cell lymphoma, mycosis fungoides, Sezary syndrome, ductal carcinoma in situ (DCIS), embryonal tumors, medulloblastoma, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, malignant gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, hepatocellular cancer, Langerhans cell histiocytosis, Hodgkin lymphoma, islet cell tumors, pancreatic neuroendocrine tumors, Kaposi sarcoma, kidney cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, male breast cancer, intraocular melanoma, Merkel cell carcinoma, malignant mesothelioma, metastatic cancer, metastatic squamous neck cancer, midline tract carcinoma with nut gene changes, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma/plasma cell neoplasms, myelodysplastic syndromes, myelodysplastic neoplasms, myeloproliferative neoplasms, chronic myeloproliferative neoplasm, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, lip and oral cavity cancer, oropharyngeal cancer, malignant fibrous histiocytoma of bone, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors (islet cell tumors), papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, plasma cell neoplasm, multiple myeloma, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, recurrent cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, childhood vascular tumors, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma of the skin, testicular cancer, oropharyngeal cancer, hypopharyngeal cancer, thymoma, thymic carcinoma, thyroid cancer, tracheobronchial tumors, transitional cell cancer of the renal pelvis and ureter, urethral cancer, uterine sarcoma, vaginal cancer, vascular tumors, vulvar cancer, and Wilms tumor.
In some embodiments, the cancer is Endometrial cancer, Breast cancer, Oesophageal squamous-cell cancer, Cervical squamous-cell carcinoma, Cervical adenocarcinoma, Colorectal adenocarcinoma, Bladder Urothelial Carcinoma, Glioblastoma, Ovarian cancer, Non-small-cell Lung cancer, Esophagogastric cancer, Nerve-sheath tumor, Head and neck squamous-cell carcinoma, Melanoma, Esophagogastric adenocarcinoma, Soft-tissue sarcoma, Prostate cancer, Fibrolamellar carcinoma, Hepatocellular carcinoma, Diffuse glioma, Colorectal cancer, Pancreatic cancer, Cholangiocarcinoma, B-cell lymphoma, Mesothelioma, Adrenocortical carcinoma, Renal non-clear-cell carcinoma, Renal clear-cell carcinoma, Germ-cell carcinoma, Thymic tumor, Pheochromocytoma, Miscellaneous neuroepithelial tumor, thyroid cancer, leukemia, or encapsulated glioma.
In some embodiments, the cancer is a breast cancer, a prostate cancer, or a brain cancer.
In some embodiments, the cancer is a breast cancer. In some embodiments, the cancer is a prostate cancer. In some embodiments, the cancer is a brain cancer.
In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is ductal carcinoma in situ (DCIS). In some embodiments, the breast cancer is invasive ductal carcinoma. In some embodiments, the breast cancer is triple negative breast cancer. In some embodiments, the breast cancer is medullary carcinoma. In some embodiments, the breast cancer is tubular carcinoma. In some embodiments, the breast cancer is mucinous carcinoma. In some embodiments, the breast cancer is Paget disease of the breast or nipple. In some embodiments, the breast cancer is inflammatory breast cancer (IBC). In some embodiments, the breast cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced or metastatic breast cancer.
In some embodiments, the prostate cancer is an adenocarcinoma. In some embodiments, the prostate cancer is a small cell carcinoma. In some embodiments, the prostate cancer is a neuroendocrine tumor. In some embodiments, the prostate cancer is a transitional cell carcinoma. In some embodiments, the prostate cancer is a sarcoma.
In some embodiments, the brain cancer is an acoustic neuroma. In some embodiments, the brain cancer is an astrocytoma. In some embodiments, the brain cancer is a brain metastasis. In some embodiments, the brain cancer is choroid plexus carcinoma. In some embodiments, the brain cancer is craniopharyngioma. In some embodiments, the brain cancer is an embryonal tumor. In some embodiments, the brain cancer is an ependymoma. In some embodiments, the brain cancer is a glioblastoma. In some embodiments, the brain cancer is a glioma. In some embodiments, the brain cancer is a medulloblastoma. In some embodiments, the brain cancer is a meningioma. In some embodiments, the brain cancer is an oligodendroglioma. In some embodiments, the brain cancer is a pediatric brain tumor. In some embodiments, the brain cancer is a pineoblastoma. In some embodiments, the brain cancer is a pituitary tumor.
In some embodiments, the disease or disorder associated with PI3K includes, but is not limited to, CLOVES syndrome, PROS, breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer.
In some embodiments, the diseases or disorder associated with PI3K is CLOVES syndrome.
In some embodiments, the disease or disorder associated with PI3K is PROS.
In some embodiments, the disease or disorder associated with PI3K is breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer.
In some embodiments, the disease or disorder associated with PI3K is a breast neoplasm, a thyroid neoplasm, an ovarian neoplasm, non-small-cell lung carcinoma, an endometrial neoplasm, or a pancreatic neoplasm. In some embodiments, the disease or disorder associated with PI3K is a breast neoplasm. In some embodiments, the disease or disorder associated with PI3K is a thyroid neoplasm. In some embodiments, the disease or disorder associated with PI3K is an ovarian neoplasm. In some embodiments, the disease or disorder associated with PI3K is non-small-cell lung carcinoma. In some embodiments, the disease or disorder associated with PI3K is an endometrial neoplasm. In some embodiments, the disease or disorder associated with PI3K is a pancreatic neoplasm.
In some embodiments, the disease or disorder associated with PI3K is breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer.
In some embodiments, the disease or disorder associated with PI3K is leukemia, lymphoma, or sarcoma.
In some embodiments, the cancer is endometrial cancer, head and neck cancer, or a sarcoma.
In some embodiments, the cancer is endometrial cancer. In some embodiments the cancer is head and neck cancer. In some embodiments, the cancer is a sarcoma.
In some embodiments, the sarcoma is soft tissue sarcoma, osteosarcoma, chondrosarcoma, Ewing sarcoma, hemangioendothelioma, angiosarcoma, fibrosarcoma, myofibrosarcoma, chordoma, adamantinoma, liposarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, synovial sarcoma, or malignant solitary fibrous tumor.
In some embodiments, the sarcoma is soft tissue sarcoma. In some embodiments the soft tissue sarcoma is liposarcoma, atypical lipomatous tumor, dermatofibrosarcoma protuberans, malignant solitary fibrous tumor, inflammatory myofibroblastic tumor, low-grade myofibroblastic sarcoma, fibrosarcoma, myxofibrosarcoma, low-grade fibromyxoid sarcoma, giant cell tumor of soft tissues, leiomyosarcoma, malignant glomus tumor, rhabdomyosarcoma, hemangioendothelioma, angiosarcoma of soft tissue, extraskeletal osteosarcoma, gastrointestinal stromal tumor, malignant gastrointestinal stromal tumor (GIST), malignant peripheral nerve sheath tumor, malignant Triton tumor, malignant granular cell tumor, malignant ossifying fibromyxoid tumor, stromal sarcoma, myoepithelial carcinoma, malignant phosphaturic mesenchymal tumor, synovial sarcoma, epithelioid sarcoma, alveolar soft part sarcoma, clear cell sarcoma of soft tissue, extraskeletal myxoid chondrosarcoma, extraskeletal Ewing sarcoma, desmoplastic small round cell tumor, extrarenal rhabdoid tumor, perivascular epithelioid cell tumor, intimal sarcoma, undifferentiated spindle cell sarcoma, undifferentiated pleomorphic sarcoma, undifferentiated round cell sarcoma, undifferentiated epithelioid sarcoma, or undifferentiated sarcoma, not otherwise specified.
In some aspects, the present disclosure provides a method of treating or preventing a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
In some aspects, the present disclosure provides a method of treating a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
In some aspects, the present disclosure provides a method of treating or preventing a breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
In some aspects, the present disclosure provides a method of treating a breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
In some aspects, the present disclosure provides a method of treating or preventing a prostate cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
In some aspects, the present disclosure provides a method of treating a prostate cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
In some aspects, the present disclosure provides a method of treating or preventing a brain cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
In some aspects, the present disclosure provides a method of treating a brain cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
In some aspects, the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof for use in therapy.
In some aspects, the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof for use in modulating PI3K (e.g., PI3Kα) activity (e.g., in vitro or in vivo).
In some aspects, the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein.
In some aspects, the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein.
In some aspects, the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof for use in treating or preventing a cancer.
In some aspects, the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof for use in treating a cancer.
In some aspects, the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof for use in treating or preventing a breast cancer.
In some aspects, the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof for use in treating a breast cancer.
In some aspects, the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof for use in treating or preventing a prostate cancer.
In some aspects, the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof for use in treating a prostate cancer.
In some aspects, the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof for use in treating or preventing a brain cancer.
In some aspects, the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof for use in treating a brain cancer.
In some aspects, the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating PI3K (e.g., PI3Kα) activity (e.g., in vitro or in vivo).
In some aspects, the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
In some aspects, the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.
In some aspects, the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a cancer in a subject in need thereof.
In some aspects, the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a cancer in a subject in need thereof.
In some aspects, the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a breast cancer in a subject in need thereof.
In some aspects, the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a breast cancer in a subject in need thereof.
In some aspects, the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a prostate cancer in a subject in need thereof.
In some aspects, the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a prostate cancer in a subject in need thereof.
In some aspects, the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a brain cancer in a subject in need thereof.
In some aspects, the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a brain cancer in a subject in need thereof.
The present disclosure provides compounds that function as modulators of PI3K activity. The present disclosure therefore provides a method of modulating PI3K activity in vitro or in vivo, said method comprising contacting a cell with a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as defined herein.
In some embodiments, PI3K modulation is inhibition of PI3K.
In some embodiments, the PI3K inhibitor is a PI3Kα inhibitor. In some embodiments, the PI3K inhibitor is a PI3Kα H1047R mutant inhibitor.
Effectiveness of compounds of the disclosure can be determined by industry-accepted assays/disease models according to standard practices of elucidating the same as described in the art and are found in the current general knowledge.
The present disclosure also provides a method of treating a disease or disorder in which PI3K activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.
The compounds of Formula (I), (II), or (III), or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action).
Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.
Exemplary compounds of Formula (I), (II), and (III) are synthesized and tested in the examples. It is understood that compounds of Formula (I), (II), and (III) may be converted to the corresponding pharmaceutically acceptable salts of the compounds using routine techniques in the art.
Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz or 300 MHz as stated and at 300.3 K unless otherwise stated; the chemical shifts (6) are reported in parts per million (ppm). Spectra were recorded using a Bruker or Varian instrument with 8, 16 or 32 scans.
LC-MS chromatograms and spectra were recorded using an Agilent 1200 or Shimadzu LC-20 AD&MS 2020 instrument using a C-18 column such as a Luna-C18 2.0×30 mm or Xbridge Shield RPC18 2.1×50 mm. Injection volumes were 0.7-8.0 μl and the flow rates were typically 0.8 or 1.2 ml/min. Detection methods were diode array (DAD) or evaporative light scattering (ELSD) as well as positive ion electrospray ionization. MS range was 100-1000 Da. Solvents were gradients of water and acetonitrile both containing a modifier (typically 0.01-0.04%) such as trifluoroacetic acid or ammonium carbonate.
A solution of 6-bromo-2,3-difluoro-benzoic acid (2.9 g, 12 mmol) in THF (24 mL) was treated with tert-butyl (Z)—N,N′-diisopropylcarbamimidate (9.8 g, 49 mmol) dropwise and the resulting mixture sealed and heated at 65° C. for 18 h. The reaction was cooled to rt and diluted with MTBE. The suspension was filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 0% to 30% EtOAc in hexane to give the title compound (3.3 g, 92%) as a colorless oil.
A vial was charged with tert-butyl piperazine-1-carboxylate (0.43 g, 2.28 mmol), 3-bromo-6-chloro-2-fluoro-pyridine (0.20 g, 0.95 mmol), cesium carbonate (0.93 g, 2.85 mmol), and DMF (4 mL). The vial was sealed and stirred overnight at rt. The reaction was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc. The organic layers were combined, washed with saturated aqueous NaCl, collected, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 0% to 50% EtOAc in heptane to give the title compound (0.34 g, 94%) as a colorless oil. ES/MS m/z 322 (M−tBu).
The following compounds in Table 1 were made in a similar way as described for tert-butyl 4-(3-bromo-6-chloro-2-pyridyl)piperazine-1-carboxylate. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
1DIPEA used as the base.
Combined 2-fluorobenzenesulfonyl chloride (0.70 g, 3.60 mmol) and potassium carbonate (1.09 g, 7.91 mmol) in EtOH (5 mL) and water (5 mL) and allowed to stir at rt overnight. The reaction was diluted with water (20 mL) and the title compound removed by filtration (0.40 g, 54%). ES/MS m/z 206 (M+H).
A solution of 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (4 g, 16.06 mmol) in acetone (40 mL) and water (20 mL) was treated dropwise with concentrated aqueous HCl (20 mL, 36.5%) at rt under a nitrogen atmosphere. The reaction was stirred for 3 h at rt. The reaction was basified to pH 8 with NH4OH and concentrated under reduced pressure. The residue was purified by reversed phase chromatography on C18 eluted with 40% to 60% ACN in water (with 0.1% NH4OH) to give the title compound (2.0 g, 75%) as an off-white solid. ES/MS m/z 168 (M+H).
A solution of 1-(5-bromo-2-pyridyl)cyclopropanecarbonitrile (0.21 g, 0.94 mmol), bis(pinacolato)diborane (0.36 g, 1.41 mmol), and potassium acetate (0.28 g, 2.82 mmol) in dry 1,4-dioxane (10 mL) was purged with argon for 10 min. Added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (69 mg, 0.09 mmol) and purged the reaction an additional 3 min with argon. The reaction was stirred at 100° C. for 2 h. After cooling to rt, the reaction was filtered through diatomaceous earth and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 0% to 20% MeOH in DCM to give the title compound (0.35 g, 83%, 60% purity). ES/MS m/z 189 (M+H).
The following compound in Table 2 was made in a similar way as described for 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]cyclopropanecarbonitrile. Various methods were used to purify this compound, which would be apparent to one skilled in the art.
A solution of 2,5-difluoropyridine (2.0 g, 17.38 mmol) in THF (10 mL) at −78° C. was treated with lithium diisopropylamide solution (1M in THF, 2.79 g, 26.07 mmol). The reaction was stirred at −78° C. for 1 h. Tributyltin chloride (5.94 g, 18.25 mmol) in 20 mL of THF was added dropwise to the reaction at −78° C. and then the reaction stirred for 1 h at −78° C. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc (3×). The combined extracts were dried over Na2SO4, filtered, and the reaction concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 0% to 20% EtOAc in heptane to give the title compound (4.46 g, 64%). ES/MS m/z 406 (M+H).
A solution of 3-bromopyridine-2-sulfonyl chloride (2.0 g, 7.80 mmol) in DCM was cooled to −20° C. and treated dropwise with tert-butylamine. The reaction was stirred at −20° C. for 30 min. The reaction was concentrated under reduced pressure and the residue purified by silica gel chromatography eluted with 50% EtOAc in petroleum ether to give the title compound (0.50 g, 22%) as a dark red solid. ES/MS m/z 293/295 (M+H).
A mixture of 5-chloro-1H-pyrazolo[4,3-b]pyridine (3.2 g, 20.84 mmol) and iodomethane (4.44 g, 31.26 mmol) in THF (30 mL) at 0° C. was treated in portions with sodium hydride (1.0 g, 60% in oil, 25.0 mmol). The reaction was stirred at rt for 1 h, quenched with water (30 mL), and extracted with EtOAc (3×80 mL). The combined organic layers were washed with saturated aqueous sodium chloride (3×30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 30% EtOAc in petroleum ether to give the title compound (1.34 g, 38%) as a white solid. ES/MS m/z 168 (M+H).
A solution of 5-chloro-2-methyl-pyrazolo[4,3-b]pyridine (4.0 g, 23.87 mmol) in 1,4-dioxane (80 mL) was treated with hexamethylditin (11.73 g, 35.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (5.52 g, 4.77 mmol). The reaction was stirred for 2 h at 100° C. The reaction was cooled to rt, quenched with saturated aqueous potassium fluoride, filtered, and the solids washed with EtOAc (3×100 mL). The filtrate was concentrated under reduced pressure to give the title compound (6.0 g) as a black solid. ES/MS m/z 298 (M+H).
An oven dried flask equipped with stir bar and septum was charged with lithium chloride (1.62 g, 38.17 mmol) and heated under high vacuum at 170° C. for 20 min. The vacuum was removed and nitrogen gas introduced into the flask as it was cooling. Zinc (2.50 g, 38.17 mmol) was added to the flask when cool and dried under high vacuum at 170° C. for 20 min and backfilled with nitrogen as it was cooling. When cooled to rt, THF (20 mL) and 1,2-dibromoethane (0.18 g, 38.17 mmol) were added via syringe and the reaction heated at 60° C. until bubbling occurred. After cooling to rt, chlorotrimethylsilane (0.02 g, 0.19 mmol) and iodine (0.02 g, 0.1 mmol) in THF (1 mL) were added via syringe and the reaction heated at 60° C. for 20 min and then cooled to rt. Added 1-iodo-3-(trifluoromethyl)bicyclo[1.1.1]pentane (5.0 g, 19.08 mmol) and stirred the reaction at 50° C. overnight. The reaction was allowed to stand at rt for 1 h and the clear solution on top of the solids carefully transferred via cannula to a dry flask for use without purification assuming ˜0.45 M concentration.
The following compounds in Table 3 were made in a similar way as described for iodo-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]zinc.
1-(5-Fluoro-2-hydroxy-phenyl)ethanone (2.0 kg, 13 mol) was dissolved in DMF (20 L) and treated with N-bromosuccinimide (2.8 kg, 15.6 mol) keeping the temperature below 20° C. Stirred at 0 to 10° C. for 5 to 6 h. Slowly added water (20 L) to the reactor, stirred at rt for 2 h, and filtered off the crude product. This material was slurried in heptane (10 L) at 0 to 25° C. for 2 h and removed the title compound (2.5 kg, 83%) by filtration as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.69 (3H, s), 7.90 (2H, m), 12.53 (1H, s).
A mixture of 2-bromo-4-methyl-phenol (10.0 g, 53.5 mmol) and pyridine (6.34 g, 80.2 mmol) in DCM (100 mL) was treated with propanoyl chloride (5.44 g, 58.8 mmol) at 0° C. and stirred at 25° C. for 16 h. The mixture was diluted with water (100 mL), the pH adjusted to 5 with HCl (2 M), and extracted with DCM (2×100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (2×150 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the product as an oil (13 g, crude). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (t, J=7.6 Hz, 3H), 2.30 (s, 3H), 2.62 (q, J=7.6 Hz, 2H), 7.11-7.18 (m, 1H), 7.19-7.26 (m, 1H), 7.50-7.55 (m, 1H).
2-Bromo-4-fluoro-phenol (3.0 kg, 15.7 mol) and EtOAc (15 L) were added to a 50 L reactor and stirred for 15 min. The solution was slowly treated with triethylamine (1.9 kg, 18.8 mol). The reaction was cooled and propionyl chloride (1.6 kg, 17.3 mol) was added dropwise keeping the temperature between 0 and 10° C. After addition was completed, the reaction was stirred at rt for 15 h. The reaction was carefully diluted with water (15 L) keeping the temperature of the reaction below 30° C. and then stirred at rt for 30 min. The organic phase was separated, washed with water (10 L), collected, dried over MgSO4, filtered, and concentrated under reduced pressure at 45° C. to give the title compound (3.6 kg, 93%) as a yellow liquid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (t, 3H), 2.65 (dd, 2H), 7.30 (m, 2H), 7.75 (m, 1H).
A 0° C. solution of 3-bromo-6-chloro-pyridine-2-sulfonyl chloride (1.94 g, 6.68 mmol) in 40 mL of DCM was treated dropwise with 2-methylpropan-2-amine (3.90 g, 53.28 mmol) in 5 mL of DCM over 2 min. After addition, the reaction was allowed to stir at rt for 1 h. The reaction was diluted with 50 mL of water and extracted with DCM (3×50 mL). The combined organics were washed with saturated aqueous sodium chloride (3×50 mL), collected, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluted with 10% to 25% EtOAc in petroleum ether to give the title compound (1.2 g, 69%) as a white solid. MS ES+ m/z 327, 329 [M+H]+.
A solution of phenylmethanethiol (0.97 g, 7.80 mmol) in THF (20 mL) was cooled to 0° C. and treated with sodium hydride (0.31 g, 7.80 mmol). After stirring at 0° C., the reaction was treated with 3-bromo-6-chloro-2-fluoropyridine (1.5 g, 7.10 mmol). The reaction was allowed to stir at rt for 1.5 h. The reaction was concentrated and purified by silica gel chromatography eluted with 0% to 100% EtOAc in heptane to give the title compound (2.10 g, 94%). MS ES+ m/z 314 [M+H]+.
Dissolved 8-bromo-3,4-dihydro-2H-isoquinolin-1-one (200 mg, 0.89 mmol) in 5 mL of THF and cooled to 0° C. When cold, treated the solution with sodium hydride (38.9 mg, 60%, 0.97 mmol). After stirring at 0° C. for 20 min, treated the reaction with 4-methoxybenzyl chloride (152 mg, 0.97 mmol) and allowed to stir at rt for 2 h. Added an additional 152 mg of 4-methoxybenzyl chloride and stirred at 50° C. for 23 h. The reaction was partitioned between water and EtOAc. The organic layer was removed and the aqueous layer extracted with EtOAc (2×). The organic layers were combined, washed with saturated aqueous sodium chloride, and dry loaded onto celite. Purified by silica gel chromatography eluted with 0% to 40% EtOAc in heptane to give the title compound (355 mg, >100%) as a colorless oil containing some 4-methoxybenzyl chloride. MS ES+ m/z 347 [M+H]+.
A 20 mL vial was charged with 8-bromo-2H-isoquinolin-1-one (0.34 g, 1.53 mmol) and DMF (5 mL), treated with sodium hydride (73.5 mg, 60%, 1.84 mmol), and stirred at rt for 10 min. The reaction was treated with 2-(trimethylsilyl)ethoxymethyl chloride (0.51 g, 3.06 mmol) and stirred at rt for 1 h. The reaction was treated with another 0.51 g of 2-(trimethylsilyl)ethoxymethyl chloride and the reaction stirred at 50° C. over the weekend. The reaction was partitioned between water and EtOAc. The organic layer was collected and the aqueous layer extracted with EtOAc (2×). The organic layers were combined, washed with saturated aqueous sodium chloride, and concentrated. The residue was purified by silica gel chromatography eluted with 0% to 40% EtOAc in heptane to give the title compound (231 mg, 432%) as an opaque oil. MS ES+ m/z 354/356 [M+H]+.
A DCM (2.4 L) mixture of 2-bromo-4-methyl-phenol (300 g, 1.6 mol) and pyridine (152 g, 1.92 mol) at 0° C. was treated with acetyl chloride and stirred at 25° C. for 16 h. The mixture was diluted with water (1500 mL), the pH adjusted to 5 with HCl (2 M aqueous), and extracted with DCM (3×500 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (2×250 mL), dried over Na2SO4, filtered, and concentrated to give the product as an oil (400 g, crude). 1H NMR (400 MHz, CDCl3) δ ppm 2.24 (s, 3H), 2.25 (s, 3H), 6.91 (d, J=8.4 Hz, 2H), 7.01-7.02 (m, 2H), 7.33 (s, 1H).
A mixture of (2-bromo-4-methyl-phenyl) acetate (50 g, 218 mmol) and AlCl3 (102 g, 764 mmol) was degassed and purged with N2 three times and stirred at 140° C. for 1 h. After cooling to rt, the reaction was diluted with DCM (30 mL) and dropped into 150 mL of water at 0° C. The mixture was filtered and the aqueous phase extracted with DCM (2×150 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was triturated with petroleum ether (2×150 mL) to give the product as a solid (30 g, 52%). 1H NMR (400 MHz, CDCl3) δ ppm 2.30 (s, 3H), 2.68 (s, 3H), 7.73 (s, 1H), 7.33 (s, 1H), 12.64 (s, 1H).
A mixture of (2-bromo-4-methyl-phenyl) propanoate (12.5 g, 51.4 mmol) and AlCl3 (24.0 g, 180 mmol) was stirred at 140° C. for 1 h. When cooled to rt, the mixture was quenched with water (80 mL) dropwise and stirred for 30 min. The mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (2×200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated and triturated with petroleum ether (20 mL) to give the product as a solid (9.82 g, 79%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.2 Hz, 3H), 2.28 (s, 3H), 3.15 (q, J=7.2 Hz, 2H), 7.66-7.73 (m, 1H), 7.77-7.83 (m, 1H), 12.66 (s, 1H).
(2-Bromo-4-fluoro-phenyl) propanoate (3.5 kg, 14.2 mol) in a reactor was heated to 75˜85° C. and treated with AlCl3 (1.0 kg, 7.4 mol) in batches while the internal temperature increased to 100˜110° C. The reaction was heated to 100˜120° C. and treated with more AlCl3 (1.1. kg, 8.2 mol). The reaction was stirred at 110˜130° C. for 18 h. The reaction was cooled to rt and poured into a mixture of MTBE (20 L) and 1M aqueous HCl (20 L) at 0˜10° C. The reaction was stirred at 0˜15° C. for 1 h. The organic layer was separated and washed with water (2×10 L). The organic phase was dried over MgSO4 and concentrated under reduced pressure to afford a crude product. The crude material was slurried with n-heptane (7 L) at rt for 6 h and then filtered to give the title compound (2.0 kg, 57%) as a brown solid after drying at 45° C. for 12 h. H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (t, 3H), 3.20 (m, 2H), 7.95 (m, 2H), 12.50 (s, 1H).
Trifluoromethanesulfonic acid (237 g, 1.58 mol) was cooled to below −5° C. and treated dropwise with (2-bromo-4-methyl-phenyl) propanoate (80 g, 329 mmol) over 1 h keeping the temperature between −5° C. and −20° C. After addition was completed, the cooling bath was removed and the reaction heated at 55-60° C. for 1.5 h. The mixture was cooled to 5-10° C., poured into ice water (5V), stirred for 30 min, and the solid removed by filtration. The cake was rinsed with water (2V), slurried in water (5V) for 30 min, and filtered to give the title compound (72.2 g, 90%) as an off-white solid after drying. ES/MS m/z 241/243 (M−H).
A 10 L reactor was charged with trifluoromethanesulfonic acid (5.54 kg, 36.90 mol) and cooled to −10° C. to −20° C. When cold, propionyl chloride (2.05 kg, 22.14 mol) was slowly added and stirred for 0.5 h. 1-Methoxy-4-(trifluoromethyl)benzene (1.30 kg, 7.38 mol) was slowly added for 2 h keeping the temperature between −10° C. and −20° C. The resulting solution was stirred for 20 h. The solution was slowly added to ice cold water (13 L) keeping the temperature at 0° C. to 10° C. and then stirred for 1 h. The suspension was then filtered and the solids rinsed with ice-cold water (7.5 L). The cake was dissolved in MTBE (3.9 L) and the aqueous phase discarded. The organic phase was concentrated to give the title compound (1.65 kg, 96%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.13-1.25 (3H, t, J=7.24 Hz), 2.95-3.08 (2H, q, J=7.23 Hz), 3.97 (3H, s), 7.06 (1H, d, J=8.68 Hz), 7.60-7.73 (1H, m), 7.95 (1H, d, J=2.16 Hz).
A mixture of NaOH (413.4 g, 10.34 mol) in DMF (8.25 L) was treated with 1-dodecanethiol (2.09 kg, 10.34 mol) at 25° C. and the mixture stirred at 25° C. for 1 h. The reaction was treated with 1-[2-methoxy-5-(trifluoromethyl)phenyl]propan-1-one (1.60 kg, 6.89 mol) and the reaction heated to 70° C. and stirred at that temperature for 1.5 h. The mixture was diluted with water (24 L) and extracted with MTBE (16 L). The pH of the aqueous phase was adjusted to 2-3 with aqueous HCl (2 N) and extracted with MTBE (16 L). The organic phase was washed with 15% aqueous NaCl (8 L), collected, and concentrated to give the title compound (1.24 kg, 82%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.25-1.32 (3H, t, J=7.22 Hz), 3.02-3.17 (2H, q, J=7.21 Hz), 3.97 (3H, s), 7.05-7.13 (1H, d, J=8.76 Hz), 7.65-7.74 (1H, m), 8.04 (1H, d, J=1.28 Hz), 12.66 (1H, s).
A mixture of 1-[2-hydroxy-5-(trifluoromethyl)phenyl]propan-1-one (1.20 kg, 5.50 mol) in DMF (4.8 L) was treated with N-bromosuccinimide (1.08 kg, 6.05 mol) at 5° C. to 15° C. and the mixture stirred at 20° C. to 30° C. for 5 h. The reaction was diluted with water (14.4 L) and saturated aqueous Na2SO3 (3.6 L) and stirred at 25° C. for 1 h. The mixture was filtered and the cake slurried in water (6 L) at 20° C. to 25° C. for 0.5 h, filtered, rinsed with water (3.6 L), and dried at 50° C. to afford the title compound (1.38 kg, 84%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.14 (3H, t, J=7.04 Hz), 3.23-3.31 (2H, q, J=7.05 Hz), 3.97 (3H, s), 8.21-8.35 (2H, d, J=8.80 Hz), 13.21 (1H, s).
A suspension of 1-(3-bromo-2-hydroxy-5-methyl-phenyl)propan-1-one (300 g, 1.23 mol) in THF (600 mL) was cooled to −70˜−75° C. and treated with lithium bis(trimethylsilyl)amide (5.4 L, 1M in THF, 5.4 mol) over 14 h maintaining the internal temperature below −60° C. After addition was complete, stirred at ˜60 to −75° C. for 30 min. The reaction was cooled to −70 to ˜75° C. and treated with pyridine-3-carbonyl chloride hydrochloride (285.6 g, 1.60 mol) portionwise maintaining the internal temperature below −60° C. After addition, the reaction was stirred at rt for 15 h. The reaction was cooled to 0 to −10° C. and quenched with AcOH/water (3V/3V) until the pH reached 5-6. The reaction was concentrated under reduced pressure and the title compound (600 g, 100%) removed by filtration, rinsed with water, and air dried. ES/MS m/z 348/350 (M+H).
A solution of 1-(3-bromo-2-hydroxy-5-methyl-phenyl)ethanone (65 g, 284 mmol) in THF (800 mL) was treated with NaHMDS (851 mL, 1 M) at −50° C. over 30 min, allowed to warm to between −5° C. and 0° C., and stirred for 1 h. The reaction was cooled to −20° C. and treated with CS2 (64.8 g, 851 mmol) dropwise over 1 h, allowed to warm to 25° C., and stirred for another 16 h. The reaction was quenched with H2SO4 (800 mL, 15%) at −50° C. over 1 h, allowed to warm to rt, and extracted with EtOAc (2×1L). The combined organic extracts were washed with saturated aqueous sodium chloride (1L), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was triturated with EtOAc (0.5 L) to give the product as a solid (210 g crude, 64%, purity ˜76%).
Potassium tert-butoxide (3.2 kg, 28.3 mol) and THF (30 L) were added to a 50 L reactor and the mixture stirred for 15 min to give a light yellow solution. Added 8-bromo-6-fluoro-4-hydroxy-3-methyl-chromene-2-thione (2.0 kg, 8.1 mol) in batches to the reactor keeping the temperature between 0 and 15° C. Carbon disulfide (740 g, 9.7 mol) was added dropwise keeping the temperature below 30° C. After addition was completed, the reaction was stirred at 0 to 25° C. for 12 h. The reaction mixture was poured directly into 15% aqueous acetic acid (5 L) and stirred at rt for 30 min. The mixture was filtered and the filter cake washed with MTBE (2 L). The filtrate was washed with water (2×5 L) and saturated aqueous NaCl (5 L). The organic phase was collected, dried over MgSO4, filtered, and concentrated under reduced pressure to afford the crude product. This material was slurried in heptane (5 L), stirred for 6 h, and filtered to give the title compound (2.8 kg, 120%) as a yellow solid after drying at 45° C. for 12 h. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.10 (s, 3H), 7.65 (m, 1H), 7.90 (m, 1H).
The following compound in Table 4 was made in a similar way as described for 8-bromo-6-fluoro-4-hydroxy-3-methyl-chromene-2-thione. Various methods were used to purify this compound, which would be apparent to one skilled in the art.
A mixture of 1-(3-bromo-2-hydroxy-5-methyl-phenyl)propan-1-one (200 g, 822.72 mmol), benzaldehyde (96.04 g, 904.99 mmol), AcOH (105.23 g, 1.75 mol), and piperidine (172.33 g, 2.02 mol) in EtOH (1600 mL) was stirred at 70° C. for 16 h. The resulting dark solution was poured into water (3 L), filtered, and the solid dissolved in 6 L of DCM. The organic solution was dried over anhydrous Na2SO4, filtered, and concentrated to give the product as a dark gum. MS ES+ m/z 331, 333 [M+H]+.
A mixture of 8-bromo-4-hydroxy-6-methyl-chromene-2-thione (20.0 g, 73.8 mmol), EtI (46 g, 295 mmol), and K2CO3 (12.2 g, 88.5 mmol) in acetone (200 mL) was stirred at 60° C. for 3 h. When the reaction had cooled to rt, the mixture was diluted with water (200 mL) and extracted with DCM (2×200 mL). The combined organic extracts were concentrated and purified by silica gel chromatography eluted with 20% to 40% EtOAc in petroleum ether to give the product as a gum. 1H NMR (400 MHz, CDCl3) δ ppm 1.51 (t, J=7.2 Hz, 3H), 2.45 (s, 3H), 3.22 (q, J=7.2 Hz, 2H), 6.32 (s, 1H), 7.70 (s, 1H), 7.93 (s, 1H).
The following compound in Table 5 was made in a similar way as described for 8-bromo-2-ethylsulfanyl-6-methyl-chromen-4-one. Various methods were used to purify this compound, which would be apparent to one skilled in the art.
The crude THF solution from the synthesis of 8-bromo-6-fluoro-4-hydroxy-chromene-2-thione (3.4 kg, 30 mol) was treated with EtI (5.4 kg, 34.4 mol) at 20 to 25° C. The resulting solution was stirred at 60 to 65° C. for 12 h. The reaction was cooled to rt and a solid removed by filtration. The cake was washed with MTBE (2 L). The filtrates were combined, washed with water (2×6 L), and washed with 10% aqueous NaCl. The organic phase was collected and concentrated under reduced pressure to afford the crude product. The crude solid was slurried with heptane (12 L) and stirred at rt for 3 h. Removed the title compound (2.0 kg, 77%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (t, 3H), 3.26 (dd, 2H), 6.47 (s, 1H), 7.69 (m, 1H), 8.15 (m, 1H).
A mixture of 1-[3-bromo-2-hydroxy-5-(trifluoromethyl)phenyl]propan-1-one (1.26 kg, 4.24 mol) in THF (3.0 L) was slowly treated with lithium tert-butoxide (1.36 kg, 16.97 mol) and stirred for 0.5 h. The reaction was then treated with carbon disulfide (355.2 g, 4.67 mol) in one portion and the mixture stirred at 15° C. to 25° C. for 16 h. The reaction was added to 15% aqueous H2SO4 (12.6 L) at 0° C. to 10° C. The organic layer was removed and the aqueous layer extracted with 2-methyltetrahydrofuran (12.6 L). The organic layers were combined, washed with saturated aqueous sodium chloride (6.3 L), and concentrated to give a crude yellow solid. The solid was slurried with DCM (3.6 L) for 1 h and filtered. The cake was dried under vacuum at 40° C. to afford 8-bromo-3-methyl-2-sulfanyl-6-(trifluoromethyl)chromen-4-one as a yellow solid.
A 10 L reactor was charged with 8-bromo-3-methyl-2-sulfanyl-6-(trifluoromethyl)chromen-4-one (from above), cesium carbonate (586.6 g, 1.8 mol), and acetone (6.3 L). The reaction was slowly treated with EtI (421.1 g, 2.7 mol) at 15° C. to 25° C. and then allowed to stir for 2 h. The reaction was filtered and rinsed with acetone (3.78 L). The filtrate was concentrated to afford the title compound (650 g, 42%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40-1.48 (3H, t, J=7.30 Hz), 1.93 (3H, s), 3.33-3.40 (2H, q, J=7.32 Hz), 8.18 (1H, d, J=1.52 Hz), 8.45 (1H, d, J=2.00 Hz).
A mixture of (E)-1-(3-bromo-2-hydroxy-5-methyl-phenyl)-2-methyl-3-phenyl-prop-2-en-1-one (284 g, 857.48 mmol) and I2 (21.76 g, 85.75 mmol) in DMSO (1200 mL) was stirred at 140° C. for 2 h to give a black-brown solution. Cooled to rt, poured the reaction into 3 L of water, filtered, dissolved the solid product in DCM (4 L), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was triturated with petroleum ether/EtOAc (1:1, 1 L) to give the product as a light yellow solid (195 g, 69%). MS ES+ m/z 329, 331 [M+H]+.
Crude 1-(3-bromo-2-hydroxy-5-methyl-phenyl)-2-methyl-3-(3-pyridyl)propane-1,3-dione (600 g, 1.23 mol) was suspended in HCl (0.15 V) and AcOH (3 V) and stirred at 90 to 100° C. for 2 h. The reaction was cooled to rt and basified to pH 8-9 with 5M aqueous NaOH keeping the temperature below 50° C. The resulting precipitate was collected by filtration and rinsed with water (2×2V). The solid was slurried with MTBE (5V), stirred at rt for 40 h, and the title compound collected by filtration (368 g, 90%) after drying at 50° C. ES/MS m/z (79Br/81Br) 330/332 (M+H).
A mixture of 8-bromo-2-ethylsulfanyl-6-methyl-chromen-4-one (9.00 g, 30.0 mmol), tributyl(1-ethoxyvinyl)tin (13.3 g, 36.8 mmol) and Pd(PPh3)2Cl2 (2.11 g, 3.01 mmol) in 1,4-dioxane (90 mL) was stirred at 95° C. for 16 h. HCl (30 mL, 1 M) was added to the mixture and stirred at 50° C. for 0.5 h. When cooled to rt, the mixture was treated with saturated aqueous KF (100 mL) and stirred for 0.5 h, then filtered. The filter cake was washed with EtOAc (3×40 mL). The filtrate was extracted with EtOAc (2×80 mL). The combined organic extracts were concentrated and purified by silica gel chromatography eluted with 0% to 60% EtOAc in petroleum ether to give the product as a solid (5.8 g, 60%). MS ES+ m/z 263 [M+H]+.
A mixture of 8-bromo-3,6-dimethyl-2-phenyl-chromen-4-one (195 g, 592.37 mmol), bis(triphenylphosphine)palladium(II) dichloride (20.79 g, 29.62 mmol), and tributyl(1-ethoxyvinyl)stannane (256.72 g, 710.84 mmol, 239.92 mL) in dioxane (1600 mL) was stirred under N2 at 95° C. for 16 h to give a black-brown solution. After cooling to rt, treated the reaction with 1M aqueous HCl (100 mL) and stirred at 20° C. for 30 min. The mixture was quenched with saturated aqueous KF (2000 mL), stirred for 30 min, and filtered. The filter cake was washed with 10% MeOH in DCM (5×5000 mL). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was triturated with petroleum ether/EtOAc (5/1, 1000 mL) to give a crude product which was triturated with DCM/MeOH (10/1, 500 mL) to give the product as a light yellow solid (180 g, 96%, 92% purity). MS ES+ m/z 293 [M+H]+.
A mixture of 8-bromo-2-ethylsulfanyl-3-methyl-6-(trifluoromethyl)chromen-4-one (980 g, 2.67 mol) in 1,4-dioxane (3.3 L) was treated with tributyl(1-ethoxyvinyl)stannane (1.06 kg, 2.94 mol). The reaction was evacuated and nitrogen used to replace the air three times and then bis(triphenylphosphine)palladium(II) dichloride (74.93 g, 106.8 mmol) was added in one portion. The reaction was evacuated and the nitrogen used to replace the air three more times and the reaction heated to 85° C. to 95° C. for 14 h. The reaction was allowed to cool to 50° C. and then aqueous HCl (4.9 L, 2 M) was added and the reaction stirred for 2 h. The reaction was cooled to 20° C. to 25° C. and then extracted with EtOAc (14.7 L). The organic phase was quenched with saturated aqueous KF (4.9 L), stirred for 1 h, and filtered. The organic phase was washed with saturated aqueous sodium chloride (4.9 L) and the organic phase concentrated to 4.9 L under reduced pressure. IPA (9.8 L) was added and the mixture concentrated to 4.9 L two more times. IPA (4.9 L) was added to the mixture and heated to 70° C. The mixture was filtered, the filtrate cooled to 0° C., stirred for 14 h, filtered, and the solids rinsed with TPA (1.96 L). Repeated the above crystallization process once again and the combined solids dried in the vacuum at 40° C. to afford the title compound (455.7 g, 520) as an off-white solid. MS ES+ m/z 331 [M+H]+.
The following compounds in Table 6 were made in a similar way as described for 8-acetyl-2-ethylsulfanyl-3-methyl-6-(trifluoromethyl)chromen-4-one. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
A solution of 8-acetyl-2-ethylsulfanyl-6-methyl-chromen-4-one (8.30 g, 31.6 mmol) in DCM (30 mL) and MeOH (30 mL) was treated with NaBH4 (1.32 g, 34.8 mmol) in portions at 0° C., and stirred at 15° C. for 1 h. The mixture was diluted with water (50 mL) and extracted with DCM (2×100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluted with 0% to 4% MeOH in DCM to give the product as a solid (6.0 g, 60%). MS ES+ m/z 265 [M+H]+.
The following compound in Table 7 was made in a similar way as described for 2-ethylsulfanyl-8-(1-hydroxyethyl)-6-methyl-chromen-4-one. Various methods were used to purify the compound, which would be apparent to one skilled in the art.
1H NMR (400 MHz, DMSO-d6) δ ppm: 1.47~1.51 (m, 3H), 1.56~1.58 (m, 6H), 2.06 (s, 3H), 2.63 (m, 1H) 3.19~3.25 (m, 2H), 5.39~5.44 (m, 1H), 5.62~5.63 (m, 1H), 7.50~7.53 (m, 1H), 7.61~7.64 (m, 1H)
1HNMR (400 MHz, CDCl3) δ ppm 1.46~1.50 (m, 3H), 1.58~1.60 (m, 3H), 2.23~2.24 (m, 1H), 3.08~3.13 (m, 2H), 5.41~5.47 (m, 1H), 6.26 (s, 1H), 7.58~7.61 (m, 1H), 7.69~7.71 (m, 1H)
A solution of 8-acetyl-2-ethylsulfanyl-3-methyl-6-(trifluoromethyl)chromen-4-one (140 g, 0.42 mol) in DCM (1.4 L) was cooled to −5° C. under a nitrogen atmosphere. Formic acid (58.5 g, 1.27 mol) was added slowly followed by dropwise addition of triethylamine (86.4 g, 0.85 mol) maintaining the temperature below 10° C. The Noyori catalyst (CAS: 74813-81-1, 2.7 g, 4.24 mmol) was added in one portion and the reaction allowed to warm to rt and stir for 18 h. The reaction was washed with 1 M aqueous HCl (2×500 mL), water (200 mL), and saturated aqueous NaCl (100 mL). The organic layer was collected, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (146 g, 100%, 99% purity) as a brown solid with a 93:7 enantiomeric ratio. ES/MS m/z 333 (M+H).
A mixture of 2-ethylsulfanyl-8-(1-hydroxyethyl)-6-methyl-chromen-4-one (5.50 g, 20.8 mmol) in DCM (50 mL) was treated dropwise with PBr3 (16.9 g, 62.4 mmol) at 0° C., then stirred at 30° C. for 4 h. The reaction was quenched with water (20 mL) at 0° C. and the pH adjusted to 8 with saturated aqueous NaHCO3. The mixture was extracted with DCM (2×80 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous Na2SO4, filtered, and concentrated to give the product as an oil (4.7 g, 61%). MS ES+ m/z 329 [M+2+H]+.
The following compounds in Table 8 were made in a similar way as described for 8-(1-bromoethyl)-2-ethylsulfanyl-6-methyl-chromen-4-one. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
11HNMR (400 MHz, CDCl3) δ ppm: 1.50~1.54 (m, 3H), 2.10 (s, 3H), 2.15~2.17 (m, 3H), 3.27~3.42 (m, 2H), 5.64~5.69(m, 1H), 7.50~7.53 (m, 1H), 7.82~7.84 (m, 1H).
21HNMR (400 MHz, CDCl3) δ ppm 1.48~1.51 (m, 3H), 2.13~2.15 (m, 3H), 3.12~3.27 (m, 2H), 5.64~5.69 (m, 1H), 6.32 (s, 1H), 7.55~7.57 (m, 1H), 7.79~7.81 (m, 1H).
A mixture of 8-acetyl-2-ethylsulfanyl-6-methyl-chromen-4-one (9.49 g, 36.2 mmol) and (R)-2-methylpropane-2-sulfinamide (8.77 g, 72.4 mmol) in THF (100 mL) was treated with Ti(i-PrO)4 (41.1 g, 145 mmol) and stirred at 75° C. for 16 h. The reaction was treated with additional (R)-2-methylpropane-2-sulfinamide (6.58 g, 54.3 mmol) and Ti(i-PrO)4 (30.9 g, 109 mmol) and stirred at 75° C. for another 16 h. The mixture was quenched with saturated aqueous sodium chloride (200 mL), stirred for 0.5 h, and filtered. The filter cake was washed with EtOAc (300 mL). The aqueous layer was extracted with EtOAc (2×300 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (2×200 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the product as a solid (13 g, crude). MS ES+ m/z 366 [M+H]+.
To a mixture of 8-acetyl-3,6-dimethyl-2-phenyl-chromen-4-one (180 g, 615.75 mmol) and (R)-2-methylpropane-2-sulfinamide (149.26 g, 1.23 mol) in THF (1500 mL) was added tetraisopropoxytitanium (700.01 g, 2.46 mol, 726.90 mL). The mixture was stirred at 80° C. for 56 h to give a black-brown solution. After cooling to rt, quenched the reaction with saturated aqueous sodium chloride (2000 mL) and stirred for 30 min and filtered. The filter cake was washed with EtOAc (4000 mL). After separating the organic layer, the aqueous layer was extracted with EtOAc (1000 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was triturated with petroleum ether/EtOAc (1/1, 600 mL) to give the product as a white solid (186 g, 76%). MS ES+ m/z 396 [M+H]+.
The following compound in Table 9 was made in a similar way as described for (NE,R)—N-[1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethylidene]-2-methyl-propane-2-sulfinamide.
A mixture of (NE,R)—N-[1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethylidene]-2-methyl-propane-2-sulfinamide (12.0 g, 32.8 mmol) in DCM (100 mL) and MeOH (100 mL) was treated with AcOH (15.8 g, 262 mmol) and NaBH3CN (6.19 g, 98.5 mmol) at −10° C., and stirred at 25° C. for 16 h. The mixture was quenched with NH3·H2O (250 mL) and extracted with DCM (3×200 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the product as a solid (11 g, isomer ratio: 3/2, crude). MS ES+ m/z 368 [M+H]+.
To a mixture of (NE,R)—N-[1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethylidene]-2-methyl-propane-2-sulfinamide (186 g, 470.27 mmol) and CeCl3·7H2O (87.61 g, 235.14 mmol, 22.35 mL) in MeOH (1600 mL) was added NaBH4 (26.69 g, 705.41 mmol) at 15° C. The mixture was stirred at 15° C. for 1 h to give a dark suspension. The reaction was quenched with saturated aqueous NH4Cl (1500 mL) at 15° C. Extracted with DCM (2×1500 mL), washed the combined organic phases with saturated aqueous sodium chloride (1500 mL), dried the organic phase over anhydrous Na2SO4, filtered, and concentrated to give the product as a yellow solid (180 g, 96%). MS ES+ m/z 398 [M+H]+.
A solution of (NE,R)—N-[1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethylidene]-2-methyl-propane-2-sulfinamide (600 mg, 1.52 mmol) in tetradeuteromethanol (10 mL) was treated with cerium(III) chloride heptahydrate (283 mg, 0.76 mmol) and cooled to −78° C. The reaction was treated with sodium borodeuteride (127 mg, 3.03 mmol) in one portion. The reaction was allowed to stir at −78° C. After 1 h, the reaction was concentrated under reduced pressure and the residue purified by silica gel chromatography eluted with 0% to 100% EtOAc (with 25% EtOH) in heptane followed by reversed phase chromatography on C18 eluted with 0% to 100% ACN in 10 mM aqueous NH4HCO3 (with 5% MeOH) to give the title compound (530 mg, 88%). ES/MS m/z 399 (M+H).
A mixture of (R)—N-[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]-2-methyl-propane-2-sulfinamide (6.00 g, 16.3 mmol) in EtOAc (40 mL) was treated with HCl (82 mL, 4 M in EtOAc) and stirred at 25° C. for 16 h. The mixture was concentrated, diluted with water (100 mL), and washed with EtOAc (100 mL). The pH of the aqueous phase was adjusted to 8 with NH3·H2O (25%) and extracted with DCM (3×100 mL). The combined organic phases were washed with saturated aqueous sodium chloride (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the product as an oil (2.4 g, crude). MS ES+ m/z 264 [M+H]+.
A solution of (R)—N-[(1R)-1-deuterio-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]-2-methyl-propane-2-sulfinamide (530 mg, 1.33 mmol) in DCM (8 mL) was cooled to 0° C. and treated with HCl (4 N in 1,4-dioxane, 97 mg, 2.66 mmol). The reaction was allowed to stir overnight and gradually warm to rt. The reaction was diluted with DCM and washed with saturated aqueous NaHCO3. The aqueous layer was back extracted with 25% IPA in chloroform. The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound which was used without purification. ES/MS m/z 295 (M+H).
A mixture of (R)—N-[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]-2-methyl-propane-2-sulfinamide (180 g, 452.80 mmol) in MeOH (1500 mL) was treated with HCl/MeOH (4 M, 300 mL) and the mixture was stirred at 15° C. for 1 h to give a white suspension. Concentrated the reaction, poured the residue into water (1000 mL) and DCM (2000 mL), adjusted the pH to 12 with NH3 in H2O (25%), and extracted with DCM (2×1000 mL). The combined organic phases were washed with saturated aqueous sodium chloride (1000 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was triturated with DCM (200 mL) to give the product as a white solid (122 g, 89%). MS ES+ m/z 294 [M+H]+.
A mixture of 8-acetyl-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (50 g, 0.18 mol) in 500 mL of toluene was treated with (R)-2-methylpropane-2-sulfinamide (32.7 g, 0.27 mol) and titanium ethoxide (82.1 g, 0.36 mol) in one portion. The reaction was heated at 80° C. for 24 h, then cooled to rt.
The toluene solution of (NE,R)—N-[1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethylidene]-2-methyl-propane-2-sulfinamide (0.18 mol) was cooled to between −10° C. and 0° C. and treated in portions with sodium borohydride (20.4 g, 0.54 mmol) keeping the internal temperature below 0° C. After stirring at −10° C. and 0° C. for 1 h, the reaction was quenched with saturated aqueous NH4Cl. The resulting white slurry was filtered through diatomaceous earth and the solids washed with THF. The filtrate was washed with saturated aqueous sodium chloride and the organic layer concentrated onto silica gel. The material was purified by chromatography to give the product (26 g, 37% over two steps). MS ES+ m/z 382 [M+H]+.
The following compound in Table 10 was made in a similar way as described for (R)—N-[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]-2-methyl-propane-2-sulfinamide.
A solution of (R)—N-[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]-2-methyl-propane-2-sulfinamide (20 g, 52.4 mmol) in THF (200 mL) was treated dropwise with 12 M aqueous HCl (2 eq) and stirred at rt. After 1 h, the reaction was concentrated, the residue dissolved in water, and extracted with MTBE. The pH of the aqueous phase was adjusted to between 9 and 10 with 1M aqueous NaOH and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium chloride, dried over MgSO4, filtered, and concentrated to give the product (12.6 g, 87%) as a white solid. MS ES+ m/z 278 [M+H]+.
The following compound in Table 11 was made in a similar way as described for 8-[(1R)-1-aminoethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one.
A mixture of 8-[(1R)-1-aminoethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (2.5 g, 9.0 mmol) and diisopropylethylamine (2.0 g, 16 mmol) in DCM (40 mL) was treated with di-tert-butyl dicarbonate (3.0 g, 14 mmol) and stirred overnight at rt. Concentrated the reaction and purified the residue by silica gel chromatography eluted with 0% to 100% EtOAc in heptane to give the product (2.5 g, 73%). MS ES+ m/z 378 [M+H]+.
The following compounds in Table 12 were made in a similar way as described for tert-butyl N-[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]carbamate. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
tert-Butyl N-[(1R)-1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethyl]carbamate (5.00 g, 13.8 mmol) was dissolved in dry THF (27.5 mL) and cooled to 0° C. When cool, the reaction was treated dropwise with 2,2,6,6-tetramethylpiperidinylzinc chloride lithium chloride complex (41.3 mL, 41.3 mmol, 1M in THF) over 15 min. The reaction was stirred at 0° C. for 1 h. A solution of iodine (6.98 g, 27.5 mmol) in THF (20 mL) was added dropwise and the reaction stirred an additional 30 min. The reaction was concentrated under reduced pressure and the residue partitioned between water and DCM. The layers were separated and the aqueous layer re-extracted with DCM (2×). The organic layers were combined, washed with saturated aqueous Na2S2O3, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 0% to 100% EtOAc in heptane to give the title compound (8.33 g, 124%) as a brown foam. ES/MS m/z 490 (M+H).
Transferred tert-butyl N-[(1R)-1-(2-ethylsulfanyl-3-iodo-6-methyl-4-oxo-chromen-8-yl)ethyl]carbamate (1.0 g, 2.04 mmol) and oxazol-4-ylboronic acid (0.46 g, 4.09 mmol) to a tube. Added 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.33 g, 0.51 mmol) and cesium carbonate (2.0 g, 6.13 mmol) suspended in 9:1 1,4-dioxane/water (4.1 mL). The reaction was sparged with argon gas for 5 min and then stirred at 65° C. for 2 h. After cooling to rt, the reaction was filtered through diatomaceous earth and the solids washed with DCM. The filtrate was concentrated under reduced pressure and the residue purified by silica gel chromatography eluted with 0% to 40% EtOAc in heptane to give the title compound (0.29 g, 33%). ES/MS m/z 431 (M+H).
Charged a 20 mL vial with 8-[(1R)-1-aminoethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (0.30 g, 1.08 mmol), (2-methylindazol-5-yl)boronic acid (0.57 g, 3.24 mmol), tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.11 mmol), copper(I) thiophene-2-carboxylate (0.31 g, 1.62 mmol), and EtOH (15 mL). Degassed the reaction with argon, capped the vial, and stirred at 55° C. for 16 h. The reaction mixture was loaded onto celite and purified by reverse phase C18 flash chromatography eluted with 1000 to 100% ACN in 10 mM aqueous NH4HCO3 with 500 MeOH to give the title compound (0.23 g, 600%). MS ES+ m/z 348 [M+H]+.
The following compounds in Table 13 were made in a similar way as described for 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-(2-methylindazol-5-yl)chromen-4-one. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
1Stananne used as coupling partner.
A vial was charged with 8-[(1R)-1-aminoethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (0.50 g, 1.80 mmol), 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.35 g, 5.41 mmol), tetrakis(triphenylphosphine)palladium(0) (0.52 g, 0.45 mmol), copper(I) 3-methylsalicylate (0.58 g, 2.70 mmol), and EtOH (8 mL). Nitrogen was bubbled through the reaction for 2 min, the vial was sealed, and the reaction stirred at 60° C. for 16 h. The reaction was retreated with the same amounts of 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole, tetrakis(triphenylphosphine)palladium(0), and copper(I) 3-methylsalicylate, and nitrogen was bubbled through the reaction for 5 min. The reaction was heated at 60° C. for 16 h. The reaction was cooled, filtered through diatomaceous earth, solids washed with DCM/MeOH, and the filtrate concentrated under reduced pressure. The residue was purified by reversed phase chromatography on C18 eluted with 10% to 65% ACN in 10 mM aqueous NH4HCO3 to give the title compound (0.31 g, 51%). ES/MS m/z 340 (M+H).
The following compounds in Table 14 were made in a similar way as described for 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-[1-(oxetan-3-yl)pyrazol-4-yl]chromen-4-one. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
1Stannane used as coupling partner.
Combined tert-butyl N-[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]carbamate (0.50 g, 1.32 mmol), copper(I) thiophene-2-carboxylate (0.63 g, 3.31 mmol), triphenylphosphine (0.28 g, 1.06 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.12 g, 0.13 mmol), and pyridine-2-ylboronic acid (0.37 g, 3.05 mmol) in 8 mL of EtOH and degassed with argon for 5 min. The reaction was allowed to stir at 35° C. for 72 h. The reaction was recharged with 300 mg of all reagents, degassed, and allowed to stir at 35° C. overnight. The reaction was filtered and purified by silica gel chromatography eluted with 0% to 100% EtOAc in heptane to give the title compound (0.50 g, 96%). MS ES− m/z 395 [M−H]−.
Combined 8-[(1R)-1-aminoethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (0.50 g, 1.80 mmol), zinc(II) 2,6-difluorobenzen-1-ide bromide (0.93 g, 3.61 mmol, 0.5 M), copper(I) thiophene-2-carboxylate (0.51 g, 2.70 mmol), and methanesulfonato{[4-(N,N-dimethylamino)phenyl]di-t-butylphosphino)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (0.34 g, 0.54 mmol) in THF (5 mL) and degassed for 10 min. The reaction was capped and allowed to stir at 130° C. overnight. The reaction was allowed to cool to rt, diluted with 10 mL of DCM, filtered through celite, and concentrated. The residue was purified by silica gel chromatography eluted with 0% to 100% EtOAc in DCM and then 0% to 20% MeOH in DCM. The desired fractions were then repurified by reversed phase chromatography eluted with 10% to 100% ACN (with 0.1% formic acid) in water (with 0.1% formic acid). The product was then purified by reversed phase chromatography eluted with 10% to 100% ACN in 10 mM NH4HCO3 (with 5% MeOH) to give the title compound (0.20 g, 34%). MS ES+ m/z 330 [M+H]+.
8-(1-Bromoethyl)-2-ethylsulfanyl-6-methyl-chromen-4-one (25.0 g, 76.4 mmol), tert-butyl 2-aminobenzoate (29.5 g, 153 mmol) and DIEA (14.8 g, 20.0 mL, 115 mmol) were combined with DMF (150 mL) in a 500 mL round bottom flask and heated at 80° C. After cooling to rt, the reaction was partially concentrated to ˜100 mL, poured into 1.1 L of water, and extracted with EtOAc (2×350 mL). The combined organic layers were washed with saturated aqueous sodium chloride (400 mL). The combined aqueous layers were re-extracted with fresh EtOAc. The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated to give a thick oil. Purified the residue via silica gel chromatography using EtOAc in DCM (0% to 10%) to provide an off-white foam. Triturated with heptanes/DCM and washed with heptanes to give the product as a white solid (27.1 g, 81%). MS ES+ m/z 440 [M+H]+.
Dissolved 8-(1-bromoethyl)-2-ethylsulfanyl-6-fluoro-chromen-4-one (66.0 g, 200 mmol) in CHCl3 (660 mL) and treated with pyridine (17.34 g, 219 mmol) and tert-butyl 2-aminobenzoate (42.36 g, 219 mmol) at rt. The reaction was stirred at 80° C. for 66 h. The reaction was allowed to cool to rt and concentrated under reduced pressure. The crude product was suspended in EtOAc (200 mL), sonicated, and filtered. This procedure was repeated three times. The filtrates were concentrated under reduced pressure and the residue slurried in 300 mL of heptane for 30 min. The solid was removed by filtration, washed with heptane (3×150 mL) and dried to give the title compound (43 g, 49%). 1HNMR (400 MHz, CDCl3) δ ppm 1.48˜1.51 (m, 3H), 1.65 (s, 9H), 1.68˜1.70 (d, 3H), 3.11˜3.17 (m, 2H), 5.06˜5.13 (m, 1H), 6.23˜6.26 (d, 1H), 6.33 (s, 1H), 6.59˜6.63 (m, 1H), 7.16˜7.21 (m, 1H), 7.41˜7.44 (m, 1H), 7.69˜7.71 (m, 1H), 7.91˜7.93 (m, 1H), 8.31˜8.32 (m, 1H).
A solution of 8-[(1R)-1-bromoethyl]-2-ethylsulfanyl-3-methyl-6-(trifluoromethyl)chromen-4-one (223 g, 0.56 mol) and 3-amino-6-chloro-pyridine-2-carboxylic acid (146 g, 0.85 mol) in DMF (1.8 L) was stirred at 85° C. for 3 days. The reaction was cooled to rt and slowly added to water (6.7 L). The resulting precipitate was collected by filtration and the solid slurried in water (3.3 L), filtered, and dried in an oven to give the title compound (232 g, 84%, 73% purity). ES/MS m/z 487 (M+H).
A solution of 8-(1-bromoethyl)-2-ethylsulfanyl-6-fluoro-3-methyl-chromen-4-one (100 g, 290 mmol) in DMF (800 mL) was treated with 3-amino-6-chloro-pyridine-2-carboxylic acid (50 g, 290 mmol). The reaction was stirred at 80 to 90° C. for 58 h. The reaction was concentrated under reduced pressure at 60° C. and the residue slurried with MTBE (500 mL) and water (100 mL). After 30 min under sonication, the reaction was filtered and the solids washed with MTBE (2×500 mL) to give the title compound (64 g, 51%) as a light yellow solid. 1HNMR (400 MHz, CDCl3) δ ppm 1.47˜1.51 (m, 3H), 1.64˜1.66 (m, 3H), 1.98 (s, 3H) 3.09˜ 3.36 (m, 2H), 5.15˜5.21 (m, 1H), 7.00˜7.02 (d, 1H), 7.30˜7.35 (m, 1H), 7.49˜7.51 (m, 1H), 7.58˜7.61 (m, 1H) 8.29˜8.31 (m, 1H), 13.15 (br, 1H).
A solution of 6-chloro-3-[1-(2-ethylsulfanyl-6-fluoro-3-methyl-4-oxo-chromen-8-yl)ethylamino]pyridine-2-carboxylic acid (79 g, 181 mmol) in THF (800 mL) was cooled to 10° C. and treated dropwise with 2-tert-butyl-1,3-diisopropyl-isourea (126.78 g, 633 mmol). The reaction was stirred at 20° C. for 2 h, filtered, and the solids washed with THF (2×100 mL). The filtrate was concentrated under reduced pressure and the residue was slurried in 200 mL of MTBE under sonication for 30 min giving the title compound (76.3 g, 86%) after filtration, washing with MTBE (100 mL) and drying. 1HNMR (400 MHz, CDCl3) δ ppm 1.47˜1.51 (m, 3H), 1.63˜1.74 (m, 12H), 2.12 (s, 3H), 3.21˜ 3.26 (m, 2H), 5.01˜5.07 (m, 1H), 6.59˜6.61 (d, 1H), 7.09˜7.11 (d, 1H), 7.30˜7.33 (m, 1H), 7.75˜7.78 (m, 1H), 8.32˜8.33 (d, 1H).
The following compound in Table 15 was made in a similar way as described for tert-butyl 6-chloro-3-[1-(2-ethylsulfanyl-6-fluoro-3-methyl-4-oxo-chromen-8-yl)ethylamino]pyridine-2-carboxylate. Various methods were used to purify the compound, which would be apparent to one skilled in the art.
Combined 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-(2-methylindazol-5-yl)chromen-4-one (100 mg, 0.29 mmol), methyl 4-chloro-6-methyl-2-oxo-1H-pyridine-3-carboxylate (87 mg, 0.43 mmol), and triethylamine (58.3 mg, 0.58 mmol) in MeOH (1 mL) and stirred the reaction at 75° C. for 60 h. Cooled the reaction to rt and concentrated under reduced pressure to give the title compound (148 mg, 100%). ES/MS m/z 513 (M+H).
The following compound in Table 16 was made in a similar way as described for methyl 4-[[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethyl]amino]-6-methyl-2-oxo-1H-pyridine-3-carboxylate. Various methods were used to purify the compound, which would be apparent to one skilled in the art.
tert-Butyl 2-[1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoate (22.04 g, 50.14 mmol) was separated into component isomers using a Chiralcel OJ column (8×34 cm; 20 micron) eluted with 100% MeOH with 0.2% DMEA to give isomer 1 (wet 11.3 g) and isomer 2 (wet 12.9 g). MS ES+ m/z 440 [M+H]+.
tert-Butyl 6-chloro-3-[1-(2-ethylsulfanyl-6-fluoro-3-methyl-4-oxo-chromen-8-yl)ethylamino]pyridine-2-carboxylate (76.3 g, 155 mmol) was separated into component isomers using a ChiralPak IC column (250×50 mm, 10 μm) eluted with 45% i-PrOH (with 0.1% NH4OH) in CO2 to give crude Isomer 1 (38.40 g) and crude Isomer 2 (27 g). Isomer 1 was repurified by preparative HPLC using a Sharpsil-T C18 column (50×250 mm, 8 microns) eluted with 85% to 98% ACN in water (with 0.05% TFA) to give Isomer 1 (28.60 g, 37%) as an off-white solid. ES/MS m/z 493 (M+H).
tert-Butyl 2-[1-(2-ethylsulfanyl-6-fluoro-4-oxo-chromen-8-yl)ethylamino]benzoate (48.3 g, 109 mmol) was separated into component isomers using chiral SFC [ChiralPak IG, 250×50 mm, 10 μm; MeOH in CO2] to give Isomer 1 (22.4 g, 46%) and Isomer 2 (19.0 g, 39%) as yellow solids. ES/MS m/z 466 (M+H).
tert-Butyl 6-chloro-3-[1-[2-ethylsulfanyl-3-methyl-4-oxo-6-(trifluoromethyl)chromen-8-yl]ethylamino]pyridine-2-carboxylate was separated into component isomers using chiral SFC [WhelkO1-(R,R), 50×250 mm, 10 μm; 25% EtOH in CO2] to give Isomer 1 (first eluting; 67.7 g, 99% ee) and Isomer 2 (68.0 g, 93.6% ee). ES/MS m/z 543 (M+H).
A vial was charged with 8-[(1R)-1-aminoethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (1.0 g, 3.61 mmol), tert-butyl 3-bromo-6-chloropicolinate (1.58 g, 5.41 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.25 g, 0.27 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.42 g, 0.72 mmol), cesium carbonate (2.93 g, 9.01 mmol), and 12 mL of toluene. The suspension was purged with nitrogen gas for 10 min and the vial sealed. The reaction was stirred at 130° C. overnight. The reaction was cooled to rt, filtered, and the solids washed with DCM. The filtrate was concentrated and the residue purified by silica gel chromatography eluted with 0% to 100% EtOAc in hexane to give the title compound (0.88 g, 50%) as a pale tan solid. MS ES− m/z 433 [M+2H−tBu]+.
The following compounds in Table 17 were made in a similar way as described for tert-butyl 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
11,4-Dioxane used as solvent.
2XantPhos Pd G4 used instead of Pd2(dba)3 and Xantphos.
A solution of 8-[(1R)-1-aminoethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (10 g, 36 mmol) in DMF (150 mL) was treated with cesium carbonate (23.49 g, 72 mmol), 3-bromo-N-tert-butyl-6-chloro-pyridine-2-sulfonamide (15.36 g, 47.0 mmol), copper(I) iodide (1.37 g, 7 mmol), and N,N′-bis(furan-2-ylmethyl)oxalamide (1.79 g, 7 mmol) at rt. The reaction was stirred at 100° C. for 12 h. The reaction was allowed to cool to rt and filtered. The filtrate was concentrated under reduced pressure and the residue purified by silica gel chromatography eluted with 17% EtOAc in heptane to give the title compound (12.3 g, 65%) as an off-white solid. ES/MS m/z 524 (M+H).
A solution of tert-butyl 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate (1.0 g, 2.05 mmol) in DCM (10 mL) was cooled to 0° C. and treated in portions with mCPBA (0.50 g, 77%, 2.25 mmol). After addition was complete, the reaction was stirred at 0° C. for 1 h. The reaction was diluted with DCM and washed with saturated aqueous NaHCO3. The organic layer was removed and the aqueous layer extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 0% to 100% EtOAc in heptane to give the title compound (1.0 g, 97%) as a pale tan solid. ES/MS m/z 503 (M−H).
The following compounds in Table 18 were made in a similar way as described for tert-butyl 6-chloro-3-[[(1R)-1-(2-ethylsulfinyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
A solution of tert-butyl 6-chloro-3-[[(1R)-1-(2-ethylsulfinyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate (0.95 g, 1.87 mmol) and benzyl(triethyl)ammonium chloride (0.21 g, 0.94 mmol) in DCM (30 mL) was treated with HCl (0.78 mL, 37% aqueous, 9.37 mmol). The reaction was stirred at rt for 1 h, treated with additional aqueous HCl (0.18 mL, 37% aqueous), and allowed to stir 30 min. The reaction was quenched with saturated aqueous NaHCO3 and extracted with DCM. The organic layer was washed with saturated aqueous NaCl, collected, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 0% to 50% EtOAc in heptane to give the title compound (0.42 g, 49%) as a white foam. ES/MS m/z 407 (MH-tBu).
The following compounds in Table 19 were made in a similar way as described for tert-butyl 6-chloro-3-[[(1R)-1-(2-chloro-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
A dry vial was charged with tert-butyl 6-chloro-3-[[(1R)-1-(2-chloro-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate (208 mg, 0.45 mmol), palladium(II) acetate (10.1 mg, 0.05 mmol), and 2-dicyclohexylphosphino-2′,6′-bis(N,N-dimethylamino)biphenyl (CPhos, 39.2 mg, 0.09 mmol). The vial was evacuated and refilled with nitrogen three times. Added THF (2 mL) via syringe and cooled the reaction to 0° C. Added iodo-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]zinc (220 mg, ˜0.45 M in THF, 0.67 mmol) via syringe, removed the cooling bath, and stirred overnight at rt. The reaction was cooled to 0° C. and recharged with palladium(II) acetate (10.1 mg, 0.05 mmol), CPhos (39.2 mg, 0.09 mmol), and iodo-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]zinc (220 mg, 0.67 mmol). The cooling bath was removed and the reaction stirred at rt for 8 h. The reaction was diluted with EtOAc and washed with saturated aqueous NH4Cl. The organic layer was removed and the aqueous layer re-extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 0% to 50% EtOAc in heptane to give the title compound (183.2 mg, 73%) as a brown foam. ES/MS m/z 561 (M+H).
The following compounds in Table 20 were made in a similar way as described for tert-butyl 6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]chromen-8-yl]ethyl]amino]pyridine-2-carboxylate. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
A solution of 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carbonitrile (3.10 g, 7.75 mmol) in THF (50 mL) was purged with nitrogen gas and cooled to 0° C. The reaction was treated dropwise with 2,2,6,6-tetramethylpiperidinylzinc chloride lithium chloride complex solution (1M, 23.26 mL, 23.26 mmol). The reaction was stirred for 1 h while slowly warming to rt before iodine (5.90 g, 23.26 mmol) was added and the reaction stirred for another 30 min. The reaction was quenched with saturated aqueous NH4Cl, concentrated under reduced pressure, and the residue resuspended in 100 mL of DCM. The suspension was filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 10% to 100% EtOAc in heptane to give the title compound (3.20 g, 75%) as a brown solid. ES/MS m/z 544 (M+H).
Combined tert-butyl 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate (600 mg, 1.26 mmol), N-chlorosuccinimide (202 mg, 1.52 mmol), and benzoyl peroxide (30.6 mg, 0.13 mmol) in ACN (10 mL) and stirred at 25° C. for 2 h. The reaction was concentrated under reduced pressure and purified by silica gel chromatography eluted with 10% to 100% EtOAc in heptane to give the title compound (580 mg, 90%) as a white solid. ES/MS m/z 453 (M+H).
Combined 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3-iodo-6-methyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carbonitrile (4.0 g, 7.61 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (2.97 g, 15.2 mmol), cesium carbonate (7.44 g, 22.8 mmol), and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium(II) dichloride (0.50 g, 0.76 mmol) in 1,4-dioxane (90 mL) and water (10 mL). The reaction was stirred at 65° C. for 1.5 h. The reaction was cooled to rt, filtered through a pad of silica gel, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 10% to 80% EtOAc in hexane to give the title compound (3.1 g, 83%) as a white solid. ES/MS m/z 467 (M+H).
Intermediate-155C: 2-Ethylsulfanyl-8-[(1R)-1-[[2-(2-fluorophenyl)-3-pyridyl]amino]ethyl]-3,6-dimethyl-chromen-4-one
Combined 8-[(1R)-1-[(2-chloro-3-pyridyl)amino]ethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (1.37 g, 3.52 mmol), (2-fluorophenyl)boronic acid (0.49 g, 3.52 mmol), potassium carbonate (0.97 g, 7.05 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.20 g, 0.17 mmol) in 1,4-dioxane (12 mL) and water (3 mL). Sparged the reaction with argon for 5 min and then stirred at 100° C. for 16 h. The reaction was purified by silica gel chromatography eluted with 0% to 60% EtOAc in heptane to give the title compound (1.10 g, 70%) as a yellow foam. ES/MS m/z 449 (M+H).
A solution of tert-butyl N-[(1R)-1-[2-(2-fluorophenyl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]carbamate (0.68 g, 1.65 mmol) in 10 mL of DCM was treated with TFA (5 mL) and the reaction stirred at 60° C. for 2 h. The reaction was concentrated and the residue purified by reversed phase C18 flash chromatography eluted with 0% to 100% ACN in 10 mM aqueous NH4HCO3 with 5% MeOH. Fractions containing product were pooled, washed with saturated aqueous sodium chloride, and extracted with IPA/CHCl3 (1:3). The organics were collected, dried over MgSO4, filtered, and concentrated to give the title compound (0.26 g, 51%) as a yellow foam. MS ES+ m/z 312 [M+H]+.
The following compounds in Table 21 were made in a similar way as described for 8-[(1R)-1-aminoethyl]-2-(2-fluorophenyl)-3,6-dimethyl-chromen-4-one. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
A solution of tert-butyl N-[(1R)-1-[6-methyl-2-(1-methylpyrazol-4-yl)-4-oxo-chromen-8-yl]ethyl]carbamate (100 mg, 0.26 mmol) in 3 mL of DCM was treated with HCl (4 M in 1,4-dioxane, 190 mg, 5.22 mmol) and stirred at rt for 6 h. The reaction was concentrated and the residue purified by reverse phase chromatography eluted with 10% to 100% ACN (with 5% MeOH) in 10 mM aqueous NH4HCO3 to afford the title compound (54 mg, 69%) as a white solid. MS ES+ m/z 284 [M+H]+.
The following compounds in Table 22 were made in a similar way as described for 8-[(1R)-1-aminoethyl]-6-methyl-2-(1-methylpyrazol-4-yl)chromen-4-one. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
A mixture of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (30 g, 102.3 mmol), 2-iodobenzoic acid (25.36 g, 102.26 mmol), copper (13.00 g, 204.5 mmol), and potassium carbonate (21.20 g, 153.4 mmol) was suspended in DMF (300 mL) and stirred at 100° C. for 3 h. A mixture of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (30 g, 102.3 mmol), 2-iodobenzoic acid (25.36 g, 102.26 mmol), copper (13.00 g, 204.5 mmol), and potassium carbonate (21.20 g, 153.4 mmol) was suspended in DMF (300 mL) and stirred at 100° C. for 3 h. The two reactions were combined, the pH adjusted to ˜3 with 2M aqueous HCl, diluted with DCM (1 L) and water (500 mL), filtered, and the layers separated. The organic layer was washed with saturated aqueous sodium chloride (3×1 L), dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (5-50% EtOAc in petroleum ether). The resulting solid was triturated with EtOAc (300 mL) and collected by filtration. The resulting solid was suspended in boiling I (500 mL) and collected by filtration to give the product (33 g; 39%) as a white solid. MS ES+ m/z 414 [M+H]+.
A mixture of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-(3-pyridyl)chromen-4-one (0.60 g, 2.04 mmol) and 3-bromo-N-tert-butyl-6-chloro-pyridine-2-sulfonamide (0.80 g, 2.45 mmol) in 6 mL of DMSO was treated with 4,7-dimethoxy-1,10-phenanthroline (97 mg, 0.41 mmol), cesium carbonate (1.33 g, 4.08 mmol), and copper(I) iodide (38 mg, 0.20 mmol) in portions at rt under nitrogen. The reaction was heated to 150° C. for 30 min in a microwave. The reaction was allowed to cool to rt, filtered, and the solids washed with EtOAc (3×10 mL). The filtrate was diluted with water (50 mL) and extracted with EtOAc (3×30 mL). The combined organics were washed with saturated aqueous sodium chloride (3×30 mL), collected, dried over Na2SO4, filtered, and concentrated. The residue was purified by reversed phase chromatography eluted with 40% to 70% ACN in water (with 0.1% formic acid) to give the title compound (0.18 g, 160%) as a yellow solid. MS ES+ m/z 541 [M+H]+.
The following compounds in Table 23 were made in a similar way as described for N-tert-butyl-6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(3-pyridyl)chromen-8-yl]ethyl]amino]pyridine-2-sulfonamide. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
A solution of 5-[8-[(1R)-1-aminoethyl]-6-methyl-4-oxo-chromen-2-yl]-1,3-dimethyl-pyridin-2-one (200 mg, 0.62 mmol) and 3-bromo-N-tert-butyl-6-chloro-pyridine-2-sulfonamide (404 mg, 1.23 mmol) in DMF (6 mL) was treated with cesium carbonate (402 mg, 1.23 mmol) and copper(I) iodide (23.5 mg, 0.12 mmol) in portions at rt under a nitrogen atmosphere. The reaction was stirred at 120° C. overnight. The mixture was concentrated under reduced pressure and the residue purified by reversed phase chromatography on C18 eluted with 20% to 50% ACN in water (with 0.1% NH4OH) to give the title compound (88 mg, 25% as a white solid. ES/MS m/z 571 (M+H).
The following compounds in Table 24 were made in a similar way as described for N-tert-butyl-6-chloro-3-[[(1R)-1-[2-(1,5-dimethyl-6-oxo-3-pyridyl)-6-methyl-4-oxo-chromen-8-yl]ethyl]amino]pyridine-2-sulfonamide. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
A solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-(2-methylpyrazolo[4,3-b]pyridin-5-yl)chromen-4-one (0.57 g, 1.64 mmol) in DMF (10 mL) was treated with 6-chloro-3-fluoro-pyridine-2-carbonitrile (0.77 g, 4.91 mmol), potassium carbonate (2.26 g, 16.36 mmol), and DIPEA (0.63 g, 4.91 mmol) at rt. The reaction was stirred at 100° C. for 2 h. After cooling to rt, the reaction was diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 99% EtOAc in petroleum ether to give the title compound (0.25 g, 32%) as a brown solid. ES/MS m/z 485 (M+H).
The following compound in Table 25 was made in a similar way as described for 6-chloro-3-[[(1R)-1-[3,6-dimethyl-2-(2-methylpyrazolo[4,3-b]pyridin-5-yl)-4-oxo-chromen-8-yl]ethyl]amino]pyridine-2-carbonitrile. Various methods were used to purify the compound, which would be apparent to one skilled in the art.
1No DIPEA used in the reaction.
Combined tert-butyl 2-[[(1R)-1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethyl]amino]benzoate (1.00 g, 2.27 mmol; Intermediate 106, tert-butyl 2-[1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoate, Isomer 2), phenylboronic acid (0.56 g, 4.55 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.21 g, 0.23 mmol), copper(I) thiophene-2-carboxylate (0.87 g, 4.55 mmol), zinc(II) acetate (0.84 g, 4.55 mmol), and tri(2-furyl)phosphine (0.26 g, 1.14 mmol) in 1,4-dioxane (20 mL) and heated at 85° C. for 12 h. The crude product mixture was purified by silica gel chromatography eluted with 10% to 60% EtOAc in heptane, then reversed phase chromatography eluted with 0% to 100% ACN in water (with 0.1% TFA) to afford the product (0.53 g, 48%). MS ES+ m/z 456 [M+H]+.
The following compound in Table 26 was made in a similar way as described for tert-butyl 2-[[(1R)-1-(6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoate. Various methods were used to purify the compound, which would be apparent to one skilled in the art.
A vial containing 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carbonitrile (0.31 g, 0.74 mmol), 1H-pyrazol-4-ylboronic acid, (0.25 g, 2.23 mmol), tetrakis(triphenylphosphine)palladium (0) (0.21 g, 0.19 mmol), copper(I) 3-methylsalicylate (0.24 g, 1.11 mmol) was suspended in EtOH (3 mL) and THF (3 mL). Nitrogen was bubbled through the reaction for 2 min, the vial was sealed, and the reaction stirred at 60° C. for 4 h. The reaction was recharged with the same amounts of 1H-pyrazol-4-ylboronic acid, tetrakis(triphenylphosphine)palladium (0), and copper(I) 3-methylsalicylate. Nitrogen was bubbled through the reaction for 5 min, the vial sealed, and the reaction stirred at 60° C. for 16 h. The reaction was cooled, filtered through diatomaceous earth, and solids washed with DCM. The filtrate was concentrated under reduced pressure and the residue purified by reversed phase chromatography on C18 eluted with 16% to 44% ACN in water (with 0.1% formic acid) to give the title compound (60 mg, 19%). ES/MS m/z 420 (M+H).
The following compounds in Table 27 were made in a similar way as described for 6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(1H-pyrazol-4-yl)chromen-8-yl]ethyl]amino]pyridine-2-carbonitrile. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
1Stannane used as coupling partner.
Combined tris(dibenzylideneacetone)dipalladium(0) (1.17 g, 1.28 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.97 g, 3.41 mmol), (8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (5.00 g, 17.0 mmol), tert-butyl 3-bromopicolinate (5.28 g, 20.5 mmol), and Cs2CO3 (13.9 g, 42.6 mmol) in toluene (80 mL). The reaction was heated to 115° C. for 16 h. The mixture was filtered over diatomaceous earth and the solids were rinsed with EtOAc and DCM. The filtrate was concentrated and the residue was purified by silica gel chromatography eluted with a gradient of 0 to 80% EtOAc in heptane to give the title compound (7.1 g, 89%). MS ES+ m/z 471 [M+H]+.
The following compounds in Table 28 were made in a similar way as described for tert-butyl 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
1Xantphos Pd G4 used instead of Pd2(dba)3 and Xantphos.
2RuPhos Pd G4 used instead of Pd2(dba)3 and Xantphos.
tert-Butyl 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate (0.30 g, 0.61 mmol), 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (0.40 g, 1.53 mmol), tetrakis(triphenylphosphine)palladium(0) (0.35 g, 0.31 mmol), copper(I) thiophene-2-carboxylate (0.29 g, 1.53 mmol), and cesium carbonate (0.50 g, 1.53 mmol) were suspended in 6 mL of THF in a tube which was degassed for 10 min, capped, and stirred at 70° C. for 2 h. The reaction was allowed to cool to rt, diluted with 10 mL of DCM, filtered through celite, and concentrated. The residue was purified by silica gel chromatography eluted with 0% to 100% DCM in heptane to give the title compound (0.18 g, 53%). MS ES+ m/z 559 [M+H]+.
The following compounds in Table 29 were made in a similar way as described for tert-butyl 6-chloro-3-[[(1R)-1-[3,6-dimethyl-2-(2-methylimidazo[1,2-a]pyridine-6-yl)-4-oxo-chromen-8-yl]ethyl]amino]pyridine-2-carboxylate. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
1No cesium carbonate used in this reaction.
2No cesium carbonate used in this reaction and EtOH used as the solvent.
Combined 8-[(1R)-1-[(2-chloro-3-pyridyl)amino]ethyl]-6-methyl-2-(3-pyridyl)chromen-4-one (2.46 g, 6.28 mmol), (2-fluorophenyl)boronic acid (0.88 g, 6.28 mmol), potassium carbonate (1.74 g, 12.6 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.36 g, 0.31 mmol) in 1,4-dioxane (20.9 mL) and water (5.46 mL), sparged with argon for 5 min, and stirred at 100° C. for 16 h. The dry reaction was resuspended in DCM and purified by silica gel chromatography eluted with 0% to 100% EtOAc in heptane to give the title compound (0.77 g, 27%) as a yellow foam. ES/MS m/z 452 (M+H).
Combined tert-butyl 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate (0.50 g, 1.02 mmol), zinc(II) 2,6-difluorobenzen-1-ide bromide (0.79 g, 0.5 M, 3.07 mmol), methanesulfonato{[4-N,N-dimethylamino)phenyl]di-t-butylphosphino}(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (0.20 g, 0.31 mmol), and copper(I) thiophene-2-carboxylate (0.29 g, 1.53 mmol) in THF (3 mL) and degassed for 5 min. The reaction was stirred at 75° C. for 6 h. The reaction was filtered through diatomaceous earth and the solids washed with 20 mL of DCM. The filtrate was concentrated under reduced pressure to give the title compound (0.90 g, 160%) which was used without purification. ES/MS m/z 485 (MH−tBu).
Dissolved tert-butyl 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate (7.1 g, 15 mmol) in DCM (1 mL) and TFA (1 mL). Sealed and heated the reaction at 50° C. for 16 h. Concentrated and purified by reverse phase chromatography eluted with a gradient of 0% to 100% ACN in aqueous NH4HCO3 (10 mM, plus 5% MeOH) to give crude product. Recrystallization from MeOH (50 mL) and MTBE (50 mL) gave the title compound (3.4 g, 54%). MS ES+ m/z 415 [M+H]+.
The following compounds in Table 30 were made in a similar way as described for 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
A solution of tert-butyl 3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(3-pyridyl)chromen-8-yl]ethyl]amino]-6-fluoro-pyridine-2-carboxylate (0.23 g, 0.47 mmol) in DCM (5 mL) was treated with HCl (4 M in 1,4-dioxane) and allowed to stir for 1 h at rt under nitrogen. The reaction was concentrated to give the title compound (0.21 g) which was used without purification. MS ES+ m/z 434 [M+H]+.
A solution of 6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)chromen-8-yl]ethyl]amino]pyridine-2-carboxylic acid (100 mg, 0.20 mmol) in 1,4-dioxane (5 mL) was treated with DIPEA (262 mg, 2.02 mmol) and di-tert-butyl decarbonate (66.3 mg, 0.30 mmol). The reaction was stirred at rt for 3 h. The reaction was washed with saturated aqueous NaHCO3, saturated aqueous NH4Cl, and then saturated aqueous NaCl. The organic layer was collected and concentrated under reduced pressure to give the title compound (180 mg, 90% purity, 130%) which was used without purification. ES/MS m/z 592 (M−H).
A vial was charged with 8-[(1R)-1-[2-(1,3-dioxolan-2-yl)anilino]ethyl]-3,6-dimethyl-2-(3-pyridyl)chromen-4-one (479 mg, 1.08 mmol), 1,4-dioxane (10 mL), and water (3 mL). The reaction was treated with HCl (5 M in 1,4-dioxane, 1 g, 5 mmol) and then stirred for 2 h at rt. The reaction was diluted with DCM and neutralized with 1M aqueous NaOH. After removal of the organic layer, the aqueous layer was extracted 3 times with DCM. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (400 mg, 93%) which was used without purification. ES/MS m/z 399 (M+H).
The following compound in Table 31 was made in a similar way as described for 2-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(3-pyridyl)chromen-8-yl]ethyl]amino]benzaldehyde. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
A solution of methyl 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-6-fluoro-benzoate (0.67 g, 1.51 mmol) in THF (9 mL) and water (3 mL) was treated with lithium hydroxide (0.11 g, 4.53 mmol) and allowed to stir at rt overnight. Another 0.11 g of lithium hydroxide was added the reaction stirred at 50° C. for 6 h. An additional 2 eq of lithium hydroxide was added and the reaction stirred at 60° C. overnight. The reaction was allowed to cool to rt, diluted with DCM, washed with saturated aqueous ammonium chloride, and extracted twice with IPA/CHCl3 (1:3). The organics were combined, dried over MgSO4, filtered, and concentrated to give the title compound (0.76 g, 93%, 80% purity) as a white solid. MS ES+ m/z 432 [M+H]+.
The following compounds in Table 32 were made in a similar way as described for 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-6-fluoro-benzoic acid. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Cooled a solution of 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid (0.600 g, 1.45 mmol) in DCM (6 mL) to 0° C. Added thionyl chloride (1.45 mL, 2.90 mmol) and stirred the reaction at rt for 1 h. Added thionyl chloride (1.45 mL, 2.90 mmol) and stirred at 60° C. for 2 h. Concentrated to dryness, added DCM (6 mL) and triethylamine (0.61 mL, 4.34 mmol), and cooled to 0° C. Added N-BOC-hydrazine (0.48 g, 3.62 mmol) and stirred the reaction at rt for 1 h. Concentrated to dryness, added DCM (6 mL) and HCl (4M in 1,4-dioxane, 1.81 mL, 7.24 mmol), and stirred at rt for 3 days. Concentrated and purified by reverse phase chromatography eluted with a gradient of 0% to 100% ACN in aqueous NH4HCO3 (10 mM, plus 5% MeOH). Fractions containing product were diluted with saturated aqueous NaHCO3 and EtOAc. The organics were dried over Na2SO4, filtered, and concentrated. Filtration from DCM/hexanes gave the title compound (0.36 g, 58%). MS ES+ m/z 429 [M+H]+.
Combined 6-chloro-3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid (0.40 g, 0.89 mmol), DIPEA (0.35 g, 2.67 mmol), 2,4,6-tripropyl-1,3,5-trioxa-2,4,6-triphosphinane-2,4,6-trioxide (1.69 g, 2.67 mmol), and hydrazine hydrate (0.21 g, 2.67 mmol) in DMA (4 mL) and stirred at 25° C. for 12 h. After 12 h, the reaction was treated with the same amount of DIPEA, 2,4,6-tripropyl-1,3,5-trioxa-2,4,6-triphosphinane-2,4,6-trioxide, and hydrazine hydrate and allowed to stir at rt. The reaction was purified by reversed phase chromatography eluted with 10% to 100% ACN in 0.1% aqueous formic acid to give the title compound (0.12 g, 29%). MS ES+ m/z 463 [M+H]+.
The following compounds in Table 33 were made in a similar way as described for 6-chloro-3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carbohydrazide. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
A solution of 3-[[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethyl]amino]-6-methyl-pyridine-2-carboxylic acid (0.40 g, 0.83 mmol) in DMF (6 mL) was treated with HATU (0.95 g, 2.50 mmol) and DIPEA (0.54 g, 4.17 mmol). The mixture was stirred at rt for 5 min, treated with N-BOC hydrazine (0.33 g, 2.50 mmol), and stirred at rt overnight. The reaction was diluted with EtOAc and washed with 10% aqueous LiCl. The organic layer was washed with saturated aqueous sodium chloride, collected, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluted with 0% to 10000 EtOAc/EtOH (3:1) in heptane to give the title compound (0.50 g, 91%, 91% purity) as a tan gel. MS ES+ m/z 597 [M+H]+.
The following compounds in Table 34 were made in a similar way as described for tert-butyl N-[[3-[[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethyl]amino]-6-methyl-pyridine-2-carbonyl]amino]carbamate. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
1Material used without purification.
A mixture of 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid (0.10 g, 0.24 mmol), 2-chloro-1-methyl-pyridin-1-ium iodide (92.5 mg, 0.36 mmol), tert-butyl sulfamoylcarbamate (94.7 mg, 0.48 mmol) and DMAP (2.95 mg, 0.02 mmol) were dissolved in DCM (2 mL) and allowed to stir. After 5 min, triethylamine (73.2 mg, 0.72 mmol) was added to the reaction and allowed to stir overnight at rt. The reaction was concentrated and the residue purified by reverse phase C18 flash chromatography eluted with ACN in water with 0.1% formic acid. Fractions containing the product were combined, washed with saturated aqueous sodium chloride, extracted with IPA/CHCl3 (1:3), the organics collected, dried over MgSO4, filtered, and concentrated to give the title compound (0.12 g, 83%) as a foam. MS ES+ m/z 591 [M−H]−.
The following compound in Table 35 was made in a similar way as described for tert-butyl N-[[3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carbonyl]sulfamoyl]carbamate. Various methods were used to purify the compound, which would be apparent to one skilled in the art.
Methyl 6-bromo-3-fluoropicolinate (0.25 g, 1.07 mmol) and 8-[(1R)-1-aminoethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (0.25 g, 0.89 mmol) were dissolved in DMSO (1 mL) and DIPEA (0.78 mL, 4.45 mmol) was added. The vial was sealed and the reaction heated to 120° C. for 24 h. Concentrated with a small amount of diatomaceous earth and purified by reverse phase chromatography eluted with a gradient of 10 to 70% ACN in aqueous NH4HCO3 (10 mM, plus 5% MeOH) to give the title compound (0.18 g, 40%). MS ES+ m/z 491 [M+H]+.
The following compound in Table 36 was made in a similar way as described for methyl 6-bromo-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate.
1ACN used as the solvent.
A vial containing trimethylsulfoxonium iodide (291 mg, 1.32 mmol) was dried for 2 h at 65° C. and then treated with dry THF (5 mL) when cool. The reaction was treated with potassium tert-butoxide (148 mg, 1.32 mmol), the vial sealed, and the reaction stirred at 66° C. for 2 h. In a separate vial, 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid (455 mg, 1.10 mmol) was suspended in toluene (5.5 mL), treated dropwise with thionyl chloride (131 mg, 1.10 mmol), and the reaction stirred at 80° C. for 15 min. The second vial was allowed to cool to rt and concentrated under reduced pressure to give an acid chloride. Both vials were cooled in ice baths and the contents of the first vial were added via syringe to the acid chloride. The reaction was removed from the cooling bath and allowed to warm to rt. The reaction was not complete so was treated with a second batch of the first vial except that is was only stirred at 66° C. for 15 min. The reaction was quenched with water and the mixture concentrated under reduced pressure to remove the THF. The reaction was diluted with DCM, the layers separated, and the remaining aqueous layer re-extracted with fresh DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue purified by silica gel chromatography eluted with 0% to 100% EtOAc in DCM and repurified by reversed phase chromatography on C18 eluted with 0% to 100% ACN in 10 mM aqueous NH4HCO3 (with 5% MeOH) to give the title compound. ES/MS m/z 488 (M+H).
A vial was charged with 8-[(1R)-1-[2-[2-[dimethyl(oxo)-lambda6-sulfanylidene]acetyl]anilino]ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one and 1,4-dioxane (6.2 mL) and then treated with HCl in 1,4-dioxane (4 M, 227 mg, 6.21 mmol). The reaction was heated at 90° C. for 13 h. The reaction was concentrated under reduced pressure and the residue purified by reversed phase chromatography on C18 eluted with 0% to 100% ACN in 10 mM aqueous NH4HCO3 (with 5% MeOH) and repurified by silica gel chromatography eluted with 0% to 100% EtOAc in DCM to give the title compound (110.8 mg, 40%) as a yellow powder. ES/MS m/z 446 (M+H).
A solution of 6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]chromen-8-yl]ethyl]amino]pyridine-2-carboxamide (97 mg, 0.19 mmol) in DCM (3 mL) was treated with triethylamine (0.29 g, 2.9 mmol) and then trifluoroacetic anhydride (0.20 g, 0.96 mmol) at 0° C. The reaction was warmed to rt and stirred for 2 h. The reaction was diluted with EtOAc and washed with saturated aqueous NaHCO3. The organic layer was collected, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 0% to 100% EtOAc in heptane to give the title compound (192 mg, 50% purity, 100%) as a yellow gel. ES/MS m/z 488 (M+H).
The following compound in Table 37 was made in a similar way as described for 6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]chromen-8-yl]ethyl]amino]pyridine-2-carbonitrile. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Dissolved 8-acetyl-3,6-dimethyl-2-phenyl-chromen-4-one (5.0 g, 17 mmol) in MeOH (6 mL) and DCM (6 mL). Cooled to −10° C., added NaBH4 (0.78 g, 21 mmol), and stirred for 30 min. Added water (50 mL) and extracted with DCM (2×60 mL). The combined organic extracts were dried over anhydrous Na2SO4, concentrated, and purified by silica gel chromatography eluted with a gradient of 0 to 5% MeOH in DCM to give the title compound (4.2 g, 83%). MS ES+ m/z 295 [M+H]+.
Combined 8-(1-chloroethyl)-3,6-dimethyl-2-phenyl-chromen-4-one (2.0 g, 6.8 mmol) in DCM (25 mL). Cooled to 0° C., added PBr3 (1.3 mL, 14 mmol) dropwise, and stirred the reaction for 2 h at rt. Slowly added saturated aqueous bicarbonate, then separated the layers. The organics were dried over anhydrous Na2SO4 and concentrated to give the title compound (1.4 g, 58%). MS ES+ m/z 359 [M+H]+.
A solution of 8-acetyl-3,6-dimethyl-2-phenyl-chromen-4-one (10 g, 34.2 mmol) and RuCl(p-cymene)[(R,R)-Ts-DPEN] (CAS 192139-92-7, 0.653 g, 1.03 mmol) in MeOH (50 mL) was stirred at 0-5° C. 1,8-Diazabicyclo[5.4.0]undec-7-ene (15.3 mL, 103 mmol) was added slowly, maintaining the temperature below 25° C. Formic acid (3.87 mL, 103 mmol) was added in portions, maintaining the temperature below 15° C. The reaction was stirred at 55° C. for 3 h, then cooled to rt. 4M aqueous HCl (50 mL) was slowly added. The resulting slurry was stirred overnight, filtered, and washed with water to give the title compound (9.9 g, 93%, 87% ee).
A solution of 8-[(1R)-1-hydroxyethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (20 g, 68.0 mmol) in cyclopentyl methyl ether (200 mL) was stirred at room temperature. 2,4,6-Trichloro[1,3,5]triazine (12.5 g, 68.0 mmol) was added, followed by DMF (7.9 mL, 102 mmol). The reaction was stirred at room temperature for 14 h. Diluted with 2M aqueous sodium hydroxide (100 mL) and separated the layers. The organics were washed with water (100 mL)/saturated aqueous sodium bicarbonate (100 mL) and 5% aqueous lithium chloride (100 mL). The organics were concentrated and diluted with isopropanol (120 mL). The slurry was heated at 45° C. for 2 h and cooled to room temperature. Water (80 mL) was slowly added. Filtered to give the title compound (18.4 g, 87%, 94% ee). MS ES+ m/z 313 [M+H]+.
8-[(1S)-1-Chloroethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (0.60 g, 1.92 mmol), 2-iodoaniline (1.26 g, 5.75 mmol), and DIPEA (1.24 g, 9.59 mmol) were combined in IPA (6 mL) and stirred at 60° C. overnight. The reaction was recharged twice with 1 g of 2-iodoaniline and 0.5 mL of DIPEA over the course of 8 h before stirring overnight. The reaction was concentrated and purified by silica gel chromatography eluted with 0% to 100% EtOAc in heptane to give the title compound (0.70 g, 74%). MS ES+ m/z 496 [M+H]+.
A dry argon flushed flask was charged with tert-butyl 2-[[(1R)-1-(6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoate (1.40 g, 3.06 mmol) and THF (5 mL). The resulting solution was cooled to 0° C. and treated with 2,2,6,6-tetramethylpiperidinyzinc chloride lithium chloride complex solution (3.49 g, 1M, 12.30 mmol) dropwise over 30 min and then the reaction was allowed to stir at 25° C. for 7 h. Another 6 mL of 2,2,6,6-tetramethylpiperidinyzinc chloride lithium chloride complex solution was added and the reaction stirred overnight at rt. The reaction was cooled to 0° C. and treated with a freshly prepared solution of iodine (1.56 g, 1M in THF, 6.15 mmol) dropwise over 30 min. The reaction was stirred at 0° C. for 1 h and then at rt for 12 h. The reaction was cooled to −40° C. and quenched with MeOH. The reaction was diluted with ammonium chloride/ammonia solution (50 mL, 2M in water) and extracted with DCM (3×300 mL). The combined organics were washed with aqueous Na2CO3 (50 mL), collected, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluted with 0% to 10% EtOAc in heptane to give the title compound (1.64 g, 87%). MS ES+ m/z 582 [M+H]+.
The following compounds in Table 38 was made in a similar way as described for tert-butyl 2-[[(1R)-1-(3-iodo-6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoate. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
A solution of N-tert-butyl-6-chloro-3-[[(1R)-1-(6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-sulfonamide (1.1 g, 2.09 mmol) in THF (10 mL) was cooled to −40° C. under a nitrogen atmosphere and treated with 2,2,6,6-tetramethylpiperdinylmagnesium chloride lithium chloride complex (13 mL, 12.55 mmol, 1 M in THF). The reaction was stirred at −10° C. for 2 h. A THF solution of iodine (4 mL, 4.18 mmol) was added dropwise over 30 min at −40° C. and then stirred at rt for 2 h. The reaction was quenched with saturated aqueous NH4Cl at 0° C. The reaction was extracted with EtOAc (3×100 mL). The combined organics were washed with brine (100 mL), collected, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 50% EtOAc in petroleum ether to give the title compound (0.30 g, 22%) as a yellow solid. ES/MS m/z 652 (M+H).
A mixture of N-tert-butyl-6-chloro-3-[[(1R)-1-[6-methyl-2-(1-methylpyrazol-4-yl)-4-oxo-chromen-8-yl]ethyl]amino]pyridine-2-sulfonamide (400 mg, 0.75 mmol) and N-bromosuccinimide (134 mg, 0.75 mmol) in ACN was stirred at rt for 1 h. The reaction was concentrated under reduced pressure and the residue purified by reversed phase chromatography on C18 eluted with 65% to 70% ACN in water (with 0.1% NH4OH) to give the title compound (250 mg, 54%) as a colorless solid. ES/MS m/z 608/610 (M+H).
A solution of N-tert-butyl-6-chloro-3-[[(1R)-1-(3-iodo-6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-sulfonamide (180 mg, 0.28 mmol) in NMP (4 mL) was treated with copper(I) cyanide (124 mg, 1.38 mmol) at rt. The reaction was stirred overnight at 120° C. under a nitrogen atmosphere. The reaction was cooled to rt, diluted with water (50 mL), and extracted with EtOAc (3×50 mL). The combined organics were washed with saturated aqueous NaCl (100 mL), collected, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reversed phase chromatography on C18 eluted with 80% to 95% ACN in water to give the title compound (73 mg, 48%) as a light yellow solid. ES/MS m/z 551 (M+H).
Charged a tube with tert-butyl 2-[[(1R)-1-(3-iodo-6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoate (300 mg, 0.52 mmol), 1,1′-bis(diphenylphophino)ferrocene-palladium(II) dichloride (75.5 mg, 0.10 mmol), cuprous chloride (51 mg, 0.52 mmol), sodium carbonate (109 mg, 1.03 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (436 mg, 2.06 mmol) and toluene (15 mL). The reaction was heated at 80° C. under a nitrogen atmosphere for 20 h. The reaction was recharged and allowed to stir at 80° C. overnight. The reaction was allowed to cool, filtered through celite, concentrated, and the residue purified by silica gel chromatography eluted with 0% to 100% EtOAc in heptane to give the title compound (208 mg, 75%). MS ES+ m/z 539 [M+H]+.
A solution of N-tert-butyl-6-chloro-3-[[(1R)-1-(3-iodo-6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-sulfonamide (80 mg, 0.12 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (48 mg, 0.25 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was treated with potassium carbonate (34 mg, 0.25 mmol) and 1,1′-bis (di-t-butylphosphino)ferrocene palladium dichloride (16 mg, 0.03 mmol) at rt under a nitrogen atmosphere. The reaction was stirred at 80° C. for 4 h. After cooling to rt, the reaction was concentrated under reduced pressure and the residue purified by silica gel chromatography eluted with 33% EtOAc in petroleum ether to give the title compound (50 mg, 69%) as a light yellow solid. ES/MS m/z 593 (M+H).
A mixture of 3-[[(1R)-1-[3-bromo-6-methyl-2-(1-methylpyrazol-4-yl)-4-oxo-chromen-8-yl]ethyl]amino]-N-tert-butyl-6-chloro-pyridine-2-sulfonamide (190 mg, 0.31 mmol), triethylamine (63.2 mg, 0.62 mmol), 1,1′-bis (di-t-butylphosphino)ferrocene palladium dichloride (20.34 mg, 0.03 mmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (121.71 mg, 0.62 mmol) in THF (2 mL) and water (0.5 mL) was stirred overnight at rt under a nitrogen atmosphere. The reaction was filtered and the solids washed with THF (2×10 mL). The filtrate was concentrated under reduced pressure and the residue purified by reversed phase chromatography on C18 eluted with 75% to 85% ACN in water (with 0.1% NH4OH) to give the title compound (92 mg, 46%) as a colorless solid. ES/MS m/z 597 (M+H).
A THF (3 mL) solution of tert-butyl 6-chloro-3-[[(1R)-1-(6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate (0.47 g, 0.96 mmol) was treated with 2,2,6,6-tetramethylpiperidinyzinc chloride lithium chloride complex solution (0.68 mg, 1 M, 2.39 mmol) and allowed to stir at rt for 3 h. The reaction was quenched with iodine (0.97 g, 3.83 mmol) dissolved in THF, and the reaction allowed to stir for 1 h. The reaction was diluted with 20 mL of EtOAc/water. The organic layer was collected, dried over MgSO4, filtered, and concentrated. The residue was purified by reversed phase chromatography eluted with 10% to 100% ACN (with 0.1% formic acid) in water (with 0.1% formic acid) to give the title product (0.20 g, 37%). MS ES+ m/z 561 [M+H]+.
To a solution of 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carbonitrile (0.242 g, 0.612 mmol) in ethanol (5 mL) was added triethylamine (0.26 mL, 1.84 mmol) and hydroxylamine hydrochloride (0.085 g, 1.22 mmol). The reaction was heated at 80° C. for 18 h. Concentrated and purified by reverse phase chromatography eluted with a gradient of 0 to 100% ACN in H2O+0.1% formic acid to give the title compound (0.26 g, 89%). MS ES+ m/z 429 [M+H]+.
The following compounds in Table 39 were made in a similar way as described for 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-N′-hydroxy-pyridine-2-carboxamidine. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
1NaHCO3 used as the base in this reaction.
To a solution of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid (0.100 g, 0.242 mmol) in DMF (1 mL) was added (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.276 g, 0.726 mmol), DIPEA (0.25 mL, 1.45 mmol), and J-O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (0.107 g, 0.726 mmol). The reaction was stirred at rt for 24 h. Concentrated and purified by silica gel chromatography eluted with a gradient of 0 to 100% EtOAc in hexanes to give the title compound (0.171 g, 80% purity, 100%). MS ES+ m/z 543 [M+H]+.
The following compound in Table 40 was made in a similar way as described for N-[[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]-2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzamide.
Combined 2-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]benzonitrile (0.100 g, 0.264 mmol), (2-fluorophenyl)boronic acid (0.111 g, 0.793 mmol), tetrakis(triphenylphosphine)palladium(0) (0.046 g, 0.040 mmol), and copper(I) thiophene-2-carboxylate (0.076 g, 0.396 mmol) in ethanol (15 mL). Degassed the reaction with argon and stirred at 50° C. for 16 h. Concentrated and purified by silica gel chromatography eluted with a gradient of 0 to 100% EtOAc in hexanes to give the title compound (0.109 g, 100%). MS ES+ m/z 413 [M+H]+.
The following compounds in Table 41 were made in a similar way as described for 2-[[(1R)-1-[2-(2-fluorophenyl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]benzonitrile. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
To a solution of tert-butyl N-[(1R)-1-[3,6-dimethyl-4-oxo-2-(3-pyridyl)chromen-8-yl]ethyl]carbamate (0.950 g, 2.41 mmol) in DCM (24 mL) was added HCl (4M in 1,4-dioxane, 4 mL, 16 mmol). The reaction was stirred at rt for 2 h. Added HCl (4M in 1,4-dioxane, 1.2 mL, 4.8 mmol) and stirred at rt for 1 h. Concentrated and diluted with saturated aqueous NaHCO3 and IPA:CHCl3 (1:3). Separated the layers. The organic extracts were dried over MgSO4, filtered, and concentrated. The residue was purified by reverse phase chromatography eluted with a gradient of 0% to 100% ACN in aqueous NH4HCO3 (10 mM, plus 5% MeOH). Clean fractions were washed with saturated aqueous sodium chloride and extracted with IPA:CHCl3 (1:3). The organic extracts were dried over MgSO4, filtered, and concentrated to give the title compound (0.364 g, 51%). MS ES+ m/z 295 [M+H]+.
The following compounds in Table 42 were made in a similar way as described for tert-butyl 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
A solution of 3-[[(1R)-1-[2-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrazol-4-yl]-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]-6-chloro-N′-hydroxy-pyridine-2-carboxamidine (134 mg, 0.22 mmol) in 1,4-dioxane (4 mL) was treated with DBU (66.8 mg, 0.44 mmol) and 1,1′-carbonyldiimidazole (53.3 mg, 0.33 mmol). The reaction was stirred at 80° C. for 1 h. The reaction was cooled to rt and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 0% to 100% EtOAc/EtOH (3:1) in heptane to give the title compound (98.4 mg, 70%) as a pale tan foam. ES/MS m/z 637 (M+H).
The following compounds in Table 43 were made in a similar way as described for 3-[3-[[(1R)-1-[2-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrazol-4-yl]-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]-6-chloro-2-pyridyl]-4H-1,2,4-oxadiazol-5-one. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
A solution of tert-butyl 6-chloro-3-[[(1R)-1-[2-(2-fluorophenyl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]pyridine-2-carboxylate (0.23 g, 0.44 mmol) in 2 mL of DCM was treated with TFA/DCM (1:1; 1 mL) and the reaction stirred at 50° C. for 2 h. The reaction was concentrated and the residue purified by reversed phase C18 flash chromatography eluted with 0% to 100% ACN in 0.1% aqueous formic acid. Fractions containing the product were combined, washed with saturated aqueous sodium chloride, and extracted with IPA/CHCl3 (1:3). The organics were combined, dried over MgSO4, filtered, and concentrated to give the title compound (68.8 mg, 34%) as a tan foam. MS ES+ m/z 467 [M+H]+.
The following compounds in Table 44 was made in a similar way as described for 6-chloro-3-[[(1R)-1-[2-(2-fluorophenyl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]pyridine-2-carboxylic acid.
A solution of tert-butyl N-[[3-[[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethyl]amino]-6-methyl-pyridine-2-carbonyl]amino]carbamate (0.50 g, 0.84 mmol) in 10 mL of DCM was treated with HCl (4M in 1,4-dioxane, 0.15 g, 1.05 mL, 4.19 mmol) and stirred at 50° C. After 3 h, added another 1.05 mL of HCl in dioxane and stirred at 60° C. for 2 h. The reaction was allowed to cool to rt, concentrated, the residue taken up in DCM, and washed with saturated aqueous NaHCO3. The aqueous layer was extracted twice with IPA/CHCl3 (1:3). The organics were combined, dried over MgSO4, filtered, and concentrated to a residue which was recrystallized from DCM/MTBE/hexanes to give the title compound (0.31 g, 73%) as a pale yellow powder. MS ES+ m/z 497 [M+H]+.
The following compounds in Table 45 were made in a similar way as described for 3-[[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethyl]amino]-6-methyl-pyridine-2-carbohydrazide. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
6-Chloro-3-[[(1R)-1-(3-iodo-6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid (0.14 g, 0.25 mmol), methanesulfonamide (47.5 mg, 0.50 mmol), DCC (0.10 g, 0.50 mmol) and DMAP (0.12 g, 1.0 mmol) were combined in DCM (2 mL) and allowed to stir at 25° C. overnight. The reaction was diluted with 1 mL of MeOH and directly purified by reversed phase chromatography eluted with 10% to 100% ACN (with 0.1% formic acid) in water (with 0.1% formic acid) to give the title compound (0.12 g, 75%). MS ES+ m/z 638 [M+H]+.
A solution of 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid (0.50 g, 1.15 mmol) in DCM (1.2 mL) was cooled to 0° C. and treated with methanesulfonamide (0.19 g, 1.96 mmol) and chlorodipyrrolidinecarbenium hexafluorophosphate (0.58 g, 1.73 mmol) followed by the dropwise addition of DIPEA (0.75 g, 5.77 mmol). The reaction was stirred at 0° C. for 5 min and then at rt over the weekend. Adsorbed the reaction onto silica gel and eluted with 0% to 10% MeOH in DCM to give the title compound (0.34 g, 58%). ES/MS m/z 510 (M+H).
The following compound in Table 46 was made in a similar way as described for 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]-N-methylsulfonyl-pyridine-2-carboxamide. Various methods were used to purify the compound, which would be apparent to one skilled in the art.
A solution of N′-[2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]phenyl]sulfonyl-N,N-dimethyl-formamidine (0.45 g, 0.89 mmol) in 8 mL of EtOH was treated with concentrated HCl (0.16 g, 4.45 mmol) and the reaction stirred at reflux for 2 h. Another 1 mL of concentrated HCl was added and the reaction stirred at 80° C. for another 2 h. The reaction was allowed to cool to rt, diluted with DCM, and neutralized with saturated aqueous NaHCO3. The organic layer was removed and the aqueous layer extracted with IPA/CHCl3 (1:3). The combined extracts were dried over MgSO4, filtered, and concentrated. The residue was purified by reversed phase chromatography eluted with 0% to 100% ACN in water (with 0.1% formic acid). Fractions containing the product were pooled and extracted with IPA/CHCl3 (1:3). The organics were combined, dried over MgSO4, filtered, and concentrated to give the title compound (0.12 g, 30%) as a white solid. MS ES+ m/z 449 [M+H]+.
8-[(1R)-1-(2-Bromoanilino)ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (1.12 g, 2.50 mmol), potassium acetate (0.736 g, 7.49 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (0.183 g, 0.250 mmol), and bis(pinacolato)diboron (0.761 g, 3.00 mmol) were combined in dimethoxyethane (12 mL). The reaction was degassed with argon for 1 min and stirred at 95° C. for 16 h. Filtered through diatomaceous earth, concentrated, and purified by silica gel chromatography eluted with EtOAc in heptane to give the title compound (1.1 g, 89%). MS ES+ m/z 496 [M+H]+.
The following compound in Table 47 was made in a similar way as described for 3,6-dimethyl-2-phenyl-8-[(1R)-1-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]ethyl]chromen-4-one.
Combined 2-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]benzonitrile (0.500 g, 1.32 mmol), sodium azide (0.258 g, 3.96 mmol), and ammonium chloride (0.212 g, 3.96 mmol) in DMF (3 mL). The reaction was sealed and stirred at 140° C. for 3 h. Purified by reverse phase chromatography to give the title compound (0.190 g, 34%). MS ES+ m/z 422 [M+H]+.
To a solution of 8-[(1R)-1-(2-bromoanilino)ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (0.35 g, 0.78 mmol) in DMF (4 mL) was added ethynyl-trimethyl-silane (0.46 g, 4.68 mmol) and triethylamine (0.65 mL, 4.68 mmol). The reaction was degassed with nitrogen and cuprous iodide (0.030 g, 0.16 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.18 g, 0.16 mmol) were added. The vial was sealed under nitrogen and heated in a microwave reactor at 100° C. for 18 h. The mixture was diluted with 10% aqueous LiCl and extracted twice with EtOAc. The organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluted with a gradient of 0 to 100% EtOAc in hexanes to give the title compound (0.35 g, 70% purity, 67%). The crude material was used without further purification.
To a solution of 3,6-dimethyl-2-phenyl-8-[(1R)-1-[2-(2-trimethylsilylethynyl)anilino]ethyl]chromen-4-one (0.35 g, 70% purity, 0.52 mmol) in MeOH (4 mL) was added potassium carbonate (0.31 g, 2.25 mmol). The reaction was stirred at rt for 1 h. Filtered, washed with DCM, and concentrated. The residue was purified by silica gel chromatography eluted with a gradient of 0 to 60% EtOAc in hexanes to give the title compound (0.21 g, 90% purity, 90%). MS ES+ m/z 394 [M+H]+.
8-[(1R)-1-(2-Bromoanilino)ethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (0.10 g, 0.23 mmol), cesium carbonate (82.2 mg, 0.25 mmol), and tetrakis(triphenylphosphine)palladium(0) (12.1 mg, 0.01 mmol) were transferred to a microwave vial. The vial was evacuated and refilled with nitrogen three times before the addition of THF (0.5 mL) and phosphonic acid dimethyl ester (23.1 mg, 0.21 mmol). The vial was capped and the reaction stirred at 120° C. 10 min. The vial was recharged with phosphonic acid dimethyl ester (23.1 mg, 0.21 mmol) and the reaction heated at 120° C. for another 10 min. The reaction was adsorbed onto celite and purified by reversed phase chromatography eluted with 0% to 80% ACN in 10 mM NH4HCO3 (with 5% MeOH). MS ES+ m/z 462 [M+H]+.
A 20 mL pressure vial was charged with 8-bromo-2-[(4-methoxyphenyl)methyl]-3,4-dihydroisoquinolin-1-one (177 mg, 0.51 mmol), 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-(3-pyridyl)chromen-4-one (150 mg, 0.51 mmol), cesium carbonate (333 mg, 1.02 mmol), BINAP (95.5 mg, 0.15 mmol), palladium(II) acetate (11.5 mg, 0.05 mmol), and 1,4-dioxane (5 mL). The mixture was degassed with nitrogen gas for 5 min and then stirred at 90° C. for 17 h. The reaction was passed through a syringe filter and purified by reversed phase chromatography eluted with 10% to 100% ACN in 10 mM aqueous NH4HCO3 to give the title compound (149 mg, 52%) a yellow semi-solid. MS ES+ m/z 560 [M+H]+.
The following compound in Table 48 was made in a similar way as described for 8-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(3-pyridyl)chromen-8-yl]ethyl]amino]-2-[(4-methoxyphenyl)methyl]-3,4-dihydroisoquinolin-1-one.
A vial was charged with 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]-N-methylsulfonyl-pyridine-2-carboxamide (170 mg, 0.33 mmol), (1-tert-butoxycarbonylindol-2-yl)boronic acid (131 mg, 0.50 mmol), copper(I) 3-methylsalicylate (107 mg, 0.50 mmol), and tetrakis(triphenylphosphine)palladium(0) (77 mg, 0.07 mmol), and EtOH (5 mL). The reaction was degassed with argon, sealed, and stirred at 65° C. for 16 h. After cooling, the reaction was filtered and the filtrate concentrated under reduced pressure. The residue was purified by reversed phase chromatography on C18 eluted with 10% to 100% ACN (with 0.1% formic acid) in water (with 0.1% formic acid) to give the title compound (15 mg, 7%). ES/MS m/z 665 (M+H).
A mixture of 2-bromo-4-methyl-phenol (10.0 g, 53.5 mmol) and pyridine (6.34 g, 80.2 mmol) in DCM (100 mL) was treated with propanoyl chloride (5.44 g, 58.8 mmol) at 0° C. and stirred at 25° C. for 16 h. The mixture was diluted with water (100 mL), the pH adjusted to 5 with HCl (2M), and extracted with DCM (2×100 mL). The combined organic extracts were washed with saturated aqueous NaCl (2×150 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the product as an oil (13 g, crude). 1H NMR (DMSO-d6) δ ppm 1.17 (t, J=7.6 Hz, 3H), 2.30 (s, 3H), 2.62 (q, J=7.6 Hz, 2H), 7.11-7.18 (m, 1H), 7.19-7.26 (m, 1H), 7.50-7.55 (m, 1H).
A mixture of (2-bromo-4-methyl-phenyl) propanoate (12.5 g, 51.4 mmol) and AlCl3 (24.0 g, 180 mmol) was stirred at 140° C. for 1 h. When cooled to rt, the mixture was quenched with water (80 mL) dropwise and stirred for 30 min. The mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were washed with saturated aqueous NaCl (2×200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated and triturated with petroleum ether (20 mL) to give the product as a solid (9.82 g, 79%). 1H NMR (DMSO-d6) δ ppm 1.10 (t, J=7.2 Hz, 3H), 2.28 (s, 3H), 3.15 (q, J=7.2 Hz, 2H), 7.66-7.73 (m, 1H), 7.77-7.83 (m, 1H), 12.66 (s, 1H).
A mixture of 1-(3-bromo-2-hydroxy-5-methyl-phenyl)propan-1-one (1700 g, 6.99 mol), carbon disulfide (798.3 g, 10.49 mol), and THF (17 L) was cooled to −25° C. and treated with sodium bis(trimethylsilyl)amide (12.24 L, 2M) over 2 h. After addition was complete, warmed the reaction to 20-30° C. and stirred for 12 h. The reaction was cooled to 0° C. and quenched with sulfuric acid (17 L, 15%) over 2 h. The organic phase was removed and the aqueous layer extracted with EtOAc (1.7 L). The organic phases were combined, concentrated, and the resulting residue suspended in heptane giving the title compound (2000 g, 100%) as a yellow solid after filtration and drying. 1H NMR (DMSO-d6) δ ppm 2.26 (s, 3H), 2.40 (s, 3H), 7.82 (m, 2H).
A mixture of 1-(3-bromo-2-hydroxy-5-methyl-phenyl)propan-1-one (200 g, 822.72 mmol), benzaldehyde (96.04 g, 904.99 mmol), AcOH (105.23 g, 1.75 mol), and piperidine (172.33 g, 2.02 mol) in EtOH (1600 mL) was stirred at 70° C. for 16 h. The resulting dark solution was poured into water (3 L), filtered, and the solid dissolved in 6 L of DCM. The organic solution was dried over anhydrous Na2SO4, filtered, and concentrated to give the product as a dark gum (284 g). MS ES+ m/z 331, 333 [M+H]+.
A mixture of (E)-1-(3-bromo-2-hydroxy-5-methyl-phenyl)-2-methyl-3-phenyl-prop-2-en-1-one (284 g, 857.48 mmol) and 12 (21.76 g, 85.75 mmol) in DMSO (1200 mL) was stirred at 140° C. for 2 h to give a black-brown solution. Cooled to rt, poured the reaction into 3 L of water, filtered, dissolved the solid product in DCM (4 L), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was triturated with petroleum ether/EtOAc (1:1, 1 L) to give the product as a light yellow solid (195 g, 69%). MS ES+ m/z 329, 331 [M+H]+.
A mixture of 8-bromo-4-hydroxy-3,6-dimethyl-chromene-2-thione (1900 g, 6.66 mol), 1-iodoethane (1558 g, 9.99 mol), potassium carbonate (920.9 g, 6.66 mol) in acetone (19 L) was stirred at 60° C. for 1 h. The reaction was cooled to rt, filtered, and the solids washed with THF. The filtrate was concentrated and the residue suspended in heptane (3.8 L) and the title compound (1900 g, 91%) was removed by filtration as a brown solid.
A mixture of 8-bromo-3,6-dimethyl-2-phenyl-chromen-4-one (195 g, 592.37 mmol), bis(triphenylphosphine)palladium(II) dichloride (20.79 g, 29.62 mmol), and tributyl(1-ethoxyvinyl)stannane (256.72 g, 710.84 mmol, 239.92 mL) in dioxane (1600 mL) was stirred under N2 at 95° C. for 16 h to give a black-brown solution. After cooling to rt, treated the reaction with 1M aqueous HCl (100 mL) and stirred at 20° C. for 30 min. The mixture was quenched with saturated aqueous KF (2000 mL), stirred for 30 min, and filtered. The filter cake was washed with 10% MeOH in DCM (5×5000 mL). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was triturated with petroleum ether/EtOAc (5/1, 1000 mL) to give a crude product which was triturated with DCM/MeOH (10/1, 500 mL) to give the product as a light yellow solid (180 g, 96%, 92% purity). MS ES+ m/z 293 [M+H]+.
The following compound in Table 49 were made in a similar way as described for 8-acetyl-3,6-dimethyl-2-phenyl-chromen-4-one. Various methods were used to purify the compound, which would be apparent to one skilled in the art.
A solution of 8-acetyl-3,6-dimethyl-2-phenyl-chromen-4-one (10 g, 34.2 mmol) and RuCl(p-cymene)[(R,R)-Ts-DPEN] (CAS 192139-92-7, 0.653 g, 1.03 mmol) in MeOH (50 mL) was stirred at 0-5° C. 1,8-Diazabicyclo[5.4.0]undec-7-ene (15.3 mL, 103 mmol) was added slowly, maintaining the temperature below 25° C. Formic acid (3.87 mL, 103 mmol) was added in portions, maintaining the temperature below 15° C. The reaction was stirred at 55° C. for 3 h, then cooled to rt. 4M aqueous HCl (50 mL) was slowly added. The resulting slurry was stirred overnight, filtered, and washed with water to give the title compound (9.9 g, 93%, 87% ee).
A solution of 8-acetyl-3,6-dimethyl-2-(3-pyridyl)chromen-4-one (110 g, 375 mmol) in DCM (1.1 L) was cooled to 0 to 5° C. Formic acid (52 g, 1.13 mmol) was added in one portion followed by slow addition of triethylamine (76.5 g, 756 mmol) at 5 to 20° C. The reaction was cooled to 0 to 5° C. and treated with Noyori catalyst (CAS: 174813-82-2) (2.42 g, 3.81 mmol) in one portion. The reaction was stirred at rt for 22 h. The mixture was washed with saturated aqueous NaHCO3 (2×5V) and water (2×5V). The organic phase was concentrated under reduced pressure and solvent swapped with MTBE. The resulting slurry was filtered and the solid rinsed with MTBE to give the title compound (122 g, 99%) as a yellow solid. ES/MS m/z 296 (M+H).
A solution of 8-[(1R)-1-hydroxyethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (20 g, 68.0 mmol) in cyclopentyl methyl ether (200 mL) was stirred at room temperature. 2,4,6-trichloro[1,3,5]triazine (12.5 g, 68.0 mmol) was added, followed by DMF (7.9 mL, 102 mmol). The reaction was stirred at room temperature for 14 h. Diluted with 2M aqueous sodium hydroxide (100 mL) and separated the layers. The organics were washed with water (100 mL)/saturated aqueous sodium bicarbonate (100 mL) and 5% aqueous lithium chloride (100 mL). The organics were concentrated and diluted with IPA (120 mL). The slurry was heated at 45° C. for 2 h and cooled to room temperature. Water (80 mL) was slowly added. Filtered to give the title compound (18.4 g, 87%, 94% ee). MS ES+ m/z 313 [M+H]+.
A solution of DMF (80 g, 1.09 mol) in DCM (550 mL) was treated with 2,4,6-trichloro-1,3,5-triazine (72 g, 390.43 mmol) at rt. The mixture was stirred for 2 h to form a white solid precipitate. A solution of 8-[(1R)-1-hydroxyethyl]-3,6-dimethyl-2-(3-pyridyl)chromen-4-one (110 g, 372.5 mmol) in DCM (550 mL) was added and the solution stirred at rt for 14 h. The reaction was quenched by adding water (1100 mL) and stirred for 30 min. The mixture was filtered through diatomaceous earth and cake rinsed with DCM (220 mL). The filtrate was washed with saturated aqueous NaHCO3 (1100 mL) and water (1100 mL). The organic layer was collected, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 25% THF in heptane to give a yellow solid (29 g, 93.9% ee). ES/MS m/z 314 (M+H).
To a mixture of 8-acetyl-3,6-dimethyl-2-phenyl-chromen-4-one (180 g, 615.75 mmol) and (R)-2-methylpropane-2-sulfinamide (149.26 g, 1.23 mol) in THF (1500 mL) was added tetraisopropoxytitanium (700.01 g, 2.46 mol, 726.90 mL). The mixture was stirred at 80° C. for 56 h to give a black-brown solution. After cooling to rt, quenched the reaction with saturated aqueous NaCl (2000 mL) and stirred for 30 min and filtered. The filter cake was washed with EtOAc (4000 mL). After separating the organic layer, the aqueous layer was extracted with EtOAc (1000 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was triturated with petroleum ether/EtOAc (1/1, 600 mL) to give the product as a white solid (186 g, 76%). MS ES+ m/z 396 [M+H]+.
To a mixture of (NE,R)—N-[1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethylidene]-2-methyl-propane-2-sulfinamide (186 g, 470.27 mmol) and CeCl3·7H2O (87.61 g, 235.14 mmol, 22.35 mL) in MeOH (1600 mL) was added NaBH4 (26.69 g, 705.41 mmol) at 15° C. The mixture was stirred at 15° C. for 1 h to give a dark suspension. The reaction was quenched with saturated aqueous NH4Cl (1500 mL) at 15° C. Extracted with DCM (2×1500 mL), washed the combined organic phases with saturated aqueous NaCl (1500 mL), dried the organic phase over anhydrous Na2SO4, filtered, and concentrated to give the product as a yellow solid (180 g, 96%). MS ES+ m/z 398 [M+H]+.
A mixture of (R)—N-[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]-2-methyl-propane-2-sulfinamide (180 g, 452.80 mmol) in MeOH (1500 mL) was treated with 4M HCl/MeOH (4M, 300 mL) and the mixture was stirred at 15° C. for 1 h to give a white suspension. Concentrated the reaction, poured the residue into water (1000 mL) and DCM (2000 mL), adjusted the pH to 12 with NH3 in H2O (25%), and extracted with DCM (2×1000 mL). The combined organic phases were washed with saturated aqueous NaCl (1000 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was triturated with DCM (200 mL) to give the product as a white solid (122 g, 89%). MS ES+ m/z 294 [M+H]+.
A mixture of 8-acetyl-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (50 g, 0.18 mol) in 500 mL of toluene was treated with (R)-2-methylpropane-2-sulfinamide (32.7 g, 0.27 mol) and titanium ethoxide (82.1 g, 0.36 mol) in one portion. The reaction was heated at 80° C. for 24 h, then cooled to rt.
The toluene solution of (NE,R)—N-[1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethylidene]-2-methyl-propane-2-sulfinamide (0.18 mol) was cooled to between −10° C. and 0° C. and treated in portions with sodium borohydride (20.4 g, 0.54 mmol) keeping the internal temperature below 0° C. After stirring at −10° C. and 0° C. for 1 h, the reaction was quenched with saturated aqueous NH4Cl. The resulting white slurry was filtered through diatomaceous earth and the solids washed with THF. The filtrate was washed with saturated aqueous NaCl and the organic layer concentrated onto silica gel. The material was purified by chromatography to give the product (26 g, 37% over two steps). MS ES+ m/z 382 [M+H]+.
A solution of (R)—N-[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]-2-methyl-propane-2-sulfinamide (20 g, 52.4 mmol) in THF (200 mL) was treated dropwise with 12M aqueous HCl (8.7 mL, 104.8 mmol) and stirred at rt. After 1 h, the reaction was concentrated, the residue dissolved in water, and extracted with MTBE. The pH of the aqueous phase was adjusted to between 9 and 10 with 1M aqueous NaOH and extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated to give the product (12.6 g, 87%) as a white solid. MS ES+ m/z 278 [M+H]+.
A mixture of 8-[(1R)-1-aminoethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (2.5 g, 9.0 mmol) and diisopropylethylamine (2.0 g, 16 mmol) in DCM (40 mL) was treated with di-tert-butyl dicarbonate (3.0 g, 14 mmol) and stirred overnight at rt. Concentrated the reaction and purified the residue by silica gel chromatography eluted with 0 to 100% EtOAc in heptane to give the product (2.5 g, 73%). MS ES+ m/z 378 [M+H]+.
Combined tris(dibenzylideneacetone)dipalladium(0) (0.099 g, 0.11 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.19 g, 0.32 mmol) in toluene (18 mL). Stirred at rt for 10 min. 8-[(1R)-1-Aminoethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (0.30 g, 1.1 mmol), 5-bromo-2-chloropyridine (0.21 g, 1.1 mmol), and Cs2CO3 (0.71 g, 2.2 mmol) were then added to the mixture, which was flushed with nitrogen. The reaction was sealed and heated to 115° C. overnight. The mixture was filtered over a pad of diatomaceous earth and the solids were rinsed with DCM. The filtrate was concentrated and the residue was purified by reverse phase chromatography eluted with a gradient of 10 to 100% ACN in aqueous NH4HCO3 (10 mM, plus 5% MeOH) to give the title compound (0.090 g, 21%). MS ES+ m/z 389 [M+H]+.
The following compounds in Table 50 were made in a similar way as described for 8-[(1R)-1-[(6-chloro-3-pyridyl)amino]ethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
1Iodo reagent used for this coupling reaction.
A 20 mL pressure vial was charged with 3-bromo-2,6-dimethylpyridine (0.34 g, 1.80 mmol), 8-[(1R)-1-aminoethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (0.50 g, 1.80 mmol), cesium carbonate (1.17 g, 3.61 mmol), BINAP (0.34 g, 0.54 mmol), palladium(II) acetate (0.04 g, 0.18 mmol), and 1,4-dioxane (10 mL). Nitrogen gas was bubbled through the mixture for 5 min and the reaction stirred at 90° C. for 15 h. The reaction was allowed to cool to rt, passed through a syringe filter, and purified by reversed phase chromatography eluted with 10 to 100% ACN in 10 mM NH4HCO3 with 5% MeOH to give the title compound (0.21 g, 30%) as an off-white foam. MS ES+ m/z 383 [M+H]+.
Combined 8-[(1R)-1-aminoethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (200 mg, 0.72 mmol), 3-bromo-6-methoxy-2-methylpyridine (189 mg, 0.94 mmol), tris(dibenzylideneacetone)dipalladium(0) (66 mg, 0.07 mmol), dicyclohexyl(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphane (38.7 mg, 0.07 mmol), and sodium tert-butoxide (139 mg, 1.44 mmol) in 5 mL of 1,4-dioxane. Heated the reaction at 70° C. for 16 h. The reaction was cooled and filtered through diatomaceous earth and the solids washed with EtOAc and DCM. Concentrated the filtrate and purified by silica gel chromatography eluted with 0 to 100% EtOAc in hexane to give the title compound (172 mg, 60%). MS ES+ m/z 399 [M+H]+.
Combined 8-[(1R)-1-aminoethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (5.00 g, 18.0 mmol), 2-(difluoromethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (13.8 g, 54.1 mmol), tetrakis(triphenylphosphine)palladium(0) (2.08 g, 1.80 mmol), and copper(I) thiophene-2-carboxylate (5.16 g, 27.0 mmol) in EtOH (150 mL). Degassed the reaction with nitrogen and stirred at 85° C. for 16 h. The mixture was filtered over a pad of diatomaceous earth and the solids were rinsed with DCM. The filtrate was concentrated and the residue was purified by reverse phase chromatography eluted with a gradient of 5 to 100% ACN in aqueous NH4HCO3 (10 mM, plus 5% MeOH) to give the title compound (2.00 g, 30%). MS ES+ m/z 345 [M+H]+.
The following compounds in Table 51 were made in a similar way as described for 8-[(1R)-1-aminoethyl]-2-[6-(difluoromethyl)-2-pyridyl]-3,6-dimethyl-chromen-4-one. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
tert-Butyl N-[(1R)-1-[3,6-dimethyl-2-(1-methyl-6-oxo-3-pyridyl)-4-oxo-chromen-8-yl]ethyl]carbamate (0.23 g, 0.53 mmol) was dissolved in DCM (5 mL) and treated with TFA (3 mL). The reaction was stirred at 40° C. for 1 h. The reaction was concentrated and purified by reverse phase chromatography eluted with 10 to 100% ACN in 10 mM NH4HCO3 with 5% MeOH to give the title compound (0.17 g, 97%). MS ES+ m/z 325 [M+H]+.
The following compound in Table 52 was made in a similar way as described for 5-[8-[(1R)-1-aminoethyl]-3,6-dimethyl-4-oxo-chromen-2-yl]-1-methyl-pyridin-2-one.
8-[(1R)-1-[(6-Chloro-3-pyridyl)amino]ethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (0.20 g, 0.51 mmol) and copper(I) thiophene-2-carboxylate (0.15 g, 0.77 mmol) were combined in EtOH (10 mL) in a vial and degassed for 5 min with nitrogen gas. Tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.10 mmol) and tert-butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]azetidine-1-carboxylate (0.22 g, 0.62 mmol) were then added, the vial sealed, and the reaction stirred at 40° C. for 4 h. After cooling to rt, the reaction was filtered, concentrated, and purified by silica gel chromatography eluted with 0 to 100% EtOAc in heptane to give the title compound (0.18 g, 59%). MS ES+ m/z 560 [M+H]+.
8-[(1R)-1-(2-Bromoanilino)ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (0.10 g, 0.22 mmol), tributyl(vinyl)stannane (0.085 g, 0.27 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.026 g, 0.022 mmol) were combined in toluene (2 mL). The reaction was degassed with argon and stirred at 120° C. for 2 h. Purified by silica gel chromatography eluted with a gradient of 0 to 100% EtOAc in hexanes to give the title compound (0.082 g, 93%). MS ES+ m/z 396 [M+H]+.
A stirred solution of 6-chloro-1-methyl-pyrazolo[3,4-b]pyridine (1.1 g, 6.56 mmol) and hexamethyldistannane (2.58 g, 7.88 mmol) in 10 mL of 1,4-dioxane was treated with tetrakis(triphenylphosphine)palladium(0) (0.76 g, 0.66 mmol) in portions at rt under nitrogen. The resulting mixture was then stirred at 100° C. for 2 h. The reaction was allowed to cool to rt and quenched with 100 mL of saturated aqueous cesium fluoride. Extracted with EtOAc (2×100 mL). The combined organics were washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound (2.1 g, crude) as a yellow oil. MS ES+ m/z 298 [M+H]+.
The following compound in Table 53 was made in a similar way as described for trimethyl-(1-methylpyrazolo[3,4-b]pyridin-6-yl)stannane. Various methods were used to purify the compound, which would be apparent to one skilled in the art.
A solution of 8-[(1R)-1-[(6-chloro-2-methylsulfanyl-3-pyridyl)amino]ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (150 mg, 0.33 mmol) in DCM (3 mL) was treated dropwise with mCPBA (51.66 mg, 0.30 mmol) at rt. The reaction was stirred at rt for 4 h and then concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 25% EtOAc in petroleum ether to give the title compound (54 mg, 35%) as a white solid. ES/MS m/z 467 (M+H).
A mixture of tris(dibenzylideneacetone)dipalladium(0) (0.031 g, 0.034 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.059 g, 0.102 mmol) in toluene (7 mL) was stirred at rt for 10 min. 8-[(1R)-1-Aminoethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (0.100 g, 0.341 mmol), 4-bromo-3-(difluoromethyl)chlorobenzene (0.082 g, 0.341 mmol), and Cs2CO3 (0.222 g, 0.682 mmol) were then added to the mixture, which was flushed with nitrogen. The reaction was sealed and heated to 115° C. overnight. The mixture was filtered over a pad of diatomaceous earth and the solids were rinsed with DCM. The filtrate was concentrated and the residue was purified by reverse phase chromatography eluted with a gradient of 10 to 100% ACN in aqueous NH4HCO3 (10 mM, plus 5% MeOH) to give the title compound (0.122 g, 79%). MS ES+ m/z 454 [M+H]+.
The following compounds in Table 54 were made in a similar way as described for 8-[(1R)-1-[4-chloro-2-(difluoromethyl)anilino]ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one.
11,4-Dioxane used as solvent.
A solution of tert-butyl 7-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(3-pyridyl)chromen-8-yl]ethyl]amino]-1-oxo-isoindoline-2-carboxylate (0.13 g, 0.25 mmol) in 2 mL of DCM was treated with 1 mL of TFA and allowed to stir at rt for 1 h. The reaction mixture was concentrated and the residue purified by reverse phase chromatography eluted with 0% to 100% ACN in water (with 0.1% formic acid). Fractions containing the product were combined, washed with saturated aqueous sodium chloride, extracted with IPA/CHCl3 (1:3), the organics collected, dried over MgSO4, filtered, and concentrated. The residue was recrystallized from a mixture of DCM and hexane to obtain the title compound (91.5 mg, 86%) as a white solid. MS ES+ m/z 426 [M+H]+.
The following compounds in Table 55 were made in a similar way as described for 7-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(3-pyridyl)chromen-8-yl]ethyl]amino]isoindolin-1-one. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
A mixture of 3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(3-pyridyl)chromen-8-yl]ethyl]amino]pyridine-2-carbonitrile (0.040 g, 0.10 mmol), sodium azide (0.033 g, 0.51 mmol) and ammonium chloride (0.027 g, 0.50 mmol) in DMF (1 mL) was heated at 130° C. overnight. The reaction was concentrated and purified by reverse phase chromatography eluted with a gradient of 0 to 100% ACN in H2O+0.1% formic acid. Fractions containing the desired product were combined, washed with saturated aqueous sodium chloride, and extracted with IPA:CHCl3 (1:3). The combined extracts were dried over MgSO4, filtered, and concentrated. The material was further purified by reverse phase chromatography eluted with a gradient of 0 to 100% ACN in aqueous NH4HCO3 (10 mM, plus 5% MeOH). Fractions containing the desired product were combined, washed with saturated aqueous NH4Cl, and extracted with IPA:CHCl3 (1:3). The combined extracts were dried over MgSO4, filtered, and concentrated to give the title compound (0.122 g, 79%) as a white solid. MS ES+ m/z 440 [M+H]+.
The following compounds in Table 56 were made in a similar way as described for 3,6-dimethyl-2-phenyl-8-[(1R)-1-[2-(2H-tetrazol-5-yl)anilino]ethyl]chromen-4-one. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
To a solution of 8-(1-chloroethyl)-3,6-dimethyl-2-phenyl-chromen-4-one (0.200 g, 0.639 mmol) and 2-(1H-tetrazol-1-yl)aniline (0.206 g, 1.28 mmol) in IPA (2 mL) was added triethylamine (0.27 mL, 1.92 mmol). The reaction was heated in a sealed vessel at 90° C. for 18 h, then additional 2-(1H-tetrazol-1-yl)aniline (0.206 g, 1.28 mmol) and triethylamine (0.27 mL, 1.92 mmol) were added and heating continued at 90° C. for 24 h. The reaction was concentrated and the residue was purified by silica gel chromatography eluted with a gradient of 0% to 100% EtOAc in hexanes to give crude racemic product, which was recrystallized from a mixture of DCM and hexanes. The racemic mixture was separated by chiral SFC [Chiralpak IH, 20×250 mm; 35% EtOH (0.5% DMEA) in CO2] to give the title compounds (Isomer 1, first-eluting; 0.026 g, >98% ee, 90%) and (Isomer 2; 0.034 g, 9700 ee, 120%). MS ES+ m/z 438 [M+H]+.
The following compounds in Table 57 were made in a similar way as described for 3,6-dimethyl-2-phenyl-8-[1-[2-(tetrazol-1-yl)anilino]ethyl]chromen-4-one. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
a [Chiralpak AD, 20 × 250 mm; 35% IPA (0.5% DMEA) in CO2]
b [Chiralpak IH, 20 × 250 mm; 30% MeOH (0.5% DMEA) in CO2]
c [Chiralpak AS-H, 21 × 150 mm; 20% MeOH in CO2]
d [Chiralpak IG, 30 × 250 mm; 30% EtOH in CO2]
The following compound in Table 58 was made in a similar way as described for 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-N′-hydroxy-pyridine-2-carboxamidine.
To a solution of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-N′-hydroxy-benzamidine (0.100 g, 0.234 mmol) in 1,4-dioxane (2 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.071 mL, 0.468 mmol) and di(1H-imidazol-1-yl)methanone (0.057 g, 0.351 mmol). The reaction was sealed and heated in a microwave reactor at 100° C. for 1 h. The mixture was concentrated and purified by reverse phase chromatography eluted with a gradient of 0% to 100% ACN in H2O+0.1% formic acid. Fractions containing the desired product were combined, washed with saturated aqueous sodium chloride, and extracted with IPA:CHCl3 (1:3). The combined extracts were dried over MgSO4, filtered, and concentrated. The material was recrystallized from a mixture of DCM and hexanes to give the title compound (0.052 g, 49%) as a white solid. MS ES+ m/z 454 [M+H]+.
The following compounds in Table 59 were made in a similar way as described for 3-[2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]phenyl]-4H-1,2,4-oxadiazol-5-one. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
A solution of 3-[3-[[(1R)-1-[2-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrazol-4-yl]-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]-6-chloro-2-pyridyl]-4H-1,2,4-oxadiazol-5-one (98.4 mg, 0.15 mmol) in THF (3 mL) was cooled in an ice bath and treated with tetrabutylammonium fluoride (1M in THF, 48.5 mg, 0.19 mmol). The reaction was stirred at 0° C. for 1 h. The reaction was concentrated under reduced pressure and the residue purified by reversed phase chromatography on C18 eluted with 0% to 100% ACN in water (with 0.1% formic acid). The resulting material was repurified by preparative TLC eluted with 4% MeOH in DCM and 8% MeOH in DCM to give the title compound (18.2 mg, 23%) as a white solid. ES/MS m/z 523 (M+H).
The following compound in Table 60 was made in a similar way as described for 3-[6-chloro-3-[[(1R)-1-[2-[1-(2-hydroxyethyl)pyrazol-4-yl]-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]-2-pyridyl]-4H-1,2,4-oxadiazol-5-one. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
A solution of 3-[6-chloro-3-[[(1R)-1-[2-(6-methoxy-2-pyridyl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]-2-pyridyl]-4H-1,2,4-oxadiazol-5-one (70 mg, 0.13 mmol) in DMF (1 mL) was treated with p-toluenesulfonic acid monohydrate (130 mg, 0.67 mmol) and lithium chloride (29 mg, 0.67 mmol). The reaction was sealed and heated at 120° C. for 40 min in a microwave. The reaction was allowed to cool to rt, concentrated under reduced pressure, and the residue purified by reversed phase chromatography on a CSH column eluted with 10% to 44% ACN in 10 mM aqueous NH4HCO3 (with 5% MeOH). The resulting residue was triturated with MeOH/MTBE resulting in the title compound (3.8 mg, 6%) being removed by filtration. ES/MS m/z 506 (M+H).
A solution of 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-N′-hydroxy-pyridine-2-carboxamidine (0.13 g, 0.30 mmol) in ACN (2 mL) was treated with DBU (0.09 g, 0.61 mmol) and N,N′-thiocarbonyldiimidazole (0.08 g, 0.46 mmol). The reaction was sealed and stirred at 80° C. for 3 h. The reaction was concentrated and purified by reversed phase C18 flash chromatography eluted with 0% to 100% ACN in 0.1% aqueous formic acid. Fractions containing the product were combined, washed with saturated aqueous sodium chloride, and extracted with IPA/CHCl3 (1:3). The organics were collected, dried over MgSO4, filtered, and concentrated. The residue was recrystallized from DCM/hexanes to give the title compound (74 mg, 52%) as a white solid. MS ES+ m/z 471 [M+H]+.
The following compound in Table 61 was made in a similar way as described for 3,6-dimethyl-2-phenyl-8-[(1R)-1-[[2-(5-thioxo-4H-1,2,4-oxadiazol-3-yl)-3-pyridyl]amino]ethyl]chromen-4-one.
A solution of 3-[3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-2-pyridyl]-4H-1,2,4-oxadiazol-5-one (0.10 g, 0.22 mmol) in 2 mL of DMF was treated with potassium carbonate (0.11 g, 0.77 mmol) and iodomethane (37.5 mg, 0.26 mmol) and the reaction allowed to stir at rt overnight. The reaction was concentrated and the residue purified by reversed phase chromatography eluted with 0% to 100% ACN in water (with 0.1% formic acid). Fractions containing the product were pooled, washed with saturated aqueous sodium chloride, and extracted with IPA/CHCl3 (1:3). The organic layers were combined, dried over MgSO4, filtered, and concentrated. The residue was crystallized from a mixture of DCM and hexanes to give the title compound (64 mg, 62%) as a white solid. MS ES+ m/z 469 [M+H]+.
To a solution of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-N′-hydroxy-benzamidine (0.100 g, 0.234 mmol) in triethyl orthoformate (2 mL, 10 mmol) was added TFA (0.005 mL). The reaction was sealed and heated in a microwave reactor at 120° C. for 1 h. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 and saturated aqueous sodium chloride. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluted with a gradient of 0% to 100% EtOAc in heptane. Fractions with the desired product were combined and concentrated and the residue was re-purified by reverse phase chromatography eluted with a gradient of 0% to 100% ACN in aqueous formic acid (0.1%). Fractions containing the desired product were combined, washed with saturated aqueous sodium chloride, and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated to give the title compound (0.038 g, 37%) as a white solid. MS ES+ m/z 438 [M+H]+.
The following compound in Table 62 was made in a similar way as described for 3,6-dimethyl-8-[(1R)-1-[2-(1,2,4-oxadiazol-3-yl)anilino]ethyl]-2-phenyl-chromen-4-one. Various methods were used to purify the compound, which would be apparent to one skilled in the art.
Synthesized according to the method described for Intermediate 307C.
A vial was charged with 8-[(1R)-1-[2-(2-chloroacetyl)anilino]ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (17.6 mg, 0.04 mmol), sodium cyanide (11.6 mg, 0.24 mmol), and DMF (0.4 mL) at rt. The reaction was stirred for 30 min. The crude reaction was purified by reversed phase chromatography on C18 eluted with 0% to 100% ACN in 10 mM aqueous NH4HCO3 (with 5% MeOH) to give the title compound (16.2 mg, 94%) as a light yellow powder. ES/MS m/z 437 (M+H).
In an oven-dried round bottom flask, 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid (0.200 g, 0.484 mmol) was dissolved in dry THF (2 mL) and thionyl chloride (2 M solution in DCM, 0.36 mL, 0.73 mmol) was added at 0° C. The reaction was stirred at rt for 45 min, cooled to 0° C., and then ice-cold aqueous ammonium hydroxide (5 wt %) was added in one portion. The reaction was removed from the ice bath and stirred for 15 min. The mixture was extracted 3× with DCM. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by reverse phase chromatography eluted with a gradient of 0 to 100% ACN in aqueous NH4HCO3 (10 mM+5% MeOH) to give the title compound (0.160 g, 80%). MS ES+ m/z 413 [M+H]+.
The following compound in Table 63 was made in a similar way as described for 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carbohydrazide.
To a stirred suspension of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid (0.200 g, 0.484 mmol) in dry DCM (30 mL) was added thionyl chloride (2 M solution in DCM, 0.36 mL, 0.73 mmol) at 0° C., then the reaction was stirred for 1 h at rt. Triethylamine (0.20 mL, 1.45 mmol) was added followed by the addition of dimethylamine (10 wt %, 0.220 g, 0.484 mmol). The reaction was stirred at rt for 4 h, then diluted with water, followed by addition of 1N aqueous NaOH to adjust the pH>7. The aqueous layer was extracted 3× with DCM. The organic extracts were dried over Na2SO4 and concentrated. The residue was purified by reverse phase chromatography eluted with a gradient of 0 to 100% ACN in aqueous NH4HCO3 (10 mM+5% MeOH) to give the title compound (0.178 g, 84%) as a white solid. MS ES+ m/z 441 [M+H]+.
The following compounds in Table 64 were made in a similar way as described for 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-N,N-dimethyl-benzamide. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
To a solution of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid (0.200 g, 0.484 mmol) in DCM was added di(1H-imidazol-1-yl)methanone (0.078 g, 0.484 mmol). The reaction was stirred for 1 h at rt and benzylamine (0.053 mL, 0.48 mmol) was added. The reaction was stirred for 6 h at rt, then diluted with DCM and water. The aqueous layer was extracted 3×. The crude product was purified by reverse phase chromatography eluted with a gradient of ACN in aqueous NH4HCO3 (10 mM, plus 500 MeOH) to give the title compound (0.23 g, 950%). MS ES+ m/z 503 [M+H]+.
The following compounds in Table 65 were made in a similar way as described for N-benzyl-2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzamide. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Combined 6-chloro-3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid (0.10 g, 0.22 mmol), DIPEA (0.17 g, 1.34 mmol), 2,4,6-tripropyl-1,3,5-trioxa-2,4,6-triphosphinane-2,4,6-trioxide (0.85 g, 1.34 mmol), and ammonia (0.5 M, 0.23 mg, 1.34 mmol) in DMA (0.5 mL) and the reaction stirred at 25° C. for 12 h. Reaction was directly purified by reversed phase chromatography eluted with 10% to 100% ACN in aqueous 0.1 mM NH4HCO3 with 5% MeOH to give the title compound (22.3 mg, 22%). MS ES+ m/z 448 [M+H]+.
The following compounds in Table 66 were made in a similar way as described for 6-chloro-3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxamide. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
1Ammonium chloride used instead of ammonia and DMF used instead of DMA.
2DCM used as solvent.
A mixture of 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid (0.20 g, 0.48 mmol), BOP (0.43 g, 0.97 mmol), triethylamine (0.15 g, 1.45 mmol), and 1,3,4-oxadiazol-2-ylmethanamine hydrochloride (0.1 g, 0.72 mmol) in 6 mL of DMF was stirred overnight at rt under a nitrogen atmosphere. The reaction was purified by reversed phase chromatography eluted with 40% to 50% ACN in water (with 0.1% NH4OH) followed by preparative HPLC (YMC-Actus Triart C18 ExRS column) eluted with 42% to 51% ACN in water (with 0.1% NH4OH) to give the title compound (3.6 mg, 1%) as a yellow solid. MS ES+ m/z 496 [M+H]+.
A solution of 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-6-methyl-pyridine-2-carboxylic acid (75 mg, 0.18 mmol) in 3 mL of DMF was treated with HATU (87 mg, 0.23 mmol), ammonium chloride (94 mg, 1.8 mmol), and DIPEA (270 mg, 2.1 mmol) and allowed to stir at rt for 16 h. The reaction mixture was diluted with EtOAc, washed with water, and the organics collected, dried over MgSO4, filtered, and concentrated to give the title compound (28 mg, 37%). MS ES+ m/z 428 [M+H]+.
The following compounds in Table 67 were made in a similar way as described for 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-6-methyl-pyridine-2-carboxamide. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
1Ammonia (0.5M in 1,4-dioxane) used instead of ammonium chloride.
2Ammonia in 1,4-dioxane used in this reaction.
Combined 6-chloro-3-[[(1R)-1-[2-(2,6-difluorophenyl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]pyridine-2-carbonitrile (60 mg, 0.13 mmol) and dihydrogen tris(dimethylphosphinito)hydroplatinate(2-) (Ghaffar-Parkins catalyst, 28 mg, 0.06 mmol) in EtOH (0.5 mL) and water (0.5 mL), degassed for 10 min, capped, and stirred at 80° C. overnight. The reaction was cooled to room temperature and diluted with 15 mL of DCM and water. Extracted with DCM (3×10 mL). The organics were combined, passed through a phase separator frit and concentrated. The residue was purified by reversed phase chromatography eluted with ACN (with 0.1% formic acid) in water (with 0.1% formic acid) to give the title compound (40 mg, 64%). MS ES+ m/z 484 [M+H]+.
The following compound in Table 68 was made in a similar way as described for 6-chloro-3-[[(1R)-1-[2-(2,6-difluorophenyl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]pyridine-2-carboxamide. Various methods were used to purify the compound, which would be apparent to one skilled in the art.
2-[[(1R)-1-(3,6-Dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzamide (300 mg, 0.73 mmol) was dissolved in 1,1-dimethoxy-N,N-dimethylmethanamine (3 g, 20 mmol) and stirred at 120° C. for 2 h. The 1,1-dimethoxy-N,N-dimethylmethanamine was removed under reduced pressure and the residue redissolved in acetic acid (3 mL). The reaction was treated with hydrazine hydrate (1.82 g, 36.4 mmol) and then stirred at 90° C. for 20 h. Added EtOAc (10 mL) and then concentrated the reaction under reduced pressure. The resulting solid was dissolved in EtOAc (20 mL), washed with water (2×20 mL) and brine (20 mL). The organic layer was concentrated under reduced pressure and the residue purified by reversed phase chromatography on a CSH column eluted with 20% to 80% ACN in 10 mM NH4HCO3 (with 5% MeOH) to give the title compound (22.7 mg, 7%) as an off-white solid. ES/MS m/z 437 (M+H).
To a solution of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzohydrazide (0.100 g, 0.234 mmol) in EtOH (2 mL) was added K2CO3 (0.065 g, 0.47 mmol) and cyanogen bromide (0.074 g, 0.70 mmol). The reaction was sealed and heated at 70° C. for 17 h. The mixture was diluted with EtOAc and washed with water, then the aqueous layer was extracted twice with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel chromatography eluted with a gradient of 0% to 100% EtOAc in hexanes, then re-purified by reverse phase chromatography eluted with a gradient of 0% to 100% ACN in aqueous formic acid (0.1%). Fractions containing the product were combined, washed with saturated aqueous sodium chloride, and extracted with IPA:CHCl3 (1:3). The combined extracts were dried over MgSO4, filtered, and concentrated to give the title compound (0.011 g, 10%) as a white solid. MS ES+ m/z 453 [M+H]+.
The following compounds in Table 69 were made in a similar way as described for 8-[(1R)-1-[2-(5-amino-1,3,4-oxadiazol-2-yl)anilino]ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
To a solution of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzohydrazide (0.100 g, 0.234 mmol) in triethyl orthoformate (2 mL, 10 mmol) was added TFA (0.005 mL). The reaction was sealed and heated in a microwave reactor at 120° C. for 1 h. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 and saturated aqueous sodium chloride. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was recrystallized in MTBE/hexanes to obtain the title compound (0.038 g, 37%) as a tan solid. MS ES+ m/z 438 [M+H]+.
The following compounds in Table 70 were made in a similar way as described for 3,6-dimethyl-8-[(1R)-1-[2-(1,3,4-oxadiazol-2-yl)anilino]ethyl]-2-phenyl-chromen-4-one. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
To a solution of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzohydrazide (0.080 g, 0.19 mmol) in DCM (2 mL) was added DIPEA (0.065 mL, 0.37 mmol). In a separate vessel, triphosgene (0.028 g, 0.094 mmol) was dissolved in DCM (2 mL), sonicating for complete dissolution of the reagent before use. The triphosgene/DCM solution was added and the reaction was stirred at rt for 1 h. The mixture was concentrated and purified by silica gel chromatography eluted with a gradient of 0% to 100% EtOAc in hexanes. Fractions with the desired product were combined and concentrated, and the residue was recrystallized from DCM/hexanes to give the title compound (0.036 g, 42%) as a pale tan solid. MS ES+ m/z 454 [M+H]+.
To a solution of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzohydrazide (0.100 g, 0.234 mmol) in ethanol (2 mL) was added 2-methylisothiourea; sulfuric acid (0.076 mL, 0.35 mmol). The reaction was sealed and heated at 95° C. for 17 h. Added NaOH (0.028 g, 0.70 mmol), sealed, and heated at 95° C. for 2 h. Added NaOH (0.056 g, 1.4 mmol), sealed, and heated at 105° C. overnight. The mixture was diluted with DCM and saturated aqueous NH4Cl. Extracted with IPA:CHCl3 (1:3). The organic extracts were dried over MgSO4, filtered, concentrated, and the residue was recrystallized from DCM/hexanes to give the title compound (0.020 g, 19%) as a white solid. MS ES+ m/z 452 [M+H]+.
3-[[(1R)-1-(3,6-Dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carbonitrile (0.100 g, 0.253 mmol) and carbazic acid ethylester (0.080 g, 0.77 mmol) were combined in NMP (2 mL). The reaction was sealed and heated in a microwave reactor at 160° C. for 2 h. Added carbazic acid ethyl ester (0.080 g, 0.77 mmol). The reaction was sealed and heated at 160° C. overnight. The mixture was concentrated, and the residue was purified by reverse phase chromatography eluted with a gradient of 0% to 100% ACN in aqueous formic acid (0.1%). Fractions containing the desired product were combined, washed with saturated aqueous sodium chloride, and extracted with IPA:CHCl3 (1:3). The organic extracts were dried over MgSO4, filtered, concentrated, and the residue was recrystallized from DCM/hexanes to give the title compound (0.052 g, 46%) as a white solid. MS ES+ m/z 454 [M+H]+
To a solution of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid (0.20 g, 0.48 mmol) in DMF (4 mL) was added (Z)—N′-hydroxyacetimidamide (0.036 g, 0.48 mmol), propylphosphonic anhydride (50 wt % in EtOAc, 0.29 mL, 0.48 mmol) and DIPEA (0.084 mL, 0.48 mmol). The reaction was stirred at rt for 2 h, then charged with additional (Z)—N′-hydroxyacetimidamide (0.054 g, 0.73 mmol), propylphosphonic anhydride (50 wt % in EtOAc, 0.43 mL, 0.73 mmol) and DIPEA (0.13 mL, 0.73 mmol). The reaction was stirred at rt for 2 h, then heated to 110° C. overnight. The mixture was diluted with EtOAc, neutralized with 1N aqueous HCl, and extracted 3× with EtOAc. The combined organic extracts were washed with saturated aqueous NaHCO3, saturated aqueous sodium chloride, and 10% aqueous LiCl. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluted with a gradient of 0% to 100% EtOAc in heptane to give the title compound (0.10 g, 46%) as a white solid. MS ES+ m/z 452 [M+H]+.
3,6-Dimethyl-2-phenyl-8-[(1R)-1-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]ethyl]chromen-4-one (0.050 g, 0.10 mmol), 2-bromooxazole (0.018 g, 0.12 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (0.0074 g, 0.010 mmol), and K2CO3 (1M aqueous, 0.30 mL, 0.30 mmol) were combined in 1,4-dioxane (2 mL) and water (0.5 mL), degassed using argon for 1 min, and stirred at 95° C. for 16 h. The mixture was loaded directly onto a diatomaceous earth plug and purified by reverse phase chromatography eluted with a gradient of 0% to 100% ACN in aqueous NH4HCO3 (10 mM, plus 50 MeCH). Fractions containing desired product were concentrated, then dissolved in ACN/water and lyophilized to give the title compound (0.0047 g, 110%). MS ES+ m/z 437 [M+H]+.
The following compounds in Table 71 were made in a similar way as described for 3,6-dimethyl-2-phenyl-8-[(1R)-1-(2-pyridazin-3-ylanilino)ethyl]chromen-4-one. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
1ACN used as the solvent.
22M aqueous Na2CO3 used as the base.
Combined 8-[(1R)-1-[(2-chloro-3-pyridyl)amino]ethyl]-3,6-dimethyl-2-(3-pyridyl)chromen-4-one (100 mg, 0.25 mmol), (1-methylpyrazol-4-yl)boronic acid (46.5 mg, 0.37 mmol), potassium carbonate (68.1 mg, 0.49 mmol), and tetrakis(triphenylphosphine)palladium(O) (42.7 mg, 0.04 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL). Bubbled argon gas through the reaction for 5 min and then allowed to stir at 60° C. for 16 h. The reaction was filtered, the filtrate concentrated under reduced pressure, and the residue purified by silica gel chromatography eluted with 0% to 100% EtOAc in heptane. The fractions containing product were concentrated under reduced pressure and the residue purified by reversed phase chromatography on C18 eluted with 0% to 100% ACN in 10 mM aqueous NH4HCO3 (with 5% MeOH) to give the title compound (58 mg, 52%). ES/MS m/z 452 (M+H).
The following compounds in Table 72 were made in a similar way as described for 3,6-dimethyl-8-[(1R)-1-[[2-(1-methylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-2-(3-pyridyl)chromen-4-one. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
1[1.1′-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) used as catalyst and cesiumcarbonate used as base.
A mixture of 8-[(1R)-1-[(2-chloro-3-pyridyl)amino]ethyl]-3,6-dimethyl-2-(3-pyridyl)chromen-4-one (130 mg, 0.32 mmol), copper(I) iodide (24.4 mg, 0.13 mmol), tris(dibenzylideneacetone)dipalladium(0) (29.3 mg, 0.03 mmol), tri-o-tolylphosphine (58.5 mg, 0.19 mmol), and cesium fluoride (97.3 mg, 0.64 mmol) in DMF (0.5 mL) and toluene (1 mL) was treated with tributyl-(3-fluoro-2-pyridyl)stannane (247 mg, 0.64 mmol). The reaction was sparged with argon for 5 min, capped, and heated at 60° C. for 20 h. Temperature was increased to 80° C. for 4 h. Since the reaction was not progressing quickly, added tributyl-(3-fluoro-2-pyridyl)stannane (247 mg, 0.64 mmol), tris(dibenzylideneacetone)dipalladium(0) (29.3 mg, 0.03 mmol), tri-o-tolylphosphine (58.5 mg, 0.19 mmol), copper(I) iodide (24.4 mg, 0.13 mmol), and cesium fluoride (97.3 mg, 0.64 mmol) were added and the reaction stirred at 60° C. over 4 days. Reaction was filtered through diatomaceous earth and the solids washed with DCM (5 mL). The filtrate was concentrated under reduced pressure and the residue purified by silica gel chromatography eluted with 0% to 100% EtOAc in heptane to give an impure product. This material was purified by reversed phase chromatography on C18 eluted with 80% ACN in water (with 0.1% formic acid) to give the title compound (8.6 mg, 6%). ES/MS m/z 467 (M+H).
Combined 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid (0.20 g, 0.48 mmol), triethyl orthoformate (0.40 mL, 2.4 mmol), and ammonium acetate (0.112 g, 1.45 mmol). The reaction was stirred at 120° C. for 16 h. Concentrated with DCM onto a small amount of diatomaceous earth and purified by reverse phase chromatography to give the title compound (0.061 g, 30%) as a white solid. MS ES+ m/z 423 [M+H]+.
Combined 8-[(1R)-1-(2-bromoanilino)ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (0.066 g, 0.15 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isothiazole (0.062 g, 0.29 mmol), tetrakis(triphenylphosphine)palladium(0) (0.043 g, 0.037 mmol), and cesium carbonate (0.14 g, 0.44 mmol) 1,4-dioxane (2 mL) and water (0.4 mL). Degassed with argon for 1 min and stirred the reaction at 100° C. for 16 hour. Loaded the mixture directly onto a small plug of diatomaceous earth and purified by reverse phase chromatography to give the title compound (0.0078 g, 12%) as a white solid. MS ES+ m/z 453 [M+H]+.
The following compound in Table 73 was made in a similar way as described for 8-[(1R)-1-(2-isothiazol-5-ylanilino)ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one.
The following compounds in Table 74 were made in a similar way as described for N-[[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]-2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzamide. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Combined methyl 6-bromo-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate (0.050 g, 0.10 mmol), phenylboronic acid (0.016 g, 0.13 mmol), copper(I) thiophene-2-carboxylate (0.039 g, 0.20 mmol), phosphine, tri-2-furanyl- (0.012 g, 0.051 mmol), tris(dibezylideneacetone)dipalladium (0.0093 g, 0.010 mmol), and zinc diacetate (0.0037 g, 0.20 mmol) in 1,4-dioxane (3 mL). Degassed with nitrogen for 5 min and stirred the reaction at 80° C. for 16 h. Added phenylboronic acid (0.016 g, 0.13 mmol), copper(I) thiophene-2-carboxylate (0.039 g, 0.20 mmol), phosphine, tri-2-furanyl- (0.012 g, 0.051 mmol), tris(dibezylideneacetone)dipalladium (0.0093 g, 0.010 mmol), and zinc diacetate (0.0037 g, 0.20 mmol). Degassed with nitrogen for 5 min and stirred the reaction at 100° C. for 16 h. The mixture was filtered over diatomaceous earth. Poured the filtrate into saturated aqueous NH4Cl with tetramethylethylenediamine (˜1 mL). Extracted with DCM 3×. The combined organic extracts were washed with saturated aqueous NH4Cl, dried over Na2SO4, and concentrated. The crude product was purified by reverse phase chromatography eluted with a gradient of 10 to 10000 ACN in aqueous NH4HCO3 (10 mM, plus 500 MeOH) to give the title compound (0.026 g, 490%) as a white solid. MS ES+ m/z 507 [M+H]+.
The following compounds in Table 75 were made in a similar way as described for 2-[[(1R)-1-[2-(2-fluorophenyl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]benzonitrile. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Combined 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]-N-methylsulfonyl-pyridine-2-carboxamide (48 mg, 0.09 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[3,4-b]pyridine (73 mg, 0.28 mmol), copper(I) thiophene-2-carboxylate (27 mg, 0.14 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6.9 mg, 0.09 mmol) in EtOH (0.9 mL) degassed with argon for 5 min. The reaction was flushed with argon and stirred at 65° C. for 17 h. Added DCM and water to the cooled reaction and separated the layers with a phase separator. The aqueous layer was extracted with DCM. The combined organic layers were concentrated under reduced pressure and the residue purified by reversed phase chromatography eluted with 10% to 100% ACN in 10 mM aqueous NH4HCO3 (with 5% MeOH) to give the title compound (13.3 mg, 24%). ES/MS m/z 581 (M+H).
The following compound in Table 76 was made in a similar way as described for 6-chloro-3-[[(1R)-1-[3,6-dimethyl-2-(1-methylpyrazolo[3,4-b]pyridin-5-yl)-4-oxo-chromen-8-yl]ethyl]amino]-N-methylsulfonyl-pyridine-2-carboxamide. Various methods were used to purify the compound, which would be apparent to one skilled in the art.
1Cesium carbonate added to this reaction.
To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (0.500 g, 1.70 mmol) in ACN (8 mL) was added potassium carbonate (0.589 g, 4.26 mmol) and 1-fluoro-2-nitrobenzene (0.361 g, 2.56 mmol). The reaction was stirred at 80° C. overnight, filtered, and the solids were washed with DCM. The filtrate was concentrated and purified by silica gel chromatography eluted with a gradient of 0% to 100% EtOAc in hexanes. Fractions with the desired product were combined and concentrated, and the residue was recrystallized from DCM/hexanes to give the title compound (0.675 g, 96%) as a yellow solid. MS ES+ m/z 415 [M+H]+.
To a suspension of 3,6-dimethyl-8-[(1R)-1-(2-nitroanilino)ethyl]-2-phenyl-chromen-4-one (0.675 g, 1.63 mmol) and iron (0.273 g, 4.89 mmol) in ethanol (8 mL) was added saturated aqueous NH4Cl (8 mL). The reaction was stirred at 75° C. for 30 min, filtered through diatomaceous earth, and the solids were washed with DCM and MeOH. The filtrate was concentrated to remove most of the alcohols. The remaining liquids were extracted with DCM. The organic extracts were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluted with a gradient of 0 to 100% EtOAc in hexanes to give 8-[(1R)-1-(2-aminoanilino)ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (0.560 g, 89%). MS ES+ m/z 385 [M+H]+. To a portion of the intermediate aniline (0.050 g, 0.13 mmol) in pyridine (1 mL) at 0° C. was added a solution of methanesulfonyl chloride (0.011 mL, 0.14 mmol) in DCM (0.5 mL). After 30 min, diluted with EtOAc and 1N aqueous HCl. Extracted the aqueous layer twice more with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, concentrated, and the residue was recrystallized from DCM/hexanes to give the title compound (0.040 g, 66%). MS ES+ m/z 463 [M+H]+.
A vial containing cuprous iodide (0.003 g, 0.02 mmol) and potassium carbonate (0.034 g, 0.25 mmol) in toluene (1 mL) was degassed and purged with nitrogen. Pyrrolidin-2-one (0.016 g, 0.19 mmol), methyl[2-(methylamino)ethyl]amine (0.0022 g, 0.025 mmol), and 8-[(1R)-1-[(2-chloro-3-pyridyl)amino]ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (0.050 g, 0.12 mmol) were added. The reaction was sealed and heated at 120° C. overnight. The mixture was concentrated and purified by reverse phase chromatography eluted with a gradient of 0% to 100% ACN in H2O+0.1% formic acid. Fractions containing the desired product were combined, washed with saturated aqueous sodium chloride, and extracted with IPA:CHCl3 (1:3). The combined extracts were dried over MgSO4, filtered, and concentrated. The material was recrystallized from a mixture of DCM and hexanes to give the title compound (0.010 g, 19%) as a white solid. MS ES+ m/z 454 [M+H]+.
To a solution of 2-[1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethylamino]benzenesulfonamide (0.070 g, 0.16 mmol) in pyridine (1 mL) was added acetic anhydride (0.044 mL, 0.47 mmol) and 4-dimethylaminopyridine (0.0057 g, 0.047 mmol). The reaction was stirred at rt overnight and concentrated. Diluted with toluene and concentrated 2×. Purified by reverse phase chromatography to give the title compound (0.039 g, 51%). MS ES+ m/z 491 [M+H]+.
N-[2-[1-(3,6-Dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethylamino]phenyl]sulfonylacetamide (0.035 g) was separated by chiral SFC [Chiralpak AS-H, 21×150 mm; 20% EtOH in CO2] to give the title compounds (Isomer 1, first-eluting; 0.010 g, >98% ee) and (Isomer 2; 0.018 g, >98% ee). MS ES+ m/z 491 [M+H]+.
To a solution of N-[[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]-2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzamide (0.171 g, 0.315 mmol) in MeOH (2 mL) was added p-toluenesulfonic acid monohydrate (0.012 g, 0.063 mmol). The reaction stirred at rt overnight. The mixture was concentrated and purified by silica gel chromatography eluted with 0% to 100% EtOAc:EtOH (3:1) in heptane. Fractions with the desired product were combined and concentrated, and the residue was recrystallized from MTBE/hexanes to give the title compound (0.061 g, 39%) as a white solid. MS ES+ m/z 503 [M+H]+.
To a solution of 8-[(1R)-1-(2-aminoanilino)ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (0.100 g, 0.260 mmol) and DIPEA (0.068 mL, 0.390 mmol) in DCM (1.5 mL) was added methyl carbonochloridate (0.030 mL, 0.390 mmol). After 1 h, purified by silica gel chromatography eluted with 0% to 100% EtOAc in heptane. Fractions with the desired product were combined, concentrated, and purified by reverse phase chromatography eluted with a gradient of 10 to 100% ACN in H2O+0.1% formic acid to give the title compound (0.043 g, 37%) after lyophilization. MS ES+ m/z 443 [M+H]+.
A vial containing cuprous iodide (0.0065 g, 0.034 mmol) and cesium carbonate (0.222 g, 0.682 mmol) in DMSO (2 mL) was degassed and purged with nitrogen. 8-[(1R)-1-Aminoethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (0.100 g, 0.341 mmol), 2-bromo-N-methyl benzenesulfonamide (0.102 g, 0.409 mmol) and o-phenanthroline (0.012 g, 0.068 mmol) were added. The reaction was sealed and heated at 150° C. for 30 min. Diluted with water and extracted twice with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The material was purified by silica gel chromatography eluted with 0% to 100% EtOAc in hexanes to give the title compound (0.035 g, 22%) as a white solid. MS ES+ m/z 463 [M+H]+.
The following compound in Table 77 was made in a similar way as described for 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-N-methyl-benzenesulfonamide. Various methods were used to purify the compound, which would be apparent to one skilled in the art.
Combined 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid (0.200 g, 0.484 mmol), 2-chloro-1-methyl-pyridin-1-ium iodide (0.148 g, 0.580 mmol), methylsulfonamide (0.092 g, 0.967 mmol), and 4-dimethylaminopyridine (0.0059 g, 0.048 mmol) in DCM (4 mL). After 5 min, triethylamine (0.20 mL, 1.45 mmol) was added. The reaction was stirred at rt for 1 h. Diluted with DCM and washed with 1N aqueous HCl. The aqueous layer was extracted twice with DCM. The combined organic extracts were dried over MgSO4, filtered, and concentrated. The residue was purified by reverse phase chromatography eluted with a gradient of 0% to 100% ACN in H2O+0.1% formic acid. Fractions containing the desired product were combined, washed with saturated aqueous sodium chloride, and extracted with IPA:CHCl3 (1:3). The combined extracts were dried over MgSO4, filtered, and concentrated. The material was recrystallized from a mixture of DCM and hexanes to give the title compound (0.0044 g, 1.9%) as a white solid. MS ES+ m/z 491 [M+H]+.
The following compounds in Table 78 were made in a similar way as described for 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-N-methylsulfonyl-benzamide. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
6-Chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(2-pyridyl)chromen-8-yl]ethyl]amino]pyridine-2-carboxylic acid (0.10 g, 0.22 mmol), methanesulfonamide (0.03 g, 0.29 mmol), and N,N′-dicyclohexylcarbodiimide (0.06 g, 0.29 mmol) were combined in 6 mL of DCM and the reaction allowed to stir at 25° C. When the reaction was complete, reaction was directly loaded and purified by reversed phase chromatography eluted with 10% to 100% ACN (with 0.1% formic acid) in water (with 0.1% formic acid) to give the title compound (62.1 mg, 53%). MS ES+ m/z 527 [M+H]+.
The following compounds in Table 79 were made in a similar way as described for 6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(2-pyridyl)chromen-8-yl]ethyl]amino]-N-methylsulfonyl-pyridine-2-carboxamide. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
14-Dimethylaminopyridine used in reaction.
2EDC and DMAP used for this reaction.
Combined 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carbonitrile (0.095 g, 0.24 mmol), thiosemicarbazide (0.033 g, 0.36 mmol) and TFA (2 mL). The reaction was heated at 80° C. for 4 h, concentrated, and diluted with DCM and saturated aqueous NaHCO3. The aqueous layer was extracted 3× with IPA:CHCl3 (1:3). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The residue was purified by reverse phase chromatography eluted with a gradient of 0% to 100% ACN in H2O+0.1% formic acid. Fractions containing the desired product were combined, washed with saturated aqueous sodium chloride, and extracted with IPA:CHCl3 (1:3). The combined extracts were dried over MgSO4, filtered, and concentrated. The material was recrystallized from a mixture of DCM and hexanes to give the title compound (0.025 g, 22%) as a white solid. MS ES+ m/z 470 [M+H]+.
To a mixture of 8-[(1R)-1-(2-ethynylanilino)ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (0.100 g, 0.254 mmol) in tert-butanol (2 mL) and water (2 mL) was added sodium azide (0.025 g, 0.381 mmol), iodomethane (0.024 mL, 0.381 mmol), and cuprous iodide (0.0097 g, 0.051 mmol). The reaction was heated at 80° C. overnight, then diluted with EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted 2× with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluted with 0% to 100% EtOAc in hexanes. Fractions containing the desired product were combined and concentrated. The material was recrystallized from a mixture of DCM and hexanes to give the title compound (0.0042 g, 3.7%). MS ES+ m/z 451 [M+H]+.
The following compound in Table 80 was made in a similar way as described for 3,6-dimethyl-8-[(1R)-1-[2-(1-methyltriazol-4-yl)anilino]ethyl]-2-phenyl-chromen-4-one.
1,3-Dichloro-5,5-dimethylhydantoin (0.17 g, 0.85 mmol), ACN (4 mL), water (0.3 mL), and acetic acid (0.35 mL) were allowed to stir at 0° C. for 5 min and then treated with an ACN solution of (8-[(1R)-1-[(2-benzylsulfanyl-6-chloro-3-pyridyl)amino]ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (0.30 g, 0.57 mmol) and stirred at 0° C. for 2 h. Ammonia (0.1 mg, 5.69 mmol) was added and stirring continued for 30 min. Reaction was diluted with 10 mL of dichloromethane and 10 mL of water. The reaction was extracted with dichloromethane (3×5 mL, organics collected, dried over MgSO4, concentrated, and the residue purified by reverse phase chromatography eluted with 10% to 100% ACN in aqueous 0.5 μM NH4HCO3 containing 5% MeOH to give the product (0.07 g, 25%). MS ES+ m/z 484 [M+H]+.
The following compound in Table 81 was made in a similar way as described for 6-chloro-3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-sulfonamide.
Combined 6-chloro-3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-sulfonamide (20 mg, 0.04 mmol), acetic acid (7.4 mg, 0.12 mmol), DCC (34 mg, 0.17 mmol), and DMAP (30 mg, 0.25 mmol) in DCM (1 mL) and allowed to stir at 25° C. overnight. Reaction was diluted with 1 mL of MeOH and purified by reversed phase chromatography eluted with 10% to 100% ACN (with 0.1% formic acid) in water (with 0.1% formic acid) to give the title compound (5 mg, 20%). MS ES+ m/z 526 [M+H]+.
The following compound in Table 82 was made in a similar way as described for N-[[6-chloro-3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-2-pyridyl]sulfonyl]acetamide. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
A solution of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzenesulfonamide (30 mg, 0.07 mmol) in acetone (1 mL) was treated with potassium carbonate (28 mg, 0.20 mmol) and ethyl chloroformate (15 mg, 0.13 mmol) and stirred at 70° C. overnight. The reaction was allowed to cool to rt, concentrated, and the residue purified by silica gel chromatography eluted with 0% to 20% MeOH in DCM followed by purification by preparative TLC eluted with 5% MeOH in DCM to give the title compound (17.8 mg, 51%) as a white solid. MS ES+ m/z 521 [M+H]+.
A solution of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzenesulfonamide (36 mg, 0.08 mmol) in 1 mL of ACN was treated with triethylamine (24 mg, 0.24 mmol) and cyanogen bromide (17 mg, 0.16 mmol). The resulting mixture was stirred at rt overnight. The reaction was concentrated and the crude material purified by preparative TLC eluted with 5% MeOH in DCM. The desired material was crystallized from a mixture of DCM/MTBE/hexanes to give the title compound (13.6 mg, 36%) as a pale yellow solid. MS ES+ m/z 474 [M+H]+.
Combined 2-fluoro-N-methoxy-benzenesulfonamide (0.05 g, 0.24 mmol), 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (0.11 g, 0.37 mmol), and diisopropylethylamine (0.16 g, 1.2 mmol) in DMSO (1 mL). Stirred the reaction at 130° C. over the weekend. Reaction was purified twice by reversed phase chromatography eluted with 10% to 100% ACN (with 0.1% formic acid) in water (with 0.1% formic acid) to give the title compound (2.5 mg, 2%). ES/MS m/z 479 (M+H).
A solution of tert-butyl N-[[3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carbonyl]sulfamoyl]carbamate (0.12 g, 0.20 mmol) in DCM (1 mL) was treated with TFA (1 mL) and the reaction allowed to stir for 2 h. The reaction was concentrated and the residue purified by reversed phase C18 flash chromatography eluted with 0% to 100% ACN in water (with 0.1% formic acid). Fractions containing the product were pooled, washed with saturated aqueous sodium chloride, and extracted with IPA/CHCl3 (1:3). The organics were combined, dried over MgSO4, filtered, and concentrated. The residue was recrystallized from DCM/hexanes to give the title compound (9.5 mg, 10%) as a white solid. MS ES+ m/z 493 [M+H]+.
The following compound in Table 83 was made in a similar way as described for 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-N-sulfamoyl-pyridine-2-carboxamide. Various methods were used to purify the compound, which would be apparent to one skilled in the art.
The following compound in Table 84 was made in a similar way as described for 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-N-sulfamoyl-pyridine-2-carboxamide.
A mixture of N-tert-butyl-6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(3-pyridyl)chromen-8-yl]ethyl]amino]pyridine-2-sulfonamide (0.13 g, 0.24 mmol) in 3 mL of DCM was treated with 3 mL of TFA and the reaction allowed to stir at 50° C. for 1 h. The reaction was allowed to cool and concentrated. The residue was basified to pH ˜8 with DIPEA and extracted with DCM (3×10 mL). The combined organics were washed with saturated aqueous sodium chloride (3×10 mL), collected, dried over Na2SO4, filtered, and concentrated. The residue was purified by reversed phase chromatography eluted with 25% to 60% ACN in water (with 0.1% formic acid) to give the title compound (23.1 mg, 20%) as a white solid. MS ES+ m/z 485 [M+H]+.
The following compounds in Table 85 were made in a similar way as described for 6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(3-pyridyl)chromen-8-yl]ethyl]amino]pyridine-2-sulfonamide. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
A solution of 6-chloro-3-[[(1R)-1-[3,6-dimethyl-2-(1-methylpyrazol-4-yl)-4-oxo-chromen-8-yl]ethyl]amino]pyridine-2-sulfonamide trifluoroacetate (30 mg, 0.05 mmol) and DIPEA (23.8 mg, 0.18 mmol) in DCM (1 mL) was treated with acetic anhydride (9.4 mg, 0.09 mmol) at rt. The reaction was allowed to stir for 2 h. The reaction was diluted with water (20 mL) and extracted with DCM (3×60 mL). The combined organic layers were washed with brine (3×15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed phase chromatography on C18 eluted with 50% to 60% ACN in water (with 0.1% formic acid) to give the title compound (10.6 mg, 32%) as a white solid. ES/MS m/z 530 (M+H).
The following compounds in Table 86 were made in a similar way as described for N-[[6-chloro-3-[[(1R)-1-[3,6-dimethyl-2-(1-methylpyrazol-4-yl)-4-oxo-chromen-8-yl]ethyl]amino]-2-pyridyl]sulfonyl]acetamide. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
A solution of 3-[3-[[(1R)-1-[2-[1-(539zetidine-3-yl)pyrazol-4-yl]-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]-6-chloro-2-pyridyl]-4H-1,2,4-oxadiazol-5-one (30 mg, 0.06 mmol) in DCM (1 mL) was treated with triethylamine (11 mg, 0.11 mmol) and methanesulfonyl chloride (9.7 mg, 0.08 mmol). The reaction was stirred at rt for 1 h. The reaction was concentrated under reduced pressure and the residue purified by preparative TLC eluted with 4% MeOH in DCM to give the title compound (23.8 mg, 69%) as a pale tan foam. ES-MS m/z 612 (M+H).
The following compound in Table 87 was made in a similar way as described for 3-[6-chloro-3-[[(1R)-1-[3,6-dimethyl-2-[1-(1-methylsulfonylazetidin-3-yl)pyrazol-4-yl]-4-oxo-chromen-8-yl]ethyl]amino]-2-pyridyl]-4H-1,2,4-oxadiazol-5-one. Various methods were used to purify the compound, which would be apparent to one skilled in the art.
A mixture of 8-[(1R)-1-(2-dimethoxyphosphorylanilino)ethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (26 mg, 0.06 mmol), phenylboronic acid (21 mg, 0.17 mmol), copper(I) thiophene-2-carboxylate (16 mg, 0.09 mmol), and tetrakis(triphenylphosphine)palladium(0) (6.5 mg, 0.06 mmol) were combined in ethanol (1 mL). The reaction was degassed for 5 min using argon gas and then stirred at 65° C. for almost 4 h. The reaction was adsorbed onto celite and purified by reversed phase chromatography eluted with 10% to 65% ACN in 10 mM NH4HCO3 (with 5% MeOH) to give the title compound (4.3 mg, 16%. MS ES+ m/z 478 [M+H]+.
Combined 6-chloro-3-[[(1R)-1-(3-iodo-6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-N-methylsulfonyl-pyridine-2-carboxamide (20 mg, 0.03 mmol) and copper(I) cyanide (5.6 mg, 0.06 mmol) in 1 mL of DMF and stirred at 100° C. overnight. The reaction was allowed to cool to rt and diluted with 10 mL of DCM and 10 mL of saturated aqueous NaHCO3. After removal of the organic layer, the remaining aqueous layer was extracted with DCM (3×5 mL). The organics were passed through a phase separator and concentrated. The residue was purified by reversed phase chromatography eluted with 10% to 100% ACN (with 0.1% formic acid) in water (with 0.1% formic acid) to give the title compound (2.9 mg, 17%). MS ES+ m/z 537 [M+H]+.
The following compounds in Table 88 were made in a similar way as described for 6-chloro-3-[[(1R)-1-(3-cyano-6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-N-methylsulfonyl-pyridine-2-carboxamide. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Combined 6-chloro-3-[[(1R)-1-(3-iodo-6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-N-methylsulfonyl-pyridine-2-carboxamide (50 mg, 0.08 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17 mg, 0.02 mmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (46 mg, 0.02 mmol) in 1,4-dioxane (1.5 mL) and 2 M aqueous Na2CO3. The suspension was degassed with argon for 5 min and then allowed to stir at 100° C. for 1 h. The reaction was allowed to cool and diluted with DCM (10 mL) and 5 mL of saturated aqueous NH4Cl. Extracted with DCM (3×10 mL). The organic layers were combined, passed through a phase separator frit and concentrated. The residue was purified by reversed phase chromatography eluted with 10% to 100% ACN (with 0.1% formic acid) in water (with 0.1% formic acid) to give the title compound (3.9 mg, 9%). MS ES+ m/z 579 [M+H]+.
The following compound in Table 89 was made in a similar way as described for 6-chloro-3-[[(1R)-1-(6-methyl-3-oxazol-4-yl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-N-methylsulfonyl-pyridine-2-carboxamide. Various methods were used to purify the compound, which would be apparent to one skilled in the art.
Combined 8-[(1R)-1-[[2-(2-fluorophenyl)-3-pyridyl]amino]ethyl]-3-iodo-6-methyl-2-(3-pyridyl)chromen-4-one (200 mg, 0.35 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (135 mg, 0.69 mmol), cesium carbonate (339 mg, 1.04 mmol), and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (56.4 mg, 0.09 mmol) in 10% aqueous 1,4-dioxane. The mixture was sparged for 5 min with argon and then stirred at 65° C. for 3 h. After cooling, the reaction was filtered through diatomaceous earth and the solids washed with DCM. The filtrate was concentrated under reduced pressure and the residue purified by silica gel chromatography eluted with 0% to 10% MeOH in DCM to give the title compound (89.7 mg, 47% as a tan foam. ES/MS m/z 519 (M+H).
The following compound in Table 90 was made in a similar way as described for 8-[(1R)-1-[[2-(2-fluorophenyl)-3-pyridyl]amino]ethyl]-6-methyl-3-oxazol-4-yl-2-(3-pyridyl)chromen-4-one. Various methods were used to purify the compound, which would be apparent to one skilled in the art.
A 20 mL vial was charged with 8-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(3-pyridyl)chromen-8-yl]ethyl]amino]-2-[(4-methoxyphenyl)methyl]-3,4-dihydroisoquinolin-1-one (145 mg, 0.26 mmol) and TFA (5 mL, 60 mmol) and stirred at 80° C. for 4 days. The reaction was allowed to cool and concentrated. The residue was taken up in EtOAc three times and concentrated. The residue was dissolved in EtOAc, washed with water (3×), and saturated aqueous sodium chloride. The organic layer was concentrated and the residue purified by reversed phase chromatography eluted with 10% to 100% MeOH in 10 mM aqueous NH4HCO3 to give the title compound (47.3 mg, 42%) as a white solid. MS ES+ m/z 440 [M+H]+.
A solution of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid (204 mg, 0.49 mmol) in DCM (4.9 mL) was flushed with nitrogen gas and cooled in a dry ice/acetone bath for 5 min. Treated the reaction with isobutyl chloroformate (67.4 mg, 0.49 mmol) and then triethylamine (150 mg, 1.48 mmol). The reaction was removed from the bath, placed in an ice bath, and treated with pyridine-2-ylmethanethiol (61.8 mg, 0.49 mmol). The reaction was removed from the cooling bath and allowed to warm to rt. After 40 min, the reaction was placed into a −20° C. freezer overnight. The reaction was allowed to warm to rt over 30 min. The reaction was diluted with 50% aqueous NaHCO3 and the layers separated. The organic layer was concentrated and purified by silica gel chromatography eluted with 0% to 100% EtOAc in heptane to give the title compound (177.5 mg, 69%). MS ES+ m/z 521 [M+H]+.
A vial containing 8-[(1R)-1-[(6-chloro-2-fluoro-3-pyridyl)amino]ethyl]-3,6-dimethyl-2-(3-pyridyl)chromen-4-one (50 mg, 0.12 mmol) and DMF (2 mL) was treated with methylamine 2.0 M in THF, 0.14 mL, 0.28 mmol) and cesium carbonate (0.12 g, 0.35 mmol). The vial was sealed and the reaction stirred at 100° C. for 15 h. After cooling, the reaction was filtered and the filtrate purified by reversed phase chromatography on a CSH column eluted with 25% to 57% ACN in water (with 0.1% formic acid) to give the title compound (4.3 mg, 8%) as a white solid. ES/MS m/z 435 (M+H).
The following compounds in Table 91 were made in a similar way as described for 8-[(1R)-1-[[6-chloro-2-(methylamino)-3-pyridyl]amino]ethyl]-3,6-dimethyl-2-(3-pyridyl)chromen-4-one. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
A mixture of tris(dibenzylideneacetone)dipalladium(0) (0.047 g, 0.051 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.089 g, 0.15 mmol) in toluene (18 mL) was stirred at rt for 10 min. 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (0.15 g, 0.51 mmol), 3-bromo-5-chloropyridine (0.098 g, 0.51 mmol), and Cs2CO3 (0.33 g, 1.0 mmol) were then added to the mixture, which was flushed with nitrogen. The reaction was sealed and heated to 115° C. overnight. The mixture was filtered over a pad of diatomaceous earth and the solids were rinsed with DCM. The filtrate was concentrated and the residue was purified by reverse phase chromatography eluted with a gradient of 20 to 100% ACN in aqueous NH4HCO3 (10 mM, plus 5% MeOH) to give the title compound (0.062 g, 30%). MS ES+ m/z 405 [M+H]+.
The following compounds in Table 92 were made in a similar way as described for 8-[(1R)-1-[(5-chloro-3-pyridyl)amino]ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
1Iodinated pyridine reagent used in this coupling reaction.
2tBuXPhos Pd G3 used as the Pd catalyst and NaOtBu used as the base in this reaction.
3tBuBrettPhos Pd G3 used as the Pd catalyst and NaOtBu used as the base in this reaction.
4XantPhos Pd G4 used instead of Pd2(dba)3 and XantPhos.
A mixture of di-mu-chlorobis[(1,2,3-nu)-1-phenyl-2-propen-1-yl]dipalladium (0.028 g, 0.051 mmol), 5-di-tert-butylphosphino-1′,3′,5′-triphenyl-1′H-1,4′-bipyrazole (0.10 g, 0.21 mmol), 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (0.10 g, 0.34 mmol), 4-bromo-1-chloro-2-fluorobenzene (0.11 g, 0.51 mmol), and sodium tert-butoxide (0.046 g, 0.48 mmol) in toluene (2 mL) was heated to 100° C. for 14 h. The mixture was filtered over a pad of diatomaceous earth and the solids were rinsed with DCM. The filtrate was concentrated and the residue was purified by reverse phase chromatography eluted with a gradient of 10 to 100% ACN in aqueous NH4HCO3 (10 mM, plus 5% MeOH) to give the title compound (0.050 g, 35%). MS ES+ m/z 422 [M+H]+.
The following compounds in Table 93 were made in a similar way as described for 8-[(1R)-1-(4-chloro-3-fluoro-anilino)ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Combined 8-[(1R)-1-[(6-chloro-3-pyridyl)amino]ethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (0.10 g, 0.26 mmol), (3-(methoxycarbonyl)phenyl)boronic acid (0.14 g, 0.77 mmol), copper(I) thiophene-2-carboxylate (0.074 g, 0.39 mmol), and tetrakis(triphenylphosphine)palladium(O) (0.030 g, 0.026 mmol) in EtOH (3 mL). Stirred the reaction at 80° C. overnight. The mixture was filtered. The filtrate was concentrated and purified by silica gel chromatography eluted with a gradient of 0 to 100% EtOAc in hexanes to give the title compound (0.095 g, 80%). MS ES+ m/z 463 [M+H]+.
The following compounds in Table 94 were made in a similar way as described for methyl 3-[8-[(1R)-1-[(6-chloro-3-pyridyl)amino]ethyl]-3,6-dimethyl-4-oxo-chromen-2-yl]benzoate. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
1Cesium carbonate also used in this reaction.
21,1'-Bis(diphenylphosphino)ferrocenedichloropalladium(II) used as catalyst and cesium carbonate also used in this reaction.
Combined 2-ethylsulfanyl-8-[(1R)-1-[[2-(2-fluorophenyl)-3-pyridyl]amino]ethyl]-3,6-dimethyl-chromen-4-one (250 mg, 0.56 mmol), copper(I) thiophene-2-carboxylate (159 mg, 0.84 mmol), and APhos Pd G3 (106 mg, 0.17 mmol) with THF (5.6 mL) in a vial. The reaction was sparged with argon for 5 min and then was treated with (2,6-difluorophenyl)zinc(II) bromide (0.5 M in THF, 720 mg, 2.79 mmol) dropwise. After addition, the vial was sealed and the reaction stirred at 80° C. for 16 h. The reaction was cooled to rt, filtered through diatomaceous earth, and the solids washed with DCM. The filtrate was concentrated under reduced pressure and the residue purified by reversed phase chromatography on C18 eluted with 0% to 60% ACN in water to give the title compound (166 mg, 57%) as an off-white foam. ES/MS m/z 501 (M+H).
Combined 8-[(1R)-1-(2-bromoanilino)ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (50 mg, 0.11 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ol (30 mg, 0.13 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (8.2 mg, 0.1 mmol), and potassium carbonate (46 mg, 0.33 mmol) in ACN (2 mL). Degassed with argon for 1 min and stirred at 95° C. for 16 h. The reaction was loaded directly onto a diatomaceous earth cartridge and purified by reversed phase chromatography on C18 eluted with 1000 to 100% ACN in 10 mM aqueous NH4HCO3 with 500 MeOH to give the title compound (9.3 mg, 18). ES/MS m/z 463 (M+H).
The following compounds in Table 95 were made in a similar way as described for 8-[(1R)-1-[2-(6-hydroxy-3-pyridyl)anilino]ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
11,4-Dioxane and water used as the solvent.
21,1′-Bis(di-tert-butylphosphino)ferrocene palladium dichloride used as catalyst and 1,4-dioxane used as a solvent.
A 20 mL vial was charged with 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-(3-pyridyl)chromen-4-one (75 mg, 0.25 mmol), 6-chloro-3-iodo-2-methoxypyridine (82 mg, 0.31 mmol), cesium carbonate (170 mg, 0.51 mmol), palladium(II) acetate (5.7 mg, 0.03 mmol), and BINAP (48 mg, 0.08 mmol), and 1,4-dioxane (5 mL). The reaction mixture was degassed with nitrogen gas for 5 minutes and the suspension stirred at 90° C. for 17 h. The reaction was passed through a syringe filter and the filtrate purified by reversed phase chromatography eluted with 10 to 100% ACN in 10 mM NH4HCO3 with 5% MeOH. The resulting material was purified by preparative HPLC eluted with 45 to 100% ACN in 10 mM NH4HCO3 with 5% MeOH to give the title compound (16.4 mg, 15%) as a white solid. MS ES+ m/z 436 [M+H]+.
The following compounds in Table 96 were made in a similar way as described for 8-[(1R)-1-[(6-chloro-2-methoxy-3-pyridyl)amino]ethyl]-3,6-dimethyl-2-(3-pyridyl)chromen-4-one. Various methods were used to purify the compound, which would be apparent to one skilled in the art.
8-[(1R)-1-[(6-Chloro-2-methyl-3-pyridyl)amino]ethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (100 mg, 0.25 mmol), 4-bromo-2-methyl-pyrazole-3-carboxamide (76 mg, 0.37 mmol), copper(I) thiophene-2-carboxylate (142 mg, 0.75 mmol), cesium carbonate (323 mg, 0.99 mmol), bis(pinacolato)diboron (252 mg, 0.99 mmol) RuPhos Pd G4 (21.1 mg, 0.03 mmol), XPhos Pd G4 (21.4 mg, 0.03 mmol) were combined in 1,4-dioxane (5 mL) and water (0.1 mL). The reaction was degassed with argon for 5 min and then the reaction was stirred at 100° C. for 16 h. The reaction was allowed to cool, filtered, concentrated, and purified by silica gel chromatography eluted with 0 to 20% MeOH in DCM. The residue was re-purified by reversed phase chromatography eluted with 0 to 100% ACN in 10 mM NH4HCO3 with 5% MeOH to give the title compound (2.5 mg, 2%). MS ES+ m/z 466 [M+H]+.
The following compound in Table 97 was made in a similar way as described for 4-[8-[(1R)-1-[(6-chloro-2-methyl-3-pyridyl)amino]ethyl]-3,6-dimethyl-4-oxo-chromen-2-yl]-2-methyl-pyrazole-3-carboxamide. Various methods were used to purify the compound, which would be apparent to one skilled in the art.
A vial was charged with 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]-N-methylsulfonyl-pyridine-2-carboxamide (170 mg, 0.33 mmol), 1H-indol-6-ylboronic acid (80.5 mg, 0.50 mmol), copper(I) 3-methylsalicylate (107 mg, 0.50 mmol), tetrakis(triphenylphophine)palladium(0) (77 mg, 0.07 mmol), and EtOH (5 mL). The reaction was degassed with argon, sealed, and stirred at 65° C. for 16 h. After cooling, the reaction was filtered, concentrated under reduced pressure, and purified by silica gel chromatography eluted with 0% to 100% EtOAc in heptanes followed by reversed phase chromatography on C18 eluted with 10% to 100% ACN in 10 mM aqueous NH4HCO3 (with 5% MeOH) to give the title compound (28 mg, 15%). ES/MS m/z 565 (M+H).
The following compound in Table 98 was made in a similar way as described for 6-chloro-3-[[(1R)-1-[2-(1H-indol-6-yl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]-N-methylsulfonyl-pyridine-2-carboxamide. Various methods were used to purify the compound, which would be apparent to one skilled in the art.
Chloro-(2,6-difluorophenyl)zinc was stirred in THF (2 mL) and treated with NMP (1 mL). The reaction was sparged with argon for 5 min and then 8-[(1R)-1-[(2-chloro-3-pyridyl)amino]ethyl]-3,6-dimethyl-2-(3-pyridyl)chromen-4-one (100 mg, 0.25 mmol) and bis(tri-tert-butylphosphine)palladium(O) (12.6 mg, 0.025 mmol) were added and the reaction stirred at 100° C. overnight. Purified by silica gel chromatography eluted with 0% to 100% EtOAc in heptane to give an impure product. This product was purified by reversed phase chromatography eluted with 80% ACN (95:5 ACN in water) in 10 mM aqueous NH4HCO3 with 5% MeOH to give the title compound (12.7 mg, 10%). ES/MS m/z 484 (M+H).
A 20 mL vial was charged with 8-[(1S)-1-chloroethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (0.50 g, 1.6 mmol), 6-bromo-2-methyl-pyridin-3-amine (0.45 g, 2.4 mmol), potassium carbonate (0.44 g, 3.2 mmol), and ACN (10 mL). The vial was capped and the reaction stirred at 100° C. for 16 h. After cooling to rt, the reaction was filtered, concentrated, and the residue purified by silica gel chromatography eluted with 0 to 100% EtOAc in heptane. The residue was re-purified by reversed phase C-18 flash chromatography eluted with 0 to 100% ACN in aqueous 10 mM NH4HCO3 containing 5% MeOH to give the title compound (0.25 g, 34%). MS ES+ m/z 463/465 [M+H]+.
The following compounds in Table 99 were made in a similar way as described for 8-[(1R)-1-[(6-bromo-2-methyl-3-pyridyl)amino]ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
1There was a loss of chiral purity during the reaction. Chiral separation used the following conditions:
Combined 8-[1-[(2-bromo-6-chloro-3-pyridyl)amino]ethyl]-3,6-dimethyl-2-(3-pyridyl)chromen-4-one (60 mg, mmol), (2-fluorophenyl)boronic acid (52 mg, 0.37 mmol), copper(I) thiophene-2-carboxylate (47 mg, 0.25 mmol), and tetrakis(triphenylphosphine)palladium(0) (21 mg, 0.02 mmol) in EtOH (5 mL). The reaction was degassed with argon for 5 min and then stirred at 60° C. for 1 h. The reaction was filtered, the filtrate concentrated under reduced pressure, and the residue purified by silica gel chromatography eluted with 0% to 10000 EtOAc in heptane to give a slightly impure product which was re-purified by reversed phase chromatography eluted with 000 to 100% ACN in 10 mM aqueous NH4HCO3 containing 500 MeH. The racemic mixture was separated by chiral SFC [Phenomenex Lux i-Amylose-1, 30×150 mm, 5 μm; 16% MeOH in CO2]. ES/MS m/z 500 (M+H).
The following compounds in Table 100 were made in a similar way as described for 8-[1-[[6-chloro-2-(2-fluorophenyl)-3-pyridyl]amino]ethyl]-3,6-dimethyl-2-(3-pyridyl)chromen-4-one, Isomer 1 and Isomer 2. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
1[Phenomenex Lux i-Amylose-3, 30 × 150 mm, 5 μm; 25% iPrOH (with 0.1% isopropylamine in CO2]
Combined 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-(3-pyridyl)chromen-4-one (200 mg, 0.68 mmol), 4-bromo-3-methylisothiazole (101 mg, 0.57 mmol), potassium phosphate (240 mg, 1.13 mmol), copper(I) iodide (10.8 mg, 0.06 mmol), and ethylene glycol (351 mg, 5.66 mmol) in IPA (1 mL). The reaction was flushed with argon for several minutes before stirring at 80° C. overnight. The reaction was recharged with reactants and continued stirring at 80° C. The reaction was filtered through diatomaceous earth and washed with DCM. The filtrate was concentrated and purified by silica gel chromatography eluted with 0 to 100% EtOAc in heptane to provide an impure compound which was purified by reversed phase chromatography eluted with 80% ACN (with 0.1% formic acid) in water (with 0.1% formic acid) to give the title compound (3.8 mg, 2%). MS ES+ m/z 392 [M+H]+.
The following compound in Table 101 was made in a similar way as described for 3,6-dimethyl-8-[(1R)-1-[(3-methylisothiazol-4-yl)amino]ethyl]-2-(3-pyridyl)chromen-4-one. Various methods were used to purify the compound, which would be apparent to one skilled in the art.
A solution of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzaldehyde (100 mg, 0.25 mmol) in DCM (1 mL) and MeOH (1 mL) was cooled to 0° C. and treated with sodium borohydride (9.52 mg, 0.25 mmol). The reaction was stirred at 0° C. for 30 min. The reaction was diluted with saturated aqueous ammonium chloride and extracted with DCM and EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 0% to 55% EtOAc in hexane to give the title compound (62.2 mg, 62%). ES-MS m/z 400 (M+H).
The following compound in Table 102 was made in a similar way as described for 8-[(1R)-1-[2-(hydroxymethyl)anilino]ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one. Various methods were used to purify the compound, which would be apparent to one skilled in the art.
2-[[(1R)-1-(3,6-Dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzaldehyde (271 mg, 0.68 mmol) and trifluoromethyltrimethylsilane (116 mg, 0.82 mmol) were combined in DMF (2 mL) and treated with potassium carbonate (0.94 mg, 0.007 mmol). The reaction was stirred at rt for 5 min. The reaction was quenched with HCl and the reaction stirred until the silyl ether intermediate consumed. The reaction was neutralized with NaOH, extracted with DCM (3×), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed phase chromatography on C18 eluted with 20% to 100% ACN in 10 mM aqueous NH4HCO3 (with 5% MeOH) to give the racemic compound (14.2 mg, 4%). ES/MS m/z 468 (M+H). The racemic mixture was separated by chiral SFC [Chiralpak IG, 30×250 mm; 10% EtOH in CO2] to give the title compounds Isomer 1 (first-eluting; 2.67 mg, >99% ee, 0.8%) and Isomer 2 (6.15 mg, 95.6% ee, 2%). MS-ES m/z 468 (M+H).
The following compounds in Table 103 were made in a similar way as described for 3,6-dimethyl-2-phenyl-8-[(1R)-1-[2-(2,2,2-trifluoro-1-hydroxy-ethyl)anilino]ethyl]chromen-4-one, Isomer 1 and Isomer 2. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
1[Chiralcel OD-H, 20 × 150 mm; 15% MeOH in CO2]
A solution of 8-[(1R)-1-[(6-chloro-2-methylsulfanyl-3-pyridyl)amino]ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (150 mg, 0.33 mmol) in DCM (3 mL) was treated dropwise with mCPBA (51.66 mg, 0.30 mmol) at rt. The reaction was stirred at rt for 4 h and then concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 25% EtOAc in petroleum ether to give the title compound (54 mg, 35%) as a white solid. ES-MS m/z 467 (M+H). The racemic mixture was separated by chiral HPLC [Chiral Art Cellulose-SZ, 2.0×25 cm, 5 μm; 10% EtOH in hexane (10 mM NH3 in MeOH)] to give the title compounds Isomer 1 (first-eluting; 9.4 mg, 17%) and Isomer 2 (18.3 mg, 34%). ES/MS m/z 467 (M+H).
To a solution of 8-[(1R)-1-[(6-chloro-3-pyridyl)amino]ethyl]-3,6-dimethyl-2-(1-tetrahydropyran-2-ylindazol-6-yl)chromen-4-one (0.070 g, 0.13 mmol) in DCM (2 mL) was added TFA (0.051 mL, 0.66 mmol). The reaction was stirred at rt for 5 h. Added TFA (0.18 mL, 2.3 mmol). The reaction was stirred at rt overnight and purified by reverse phase chromatography eluted with a gradient of 20 to 100% ACN in aqueous NH4HCO3 (10 mM, plus 5% MeOH) to give the title compound (0.038 g, 65%). MS ES+ m/z 445 [M+H]+.
The following compound in Table 104 was made in a similar way as described for 8-[(1R)-1-[(6-chloro-2-methoxy-3-pyridyl)amino]ethyl]-3,6-dimethyl-2-(3-pyridyl)chromen-4-one. Various methods were used to purify the compound, which would be apparent to one skilled in the art.
A solution of tert-butyl 3-[4-[8-[(1R)-1-[(6-chloro-3-pyridyl)amino]ethyl]-3,6-dimethyl-4-oxo-chromen-2-yl]phenyl]azetidine-1-carboxylate (0.05 g, 0.09 mmol) in DCM was treated with HCl in 1,4-dioxane (4M, 0.05 g, 1.3 mmol) and allowed to stir until the reaction was complete. The reaction was concentrated and purified by reversed phase C18 flash chromatography eluted with 10 to 72% ACN in 10 mM aqueous NH4HCO3 with 5% MeOH to give the title compound (30 mg, 69%).
Combined 8-[(1R)-1-[(2-benzyloxy-3-pyridyl)amino]ethyl]-3,6-dimethyl-2-(3-pyridyl)chromen-4-one (35 mg, 0.07 mmol) with trifluoroacetic acid (1.1 mL) and stirred at 50° C. for 16 h. After cooling to rt, the reaction was concentrated under reduced pressure and the residue purified by reversed phase chromatography eluted with a gradient of 10% to 90% ACN in water (with 0.1% TFA). The fractions containing product were pooled, concentrated under reduced pressure, and filtered using bicarbonate resin to give the title compound (16.5 mg, 58%). ES/MS m/z 388 (M+H).
A vial containing a mixture of tert-butyl 4-[6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(3-pyridyl)chromen-8-yl]ethyl]amino]-2-pyridyl]piperazine-1-carboxylate (0.29 g, 0.49 mmol) and 1,4-dioxane (3 mL) was treated with 4M HCl in 1,4-dioxane (1.2 mL) and stirred at rt for 2 h and 50° C. for 2 h. The reaction was cooled to rt, concentrated under reduced pressure, and the residue purified by reversed phase chromatography on C18 eluted with 1000 to 100% ACN (with 0.10% TFA) in water (with 0.1% TFA) to give the title compound (0.17 g, 710%) as a white solid. ES/MS m/z 490 (M).
The following compounds in Table 105 were made in a similar way as described for 8-[(1R)-1-[(6-Chloro-2-piperazin-1-yl-3-pyridyl)amino]ethyl]-3,6-dimethyl-2-(3-pyridyl)chromen-4-one. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
To a solution of 3,6-dimethyl-2-phenyl-8-[(1R)-1-(2-vinylanilino)ethyl]chromen-4-one (0.082 g, 0.21 mmol) in acetone (1 mL) and water (0.25 mL) was added N-methylmorpholine N-oxide (0.073 g, 0.62 mmol) and osmium tetroxide (0.0016 mL, 0.031 mmol). The reaction was stirred at 25° C. for 2 h and purified by reverse phase chromatography eluted with a gradient of 10 to 100% ACN in aqueous NH4HCO3 (10 mM, plus 5% MeOH) to give the diol (0.035 g, 39%, ˜2:3 mix of diastereomers) and the hydroxy ketone (0.0060 g, 7%). MS ES+ m/z 430 [M+H]+ and 428 [M+H]+, respectively.
A solution of 8-[(1R)-1-[(6-chloro-2-methylsulfanyl-3-pyridyl)amino]ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (0.15 g, 0.33 mmol) in DCM (2 mL) was treated with mCPBA (0.17 g, 1.00 mmol) dropwise at rt under nitrogen. After addition, the reaction was allowed to stir for 4 hr at rt. The reaction was concentrated and purified by silica gel chromatography eluted with EtOAc in petroleum ether (1:3). The resulting material was re-purified by preparative HPLC (Xselect CSH C18 OBD column) eluted with 58 to 66% ACN in water (with 0.1% formic acid) to give the title compound (71.9 mg, 45%) as a white solid. MS ES+ m/z 483 [M+H]+.
PI3K-Alpha Kinase (PIK3CA) Activity, H1047R Mutant In Vitro Cell Based Assay and Determining IC50 Values for Inhibitors
The MDA-MB-453 (ATCC-HTB-131) cell line was obtained from the American Type Culture Collection (Manassas, VA). Cells were maintained in Dulbecco's Modified Eagle Media (DMEM, Gibco 11965-092) supplemented with 10% Fetal Bovine Serum, heat inactivated (FBS HI, Gibco 10082-147), 1× non-essential amino acids (NEAA, Gibco 11140-050), and 1 mM sodium pyruvate (Gibco 11360-070). Cultures were maintained in a humidified incubator at 37° C. under 5% CO2/95% air.
For compound testing in 0% FBS, MDA-MB-453 cells were seeded at a density of 1.5×104 cells per well in white 384-well plates in 20 μl of Minimum Essential Media (MEM) assay media with 1×NEAA, 1 mM sodium pyruvate, and 1 μg/mL human insulin (Sigma I9278). Compounds dissolved in 10 mM stock solutions in DMSO were serially diluted 1:3 in DMSO to generate a 10-point dilution series and plated using an acoustic liquid handler system (Echo 550 Series Liquid Handler, Labcyte). A 5× intermediate compound dilution plate in MEM with 1×NEAA and 1 mM sodium pyruvate (150 μM starting compound concentration in 1.5% DMSO) was then prepared. Five μl of the intermediate serially diluted compounds were added to the cell plate to final concentrations ranging from 30 mM to 0.0015 mM in 0.3% DMSO. 0.3% DMSO alone was used to establish the maximum (MAX) signal and GDC-0032 at a final concentration of 1 μM was used as a reference compound for the minimum (MIN) signal. After 3 hours treatment, the medium was removed, and the cells lysed in 10 μL of 1× SureFire Lysis buffer with shaking for 10 minutes at room temperature. The Acceptor Mix (Reaction Buffer 1+Reaction Buffer 2+Activation Buffer+SureFire Ultra Acceptor Beads) was prepared by diluting Activation buffer 25-fold in combined Reaction Buffer 1 and Reaction Buffer 2. The Acceptor beads were diluted 50-fold in the combined Reaction Buffers. Five μL of Acceptor Mix was added to each well, the plate was sealed and covered with foil and incubated for 1 hour at room temperature. The Donor Mix (dilution buffer+SureFire Ultra Donor Beads) was prepared by diluting Donor Beads 50-fold in dilution buffer. Five μL of the Donor Mix was added to each well and the plate sealed and covered with foil and incubated for 1 hour at room temperature in the dark. The plates were read on a Neo2 plate reader instrument from Biotek using standard AlphaLisa settings. Compounds were tested in duplicate and the average % inhibition at each compound concentration was used to generate a single dose response curve. The data were processed using the Genedata-Screener tool. Relative IC50 values were determined using luminescence units by calculating percent inhibition with respect to the in-plate “MIN” (GDC-0032 reference control) and “MAX” (DMSO) controls. The data was analyzed using a 4-parameter nonlinear logistic equation (four-parameter logistic concentration-response curve):
Y=bottom+[(top−bottom)/1+(X/IC50)slope]
where Y=% inhibition, X=concentration of inhibitor, bottom=minimum value of y attained by curve-fit, top=maximum value of y attained by curve-fit and slope=steepness of curve at the IC50.
% Inhibition=[(signal at X−median Min)/(median Max−median Min)]×100
IC50: concentration of compound that reduces a given response (ligand binding, enzyme response) by 50%. Relative IC50: concentration giving half the compound's maximum response.
In the above cell based assay the compounds of Examples 1A-3A, 5A-22A, 24A, 27A, 30A-32A, 34A-36A, 39A-46A, 48A-63A, 65A, 66A, 68A-81A, 83A, 84A, 86A-94A, 96A-181A, 183A-265A, 4B-7B, 9B, 10B, 12B, 14B, 16B-38B, 42-80B, 1C-54C, 56C-76C, 78C-80C, 82C-127C, 129C-141C, 143C-201C, 203C-217C, 219C, 222C, 224C-244C were tested and all exhibited IC50 values of less than 1 μM for the PI3K-Alpha kinase H1047R mutant.
In the above cell based assay the compounds of Examples 1A-3A, 7A-22A, 24A, 32A, 34A-36A, 39A-45A, 49A-51A, 53A-61A, 63A, 66A, 68A, 72A, 74A, 76A-81A, 83A, 84A, 86A, 89A-92A, 96A-175A, 177A, 178A, 187A-198A, 200A-206A, 208A-236A, 241A-255A, 258A-264A, 4B-7B, 9B, 10B, 14B, 17B-19B, 22B, 24B-38B, 42B-58B, 61-70B, 72-76B, 78B, and 80B 4C-40C, 42C-51C, 53C, 54C, 56C-65C, 67C-76C, 78C-80C, 82C-97C, 99C-104C, 106C-126C, 129C, 130C, 132C, 133C, 135C-141C, 143C-166C, 168C, 170C-200C, 203C-205C, 207C-209C, 212C-217C, 219C, 222C, 224C, 226C-231C, and 233C-244C were tested and all exhibited IC50 values of less than 500 nM for the PI3K-Alpha kinase H1047R mutant.
The present application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 63/496,210, filed on Apr. 14, 2023, U.S. Provisional Application No. 63/381,862, filed on Nov. 1, 2022, U.S. Provisional Application No. 63/357,689, filed on Jul. 1, 2022, and U.S. Provisional Application No. 63/336,658, filed on Apr. 29, 2022, the contents of which are incorporated herein by reference in their entireties.
| Number | Date | Country | |
|---|---|---|---|
| 63496210 | Apr 2023 | US | |
| 63381862 | Nov 2022 | US | |
| 63357689 | Jul 2022 | US | |
| 63336658 | Apr 2022 | US |
