Patent Application
20190151312
Described herein are compounds, methods of making the compounds, pharmaceutical compositions and medicaments containing the compounds, and methods of using the compounds to treat or prevent diseases or conditions in need of heparan sulfate biosynthesis inhibition.
In lysosomal storage diseases, a person is missing a key enzyme (or has an enzyme which does not function normally) where the degradation of glycosylaminoglycans (GAGs) is impaired resulting in abnormal accumulation of these GAGs and disease. Substrate reduction therapy (SRT) offers an approach to treating diseases by inhibiting the formation of the substrate upon which the missing or abnormally-functioning enzyme acts. The aim is to reduce the rate of biosynthesis of the GAG to offset the catabolic defect, restoring the balance between the rate of biosynthesis and the rate of catabolism. Small molecule inhibitors of GAG biosynthesis can reduce the amount of substrate formed and, if able to cross the blood-brain barrier, have the potential to treat diseases with CNS pathology.
Heparan sulfate (HS) is one such GAG found in mammals comprising glucosamine and uronic acid groups. In certain instances, heparan sulfate is bound to a core protein via a linkage tetrasaccharide, which generally has the structure -GlcAβ3Galβ3Galβ4Xylβ-O—. The cell surface of most mammalian cells contains membrane anchored heparan sulfate proteoglycans (HSPGs) which have important functions in cell adhesion processes (Biochimica et Biphysica Acta-Molecular Cell Research 2001, 1541(3), 135). In certain lysosomal storage disorders, the ability of the lysosome to degrade and turnover HS is impaired.
Diseases associated with abnormal heparan sulfate accumulation include lysosomal storage disorders, such as mucopolysaccharidosis (MPS) I, II, IIIA, IIIB, IIIC, IIID, and VII disorders. These MPS disorders are caused by the inability to produce specific enzymes, which in turn leads to an abnormal storage of mucopolysaccharides, including heparan sulfate. (See Lawrence et al., Nat Chem Riot 2012, 8(2), 197 which is incorporated herein by reference in its entirety.) MPS I, II, IIIA, IIIB, IIIC, IIID, and VII disorders include Hurler syndrome (MPS I H), Scheie syndrome (MPS I S), Hurler-Scheie syndrome (MPS I H-S), Hunter syndrome (MPS II), Sanfilippo syndrome (e.g. Sanfilippo A (MPS III A), Sanfilippo B (MPS III B), Sanfilippo C (MPS III C), and Sanfilippo D (MPS III D)), and Sly syndrome (MPS VII).
HSPGs have been shown to promote formation of amyloid structures typical in amyloid diseases (such as Alzheimer's disease, Parkinson's disease, type 2 diabetes, and chronic hemodialysis-related amyloid) including colocalization with the amyloid plaques and may impart stability to the amyloid fibrils (J. Biol. Chem. 2002, 277, 18421; J. Neuroscience 2011, 31(5), 1644; PNAS 2005, 102(18), 6473).
HSPGs bound to the external surface of plasma membranes play an important role in the control of cell division and growth regulation, but are also implicated in brain pattering, synapse formation, axon regeneration and guidance, and are found in dense networks in active multiple sclerosis (MS) plaques (Hum. Mol. Genet. 2009, 18(4), 767) and thus reducing the amount of HSPGs can be useful in treating MS.
The compounds disclosed herein are useful for inhibiting heparan sulfate biosynthesis and associated diseases.
In one aspect, provided is a compound of Formula I:
where
In certain embodiments, it is provided that:
Embodiments can include any one or more of the following features.
R1 can be dihydro-2H-pyran-4-yl, tetrahydro-2H-pyran-4-yl, or morpholin-4-yl, each of which is optionally substituted with 1 or 2 alkyl; R3 can be phenyl substituted with 1, 2, or 3 R3c groups independently selected from —C(═NH)NHOH, cyano, nitro, halo, alkyl, alkoxycarbonyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl, alkylsulfinyl, alkylsulfonyl, —OR3d, —NR3bR3c, —C(O)NR3bR3c, —S(O)2NR3bR3c, and heteroaryl optionally substituted with 1, 2, or 3 R5 groups; where the heterocycloalkyl either alone or as part of heterocycloalkylalkyl can be optionally substituted with 1 alkyl; provided that R3 is not 3-amino-phenyl or 3,4-dimethylphenyl; or R3 can be 6-10 membered heteroaryl each of which is substituted with 1, 2, or 3 R3c groups independently selected from —C(═NH)NHOH, cyano, nitro, halo, hydroxy, alkyl, alkoxycarbonyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl, alkylsulfinyl, alkylsulfonyl, —OR3d, —NR3bR3a, —C(O)NR3bR3a, —S(O)2NR3bR3c, and heteroaryl optionally substituted with 1, 2, or 3 R5 groups; provided that R3 is not 2-oxo-1H-benzo[d]imidazolyl, 1-ethyl-2-methyl-1H-benzo[d]imidazolyl, or 1-acetyl-indolinyl; R3b can be hydrogen or alkyl; R3c can be hydrogen, alkyl, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, alkylcarbonyl, alkylsulfonyl, alkoxycarbonyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, or cycloalkyl optionally substituted with 1 or 2 alkyl; or R3b and R3c together with the nitrogen to which they are attached can form heterocycloalkyl; R3d is haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl;
R1 can be morpholin-4-yl; R2 can be a 9-membered bicyclic ring comprising 1, 2, or 3 nitrogen atoms where one or both of the rings is aromatic, where a carbon atom in R2 is the point of attachment to the pyrimidinyl in Formula I, and where R2 is optionally substituted with 1 oxo and additionally substituted with 1, 2, or 3 R2a groups; each R2a can be independently selected from halo, alkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, 1,3-dioxo-isoindolinylalkyl, and —NR2bR2c; where each heterocycloalkyl, either alone or as part of another group, is optionally substituted with alkyl; R2b can be hydrogen or alkyl; R2c can be alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, or heterocycloalkylalkyl; R3 can be phenyl or heteroaryl each of which is optionally substituted with 1, 2, or 3 R3a groups; each R3a can be independently selected from cyano, halo, alkyl, alkoxycarbonyl, cycloalkyl, alkylcarbonyl, alkylsulfinyl, alkylsulfonyl, —OR3d, —NR3bR3a, —C(O)NR3bR3a, —S(O)2NR3bR3a, and heteroaryl optionally substituted with R5; R3b can be hydrogen or alkyl; R3c can be hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, cycloalkylalkyl, or cycloalkyl optionally substituted with alkyl; R3d can be alkyl; R4 can be hydrogen, or halo; and each R5 can be independently halo, alkyl, haloalkyl, cycloalkyl, or phenylmethyl which is optionally substituted with alkoxy; optionally as a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.
R1 can be morpholin-4-yl.
R2 can be indazolyl or pyrazolopyridinyl, each of which is optionally substituted on any atom of the ring with 1, 2, or 3 R2a groups. R2 can be benzimidazolyl or imidazopyridinyl, each of which is optionally substituted on any atom of the ring with 1, 2, or 3 R2a groups. R2 can be 2-oxo-1H-benzo[d]imidazolyl optionally substituted on any atom of the ring with 1, 2, or 3 R2a groups. R2 can be indazolyl or benzimidazolyl, each of which is optionally substituted on any atom of the ring with 1, 2, or 3 R2a groups.
R2 can be substituted with 1, 2, or 3 R2a groups independently selected from alkyl, hydroxyalkyl, alkoxyalkyl, halo, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl optionally substituted with one alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, 1,3-dioxo-isoindolinylalkyl, and —NR2bR2c. In certain embodiments, R2a is alkyl or heterocycloalkylalkyl. In other embodiments, R2a is C1-3 alkyl or heterocycloalkyl(C1-3)alkyl, where the heterocycloalkyl group is morpholinyl, piperzinyl, or pyrrolodinyl.
R3 can be phenyl substituted with one or two R3a groups. For example, R3 can be phenyl substituted with halo (e.g., chloro). As another example, R3 can be phenyl substituted with —C(O)NR3bR3c. As a further example, R3 can be phenyl substituted with a 5-membered heteroaryl optionally substituted with one R5. In still yet another example, R3 can be phenyl substituted with R3c where R3c is triazolyl, oxazolyl, imidazolyl, oxadiazolyl, pyrazolyl, or pyrrolyl, each of which is optionally substituted with one R5; or where.g., R3c is triazolyl, oxazolyl, imidazolyl, oxadiazolyl, pyrazolyl, or pyrrolyl, each of which is optionally substituted with alkyl, halo, haloalkyl, cycloalkyl, or phenylmethyl, where the phenylmethyl is optionally substituted with alkoxy.
R3 can be a 6-10 membered heteroaryl substituted with 1, 2, or 3 R3a groups. For example, R3 can be pyridyl substituted with 1, 2, or 3 R3c groups. As another example, R3 can be a 9-membered heteroaryl with 1, 2, or 3 nitrogen atoms, optionally substituted with 1, 2, or 3 R3a groups; e.g., R3 can be indolyl, benzoisoxazolyl, indazolyl, benzotriazolyl, benzoxazolyl, or benzimidazolyl, each of which is optionally substituted with 1, 2, or 3 alkyl groups.
R1 can be morpholin-4-yl; R2 can be indazolyl or benzimidazolyl, either of which is substituted with at least one R2a independently selected from alkyl, hydroxyalkyl, alkoxyalkyl, halo, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl optionally substituted with one alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, 1,3-dioxo-isoindolinylalkyl, and —NR2bR2c; R3 can be phenyl substituted with at least one R3a independently selected from halo, —C(O)NR3bR3c, and a 5-membered heteroaryl optionally substituted with one R5; or R3 can be pyridinyl, indolyl, benzoisoxazolyl, indazolyl, benzotriazolyl, benzoxazolyl, or benzimidazolyl, each of which is optionally substituted with 1, 2, or 3 alkyl groups.
The compounds can have Formula I(a) as defined anywhere herein, optionally as a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.
R1 can be morpholin-4-yl; R2 can be indazolyl or benzimidazolyl, either of which is substituted with at least one R2a independently selected from alkyl, hydroxyalkyl, alkoxyalkyl, halo, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl optionally substituted with 1 alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, 1,3-dioxo-isoindolinylalkyl, and —NR2bR2c; R3 can be phenyl substituted with at least one R3c independently selected from halo, —C(O)NR3bR3c, and a 5-membered heteroaryl optionally substituted with one R5; or R3 can be pyridinyl, indolyl, benzoisoxazolyl, indazolyl, benzotriazolyl, benzoxazolyl, or benzimidazolyl, each of which is optionally substituted with 1, 2, or 3 alkyl groups.
In another aspect, compounds having Formula II are featured:
wherein:
In a further aspect, provided is a pharmaceutical composition comprising 1) a Compound of Formula I optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof, and 2) a pharmaceutically acceptable excipient.
In a further aspect, provided is a method of treating a disease or disorder comprising administering to a subject in need thereof a Compound of Formula I, optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof additionally comprising a pharmaceutically acceptable excipient or pharmaceutically acceptable carrier. Methods of treatment are also provided, which include administering to a subject having any one or more of the diseases or disorders described herein a Compound of Formula I, optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof additionally comprising a pharmaceutically acceptable excipient or pharmaceutically acceptable carrier. Any of the methods described herein can further include identifying the subject (e.g., a subject in need of treatment for one or more of the diseases and disorders described herein).
In a further aspect, it is provided a method of making a compound of Formula I, comprising
To facilitate understanding of the disclosure set forth herein, a number of terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
As used throughout this application and the appended claims, the following terms have the following meanings:
“About” preceding a numerical value refers to a range of values ±10% of the value specified.
“Acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.
“Alkenyl” means a straight or branched hydrocarbon radical having from 2 to 8 carbon atoms and at least one double bond and includes ethenyl, propenyl, 1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl and the like. “Lower alkenyl” means an alkenyl group having one to six carbon atoms.
“Alkoxy” means an —OR group where R is alkyl, as defined herein. Illustrative examples include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
“Alkoxyalkenyl” means an alkenyl group, as defined herein, substituted with at least one, in another example 1, 2, or 3 alkoxy group(s), as defined herein.
“Alkoxyalkyl” means an alkyl group, as defined herein, substituted with at least one, in another example 1, 2, or 3 alkoxy group(s), as defined herein. When “C1-C6” is used before “alkoxyalkyl,” the “C1-C6” modifies both the alkyl in the alkoxy portion as well as the alkyl portion.
“Alkoxycarbonyl” means a —C(O)R group where R is alkoxy, as defined herein.
“Alkyl” means a straight or branched saturated hydrocarbon radical containing from 1-10 carbon atoms, in another example 1-6 carbon atoms. Illustrative examples include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylhexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
“Alkylamino” means a —NHR radical where R is alkyl as defined herein, or an N-oxide derivative thereof, e.g., methylamino, ethylamino, n-, iso-propylamino, n-, iso-, tert-butylamino, or methylamino-N-oxide, and the like.
“Alkylaminoalkyl” means an alkyl group substituted with at least one, in another example 1, 2, or 3 alkylamino groups, as defined herein. When “C1-C6” is used before “alkylaminoalkyl,” the “C1-C6” modifies both of the alkyl portions.
“Alkylcarbonyl” means a —C(O)R group where R is alkyl, as defined herein.
“Alkylsulfinyl” means an —S(O)R group where R is alkyl, as defined herein.
“Alkylsulfonyl” means an —S(O)2R group where R is alkyl as defined herein.
“Alkylsulfonyloxyalkyl” means an alkyl group substituted with 1 or 2 -OS(O)2alkyl group(s), e.g. —CH2CH2OS(O)2CH3.
“Amino” means an —NH2 group.
“Aminoalkyl” means an alkyl group substituted with at least one, for example one, two, or three, amino groups.
“Carboxy” means a —C(O)OH group.
“Cycloalkyl” means a monocyclic or fused bicyclic, saturated or partially unsaturated (but not aromatic), hydrocarbon radical of three to ten carbon ring atoms. Fused bicyclic hydrocarbon radical includes bridged rings. Cycloalkyl includes spirocycloalkyl rings. Unless stated otherwise, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. One or two ring carbon atoms may be replaced by a —C(O)—, —C(S)—, or —C(═NH)— group.
In one embodiment, cycloalkyl includes but is not limited to:
“Cycloalkylalkyl” means an alkyl group, as defined herein, substituted with at least one, in another example 1 or 2, cycloalkyl groups as defined herein.
“Cycloalkylcarbonyl” means a —C(O)R group where R is cycloalkyl, as defined herein.
“Dialkylamino” means an —NRR′ radical where R and R′ are independently alkyl as defined herein, or an N-oxide derivative, or a protected derivative thereof, e.g., dimethylamino, diethylamino, N,N-methylpropylamino or N,N-methylethylamino, and the like.
“Dialkylaminoalkyl” means an alkyl group substituted with at least one, in another example 1, 2, or 3 dialkylamino groups, as defined herein. When “C1-C6” is used before “dialkylaminoalkyl,” the “C1-C6” modifies all of the alkyl portions.
“Halo” means a halogen, or fluoro, chloro, bromo, or iodo.
“Haloalkyl” means an alkyl group substituted with one or more halo atoms, in another example by 1, 2, 3, 4, 5, or 6 halo atoms, in another example by 1, 2, or 3 halo atoms. Examples include, but are not limited to, trifluoromethyl, chloromethyl, and the like.
“Heteroaryl” means monocyclic, fused bicyclic, or fused tricyclic, radical of 5 to 14 ring atoms containing one or more, in another example one, two, three, or four ring heteroatoms independently selected from —O—, —S(O)n— (n is 0, 1, or 2), —N—, —N(H)—, and N-oxide, and the remaining ring atoms being carbon, wherein the ring comprising a monocyclic radical is aromatic and wherein at least one of the fused rings comprising a bicyclic or tricyclic radical is aromatic (but does not have to be a ring which contains a heteroatom, e.g. 2,3-dihydrobenzo[b][1,4]dioxin-6-yl). One or two ring carbon atoms of any nonaromatic rings comprising a bicyclic or tricyclic radical may be replaced by a —C(O)—, —C(S)—, or —C(═NH)— group. Fused bicyclic radical includes bridged ring systems. Unless stated otherwise, the valency may be located on any atom of any ring of the heteroaryl group, valency rules permitting.
In one embodiment, heteroaryl includes, but is not limited to, triazolyl, tetrazolyl, pyrrolyl, imidazolyl, thienyl, furanyl, pyrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, indolyl, 2,3-dihydro-1H-indolyl (including, for example, 2,3-dihydro-1H-indol-2-yl or 2,3-dihydro-1H-indol-5-yl, and the like), indazolyl, phthalimidyl, benzimidazolyl, benzoxazolyl, benzofuranyl, benzothienyl, benzopyranyl, benzothiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl (including, for example, tetrahydroisoquinolin-4-yl or tetrahydroisoquinolin-6-yl, and the like), pyrrolo[3,2-c]pyridinyl (including, for example, pyrrolo[3,2-c]pyridin-2-yl or pyrrolo[3,2-c]pyridin-7-yl, and the like), pyrrolo[1,2-b]pyridazinyl, imidazo[1,2-a]pyridinyl, thiazolyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, furo[2,3-d]thiazolyl, thieno[2,3-d]oxazolyl, thieno[3,2-b]furanyl, furo[2,3-d]pyrimidinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, and 7,8-dihydro-6H-cyclopenta[g]quinoxalinyl; and derivatives, N-oxide and protected derivatives thereof.
“Heterocycloalkyl” means a saturated or partially unsaturated (but not aromatic) monovalent monocyclic group of 3 to 9 ring atoms or a saturated or partially unsaturated (but not aromatic) monovalent fused bicyclic group of 5 to 12 ring atoms in which one or more heteroatoms, for example one, two, three, or four ring heteroatoms, independently selected from —O—, —S(O)n— (n is 0, 1, or 2), —N═, —NH—, and N-oxide, the remaining ring atoms being carbon. One or two ring carbon atoms may be replaced by a —C(O)—, —C(S)—, or —C(═NH)— group. Fused bicyclic radical includes bridged ring systems. Heterocycloalkyl groups include spiro heterocycloalkyl rings. Unless otherwise stated, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting.
In one embodiment, heterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro-1H-pyrrolinyl, 2,5-dioxo-1H-pyrrolyl, 2,5-dioxo-pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, piperidinyl, 2-oxopiperidinyl, 4-piperidonyl, morpholinyl, piperazinyl, 2-oxopiperazinyl, dioxopiperazinyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 2,4-dioxo-imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazolidinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, tetrahydrofuryl, 2-oxa-6-azaspiro[3.4]octanyl, 6-azaspiro[2.5]octanyl, 2,6-diazaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 7-azabicyclo[2.2.1]heptanyl, and 8-azabicyclo[3.2.1]octanyl, and the derivatives thereof and N-oxide (for example 1-oxido-pyrrolidin-1-yl) or a protected derivative thereof.
“Heterocycloalkylalkyl” means an alkyl group substituted with at least one, in another example 1 or 2, heterocycloalkyl groups, as defined herein.
“Hydroxyalkyl” means an alkyl group, as defined herein substituted with at least one, in another example 1, 2, or 3 hydroxy groups.
“Stereoisomers” include (but are not limited to) geometric isomers, enantiomers, diastereomers, and mixtures of geometric isomers, enantiomers or diastereomers. In some embodiments, individual stereoisomers of compounds are prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic column.
As used herein, “amelioration” of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or composition.
The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study.
“Excipient” or “pharmaceutically acceptable excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. The term excipient includes carriers and diluents. The term “carrier” includes pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical compositions. Lactose, corn starch, or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active ingredient no carriers are, however, usually required in the case of soft gelatin capsules, other than the soft gelatin itself. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like. The term “diluent” refers to chemical compounds that are used to dilute the compound of interest prior to delivery. Diluents include chemicals used to stabilize compounds because they provide a more stable environment. Salts dissolved in buffered solutions (which also can provide pH control or maintenance) are utilized as diluents In certain embodiments, including, but not limited to a phosphate buffered saline solution. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.
“Pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salt is not specifically limited as far as it can be used in medicaments. Examples of a salt that the compound of the present invention forms with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid: organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.
The term “pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to: intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration.
“Subject” refers to an animal, including, but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human.
“Treat,” “treating,” and “treatment,” in the context of treating a disease or disorder, are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or to slowing the progression, spread or worsening of a disease, disorder or condition or of one or more symptoms thereof. Often, the beneficial effects that a subject derives from a therapeutic agent do not result in a complete cure of the disease, disorder or condition.
The following paragraphs present a number of embodiments of the compounds disclosed herein. In each instance the embodiment includes both the recited compound(s) as well as a single stereoisomer or mixture of stereoisomers thereof, as well as a pharmaceutically acceptable salt thereof. The compounds include the N-oxides or pharmaceutically acceptable salts thereof. In some situations, the compounds exist as tautomers. All tautomers are included within the scope of the compounds presented herein.
Excluded from any and all embodiments is the compound N-(6-(1H-imidazo[4,5-b]pyridin-6-yl)-2-morpholinopyrimidin-4-yl)quinolin-3-amine. Excluded from any and all embodiments is the compound N-(6-(1H-pyrazolo[3,4-b]pyridin-5-yl)-2-morpholinopyrimidin-4-yl)quinolin-3-amine. Excluded from any and all embodiments is the compound where R3 is pyrazolyl substituted with one Ra where the R3a is cyclopropyl. Excluded from any and all embodiments is the compound where R3 is phenyl substituted with one R3a where the 1 R3a is a 3-7-membered cycloalkyl ring.
In certain embodiments, the compound of Formula I is that where:
In certain embodiments, the compound of Formula I is that where:
In certain embodiments of the compounds described herein, R1 is dihydro-2H-pyran-4-yl, tetrahydro-2H-pyran-4-yl, or morpholin-4-yl, each of which is optionally substituted with 1, 2, 3, or 4 alkyl, or with 1 or 2 alkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R1 is morpholinyl optionally substituted with 1, 2, 3, or 4 alkyl or with 1 or 2 alkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R1 is morpholin-4-yl optionally substituted with 1, 2, 3, or 4 alkyl or with 1 or 2 alkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R1 is unsubstituted morpholin-4-yl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R2 is
where one of the bonds in
is a single bond and the other is a double bond, X1 and X2 are independently N, NR2a, CH, or CR2a; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2 is ring (c) and is attached by a carbon in the 5- or 6-position of ring (c) to the pyrimidinyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2 is ring (c); R2a is alkyl, cycloalkyl, halo, or —NR2bR2c; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2 is ring (c); R2a is alkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2 is ring (c); R2a is alkyl, cycloalkyl, halo, or —NR2bR2c where R2b is hydrogen and R2c is alkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, ring (c) is indolyl substituted on the nitrogen with R2a and optionally substituted on the X1 or X2 carbon with R2a; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, ring (c) is indazolyl substituted with R2a on the 1-position nitrogen and optionally substituted on the X2 carbon with R2a ; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, ring (c) is indazolyl substituted with R2a on the 2-position nitrogen and optionally substituted on the X2 carbon with R2a; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, ring (c) is benzimidazolyl substituted with R2a on the 1-position nitrogen and optionally substituted on the X1 carbon with R2a; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, ring (c) is benzotriazolyl substituted on the X1 nitrogen with R2a; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, ring (c) is benzotriazolyl substituted on the X2 nitrogen with R2a; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R2 is indazolyl or pyrazolopyridinyl where a carbon atom in R2 is the point of attachment to the pyrimidinyl in Formula I and where R2 is optionally substituted with 1, 2, or 3 R2a groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2 is indazolyl or pyrazolopyridinyl where a carbon atom in R2 is the point of attachment to the pyrimidinyl in Formula I and where R2 is optionally substituted with 1 or 2 R2a groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2 is indazol-5-yl, indazl-6-yl, pyrazolo[4,5-b]pyridin-6-yl, pyrazolo[5,4-d]pyridin-6-yl, pyrazolo[4,5-e]pyridin-6-yl, each of which is optionally substituted with 1 or 2 R2a groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2 is indazol-5-yl or indazl-6-yl, each of which is optionally substituted with 1 or 2 R2a groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2 is pyrazolo[4,5-b]pyridin-6-yl, pyrazolo[5,4-d]pyridin-6-yl, or pyrazolo[4,5-e]pyridin-6-yl, each of which is optionally substituted with 1 or 2 R2a groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R2 is 2(3H)-oxo-benzoimidazolyl where a carbon atom in R2 is the point of attachment to the pyrimidinyl in Formula I and where R2 is optionally substituted with 1, 2, or 3 R2a groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R2 is benzimidazolyl or imidazopyridinyl where a carbon atom in R2 is the point of attachment to the pyrimidinyl in Formula I and where R2 is optionally substituted with 1, 2, or 3 R2a groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2 is benzimidazolyl or imidazopyridinyl where a carbon atom in R2 is the point of attachment to the pyrimidinyl in Formula I and where R2 is optionally substituted with 1 or 2 R2a groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2 is benzimidazol-5-yl, benzimidazol-6-yl, imidazo[4,5-b]pyridin-5-yl, or imidazo[4,5-b]pyridin-6-yl, each of which is optionally substituted with 1 or 2 R2a groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2 is benzimidazol-5-yl or benzimidazol-6-yl, each of which is optionally substituted with 1 or 2 R2a groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2 is imidazo[4,5-b]pyridin-5-yl, or imidazo[4,5-b]pyridin-6-yl, each of which is optionally substituted with 1 or 2 R2a groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R2 is indazolyl or benzimidazolyl where a carbon atom in R2 is the point of attachment to the pyrimidinyl in Formula I and where R2 is optionally substituted with 1, 2, or 3 R2a groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2 is indazolyl or benzimidazolyl where a carbon atom in R2 is the point of attachment to the pyrimidinyl in Formula I and where R2 is optionally substituted with 1 or 2 R2a groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2 is indazol-5-yl, indazl-6-yl, benzimidazol-5-yl, or benzimidazol-6-yl, each of which is optionally substituted with 1 or 2 R2a groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2 is indazol-5-yl or indazl-6-yl, each of which is optionally substituted with 1 or 2 R2a groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2 is benzimidazol-5-yl or benzimidazol-6-yl, each of which is optionally substituted with 1 or 2 R2a groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R2 is substituted with one R2a; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2 is substituted with one R2a where R2a is alkyl; hydroxyalkyl; alkoxyalkyl; halo; cycloalkyl; cycloalkylalkyl; heterocycloalkyl; heterocycloalkylalkyl optionally substituted with 1 alkyl; aminoalkyl; alkylaminoalkyl; dialkylaminoalkyl; 1,3-dioxo-isoindolinylalkyl; or —NR2bR2c; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2 is substituted with one R2a; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2 is substituted with one R2a where R2a is alkyl; hydroxyalkyl; alkoxyalkyl; halo; cycloalkyl; cycloalkylalkyl; heterocycloalkyl; heterocycloalkylalkyl optionally substituted with 1 alkyl; aminoalkyl; alkylaminoalkyl; dialkylaminoalkyl; 1,3-dioxo-isoindolinylalkyl; or —NR2bR2c where R2b is hydrogen or alkyl and R2c is alkyl, alkoxylalkyl, dialkylaminoalkyl or heterocycloalkylalkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R2 is substituted with one R2a where R2a is methyl; ethyl; hydroxyalkyl; methoxyalkyl; chloro; cyclopropyl; cyclobutyl; cyclopropylmethyl; oxetanyl; pyrrolidinyl; morpholinyl; piperazinyl; N-alkyl-piperazinyl; pyrrolidinylalkyl; morpholinylalkyl; N-alkyl-piperazinylalkyl; aminoalkyl; methylaminoalkyl; dimethylaminoalkyl; 1,3-dioxo-isoindolinylalkyl; or —NR2bR2c where R2b is hydrogen or methyl and R2c is methyl, methoxyalkyl, dimethylaminoalkyl, pyrrolidinylalkyl, or morpholinylalkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R2 is substituted with two R2a; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2 is substituted with two R2a where one R2a is alkyl, cycloalkylalkyl, or halo and a second R2a is alkyl; hydroxyalkyl; cycloalkyl; cycloalkylalkyl; heterocycloalkyl; heterocycloalkylalkyl optionally substituted with 1 alkyl; aminoalkyl; alkylaminoalkyl; dialkylaminoalkyl; 1,3-dioxo-isoindolinylalkyl; or —NR2bR2c; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2 is substituted with two R2a where one R2a is alkyl, cycloalkylalkyl, or halo and a second R2a is alkyl; hydroxyalkyl; cycloalkyl; cycloalkylalkyl; heterocycloalkyl; heterocycloalkylalkyl optionally substituted with 1 alkyl; aminoalkyl; alkylaminoalkyl; dialkylaminoalkyl; 1,3-dioxo-isoindolinylalkyl; or —NR2bR2c where R2b is hydrogen or alkyl and R2c is alkyl, alkoxylalkyl, dialkylaminoalkyl or heterocycloalkylalkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2 is substituted with two R2a where one R2a is alkyl and a second R2a is alkyl; hydroxyalkyl; cycloalkyl; cycloalkylalkyl; heterocycloalkyl; heterocycloalkylalkyl optionally substituted with 1 alkyl; aminoalkyl; alkylaminoalkyl; dialkylaminoalkyl; 1,3-dioxo-isoindolinylalkyl; or —NR2bR2c where R2b is hydrogen or alkyl and R2c is alkyl, alkoxylalkyl, dialkylaminoalkyl or heterocycloalkylalkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R2 is substituted with two R2a where one R2a is methyl, cyclopropylmethyl, or chloro and a second R2a is methyl; ethyl; 4-hydroxybutyl; cyclopropyl; cyclobutyl; cyclopropylmethyl; oxetanyl; pyrrolidinyl; morpholinyl; piperazinyl; N-alkyl-piperazinyl; pyrrolidinylalkyl; morpholinylalkyl; N-alkyl-piperazinylalkyl; methylaminoalkyl; methylaminoalkyl; dimethylaminoalkyl; 1,3-dioxo-isoindolinylalkyl; or —NR2bR2c where R2b is hydrogen or methyl and R2c is methyl, methoxyalkyl, dimethylaminoalkyl, pyrrolidinylalkyl, or morpholinylalkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2 is substituted with two R2a where one R2a is methyl and a second R2a is methyl; ethyl; 4-hydroxybutyl; cyclopropyl; cyclobutyl; cyclopropylmethyl; pyrrolidinyl; morpholinyl; piperazinyl; N-alkyl-piperazinyl; pyrrolidinylalkyl; morpholinylalkyl; N-alkyl-piperazinylalkyl; methylaminoalkyl; methylaminoalkyl; dimethylaminoalkyl; 1,3-dioxo-isoindolinylalkyl; or —NR2bR2c where R2b is hydrogen or methyl and R2c is methyl, methoxyalkyl, dimethylaminoalkyl, pyrrolidinylalkyl, or morpholinylalkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R2 is substituted with one or two R2a where R2a is alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cycloalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2A is alkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2A is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or heterocycloalkylalkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2A is aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2A is heterocycloalkylalkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2A is cycloalkyl or cycloalkylalkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, at least one of the 1, 2, or 3 R2a is alkyl; all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, at least one of the 1, 2, or 3 R2a is heterocycloalkyl; all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, at least one of the 1, 2, or 3 R2a is heterocycloalkylalkyl; all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, at least one of the 1, 2, or 3 R2a is aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, at least one of the 1, 2, or 3 R2a is —NR2bR2c; all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R2 is
where a carbon atom in R2 is the point of attachment to the pyrimidinyl in Formula I and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2 is (a) and is attached by the carbon in the 5- or 6-position of the (a) ring; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R2 is
and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R2 is (b) and is attached by the carbon in the 5- or 6-position of the (b) ring; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments, the compound of Formula I is according to Formula I(a):
where all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R1 is morpholin-4-yl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R3a is cyano, halo, alkyl, alkoxycarbonyl, heterocycloalkyl, alkylcarbonyl, alkylsulfinyl, alkylsulfonyl, alkoxy, —NR3bR3a, —C(O)NR3bR3a, —S(O)2NR3bR3c, or 5-membered heteroaryl optionally substituted with 1 or 2 R5 groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R3a is halo; alkyl; methoxy; methylcarbonyl; alkylsulfinyl; alkylsulfonyl; cyano; alkoxycarbonyl; —NR3bR3c where R3b is hydrogen and R3c is alkylcarbonyl, alkylsulfonyl, or alkoxycarbonyl; —C(O)NR3bR3c where R3b is hydrogen or alkyl and R3c is hydrogen, alkyl, cycloalkyl (optionally substituted with 1 alkyl), or cycloalkylmethyl; —S(O)2NR3bR3c where R3b is hydrogen and R3c is hydrogen or alkyl; 5-membered heterocycloalkyl; or a 5-membered heteroaryl optionally substituted with 1 R5 groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R3a is halo; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R3a is chloro; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R3a is —C(O)NR3bR3c; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, Ria is —C(O)NR3bR3c and R3b and R3c are independently hydrogen or alkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R3a is a 5-membered heteroaryl optionally substituted with 1 R5; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R3a is triazolyl, oxazolyl, imidazolyl, oxadiazolyl, pyrazolyl, or pyrrolyl, each of which is optionally substituted with 1 R5; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R3a is triazolyl, oxazolyl, imidazolyl, oxadiazolyl, pyrazolyl, or pyrrolyl, each of which is substituted with one alkyl, halo, haloalkyl, cycloalkyl, or phenylmethyl (substituted with one alkoxy); and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R3a is triazolyl, oxazolyl, imidazolyl, oxadiazolyl, pyrazolyl, or pyrrolyl, each of which is substituted with one methyl, isopropyl, fluoro, trifluoromethyl, cyclopropyl, or phenylmethyl (substituted with methoxy); and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R3a is a 5-membered heteroaryl with 1, 2, or 3 ring nitrogen atoms, optionally substituted with one or two R5 groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R3a is a 5-membered heteroaryl with 1 or 2 ring nitrogen atoms, optionally substituted with one or two R5 groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R3a is triazolyl, oxazolyl, imidazolyl, oxadiazolyl, pyrazolyl, or pyrrolyl, each of which is optionally substituted with one or two R5 groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R3a is triazolyl optionally substituted with one or two R5 groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R3a is oxazolyl or oxadiazolyl, each of which is optionally substituted with one or two R5 groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R3a is triazolyl, imidazolyl, pyrazolyl, or pyrrolyl, each of which is optionally substituted with one or two R5 groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R3a is imidazolyl, pyrazolyl, or pyrrolyl, each of which is optionally substituted with one or two R5 groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R4 is hydrogen; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R4 is methyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R4 is fluoro; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R4 is —CN; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R3 is heteroaryl optionally substituted with 1, 2, or 3 R3a groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R3 is a 6-10 membered heteroaryl optionally substituted with 1, 2, or 3 R3a groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R3 is a 5-9 membered heteroaryl optionally substituted with 1, 2, or 3 R3a groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R3 is a 5-6 membered or a 9 membered heteroaryl optionally substituted with 1, 2, or 3 R3a groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R3 is a 6-membered heteroaryl optionally substituted with 1, 2, or 3 R3a groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R3 is a 9-membered heteroaryl optionally substituted with 1, 2, or 3 R3a groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R3 is a 9-membered heteroaryl with 1, 2, or 3 nitrogen atoms where the heteroaryl is optionally substituted with 1, 2, or 3 R3a groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R3 is pyridinyl, indolyl, benzoisoxazolyl, indazolyl, benzotriazolyl, benzoxazolyl, or benzimidazolyl, each of which is optionally substituted with 1, 2, or 3 R3a groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R3 is pyridin-3-yl, pyridin-4-yl, indol-4-yl, indol-5-yl, indol-6-yl, benzoisoxazolyl, indazol-5-yl, indazol-6-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzoxazol-6-yl, benzimidazol-5-yl, or benzimidazol-6-yl, each of which is optionally substituted with 1, 2, or 3 R3c groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R3 is pyridinyl, indolyl, indazolyl, benzotriazolyl, or benzimidazolyl, each of which is optionally substituted with 1, 2, or 3 Ria groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R3 is pyridin-3-yl, indol-5-yl, indol-6-yl, indazol-5-yl, indazol-6-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzimidazol-5-yl, or benzimidazol-6-yl, each of which is optionally substituted with 1, 2, or 3 R3c groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R3 is a 6-10 membered heteroaryl; or R3 is pyridinyl; or R3 is a 9-membered heteroaryl; where R3 is optionally substituted with 1, 2, or 3 R3a groups and each R3a is independently alkyl, cycloalkyl, alkoxy, halo, —NR3bR3a, or —C(O)NR3bR3c; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R3 is a 6-10 membered heteroaryl; or R3 is pyridinyl; or R3 is a 9-membered heteroaryl; where R3 is optionally substituted with 1 R3a groups and each R3c is alkyl; cycloalkyl; alkoxy; halo; —NR3bR3c where R3b is hydrogen and R3c is alkyl; or —C(O)NR3bR3c where R3b is hydrogen and R3c is alkyl or cycloalkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R3 is a 6-10 membered heteroaryl; or R3 is pyridinyl; or R3 is a 9-membered heteroaryl; where R3 is optionally substituted with 2 R3a groups independently selected from alkyl and halo; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R3 is a 6-10 membered heteroaryl; or R3 is pyridinyl; or R3 is a 9-membered heteroaryl; where R3 is optionally substituted with 3 R3a groups where R3a is alkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R3 is a 6-10 membered heteroaryl; or R3 is pyridinyl; or R3 is a 9-membered heteroaryl; where R3 is optionally substituted with 1 R3a group which is alkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R3 is a 6-10 membered heteroaryl; or R3 is pyridinyl; or R3 is a 9-membered heteroaryl; where R3 is optionally substituted with 1 R3a group which is —NR3bR3c or —C(O)NR3bR3c; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R3 is a 6-10 membered heteroaryl; or R3 is pyridinyl; or R3 is a 9-membered heteroaryl; where R3 is optionally substituted with 1 R3a group which is alkoxy; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R3 is
where one of the bonds in
is a single bond and the other is a double bond, X1 and X2 are independently N, NR3a, CH, or CR3a; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R3 is ring (c) and is attached by a carbon in the 5- or 6-position of ring (c) to the —NH— group; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R3 is ring (c); R3a is alkyl, cycloalkyl, halo, or —NR3bR3c; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R3 is ring (c); R3a is alkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R3 is ring (c); R3c is alkyl, cycloalkyl, halo, or —NR3bR3c where Rab is hydrogen and R3c is alkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, ring (c) is indolyl substituted on the nitrogen with R3a and optionally substituted on the X1 or X2 carbon with R3a; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, ring (c) is indazolyl substituted with R3a on the 1-position nitrogen and optionally substituted on the X2 carbon with R3a; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, ring (c) is indazolyl substituted with R3a on the 2-position nitrogen and optionally substituted on the X2 carbon with R3a; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, ring (c) is benzimidazolyl substituted with R3a on the 1-position nitrogen and optionally substituted on the X1 carbon with R3a; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, ring (c) is benzotriazolyl substituted on the X1 nitrogen with R3a; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, ring (c) is benzotriazolyl substituted on the X2 nitrogen with R3a; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments, the Compound of Formula I is according to Formula I(b):
where all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments, the Compound of Formula I is according to Formula I(c):
where all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments, the compound of Formula I is according to Formula I(d):
where all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments, the compound of Formula I is according to Formula I(e):
where all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments, the compound of Formula I is according to Formula I(f):
where all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments, the compound of Formula I is according to Formula I(g):
where all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments, the compound of Formula I is according to Formula I(h):
where all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R1 is morpholin-4-yl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R3 is phenyl optionally substituted with 1, 2, or 3 R3a groups, or with 1 or 2 R3a groups, or with 1 R3a group; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R3 is phenyl substituted with 1 R3a group or R3 is phenyl substituted with 1 R3a group at the para position; and R3a is cyano, halo, alkyl, alkoxycarbonyl, heterocycloalkyl, alkylcarbonyl, alkylsulfinyl, alkylsulfonyl, alkoxy, —NR3bR3a, —C(O)NR3bR3a, —S(O)2NR3bR3a, or 5-membered heteroaryl optionally substituted with 1 or 2 R5 groups; or R3a is halo, alkyl, methoxy, methylcarbonyl, alkylsulfinyl, alkylsulfonyl, cyano, alkoxycarbonyl, —NHR3c, —C(O)NR3bR3c; —S(O)2NR3bR3c, 5-membered heterocycloalkyl, or a 5-membered heteroaryl optionally substituted with 1 R5 groups; where for —NHR3a, R3c is alkylcarbonyl, alkylsulfonyl, or alkoxycarbonyl; and for —C(O)NR3bR3c, R3b is hydrogen or alkyl and R3c is hydrogen, alkyl, cycloalkylmethyl, or cycloalkyl (where cycloalkyl is optionally substituted with 1 alkyl); and for —S(O)2NR3bR3a, R3b is hydrogen and R3c is hydrogen or alkyl; or R3a is halo, alkoxycarbonyl, —NR3bR3a, —C(O)NR3bR3c, or 5-membered heteroaryl optionally substituted with 1 or 2 R5 groups; or R3c is halo, alkoxycarbonyl, —C(O)NR3bR3a, or 5-membered heteroaryl optionally substituted with 1 or 2 R5 groups; or R3a is halo; or R3a is chloro; or R3a is —C(O)NR3bR3c; or R3c is —C(O)NR3bR3c, where R3b and R3c are independently hydrogen or alkyl; or R3a is a 5-membered heteroaryl optionally substituted with 1 R5; or R3a is triazolyl, oxazolyl, imidazolyl, oxadiazolyl, pyrazolyl, or pyrrolyl, each of which is optionally substituted with 1 R5; or R3a is triazolyl, oxazolyl, imidazolyl, oxadiazolyl, pyrazolyl, or pyrrolyl, each of which is substituted with one alkyl, halo, haloalkyl, cycloalkyl, or phenylmethyl (optionally substituted with one alkoxy); or R3a is triazolyl, oxazolyl, imidazolyl, oxadiazolyl, pyrazolyl, or pyrrolyl, each of which is substituted with one methyl, isopropyl, fluoro, trifluoromethyl, cyclopropyl, or phenylmethyl (substituted with methoxy); and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R3 is pyridinyl, indolyl, benzoisoxazolyl, indazolyl, benzotriazolyl, benzoxazolyl, or benzimidazolyl, each of which is optionally substituted with 1, 2, or 3 R3c groups; or R3 is pyridin-3-yl, pyridin-4-yl, indol-4-yl, indol-5-yl, indol-6-yl, benzoisoxazolyl, indazol-5-yl, indazol-6-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzoxazol-6-yl, benzimidazol-5-yl, or benzimidazol-6-yl, each of which is optionally substituted with 1, 2, or 3 R3a groups; or R3 is pyridinyl, indolyl, indazolyl, benzotriazolyl, or benzimidazolyl, each of which is optionally substituted with 1, 2, or 3 R3a groups; or R3 is pyridin-3-yl, indol-5-yl, indol-6-yl, indazol-5-yl, indazol-6-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzimidazol-5-yl, or benzimidazol-6-yl, each of which is optionally substituted with 1, 2, or 3 R3a groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R3 is phenyl substituted at the para position with one halo, cyano, alkylcarbonyl, alkylsulfonyl, alkylsulfinyl, alkoxy, alkoxycarbonyl, alkyl, —NR3bR3c, —C(O)NR3bR3c, —S(O)2NR3bR3c, or 5-membered heteroaryl optionally substituted with 1 or 2 R5 groups; or R3 is pyridinyl substituted with one alkoxy or —C(O)NR3bR3c; or R3 is a 9-membered heteroaryl substituted with one alkyl or cycloalkyl; or R3 is a 9-membered heteroaryl substituted with 2 or 3 alkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R3 is phenyl substituted at the para position with one halo, cyano, carboxy, alkylcarbonyl, alkylsulfonyl, alkylsulfinyl, alkoxy, alkoxycarbonyl, alkyl, —NR3bR3c, —C(O)NR3bR3c, —S(O)2NR3bR3c, or 5-membered heteroaryl optionally substituted with 1 or 2 R5 groups; or R3 is pyridinyl substituted with one alkoxy or —C(O)NR3bR3c; or R3 is a 9-membered heteroaryl substituted with one alkyl or cycloalkyl; or R3 is a 9-membered heteroaryl substituted with 2 or 3 alkyl; and R3b is hydrogen or alkyl and R3c is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkylsulfonyl, alkylcarbonyl, or alkoxycarbonyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R3 is phenyl substituted at the para position with one halo, carboxy, alkoxycarbonyl, —NR3bR3c, —C(O)NR3bR3c, or 5-membered heteroaryl optionally substituted with 1 or 2 R5 groups; or R3 is pyridinyl substituted with one alkoxy or —C(O)NR3bR3c; or R3 is a 9-membered heteroaryl substituted with one alkyl or cycloalkyl; or R3 is a 9-membered heteroaryl substituted with 2 or 3 alkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, R3 is phenyl substituted at the para position with one halo, carboxy, alkoxycarbonyl, —C(O)NR3bR3a, or 5-membered heteroaryl optionally substituted with 1 or 2 R5 groups; or R3 is pyridinyl substituted with one —C(O)NR3bR3c; or R3 is a 9-membered heteroaryl substituted with one alkyl or cycloalkyl; or R3 is a 9-membered heteroaryl substituted with 2 or 3 alkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R3 is pyridinyl substituted with one alkoxy or —C(O)NR3bR3c; or R3 is a 9-membered heteroaryl substituted with one alkyl or cycloalkyl; or R3 is a 9-membered heteroaryl substituted with 2 or 3 alkyl; and R3b optionally is hydrogen or alkyl and R3c is optionally hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkylsulfonyl, alkylcarbonyl, or alkoxycarbonyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R2 is ring (a) or ring (b); and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R2 is substituted with 1 or 2 R2a where each R2a is independently alkyl, cycloalkyl, cycloalkylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, heterocycloalkyl, or heterocycloalkylalkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R2 is substituted with one R2a where R2a is alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or heterocycloalkylalkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R2 is substituted with two R2a groups, where one R2a is alkyl, heterocycloalkyl, cycloalkyl, or cycloalkylalkyl and the other R2a is alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, heterocycloalkyl, or heterocycloalkylalkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R2 is substituted with 1 or 2 R2a groups, where one R2a is alkyl and the other R2a, when present, is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments of the compounds described herein, R2 is substituted with two R2a groups, where one R2a is alkyl and the other R2a is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments, the compound of Formula I is according to Formula I(i):
where all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments, the compound of Formula I(i) is that where:
In certain embodiments, the compound of Formula I is according to Formula I(j):
where all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments, the compound of Formula I(j) is that where:
In certain embodiments, the compound of Formula I is according to Formula I(k):
wherein:
is a single pond and the other is a double bond, X1 and X2 are independently N, NR2a, CH, or CR2a;
In certain embodiments, the compound is according to Formula II
where
In certain embodiments, the compound of Formula II is that wherein R1 is morpholin-4-yl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments, the compound of Formula II is that wherein R2 is indazolyl, pyrrolopyridinyl, benzimidazolyl, or imidazopyridinyl, each of which is optionally substituted with 1, 2, or 3 R2a groups; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
In certain embodiments, the compound of Formula II is that wherein R4 is hydrogen or methyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments. In certain embodiments, the Compound of Formula II is that wherein R4 is hydrogen; and all other groups are as defined in the Summary of the Invention or in any of the embodiments.
Any combination of the groups described above for the various variables is contemplated herein.
In certain embodiments, provided in Table 1 are compounds of the following structures:
In certain embodiments, provided are compound nos. 5-11, 15-16, 19-112, 115-126, 129-137, 147, 151-152, 157, 162-175, 179-196, 201, 203-206, 208-220, 226-234, 239-240, 242-318, 320-325, 327-331, 342-348, 350-357, 360-361, and 363. In certain embodiments, provided are compound nos. 1-4, 12-14, 17-18, 113-114, 127-128, 138-146, 148-150, 153-156, 158-161, 176-178, 197-200, 202, 207, 221-225, 235-238, 241, 319, 326, 332-341, 349, 358-359, and 362.
In certain embodiments, provided are compound nos. 1-210, 221, and 327-363. In certain embodiments, provided are compound nos. 222-326. In certain embodiments, provided are compound nos. 211-220.
In certain embodiments, provided are compound nos. 1, 4, 7, 11, 14, 16, 18, 20, and 48-52. In certain embodiments, provided are compound nos. 2-3, 5-6, 8-10, 12-13, 15, 17, 19, 21-47, 53-210, 221, and 327-363.
In certain embodiments, provided are compound nos. 13, 19, 40, 41, 42, 45, 47, 55, 81, 91, 92, 109, 117, 118, 122, 123, 124, 133, 134, 136, 149, 159, 163, 167, 168, 169, 173, 174, 176, 180, 181, 189, 190, 191, 196, 202, 207, 208, 209, 213, 214, 215, 217, 218, 226, 236, 239, 240, 247, 257, 258, 259, 260, 265, 266, 267, 277, 283, 287, 292, 302, 304, 306, 313, 316, 318, 319, 320, 323, 326, 329, 330, 336, 340, 350, 352, 353, 355, 356, 357, 360, and 372.
In certain embodiments, provided are compound nos. 2, 3, 4, 5, 12, 14, 20, 24, 28, 34, 36, 37, 43, 44, 46, 51, 53, 60, 61, 62, 64, 66, 67, 69, 70, 71, 73, 74, 75, 76, 78, 79, 82, 84, 85, 86, 96, 97, 98, 102, 110, 111, 112, 115, 119, 130, 131, 137, 139, 147, 157, 158, 161, 164, 165, 171, 172, 177, 178, 179, 184, 186, 187, 193, 194, 200, 201, 204, 205, 206, 211, 212, 221, 223, 224, 225, 227, 229, 230, 231, 232, 233, 237, 238, 241, 242, 243, 244, 245, 246, 248, 249, 252, 254, 255, 263, 269, 271, 274, 276, 279, 280, 282, 285, 286, 288, 295, 299, 305, 308, 310, 315, 317, 321, 322, 332, 333, 334, 341, and 348.
In certain embodiments, provided is a pharmaceutical composition comprising 1) a compound described herein, optionally as a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof, and 2) a pharmaceutically acceptable excipient or pharmaceutically acceptable carrier.
In certain embodiments, provided is a pharmaceutical composition comprising 1) a Compound of Formula I, I(a), I(b), I(c), I(d), I(e), I(f), I(g), I(h), I(i), I(j), or I(k), or a compound in Table 1 optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof, and 2) a pharmaceutically acceptable excipient or pharmaceutically acceptable carrier.
In certain embodiments, provided is a pharmaceutical composition comprising 1) a Compound of Formula I, I(a), I(b), I(c), I(d), I(e), I(f), I(g), I(h), I(i), I(j), or I(k), or Formula II, or a compound in Table 1, optionally as a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof, and 2) a pharmaceutically acceptable excipient or pharmaceutically acceptable carrier.
In certain embodiments, the compounds presented herein can be administered to subject in need thereof by any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumor, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal.
In certain embodiments, the compounds presented herein can be administered in any acceptable solid, semi-solid, liquid or gaseous dosage form. Acceptable dosage forms include, but are not limited to, aerosols, capsules, creams, elixirs, emulsions, gases, gels, grains, liniments, lotions, lozenges, ointments, pastes, powders, solutions, suspensions, syrups and tablets. Acceptable delivery systems include, but are not limited to, biodegradable implants (e.g., poly(DL-lactide), lactide/glycolide copolymers and lactide/caprolactone copolymers), capsules, douches, enemas, inhalers, intrauterine devices, nebulizers, patches, pumps and suppositories. Methods for preparing the dosage forms of the invention are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990).
In certain embodiments, a dosage form of the invention may be comprised solely of a compound of the invention or the compound of the invention may be formulated along with conventional excipients, including pharmaceutical carriers, adjuvants, and/or other medicinal or pharmaceutical agents. Acceptable excipients include, but are not limited to, (a) antiadherents, such as croscarmellose sodium, crosprovidone, sodium starch glycolate, microcrystalline cellulose, starch and talc; (b) binders, such as acacia, cellulose, gelatin, hydroxypropyl cellulose, lactose, maltitol, polyethylene glycol, polyvinyl pyrrolidone, sorbitol, starch, sugar, sucrose and xylitol; (c) coatings, such as cellulose, shellac, zein and enteric agents; (d) disintegrants, such as cellulose, crosslinked polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methylcellulose, microcrystalline cellulose, sodium starch glycolate, starch, and alginic acid; (e) diluents or filling agents, such as calcium or sodium carbonate, calcium or sodium phosphate, sugars (such as glucose, lactose, mannitol, sorbitol and sucrose), cellulose, croscarmellose sodium, and povidone; (f) flavoring agents; (g) coloring agents; (h) glidants, such as calcium stearate, colloidal silicon dioxide, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated vegetable oil, magnesium stearate, magnesium trisilicate, mineral oil, polyethylene glycols, silicon dioxide, starch, stearate, stearic acid, talc, sodium stearyl fumarate, sodium benzoate and zinc; (i) lubricants, such as calcium stearate, hydrogenated vegetable oils, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearin, stearic acid and talc; and (j) preservatives, such as chlorobutanol, citric acid, cysteine, methionine, methyl paraben, phenol, propyl paraben, retinyl palmitate, selenium, sodium citrate, sorbic acid, vitamin A, vitamin C and vitamin E. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed. Capsules may contain any of the excipients listed above, and may additionally contain a semi-solid or liquid carrier, such as a polyethylene glycol or oil. Pharmaceutical carriers include soluble polymers, microparticles made of insoluble or biodegradable natural and synthetic polymers, microcapsules or microspheres, lipoproteins, liposomes and micelles.
In certain embodiments, the pharmaceutical compositions may be in the form of a liquid, such as a solution, suspension, emulsion, syrup, elixir, or other like forms or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Liquid preparations may contain conventional additives such as (a) liquid diluents, such as water, saline, Ringer's solution, alcohols including monohydric alcohols and polyhydric alcohols such as polyethylene or propylene glycols and their derivatives, glycerin, fixed oils such as synthetic mono or diglycerides, or other solvents; (b) surfactants, suspending agents, or emulsifying agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, polyoxyethylene sorbitan fatty acid esters, saturated polyglycolized glycerides, monoglycerides, fatty acid esters, block copolymers of ethylene oxide and propylene oxide, polyoxyl stearates, ethoxylated castor oils, and ethoxylated hydroxystearic acids; (c) buffers, such as acetates, citrates or phosphates; (d) chelating agents, such as ethylenediaminetetraacetic acid, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, or saturated fatty acids, such as stearic acid; (e) antibacterial agents, such as chlorobutanol, benzyl alcohol, phenol, sorbic acid, or parabens, such as methyl paraben; (f) antioxidants, such as ascorbic acid or sodium bisulfite; (g) isotonic agents, sodium chloride or sugars, such as dextrose; as well as sweetening and flavoring agents, dyes and preservatives.
In certain embodiments, the pharmaceutical compositions may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.
In certain embodiments, the pharmaceutical compositions will contain a therapeutically effective amount of a compound of the invention, as an individual stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, with the remainder of the pharmaceutical composition comprised of one or more pharmaceutically acceptable excipients. Generally, for oral administration, a compound of the invention, as an individual stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof will comprise from 1% to 99% by weight of a pharmaceutically acceptable composition, with the remainder of the composition comprised of one or more pharmaceutically acceptable excipients. Typically, a compound of the invention, as an individual stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof will comprise from 5% to 75% by weight of a pharmaceutically acceptable composition, with the remainder of the composition comprised of one or more pharmaceutically acceptable excipients. For parenteral administration, a compound of the invention, as an individual stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof will comprise from 0.01% to 1% by weight of a pharmaceutically acceptable composition.
In certain embodiments, a therapeutically effective amount of a compound of the invention will vary depending upon a sundry of factors including the activity, metabolic stability, rate of excretion and duration of action of the compound, the age, weight, general health, sex, diet and species of the subject, the mode and time of administration of the compound, the presence of adjuvants or additional therapeutically active ingredients in a composition, and the severity of the disease for which the therapeutic effect is sought.
In certain embodiments, the compounds presented herein can be administered to human subjects at dosage levels in the range of about 0.1 to about 10,000 mg per day. A normal human adult having a body weight of about 70 kilograms can be administered a dosage in the range of from about 0.15 μg to about 150 mg per kilogram of body weight per day. Typically, a normal adult human will be administered from about 0.1 mg to about 25 mg, or 0.5 mg to about 10 mg per kilogram of body weight per day. The compounds of the invention may be administered in one or more unit dose forms. The unit doses may be administered one to four times a day, or two times a day, or once a day. In an alternate method of describing an effective dose, an oral unit dose is one that is necessary to achieve a blood serum level of about 0.05 to 20 μg/ml or about 1 to 20 μg/ml in a subject. The optimum dose of a compound of the invention for a particular subject can be determined by one of ordinary skill in the art.
In certain embodiments, the compounds described herein are used in the preparation or manufacture of medicaments for the treatment of diseases or conditions in which inhibition of heparan sulfate biosynthesis ameliorates the disease or condition. In some embodiments, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.
In certain embodiments, provided is a method of treating or ameliorating a medical condition, comprising administering to a subject in need thereof a compound according to any of the various embodiments described herein or a pharmaceutical composition according to any of the various embodiments described herein.
In certain embodiments, provided herein is a method of treating or ameliorating a disease by the inhibition of heparan sulfate biosynthesis comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound of Formula I, I(a), I(b), I(c), I(d), I(e), I(f), I(g), I(h), I(i), I(j), or I(k), or a compound in Table 1 optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof. In certain embodiments, the disease is selected from amyloid diseases (such as Alzheimer's disease, Parkinson's disease, type 2 diabetes, and chronic hemodialysis-related amyloid), multiple sclerosis, and an MPS disorder (such as MPS I, II, IIIA, IIIB, IIIC, IIID, and VII). In some embodiments, the diseases associated with abnormal HS accumulation are autoimmune disorders (such as multiple sclerosis, rheumatoid arthritis, juvenile chronic arthritis, Ankylosing spondylitis, psoriasis, psoriatic arthritis, adult still disease, Becet syndrome, familial Mediterranean fever, Crohn's disease, leprosy, osteomyelitis, tuberculosis, chronic bronchiectasis, Castleman disease), CNS disorders (such as Alzheimer's disease, Parkinson's disease, Huntington's disease, spongiform encephalopathies (Creutzfeld-Jakob, Kuru, Mad Cow)), chronic hemodialysis-related amyloidosis, diabetic amyloidosis, type-2 diabetes, and MPS I, II, IIIA, IIIB, IIIC, IIID, and VII disorders.
In certain embodiments, provided herein is a method of treating or ameliorating a disease by the inhibition of heparan sulfate biosynthesis comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound of Formula I, I(a), I(b), I(c), I(d), I(e), I(f), I(g), I(h), I(i), I(j), or I(k), or a compound in Table 1 optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof in combination with enzyme replacement therapy. In certain embodiments, enzyme replacement therapy comprises administering to a patient in need thereof an enzyme which is missing or deficient in said patient. In certain embodiments, the combination therapy can be used to treat a lysosomal storage disorder (e.g. MPS).
In certain embodiments, the methods described herein can be conducted in living bodies of mammals, and in another embodiment, humans. In such a case, the compounds may be administered to the mammals, and in another embodiment, to the humans.
In certain embodiments, provided are articles of manufacture, comprising packaging material, a compound provided herein that is effective for modulating heparan sulfate biosynthesis, or for treatment, prevention or amelioration of one or more symptoms of a disease or condition in need of modulation of heparan sulfate biosynthesis, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for modulating heparan sulfate biosynthesis, or for treatment, prevention or amelioration of one or more symptoms of disease or condition in need of modulation of heparan sulfate biosynthesis, are provided.
In certain embodiments, provided are kits comprising a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In some embodiments, the containers are formed from a variety of materials such as glass or plastic.
In certain embodiments, the articles of manufacture and kits provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
The following are illustrative examples of how the compounds can be prepared and tested. Although the examples can represent only some embodiments, it should be understood that the following examples are illustrative and not limiting.
In a further aspect, it is provided a method of making a compound, comprising synthesizing a compound as any of the various embodiments described above or below. Examples of the method are further described in the Examples.
Compounds disclosed herein are commercially available or can be readily prepared from commercially available starting materials according to established methodology in the art of organic synthesis. General methods of synthesizing the compound can be found in, e.g., Stuart Warren and Paul Wyatt, Workbook for Organic Synthesis: The Disconnection Approach, second Edition, Wiley, 2010. Synthesis of some of the compounds are exemplified in detail below.
In some embodiments, individual stereoisomers of compounds are prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral axillary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic column
Materials were obtained from commercial suppliers and were used without further purification. Air or moisture sensitive reactions were conducted under argon atmosphere using oven-dried glassware and standard syringe/septa techniques. 1H NMR spectra were measured at 400 MHz unless stated otherwise and data were reported as follows in ppm (δ) from the internal standard (TMS, 0.0 ppm): chemical shift (multiplicity, integration, coupling constant in Hz).
A Compound of Formula I (where each X is halo and all groups are as defined in the Summary of the Invention for a compound of Formula I or according to any of the embodiments disclosed herein) can be prepared according to General Scheme 1. In another embodiment each X is chloro.
Step A: An intermediate of formula 100 can be prepared using procedures known to one of skill in the art or is commercially available. An intermediate of formula 101 can be prepared using standard Suzuki coupling conditions, including microwave irradiation. In one example, the intermediate of formula 100 is treated in one embodiment at elevated temperature (for example 50-120° C.) with a boronic acid or ester of formula R2B(OR)2 (where each R is hydrogen or alkyl or together with the atoms to which they are attached form a carbocyclic ring) in the presence of a base such as KF, K3PO4, Cs2CO3, K2CO3, Na2CO3, NaOtBu, KOtBu, NaOMe, NaOEt, Ba(OH)2, or CsF, in the presence of a catalyst such as Pd(OAc)2, Pd2(dba)3, PdCl2(dppf), PdCl2(P(cy)3)2, or Pd(PPh3)4, and in one or more solvents such as DMF, DMA, DCM, toluene, NMP, EtOH/DME/H2O, THF, DME, or 1,4-dioxane.
Alternatively, Step A can performed using standard Stille coupling conditions. The intermediate of formula 100 is treated in one embodiment at elevated temperature (for example 50-120° C.) with an intermediate of formula R2Sn(alkyl)3 in the presence of a catalyst such as a Pd(0) catalyst such as Pd(PPh3)4, PdCl2(PPh3)2, or Pd2(dba)3 optionally in the presence of CuI, or LiCl, in the presence of a base such as CsF, Cs2CO3, and K2CO3, in one or more solvents such as NMP, toluene, and DMF.
Step B: The Compound of Formula I can then be prepared using standard Buchwald chemistry. The intermediate of formula 101 is treated in one embodiment at elevated temperature (for example 50-120° C.) with an amine of formula R3NH2 in the presence of a base such as Cs2CO3, NaOtBu, KOtBuO, K3PO4, or K2CO3, in the presence of a catalyst such as Pd(OAc)2, Pd2(dba)3, PdCl2(dppf), CuI, or Pd(PPh3)4, and optionally in the presence of a ligand or precatalyst such as BINAP, xantphos, Brettphos, Xphos, Sphos, L-proline, in one or more solvents such as DMF, DMA, 1,4-dioxane, toluene, and DCM. The mixture can optionally be purified using procedures known to one of ordinary skill in the art.
Alternatively, Step B can performed using standard Buchwald conditions. The intermediate 100 is treated in one embodiment at elevated temperature (for example 50-120° C.) with R3NH2 in the presence of concentrated HCl in one or more solvents such as isopropanol. The mixture can optionally be purified using procedures known to one of ordinary skill in the art.
Alternatively, Step B can performed using standard Ullmann coupling conditions. The intermediate 100 is treated in one embodiment at elevated temperature (for example 50-120° C.) with R3NH2 in the presence of one or more catalysts such as Cu, CuI, and CuO, optionally in the presence of a base such as K2CO3, and K3PO4, in one or more solvent such as DMF, 2-ethoxyethanol, xylene, DMSO, and isopropanol. The mixture can optionally be purified using procedures known to one of ordinary skill in the art.
Alternatively, a Compound of Formula I (where X is halo and all groups are as defined in the Summary of the Invention for a compound of Formula I or according to any of the embodiments disclosed herein) can be prepared according to General Scheme 2 where intermediate 102 is prepared using conditions as described above for Step B in General Scheme 1 followed by conditions as described above for Step A in General Scheme 1. In another embodiment each X is chloro.
The following describes ways in which the compounds described herein were or can be prepared. A person of ordinary skill in the art would know that variations in the synthetic procedures could be used to make the compounds.
To a mixture of an intermediate of formula R2Br (1 eq), potassium acetate (3 eq) and bis(pinacolato)diboron (1.1 eq) in 1,4-dioxane, argon was bubbled through the solution for 15 min. 1,1′-Bis(diphenylphosphino) ferrocene palladium(II)dichloride dichloromethane adduct (PdCl2(dppf).CH2Cl2) (0.1 eq) was added and the reaction mixture was stirred at 90° C. for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite, evaporated to dryness to afford the desired boronate ester,
as crude product and used as such for the next step without further purification.
To a mixture of an intermediate of formula 100 (1 eq) or formula 102 (1 eq), a boronic acid of formula R2B(OH)2 or boronate ester of formula
(1 eq) in 1,4-dioxane, 2 M solution of potassium phosphate was added and purged with argon for 15 min followed by the addition of tetrakis triphenyl phosphine palladium (0.06 eq) and stirred at 90° C. for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated to dryness. The residue was taken in ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography/preparative HPLC to afford the intermediate of formula 101 or a Compound of Formula I, respectively.
A mixture of the intermediate of formula 101 (1 eq) or formula 100, R3NH2 (1 eq) and cesium carbonate (1.5 eq) in 1,4-dioxane was taken and purged with argon for 10 min, followed by the addition of BINAP (0.22 eq) and purged argon for additional 5 min. Palladium acetate (0.2 eq) was added and stirred at 100° C. for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated to dryness. The residue was taken in ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford a Compound of Formula I or formula 102, respectively.
To a stirred solution of ester (1 eq) in methanol:water (1:1), NaOH (2 eq) was added and refluxed for 2-4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, methanol was evaporated to dryness. Aqueous layer was washed with ethyl acetate. Aqueous layer was acidified using 1N HCl and dried to afford the desired product and used as such for the next step.
To a stirred solution of ester compound (1 eq) in THF:H2O (1:1), lithium hydroxide (2 eq) in minimum amount of water was added and stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was extracted with ethyl acetate. The aqueous layer was acidified with 1N HCl and the solid obtained was filtered and dried in vacuo to afford the acid. The crude product has been used as such for the next step without further purification.
To a mixture of corresponding Acid (1 eq) and PYBOP/HATU (1.5 eq) in DMF, DIPEA (3 eq) was added and stirred at room temperature for 10 min. Methyl amine hydrochloride (1.2 eq) was added slowly and stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, water was added and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography/preparative HPLC to afford the desired product.
To a stirred solution of 4-(4,6-dichloropyrimidin-2-yl)morpholine 1 (1 g, 1 eq) and 4-chloro aniline 2 (0.547 g, 1 eq) in isopropanol (10 mL), concentrated HCl (2 mL) was added and heated to reflux at 100° C. for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was taken in ethyl acetate (50 mL), washed with 1 N HCl, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 20% EtOAc-hexane to afford the title compound 3. LCMS (m/z): 325.20 (M+1).
The title compound has been synthesized by following the General Procedure for Suzuki Coupling using compound 3 and Boronate ester 4 in Scheme 3. 1H NMR (400 MHz, DMSO-d6) δ: 10.06 (s, 1H), 8.22 (s, 1H), 8.13 (s, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.75-7.65 (m, 3H), 7.41 (d, J=8.4 Hz, 2H), 6.73 (s, 1H), 4.14 (s, 3H), 3.84-3.72 (m, 8H); HPLC purity: 99.45%; LCMS Calculated for C22H21ClN6O (free base): 420.15; Observed: 421.20 (M+1).
To a stirred solution of 6-bromo-1H-indazole 1 (60 g, 1 eq) and 3 N NaOH (600 mL) in 1,4-dioxane (1200 mL), Iodine (171 g, 2.2 eq) was added and stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with 20% citric acid solution, saturated sodium bicarbonate solution and extracted with ethyl acetate (3×300 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude compound 2. LCMS (m/z): 323.05 (M+1).
To a stirred solution of 6-bromo-3-iodo-1H-indazole 2 (95 g, 1 eq) in DMF (150 mL), NaH (10.62 g, 1.5 eq) was added and stirred at room temperature for 10 min followed by the addition of methyl iodide (83.8 g, 2 eq). The reaction mixture was stirred for 30 min at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (4×75 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-120 mesh using 60% EtOAc-hexane to afford the title compound 3. LCMS (m/z): 336.95 (M+1).
The title compound has been synthesized by following the General Procedure for Suzuki Coupling using compound 3 and Boronate ester 4 in Scheme 4. LCMS (m/z): 239.05 (M+2).
To a stirred solution of compound 5 (25.6 g, 1 eq) in dry THF (400 mL), BH3:DMS (432 mL, 8 eq) was added at 0° C. and stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with 3N NaOH and 30% H2O2 solution at 0° C. The reaction mixture was stirred at room temperature for 3 h and extracted with ethyl acetate (4×75 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-120 mesh using 60% EtOAc-hexane to afford the title compound 6. LCMS (m/z): 255.05 (M+1).
To a stirred solution of compound 6 (12 g, 1 eq) in DCM (150 mL), triethylamine (9.54 g, 2 eq) was added and stirred for 15 min followed by the slow addition of mesyl chloride (8.07 g, 1.5 eq) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water, extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford compound 7. LCMS (m/z): 333.05 (M+1).
To a stirred solution of compound 8 (5.81 g, 1.5 eq) in DMF (50 mL), triethylamine (9 g, 2.0 eq) was added and stirred at room temperature for 15 min. Compound 7 (14.8 g, 1 eq) in DMF (100 mL) was added and the reaction mixture was stirred at 90° C. for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 3% MeOH-DCM to afford the title compound 9. LCMS (m/z): 325.15 (M+1).
The title compound has been synthesized by following the General Procedure for Boronate Ester Preparation described above using bromo compound 9 in Scheme 4 and Bis (pinacolato) diboron. LCMS (m/z): 372.45 (M+1).
The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using compound 11 and Boronate ester 10 in Scheme 4 to afford the title compound. 1H NMR (400 MHz, MeOD) δ: 8.11 (d, J=1.4 Hz, 1H), 8.04 (d, J=8.5 Hz, 1H), 7.65 (d, J=8.3 Hz, 2H), 7.55 (dd, J=8.5, 1.5 Hz, 1H), 7.50-7.41 (m, 2H), 6.61 (s, 1H), 4.16 (s, 3H), 4.13-4.10 (m, 2H), 3.94-3.78 (m, 10H), 3.76-3.64 (m, 4H), 3.56 (dd, J=8.5, 6.8 Hz, 2H), 3.38-3.24 (m, 2H); HPLC purity: 99.62%; LCMS Calculated for C28H32ClN7O2 (free base): 533.23; observed: 534.40 (M+1).
To a stirred solution of NaH (0.58 g, 1 eq) in dry DMF (10 mL), compound 2 (1 g, 1 eq) was added at 0° C. and stirred for 15 min followed by the addition of compound 1 (2 g, 1 eq). The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice cold water. The precipitated solid was collected by filtration, washed with water and dried under reduced pressure to afford the title compound 3 as mixture of isomers. LCMS (m/z): 190.95 (M+1).
To a stirred solution of compound 3 (2 g, 1 eq) in methanol (10 mL), PtO2 (0.19 g) was added and stirred under hydrogen atmosphere (balloon pressure) at room temperature for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite. The filtrate was evaporated under reduced pressure. The crude product was purified by flash column chromatography on silica gel 100-200 mesh using 20% EtOAc-hexane to afford the title compounds 4 and 4a. Both the compounds were confirmed by NOE. Both: LCMS (m/z): 161.05 (M+1).
The title compound has been synthesized by following the General procedure for Buchwald Coupling described above using compound 5 and amine 4 in Scheme 5. 1H NMR (400 MHz, DMSO-d6) δ: 9.67 (s, 1H), 8.17 (s, 1H), 8.08 (s, 4H), 8.03-7.82 (m, 3H), 7.73 (d, J=8.6 Hz, 1H), 6.74 (s, 1H), 4.05 (s, 3H), 3.83 (t, J=4.7 Hz, 4H), 3.74 (t, J=4.6 Hz, 4H), 3.63-3.55 (m, 4H), 3.09 (t, J=8.0 Hz, 2H), 2.71 (t, J=7.7 Hz, 2H), 2.48 (s, 4H); HPLC purity: 98.21%; LCMS Calculated for C30H34N10O2:566.29:observed: 567.50 (M+1).
A mixture of 4-(4,6-dichloropyrimidin-2-yl)morpholino 1 (0.3 g, 1 eq), 2-methoxy 4-amino pyridine 2 (0.168 g, 1 eq), cesium carbonate (0.437 g, 1.5 eq) in 1,4-dioxane (20 mL) was taken and purged with argon for 10 min, followed by the addition of BINAP (0.099 g, 0.2 eq) and purged argon for additional 5 min. Palladium acetate (0.04 g, 0.2 eq) was added and stirred at 100° C. for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated to dryness. The residue was taken in ethyl acetate (50 mL), washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 30% EtOAc-hexane to afford the desired product 3. LCMS (m/z): 322.20 (M+1).
N-(2-methoxypyridin-4-yl)-6-(1-methyl-1H-benzo[d]imidazol-5-yl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using compound 3 in Scheme 6 and (1-Methyl-1H-benzimidazol-5-yl)boronic acid. 1H NMR (MeOD, 400 MHz)δ: 9.50 (d, J=1.8 Hz, 1H), 8.60 (s, 1H), 8.44-8.36 (m, 1H), 8.13-8.03 (m, 3H), 7.55 (d, J=6.3 Hz, 1H), 6.98 (d, J=2.0 Hz, 1H), 4.20 (d, J=2.3 Hz, 6H), 4.00-3.95 (m, 4H), 3.85-3.82 (m, 4H); HPLC purity: 97.21%; LCMS Calculated for C22H23N7O2(free base): 417.19; observed: 418.20 (M+1).
N-(2-methoxypyridin-4-yl)-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using compound 3 in Scheme 6 and 1-Methyl-1H-benzoimidazole-6-boronic acid. 1H NMR (MeOD, 400 MHz) δ: 9.52 (s, 1H), 8.67 (s, 1H), 8.36 (d, J=8.2 Hz, 1H), 8.15-8.06 (m, 2H), 7.99 (d, J=7.9 Hz, 1H), 7.60 (d, J=5.9 Hz, 1H), 7.02 (s, 1H), 4.26 (s, 3H), 4.20 (s, 3H), 4.00-3.95 (m, 4H), 3.90-3.86 (m, 4H); HPLC purity: 96.55%; LCMS Calculated for C22H23N7O2(Free base): 417.19; observed: 418.20 (M+1).
N-(2-methoxypyridin-4-yl)-6-(1-methyl-1H-indazol-5-yl)-2-morpholinopyrimidin-4-amine): The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using compound 3 in Scheme 6 and (1-methyl-1H-indazol-5-yl)boronic acid. 1H NMR (DMSO-d6, 400 MHz) δ: 9.76 (s, 1H), 8.47 (s, 1H), 8.19 (m, 1H), 8.03-7.98 (m, 2H), 7.73 (d, J=8.4 Hz, 1H), 7.25 (s, 1H), 7.18 (d, J=4.4 Hz, 1H), 6.70 (s, 1H), 4.08 (s, 3H), 3.82-3.74 (m, 11H); HPLC purity: 95.10%; LCMS Calculated for C21H23N7O2: 417.19; observed: 418.20 (M+1).
N-(2-methoxypyridin-4-yl)-6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using compound 3 in Scheme 6 and 1-methylindazole-6-boronic acid pinacol ester. 1H NMR (DMSO-d6, 400 MHz) δ: 9.82 (s, 1H), 8.24 (s, 1H), 8.10 (d, J=1.0 Hz, 1H), 8.00 (d, J=5.7 Hz, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.78 (dd, J=8.5, 1.4 Hz, 1H), 7.26 (d, J=1.8 Hz, 1H), 7.19 (dd, J=5.9, 1.9 Hz, 1H), 6.77 (s, 1H), 4.13 (s, 3H), 3.82 (s, 3H), 3.82-3.72 (m, 8H); HPLC purity: 98.69%, LCMS Calculated for C22H23N7O2:417.19; observed: 418.20 (M+1).
The title compound (crude product) has been synthesized by following the General Procedure for Boronate Ester Preparation described above using 6-bromo indazole 1 and bis(pinacolato)diboron. LCMS (m/z):245.05 (M+1).
The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using compound 3 and Boronate ester 2 in Scheme 7. 1H NMR (400 MHz, DMSO-d6) δ: 10.11 (bs, 1H), 8.15 (d, J=9.1 Hz, 2H), 7.90 (d, J=8.5 Hz, 1H), 7.76-7.70 (m, 2H), 7.64 (d, J=8.6 Hz, 1H), 7.41 (d, J=8.4 Hz, 2H), 6.71 (s, 1H), 3.84-3.78 (m, 4H), 3.76-3.70 (m, 4H); HPLC purity: 98.64%; LCMS Calculated for C21H19ClN6O: 406.13; Observed: 407.15 (M+1).
Synthesis of N-(4-chlorophenyl)-6-(1H-indazol-5-yl)-2-morpholinopyrimidin-4-amine:
The title compound (crude product) has been synthesized by following the General Procedure for Boronate Ester Preparation described above using 5-bromo-1H-indazole 1 and bis(pinacolato)diboron. LCMS (m/z): 286.10 (M+1+CH3CN).
The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using compound 3 and Boronate ester 2. 1H NMR (400 MHz, DMSO-d6) δ: 8.38 (s, 1H), 8.26 (s, 1H), 7.84 (d, J=8.7 Hz, 1H), 7.75-7.66 (m, 3H), 7.43 (d, J=8.6 Hz, 2H), 6.71 (s, 1H), 3.82-3.72 (m, 8H); HPLC purity: 98.77%; LCMS Calculated for C21H19ClN6O: 406.13; Observed: 407.10 (M+1).
To a stirred solution of 6-bromo-1H-indazole 1 (0.9 g, 1 eq)in 1,4-dioxane (20 mL), 2 M NaOH solution (2.5 mL) was added and stirred at room temperature followed by the addition of Boc anhydride (1.106 g, 2 eq) and stirred for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (2×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 15% EtOAc-hexane to afford the title compound 2. LCMS (m/z): 196.90 (M−Boc).
The title compound has been synthesized by following the General Procedure for Boronate Ester Preparation described above using compound 2 and bis(pinacolato)diboron.
The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using compound 4 and Boronate ester 3. LCMS (m/z): 316.10 (M−Boc).
The title compound (crude) has been synthesized by following the General procedure for Buchwald Coupling described above using methyl 5-aminopicolinate 6 and compound 5.
The title compound has been synthesized by following the General Procedure for Ester Hydrolysis described above using compound 7 and the crude product has been used as such for the next step. LCMS (m/z): 518.25 (M+1).
The title compound has been synthesized by following the general procedure described above for Amide coupling by using compound 8 and methyl amine hydrochloride. The crude product has been stirred in methanolic HCl for 3 h and purified by preparative HPLC to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 10.52 (s, 1H), 8.95 (d, J=2.4 Hz, 1H),8.72 (s,1H), 8.28 (dd, J=2.4, 2.8 Hz, 1H), 8.17 (d, J=4 Hz, 2H), 8.05 (d, J=8.8 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.66 (dd, J=1.2, 2.0 Hz, 1H), 6.82 (s, 1H), 3.82-3.73 (m, 8H), 2.80 (s, 3H); HPLC purity: 96.46%; LCMS Calculated for C22H22N8O2: 430.19; Observed: 431.25 (M+1).
To a stirred solution of 5-bromo-1H-indazole 1 (2 g,1 eq) in DMF (20 mL), NaH (0.527 g, 1.3 eq) was added portion wise at 0° C. and stirred for 15 min followed by the addition of (bromomethyl)cyclopropane (2.05 g,1.5 eq). The reaction mixture was stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water, extracted with ethyl acetate (3×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 10% to 25% EtOAc-hexane to afford 1.6 g of compound 3 and 0.9 g of compound 4. LCMS (m/z): 250.95 (M+).
The title compound (crude product) has been synthesized by following the General Procedure for Boronate Ester Preparation described above using compound 3 and Bis (pinacolato)diboron. LCMS (m/z):299.15 (M+1).
The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using compound 7 and Boronate ester 5. 1H NMR (400 MHz, DMSO-d6) δ: 9.93 (s, 1H), 8.40 (s, 1H), 8.23 (s, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 6.65 (s, 1H), 4.36 (d, J=6.9 Hz, 2H), 3.84-3.77 (m, 4H), 3.75-3.69 (m, 4H), 1.32-1.26 (m, 1H), 0.55-0.37 (m, 4H); HPLC purity: 99.26%; LCMS Calculated for C25H25ClN6O: 460.18; Observed: 461.15 (M+1).
The title compound (crude product) has been synthesized by following the General Procedure for Boronate Ester Preparation described above using bromo compound 4 and Bis (pinacolato)diboron. LCMS (m/z):299.15 (M+1).
The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using compound 7 and Boronate ester 6. 1H NMR (400 MHz, DMSO-d6) δ:10.73 (s, 1H), 8.64 (s, 1H), 8.36 (s, 1H), 7.81-7.63 (m, 4H), 7.48-7.40 (m, 2H), 6.71 (s, 1H), 4.34 (d, J=7.2 Hz, 2H), 3.83-3.74 (m, 8H), 1.42-1.34 (m, 1H), 0.58-0.40 (m, 4H); HPLC purity: 99.77%; LCMS Calculated for C25H25ClN6O: 460.18; Observed: 461.20 (M+1).
The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using compound 1 and Boronate ester 2. LCMS (m/z): 330.05 (M+1).
The title compound (crude) has been synthesized by following the General procedure for Buchwald Coupling described above using compound 3 and methyl 4-aminobenzoate 4. LCMS (m/z): 445.20 (M+1).
The title compound has been synthesized by following the General Procedure for Ester Hydrolysis described above using compound 5 and the crude product has been used as such for the next step. LCMS (m/z): 431.25 (M+1).
Step 4: The following compounds were prepared using the above scheme.
N-cyclopropyl-4-((6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)benzamide: The title compound has been synthesized by following the general procedure described above for Amide coupling by using compound 6 and cyclopropyl amine. 1H NMR (400 MHz, DMSO-d6) 6:9.71 (s, 1H), 8.26 (d, J=13.3 Hz, 2H), 8.10 (s, 1H), 7.89-7.73 (m, 6H), 6.76 (s, 1H), 4.13 (s, 3H), 3.86-3.74 (m, 8H), 2.88-2.79 (m, 1H), 0.73-0.53 (m, 4H); HPLC purity: 96.95%; LCMS Calculated for C26H27N7O2: 469.22; Observed: 470.25 (M+1).
4-((6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)-N-(1-methyl cyclopropyl)benzamide: The title compound has been synthesized by following the general procedure described above for Amide coupling by using compound 6 and 1-methylcyclopropanamine. 1H NMR (400 MHz, DMSO-d6) δ: 9.67 (s, 1H), 8.47 (s, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.89-7.71 (m, 6H), 6.75 (s, 1H), 4.13 (s, 3H), 3.82-3.72 (m, 8H), 1.36 (s, 3H), 0.75-0.70 (m, 2H), 0.61-0.57 (m, 2H); HPLC purity: 98.00%; LCMS Calculated for C27H29N7O2: 483.24; Observed: 484.30(M+1).
Methyl 4-((2-morpholino-6-(1-(3-morpholinopropyl)-1H-indazol-6-yl)pyrimidin-4-yl) amino)benzoate: 1H NMR (400 MHz, DMSO-d6) δ: 9.84 (s, 1H), 8.30 (s, 1H), 8.13 (s, 1H), 7.94 (d, J=8.5 Hz, 2H), 7.85 (d, J=8.9 Hz, 3H), 7.74 (d, J=8.5 Hz, 1H), 6.76 (s, 1H), 4.52 (t, J=6.6 Hz, 2H), 3.83-3.74 (m, 11H), 3.50 (d, J=5.0 Hz, 4H), 2.26-1.96 (m, 8H); HPLC purity: 95.24%; LCMS Calculated for C30H35N7O4: 557.28; Observed: 558.40 (M+1).
4-((2-Morpholino-6-(1-(3-morpholinopropyl)-1H-indazol-6-yl)pyrimidin-4-yl)amino) benzoic acid: 1H NMR (400 MHz, DMSO-d6) δ: 9.82 (s, 1H), 8.31 (s, 1H), 8.12 (s, 1H), 7.83 (ddd, J=39.7, 24.5, 8.4 Hz, 6H), 6.78 (s, 1H), 4.53 (t, J=6.2 Hz, 2H), 3.87-3.70 (m, 8H), 3.50 (d, J=9.7 Hz, 4H), 2.25-2.11 (m, 6H), 2.03 (dt, J=14.1, 7.5 Hz, 2H); HPLC purity: 98.3%; LCMS Calculated for C29H33N7O4: 543.26; Observed: 544.45 (M+1).
To a stirred solution of compound 1 (4 g, 1 eq) in 40 mL acetonitrile, NCS (2.98 g, 1.1 eq) was added at room temperature and heated to 60° C. for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulphate and evaporated under reduced pressure to afford title compound 2. LCMS (m/z):232.70 (M+2).
To a stirred solution of compound 2 (1 eq) in DMF, K2CO3 (3 eq) and 3-chloro-1-bromo propane (2 eq) were added and heated at 50° C. for 13 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 60-120 mesh using 20% hexane in ethyl acetate to afford compound 6.
To a stirred solution of compound 6 (1 eq) in NMP, KI (4 eq) and morpholine (6.2 eq) were added and heated at 70° C. for 12 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 60-120 mesh using ethyl acetate/10% MeOH & DCM to afford 4-(3-(6-bromo-3-chloro-1H-indazol-1-yl)propyl)morpholine. LCMS (m/z): 360.15(M+1)
To a stirred solution of compound 2 (1 eq) in acetonitrile, DBU (2 eq) was added followed by the addition of methyl iodide (1.2 eq). The reaction mixture was stirred at room temperature for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulphate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 60-120 mesh using 20% ethyl acetate in n-hexane to afford 6-bromo-3-chloro-1-methyl-1H-indazole. 1H NMR (400 MHz, DMSO-d6) δ: 8.09 (s, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.37-7.35 (m, 1H), 4.01 (s, 3H).
The title compounds were synthesized by following the General Procedure for Boronate Ester Preparation described above using the respective compounds 3 and bis(pinacolato)diboron to obtain compound 4.
The following compounds were prepared using the General Procedure for Suzuki Coupling described above using the respective pinacol boronates 4 and compound 5.
6-(3-chloro-1-(3-morpholinopropyl)-1H-indazol-6-yl)-N-(4-chlorophenyl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 9.61 (s, 1H), 8.35 (s, 1H), 7.88-7.66 (m, 4H), 7.42-7.33 (m, 2H), 6.70 (s, 1H), 4.51 (t, J=6.4 Hz, 2H),3.82-3.70 (m, 8H), 3.47 (t, J=4.5 Hz, 4H), 2.25-2.12 (m, 6H), 2.01 (p, J=6.5 Hz, 2H); HPLC purity: 96.22%; LCMS Calculated for C28H31C12N7O2 (Free base): 567.19; observed: 568.40 (M+1).
6-(3-chloro-1-methyl-1H-indazol-6-yl)-N-(4-chlorophenyl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 9.56 (s, 1H), 8.25 (s, 1H), 7.81 (d, J=8.6 Hz, 1H), 7.70 (dd, J=17.2, 8.5 Hz, 3H), 7.34 (d, J=8.5 Hz, 2H), 6.67 (s, 1H), 4.07 (s, 3H), 3.80-3.68 (m, 8H); HPLC purity: 99.56%; LCMS Calculated for C22H20Cl2N6O (Free base): 454.11; Observed: 455.25 (M+1).
The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using compound 1 and Boronate ester 2. LCMS (m/z): 330.05 (M+1).
The title compound (crude) has been synthesized by following the General procedure for Buchwald Coupling described above using compound 3 and methyl 4-aminobenzoate 4. 1H NMR (400 MHz, DMSO-d6) δ: 9.87 (s, 1H), 8.25 (s, 1H), 8.10 (s, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.86 (d, J=8.2 Hz, 3H), 7.78 (d, J=8.5 Hz, 1H), 6.79 (s, 1H), 4.13 (s, 3H), 3.82-3.74 (m, 11H); HPLC purity: 94.79%; LCMS Calculated for C24H24N6O3: 444.19; Observed: 445.25 (M+1).
The title compound has been synthesized by following the General Procedure for Ester Hydrolysis described above using compound 5 and the crude product has been used as such for the next step. 1H NMR (400 MHz, DMSO-d6) δ: 12.62 (s, 1H), 9.81 (s, 1H), 8.25 (s, 1H), 8.10 (s, 1H), 7.95-7.74 (m, 6H), 6.78 (t, 1H), 4.13 (s, 3H), 3.82-3.61 (m, 8H); HPLC purity: 90.18%; LCMS Calculated for C23H22N6O3: 430.18; Observed: 431.25 (M+1).
Step 4: The following compounds were prepared.
N,N-dimethyl-4-((6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)amino) benzamide: The title compound has been synthesized by following the general procedure described above for Amide coupling by using compound 6 and N,N-dimethyl amine. 1H NMR (400 MHz, MeOD) δ: 8.13 (d, J=14.5 Hz, 2H), 7.99 (d, J=8.4 Hz, 1H), 7.77 (d, J=8.1 Hz, 2H), 7.53 (dd, J=8.4, 5.8 Hz, 3H), 6.64 (s, 1H), 4.19 (s, 3H), 3.95-3.82 (m, 8H), 3.12 (s, 3H), 3.04 (s, 3H); HPLC purity: 97.24%; LCMS Calculated for C25H27N7O2(free base):457.22; observed: 458.30 (M+1).
4-((6-(1-methyl-4H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)benzamide: To a stirred solution of acid6 (100mg, 1 eq) in DMF (2 mL) CDI (45 mg, 1.2 eq) was added and the resulting mixture stirred at 60° C. for 1 h. Reaction mixture was cooled to room temperature, ammonium hydroxide (0.36 mL, 10 eq) was added and the reaction mixture was stirred for 1 h at room temperature. After completion of the reaction, water was added and extracted with ethyl acetate (2×25 mL). Combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by prep HPLC to afford the desired product. 1H NMR (400 MHz, DMSO-d6) δ: 10.19 (s, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 7.89 (dd, J=8.6, 2.4 Hz, 4H), 7.81-7.74 (m, 2H), 7.69 (d, J=8.4 Hz, 1H), 7.23 (d, J=6.9 Hz, 1H), 6.79 (s, 1H), 4.14 (s, 3H), 3.84-3.75 (m, 8H); HPLC purity: 96.84%; LCMS Calculated forC23H23N7O2(free base): 429.19; observed: 430.25 (M+1).
N-ethyl-4-((6-(1-methyl-4H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)benzamide: The title compound has been synthesized by following the general procedure described above for Amide coupling by using compound 6 and ethylamine. 1H NMR (400 MHz, DMSO-d6) δ: 10.15 (s, 1H), 8.36 (t, J=5.6 Hz, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 7.93-7.83 (m, 3H), 7.82-7.75 (m, 2H), 7.69 (d, J=8.5 Hz, 1H), 6.79 (s, 1H), 4.14 (s, 3H), 3.84-3.75 (m, 8H), 3.34-3.22 (m, 2H), 1.12 (t, J=7.2 Hz, 3H); HPLC purity: 97.67%; LCMS Calculated for C25H27N7O2(free base): 457.22; observed: 458.40 (M+1).
N-isopropyl-4-((6-(1-methyl4H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)amino) benzamide:The title compound has been synthesized by following the general procedure described above for Amide coupling by using compound 6 and isopropyl amine. 1H NMR (400 MHz, DMSO-d6) δ: 9.70 (s, 1H), 8.24 (s, 1H), 8.12-8.03 (m, 2H), 7.85 (dd, J=8.6, 3.4 Hz, 3H), 7.77 (d, J=8.5 Hz, 3H), 6.76 (s, 1H), 4.16-4.03 (m, 4H), 3.83-3.74 (m, 8H), 1.16 (d, J=6.6 Hz, 6H); HPLC purity: 98.16%; LCMS Calculated for C26H29N7O2(free base): 471.24; observed: 472.40 (M+1).
To a stirred solution of 6-bromo-1H-indazole 1 (2 g, 1 eq) and 3N NaOH (20 mL) in 1,4-dioxane (40 mL), Iodine (5.67 g, 2.2 eq) was added and stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with 20% citric acid solution, saturated sodium bicarbonate solution and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude compound 2. LCMS (m/z): 323.05 (M+1).
To a stirred solution of 6-bromo-3-iodo-1H-indazole 2 (3.2 g, 1 eq) in DMF (20 mL), NaH (0.59 g, 1.5 eq) was added and stirred at room temperature for 10 min followed by the addition of methyl iodide (2.8 g, 2 eq). The reaction mixture was stirred for 5 min at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-120 mesh using 60% EtOAc-hexane to afford the title compound 3. LCMS (m/z): 336.95 (M+1).
The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using compound 3 and Boronate ester 4. LCMS (m/z): 239.05 (M+2).
To a stirred solution of compound 5 (1.9 g, 1 eq), in dry THF (40 mL), BH3:DMS (3.2 mL, 4 eq) was added at 0° C. and stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with 3N NaOH and 30% H202 solution at 0° C. The reaction mixture was stirred at room temperature for 3 h and extracted with ethyl acetate (3×50 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-120 mesh using 60% EtOAc-hexane to afford the title compound 6. LCMS (m/z): 255.05 (M+1).
The title compound (crude product) has been synthesized by following the General Procedure for Boronate Ester Preparation described above using bromo compound 6 and Bis (pinacolato) diboron. LCMS (m/z): 303.25 (M+1).
The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using compound 8 and Boronate ester 7. LCMS (m/z): 465.25 (M+1).
To a stirred solution of compound 9 (0.25 g, 1 eq), in dichloromethane (10 mL), triethylamine (0.109 g, 2 eq) was added at room temperature and stirred at same temperature for 10 min followed by the addition of mesyl chloride (0.092 g, 1 eq) and stirred at same temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with dichloromethane (50 mL), washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude compound 4. LCMS (m/z): 543.30 (M+1).
To a stirred solution of compound 10 (1 eq), in DMF, triethylamine (2 eq) was added at room temperature and stirred at same temperature for 10 min followed by the addition of corresponding amine (2 eq) and stirred at 90° C. for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography/preparative HPLC to afford the following compounds.
N-(4-chlorophenyl)-6-(3-(2-(dimethylamino)ethyl)-1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, MeOD) δ: 8.17 (d, J=1.3 Hz, 1H), 7.86-7.75 (m, 2H), 7.71-7.62 (m, 2H), 7.34-7.26 (m, 2H), 6.62 (s, 1H), 4.09 (s, 3H), 3.89-3.77 (m, 8H), 3.37-3.15 (m, 4H), 2.67 (s, 6H); HPLC purity: 96.71%; LCMS Calculated for C26H30ClN7O: 491.22; observed: 492.40 (M+1).
N-(4-chlorophenyl)-6-(1-methyl-3-(2-(pyrrolidin-1-yl)ethyl)-1H-indazol-6-yl)-2-morpholino pyrimidin-4-amine: 1H NMR (400 MHz, MeOD) δ: 8.10 (s, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.65 (s, 2H), 7.58-7.51 (m, 1H), 7.46 (dd, J=8.6, 2.1 Hz, 2H), 6.63 (s, 1H), 4.16 (s, 3H), 3.93-3.70 (m, 12H), 3.51 (t, J=7.3 Hz, 2H), 3.26-3.22 (m, 2H), 2.20 (dq, J=11.2, 6.6, 5.2 Hz, 2H), 2.07 (dt, J=11.5, 5.7 Hz, 2H); HPLC purity: 98.81%; LCMS Calculated for C28H32ClN7O (free base): 517.24; Observed: 518.40 (M+1).
A stirred solution of 6-bromo-3-iodo-1-methyl-1H-indazole 1 (6 g, 1 eq), CuI (0.338 g, 0.1 eq) and Pd(PPh3)2Cl2 (1.25 g, 0.1 eq) in triethylamine (50 mL) and stirred at room temperature for 15 min followed by the addition of prop-2-yn-1-ol (1.05 g, 1 eq) and stirred for 16 h at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel 100-200 mesh using 10% EtOAc-hexane to afford the title compound 3. LCMS (m/z): 267.05 (M+2).
To a stirred solution of compound 3 (2 g, 1 eq), in ethanol (50 mL), PtO2 (0.2 g) was added and stirred at room temperature under hydrogen atmosphere (balloon pressure) for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure to afford the crude compound 4. LCMS (m/z): 269.05 (M+1).
The title compound (crude product) has been synthesized by following the General Procedure for Boronate Ester Preparation described above using bromo compound 4 and Bis (pinacolato) diboron.
LCMS (m/z): 317.25 (M+1).
The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using compound 6 and Boronate ester 5. 1H NMR (400 MHz, DMSO-d6) δ: 9.55 (s, 1H), 8.15 (s, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.71 (td, J=6.1, 3.1 Hz, 3H), 7.41-7.29 (m, 2H), 6.69 (s, 1H), 4.52 (t, J=5.1 Hz, 1H), 4.04 (s, 3H), 3.83-3.68 (m, 8H), 3.49 (td, J=6.3, 4.9 Hz, 2H), 2.94 (t, J=7.7 Hz, 2H), 1.95-1.83 (m, 2H); HPLC purity: 96.49%; LCMS Calculated for C25H27ClN6O2: 478.19; Observed: 479.30 (M+1).
To a stirred solution of compound 6 (0.3 g, 1 eq), in dichloromethane (5 mL), triethylamine (0.18 g, 2 eq) was added at room temperature and stirred at same temperature for 10 min followed by the addition of mesyl chloride (0.107 g, 1.5 eq) and stirred at same temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with 10% MeOH-DCM. Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude compound 8. LCMS (m/z): 557.40 (M+1).
To a stirred solution of compound 8 (1 eq) in DMF, triethylamine (2 eq) was added at room temperature and stirred at same temperature for 10 min followed by the addition of corresponding amine (2 eq) and stirred at 90° C. for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography/preparative HPLC to afford the following compounds.
N-(4-chlorophenyl)-6-(1-methyl-3-(3-(pyrrolidin-1-yl)propyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, MeOD) δ: 8.10-8.04 (m, 1H), 8.02-7.95 (m, 1H), 7.65 (s, 2H), 7.55-7.42 (m, 3H), 6.61 (s, 1H), 4.14 (s, 3H), 3.94-3.81 (m, 8H), 3.69 (dd, J=11.9, 5.4 Hz, 2H), 3.38-3.31 (m, 2H), 3.20-3.05 (m, 4H), 2.36-2.09 (m, 4H), 2.12-1.99 (m, 2H); HPLC purity: 96.27%; LCMS Calculated for C29H34ClN7O (free base): 531.25; observed: 532.45 (M+1).
N-(4-chlorophenyl)-6-(1-methyl-3-(3-morpholinopropyl)-1H-indazol-6-yl)-2-morpholino pyrimidin-4-amine: 1H NMR (400 MHz, MeOD) δ: 8.10-7.94 (m, 2H), 7.65 (d, J=7.9 Hz, 2H), 7.56-7.49 (m, 1H), 7.45 (dd, J=9.2, 2.7 Hz, 2H), 6.60 (d, J=2.8 Hz, 1H), 4.19-4.03 (m, 5H), 3.93-3.74 (m, 10H), 3.58-3.50 (m, 2H), 3.38-3.25 (m, 2H), 3.24-3.11 (m, 4H), 2.33 (ddd, J=12.0, 9.6, 6.2 Hz, 2H); HPLC purity: 98.58%; LCMS Calculated for C29H34ClN7O2 (free base): 547.25; observed: 548.45 (M+1).
To a stirred solution of compound 1 (0.2 g, 1 eq) in DMF (5 mL), K2CO3 (0.087 g, 1.5 eq) and phthalimide (0.092 g, 1.5 eq) were added and stirred at 80° C. for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water extracted with ethyl acetate (2×25 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude product 2. LCMS (m/z): 608.50 (M+1).
To a stirred solution of compound 2 (0.3 g, 1 eq) in ethanol (10 mL), hydrazine monohydrate (0.049 g, 2 eq) was added and heated to reflux for 1.5 h. The reaction mixture was cooled to room temperature followed by the addition of 6 N HCl (5 mL) and heated to reflux for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with 2N NaOH solution and extracted with 10% methanol in dichloromethane (3×25 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by preparative HPLC to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 9.56 (s, 1H), 8.15 (s, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.75-7.67 (m, 3H), 7.41-7.32 (m, 2H), 6.69 (s, 1H), 4.04 (s, 3H), 3.83-3.68 (m, 8H), 2.94 (t, J=7.6 Hz, 2H), 2.60 (t, J=6.8 Hz, 2H), 1.82-1.76 (m, 2H); HPLC purity: 96.71%; LCMS Calculated for C25H28ClN7O: 477.20; observed: 478.35 (M+1).
To a stirred solution of 4-bromo-2-fluorobenzoic acid 1 (1 eq) in dichloromethane 40 mL amine 2 (1.2 eq), HATU (1.2 eq) and diisopropyl ethyl amine (3 eq) were added and stirred at room temperature for 12 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layers were washed with brine, dried over sodium sulfate, concentrated and purified to provide the following intermediates 3.
To a stirred solution of compound 3 (1 eq) in toluene was added Lawesson's reagent (1 eq) and the reaction mixture was refluxed for 15 h. After completion of the reaction the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic fractions were washed with brine, dried over sodium sulfate and concentrated and purified by column chromatography to obtain the following intermediates 4.
Compound 4 was dissolved in a 1:1 mixture of ethanol and methyl hydrazine and heated at 120° C. for 4 h. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated in vacuo, washed with water and extracted with ethyl acetate. The combined ethyl acetate fraction were dried, concentrated and purified by column chromatography to obtain the following intermediates 5.
Step 4: The following intermediates were prepared using the General procedure for Boronate ester preparation described above.
Step 5: The following compounds were prepared using the General Procedure for Suzuki Coupling described above.
N1-(6-(6-((4-chlorophenyl)amino)-2-morpholinopyrimidin-4-yl)-1-methyl-1H-indazol-3-yl)-N2,N2-dimethylethane-1,2-diamine: 1H NMR (400 MHz, DMSO-d6) δ: 9.53 (s, 1H), 7.91 (d, J=1.2 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.76-7.67 (m, 2H), 7.52 (dd, J=8.5, 1.4 Hz, 1H), 7.41-7.32 (m, 2H), 6.66 (s, 1H), 5.97 (t, J=5.7 Hz, 1H), 3.85(s, 3H), 3.83-3.68 (m, 8H), 3.39-3.29 (m, 2H), 2.53-2.43 (m, 2H), 2.20 (s, 6H); HPLC purity: 95.32%; LCMS Calculated for C26H31ClN8O: 506.23; Observed: 507.40 (M+1).
6-(6-((4-chlorophenyl)amino)-2-morpholinopyrimidin-4-yl)-1-methyl-N-(2-(pyrrolidin-1-yl)ethyl)-1H-indazol-3-amine: 1H NMR (400 MHz, DMSO-d6) δ: 9.52 (s, 1H), 7.91 (s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.75-7.67 (m, 2H), 7.52 (d, J=8.4 Hz, 1H), 7.41-7.31 (m, 2H), 6.65 (s, 1H), 6.03 (t, J=5.8 Hz, 1H), 3.81 (s,3H), 3.78-3.68 (m, 8H), 3.37 (q, J=6.5 Hz, 2H), 2.68 (t, J=6.8 Hz, 2H), 2.49-2.39 (m, 4H), 1.73-1.64 (m, 4H); HPLC purity: 99.1%; LCMS Calculated for C28H33ClN8O: 532.25; Observed: 533.45 (M+1).
6-(6-((4-chlorophenyl)amino)-2-morpholinopyrimidin-4-yl)-1-methyl-N-(3-(pyrrolidin-1-yl)propyl)-1H-indazol-3-amine: 1H NMR (400 MHz, MeOD) δ: 7.95 (s, 1H), 7.73-7.56 (m, 4H), 7.34-7.25 (m, 2H), 6.58 (s, 1H), 3.95-3.76 (m, 11H), 3.54-3.42 (m, 2H), 3.35-3.22 (m, 6H), 2.20-2.07 (m, 6H); HPLC purity: 95.47%; LCMS Calculated for C29H35ClN8O (free base): 546.26; Observed: 547.45 (M+1).
6-(6-((4-chlorophenyl)amino)-2-morpholinopyrimidin-4-yl)-1-methyl-N-(3-morpholinopropyl)-1H-indazol-3-amine: 1H NMR (400 MHz, DMSO-d6; D2O exchange) δ: 7.91-7.78 (m, 2H), 7.72-7.62 (m, 2H), 7.47-7.32 (m, 3H), 3.95 (d, J=12.7 Hz, 2H), 3.80-3.60 (m, 13H), 3.41 (d, J=12.3 Hz, 2H), 3.31 (t, J=6.6 Hz, 2H), 3.23-3.15 (m, 2H), 3.11-2.99 (m, 2H), 2.02-1.98 (m, 2H); HPLC purity: 95.95%; LCMS Calculated for C29H35ClN8O2 (free base): 562.26; Observed: 563.45 (M+1).
6-(6-((4-chlorophenyl)amino)-2-morpholinopyrimidin-4-yl)-1-methyl-N-(4-(pyrrolidin-1-yl)butyl)-1H-indazol-3-amine: 1H NMR (400 MHz, DMSO-d6) δ: 9.52 (s, 1H), 7.90 (s, 1H), 7.81-7.67 (m, 3H), 7.51 (d, J=8.5 Hz, 1H), 7.41-7.33 (m, 2H), 6.65 (s, 1H), 6.08 (t, J=5.7 Hz, 1H), 3.83-3.68 (m, 11H), 3.24 (q, J=6.5 Hz, 2H), 2.48-2.36 (m, 6H), 1.72-1.48 (m, 8H); HPLC purity: 99.3%; LCMS Calculated for C30H37ClN8O: 560.28; Observed: 561.50 (M+1).
6-(6-((4-chlorophenyl)amino)-2-morpholinopyrimidin-4-yl)-1-methyl-N-(2-morpholinoethyl)-1H-indazol-3-amine: 1H NMR (400 MHz, CD3OD) δ: 7.95 (s, 1H), 7.74-7.57 (m, 4H), 7.36-7.25 (m, 2H), 6.58 (s, 1H), 3.94-3.76 (m, 16H), 3.66 (t, J=5.9 Hz, 2H), 3.15 (d, J=9.4 Hz, 2H), 3.04 (s, 3H); HPLC purity: 98.74%; LCMS Calculated for C28H33ClN8O2: 548.24; Observed: 549.50 (M+1).
N-(4-chlorophenyl)-6-(1-methyl-3-(pyrrolidin-1-yl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 10.20 (s, 1H), 7.96-7.60 (m, 2H), 7.72(d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 3H), 6.71 (s, 1H), 3.87 (s, 3H), 3.81-3.73 (m, 8H), 3.58 (q, J=6.6 Hz, 4H), 2.02-1.92 (m, 4H); HPLC purity: 97.70%; LCMS Calculated for C26H28ClN7O (free base): 489.20; Observed: 490 (M+1).
N-(4-chlorophenyl)-6-(1-methyl-3-morpholino-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 9.56 (s, 1H), 8.07 (s, 1H), 7.88 (d, J=8.6 Hz, 1H), 7.75-7.67 (m, 2H), 7.58 (dd, J=8.6, 1.5 Hz, 1H), 7.41-7.32 (m, 2H), 6.68 (s, 1H), 3.93 (s, 3H), 3.76 (ddd, J=29.1, 6.9, 4.4 Hz, 12H), 3.31-3.22 (m, 4H); HPLC purity: 97.52%; LCMS Calculated for C26H28ClN7O2: 505.20; Observed: 506.35 (M+1).
N-(4-chlorophenyl)-6-(1-methyl-3-(4-methylpiperazin-1-yl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 10.66 (bs, 1H), 9.85 (s, 1H), 8.10 (s, 1H), 7.94 (d, J=8.6 Hz, 1H), 7.77-7.66 (m, 2H), 7.53 (dd, J=41.0, 8.7 Hz, 1H), 7.39 (d, J=8.7 Hz, 2H), 6.72 (s, 1H), 3.96 (d, J=7.8 Hz, 5H), 3.86-3.69 (m, 8H), 3.55-3.48 (m, 2H), 3.27 (t, J=8.7 Hz, 4H), 2.85 (d, J=4.5 Hz, 3H); HPLC purity: 93.58%; LCMS Calculated for C27H31ClN8O: 518.23; Observed: 519.30 (M+1).
To a stirred solution of sodium nitrite (8.44 g, 4.8 eq) in water:HCl (45:1; 460 mL), a solution of 6-bromo-1H-indole (5 g, 1 eq) in acetone (125 mL) was added and stirred at room temperature for 19 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was extracted diethyl ether and pentane. Combined organic extracts were washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 20% EtOAc-hexane to afford the title compound 2. LCMS (m/z): 224.00 (M+).
To a stirred solution of 6-bromo-1H-indazole-3-carbaldehyde 2 (2 g, 1 eq) in DMF (15 mL), NaH (0.53 g, 1.5 eq) was added and stirred at room temperature for 10 min followed by the addition of methyl iodide(1.52 g, 2 eq). The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude compound was purified by column chromatography on silica gel 100-200 mesh using 10% EtOAc-hexane to afford the title compound 3. LCMS (m/z): 240.90 (M+2).
To a stirred solution of carbonyl compound (1 eq), and corresponding amine (1 eq) in MeOH was added acetic acid (catalytic) and stirred at room temperature for 30 min. Sodium cyanoborohydride (3 eq) was added to the reaction mixture and stirred for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted using 15% MeOH:DCM. Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product has been purified by column chromatography on silica gel to afford the following intermediates.
Step 4: The following intermediates were prepared using the General Procedure for Boronate Ester Formation described above.
Step 5: The following compounds were prepared using the General procedure for Suzuki Coupling described above.
N-(4-chlorophenyl)-6-(1-methyl-3-(pyrrolidin-1-ylmethyl)-1H-indazol-6-yl)-2-morpholino pyrimidin-4-amine: 1H NMR (400 MHz, MeOD) δ: 8.24-8.18 (m, 1H), 8.13 (d, J=8.6 Hz, 1H), 7.70-7.61 (m, 3H), 7.50-7.41 (m, 2H), 6.62 (d, J=7.8 Hz, 1H), 4.84 (d, J=13.4 Hz, 2H), 4.25 (s, 3H), 3.94-3.81 (m, 8H), 3.74-3.63 (m, 2H), 3.42-3.32 (m, 2H), 2.29-2.13 (m, 2H), 2.08 (ddd, J=12.7, 8.3, 4.4 Hz, 2H); HPLC purity: 98.04%; LCMS Calculated for C27H30ClN7O (free base): 503.22; observed: 504.40 (M+1).
N-(4-chlorophenyl)-6-(1-methyl-3-(morpholinomethyl)-1H-indazol-6-yl)-2-morpholino pyrimidin-4-amine: 1H NMR (400 MHz, MeOD) δ: 8.22 (s, 1H), 8.15 (d, J=8.5 Hz, 1H), 7.70-7.62 (m, 3H), 7.49-7.40 (m, 2H), 6.62 (s, 1H), 4.26 (s, 3H), 4.17-4.04 (m, 2H), 3.94-3.74 (m, 10H), 3.64-3.55 (m, 2H), 3.35-3.24 (m, 4H); HPLC purity: 92.69%; LCMS Calculated for C27H30ClN7O2 (free base): 519.21; observed: 520.40 (M+1).
N-(4-chlorophenyl)-6-(1-methyl-3-((4-methylpiperazin-1-yl)methyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, MeOD) δ: 8.18 (d, J=9.1 Hz, 2H), 7.69-7.57 (m, 3H), 7.46 (d, J=8.1 Hz, 2H),6.61 (s,1H), 4.63 (s, 2H), 4.23 (s, 3H), 3.93-3.83 (m, 8H), 3.62-3.50 (m, 8H), 2.97 (s, 3H); HPLC purity: 96.2%; LCMS Calculated for C28H33ClN8O (free base): 532.25; observed: 533.45 (M+1).
The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using chloro compound 1 and Boronate ester 2. 1H NMR (400 MHz, DMSO-d6) δ: 10.23-10.15 (m, 1H), 8.25 (s, 1H), 8.11 (s, 1H), 7.89 (dd, J=12.5, 8.6 Hz, 3H), 7.76 (t, J=8.8 Hz, 3H), 6.81 (s, 1H), 4.13 (s, 3H), 3.82-3.74 (m, 8H); HPLC purity: 97.77%; LCMS Calculated for C23H21N7O: 411.18; Observed: 412.25 (M+1).
A stirred solution of 6-bromo-3-iodo-1-methyl-1H-indazole 1 (2 g, 1 eq), CuI (0.112 g, 0.1 eq) and Pd(PPh3)2Cl2 (0.416 g, 0.1 eq) in triethylamine:DMF (1:1; 20 mL) and stirred at room temperature for 15 min followed by the addition of but-3-yn-1-ol (0.415 g, 1 eq) and stirred for 16 h at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel 100-200 mesh using 60% EtOAc-hexane to afford the title compound 2. LCMS (m/z): 279.10 (M+1).
To a stirred solution of compound 2 (0.18 g, 1 eq), in ethanol (20 mL), PtO2 (0.018 g) was added and stirred at room temperature under hydrogen atmosphere (balloon pressure) for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure to afford the title compound 3. LCMS (m/z): 283.10 (M+1).
The title compound (crude product) has been synthesized by following the General Procedure for Boronate Ester Preparation described above using bromo compound 3 and Bis (pinacolato) diboron. LCMS (m/z): 331.25 (M+1).
The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using compound 5 and Boronate ester 4. 1H NMR (400 MHz, DMSO-d6) δ: 9.55 (s, 1H), 8.15 (s, 1H), 7.81 (d, J=8.5 Hz, 1H), 7.71 (td, J=6.7, 3.4 Hz, 3H), 7.44-7.30 (m, 2H), 6.69 (s, 1H), 4.37 (t, J=5.2 Hz, 1H), 4.04 (s, 3H), 3.83-3.68 (m, 8H), 3.43 (td, J=6.5, 5.1 Hz, 2H), 2.91 (t, J=7.5 Hz, 2H), 1.83-1.70 (m, 2H), 1.56-1.44 (m, 2H); HPLC purity: 97.74%; LCMS Calculated for C26H29ClN6O2: 492.20; Observed: 493.40 (M+1).
Methyl 4-((6-(1-cyclobutyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)benzoate: 1H NMR (400 MHz, DMSO-d6) δ: 9.85 (s, 1H), 8.28 (s, 1H), 8.18 (s, 1H), 7.94 (d, J=8.5 Hz, 2H), 7.85 (d, J=8.4 Hz, 3H), 7.76 (d, J=8.5 Hz, 1H), 6.77 (s, 1H), 5.42-5.38 (m, 1H), 3.86-3.71 (m, 11H), 2.74-2.59 (m, 2H), 2.50-2.40 (m, 2H), 1.91 (tt, J=10.2, 5.7 Hz, 2H); HPLC purity: 97.34%; LCMS Calculated for C27H28N6O3: 484.22; Observed: 485.30 (M+1).
4-((6-(1-cyclobutyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl) amino) benzoic acid: 1H NMR (400 MHz, DMSO-d6) δ: 9.80 (s, 1H), 8.28 (s, 1H), 8.17 (s, 1H), 7.95-7.73 (m, 6H), 6.78 (s, 1H), 5.42-5.38 (m, 1H), 3.82-3.74 (m, 8H), 2.74-2.59 (m, 4H), 2.01-1.85 (m, 2H); HPLC purity: 96.66%; LCMS Calculated for C26H26N6O3: 470.21; Observed: 471.35(M+1).
To a stirred solution of 4-nitrobenzene-1-sulfonyl chloride 1 (1 g, 1 eq) in THF (10 mL), methyl amine 2M solution in THF (4.5 mL, 2 eq) was added at 0° C. and stirred at room temperature for 6 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 20% EtOAc-hexane to afford the title compound 2. 1H NMR (400 MHz, DMSO-d6) δ: 8.43 (d, J=9.2 Hz, 2H), 8.02 (d, J=9.2 Hz, 2H), 7.85 (s, 1H), 2.47 (d, J=3.6 Hz, 3H).
To a stirred solution of compound 2 (0.8 g, 1 eq) in methanol (20 mL), Raney nickel (1 g) was added and stirred at room temperature for 18 h under hydrogen atmosphere. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered and evaporated under reduced pressure to afford the title compound 3. LCMS (m/z): 187.00 (M+1).
The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using chloro compound 4 and 4-amino-N-methyl benzenesulfonamide 3. 1H NMR (400 MHz, DMSO-d6) δ: 10.03 (s, 1H), 8.25 (q, J=1.0 Hz, 1H), 8.11 (d, J=1.0 Hz, 1H), 7.96-7.84 (m, 3H), 7.75 (td, J=7.7, 7.0, 1.6 Hz, 3H), 7.26 (s, 1H), 6.79 (s, 1H), 4.14 (s, 3H), 3.84-3.75 (m, 8H), 2.41 (d, J=4.1 Hz, 3H); HPLC purity: 96.2%; LCMS Calculated for C23H25N7O3S: 479.17; Observed: 480.25 (M+1).
A stirred solution of 4-nitrobenzamide 1 (1 g, 1 eq), DMFDMA (3 mL) in DMF (1 mL) was heated at 120° C. for 1.5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice water and filtered. The residue was washed with water and dried under vacuum to afford the title compound 2. LCMS (m/z): 222.00 (M+1).
To a stirred solution of compound 2 (2.8 g, 1 eq) in acetic acid (10 mL), hydrazine hydrate (0.3 mL, 1.1 eq) was added and stirred at 90° C. for 1.5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 3. LCMS (m/z): 190.95 (M+1).
To a stirred solution of compound 3 (0.05 g, 1 eq) in ethanol (5 mL), iron powder (0.074 g, 5 eq), water (3 mL) and ammonium chloride (0.069 g, 5 eq) were added slowly. The reaction mixture was heated to reflux for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and washed with brine. Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 4. LCMS (m/z): 161.00 (M+1).
The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using chloro compound 5 and 4-(4H-1,2,4-triazol-3-yl)aniline 4. 1 NMR (400 MHz, DMSO-d6) δ: 10.28 (s, 1H), 8.57 (s, 1H), 8.24 (s, 1H), 8.15 (s, 1H), 8.07-8.00 (m, 2H), 7.94-7.82 (m, 3H), 7.69 (d, J=8.3 Hz, 1H), 6.79 (s, 1H), 4.15 (s, 3H), 3.86-3.76 (m, 8H); HPLC purity: 99.85%; LCMS Calculated for C24H23N9O: 453.20; Observed: 454.35 (M+1).
To a stirred solution of compound 1 (2 g, 1 eq) in ethanol (20 mL), hydrazine monohydrate (1.54 mL, 3 eq) was added and heated to reflux for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered and residue was washed with ethanol and dried under vacuum to afford title compound 2. 1H NMR (400 MHz, DMSO-d6) δ: 10.09 (s, 1H), 8.26 (d, J=8.8 Hz, 2H), 8.01 (d, J=9.2 Hz, 2H), 4.60 (s, 2H).
To a stirred solution of compound 2 (0.5 g, 1 eq) in pyridine (5 mL), thioacetamide 3 (0.31 g, 1.5 eq) was added and heated in microwave at 150° C. for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with 1 N HCl and filtered. The residue was washed with diethyl ether to afford the title compound 4. LCMS (m/z): 205.15 (M+1).
To a stirred solution of compound 4 (0.3 g, 1 eq), in ethanol: water(1:1; 20 mL), Fe powder (0.288 g, 3.5 eq) and ammonium chloride (0.272 g,3.5 eq) were added and heated to reflux for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated to dryness. The residue was diluted with water and extracted with ethyl acetate (3×25 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 5. LCMS (m/z): 175.00 (M+1).
To a stirred solution of compound 6 (0.2 g, 1 eq), compound 5 (0.158 g, 1.5 eq) in IPA (2 mL), Conc. HCl (1 mL) was added and heated to reflux for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with aqueous sodium hydrogen carbonate (saturated) solution and extracted with ethyl acetate (3×25 mL).Combined organic extracts were washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 80% EtOAc-hexane to enrich the purity and further purified by preparative HPLC to afford the desired product. 1H NMR (400 MHz, DMSO-d6) δ: 10.14 (s, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 8.01 (d, J=8.3 Hz, 2H), 7.87 (d, J=7.9 Hz, 3H), 7.72 (d, J=8.5 Hz, 1H), 6.80 (s, 1H), 4.14 (s, 3H), 3.84-3.75 (m, 8H), 2.33 (s, 3H); HPLC purity: 99.6%; LCMS Calculated for C25H25N9O (free base): 467.22; observed: 468.35 (M+1).
The following compounds were prepared using the above procedure.
6-(1-methyl-1H-indazol-6-yl)-2-morpholino-N-phenylpyrimidin-4-amine: The title compound has been synthesized by the general procedure described above (IPA, Conc. HCl) by using compound 1 and aniline. 1H NMR (400 MHz, DMSO-d6) δ: 8.22 (s, 1H), 8.15 (s, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.67 (dd, J=24.2, 8.0 Hz, 3H), 7.38 (t, J=7.8 Hz, 2H), 7.08 (t, J=7.3 Hz, 1H), 6.74 (s, 1H), 4.14 (s, 3H), 3.84-3.74 (m, 8H); HPLC purity: 98.68%; LCMS Calculated for C22H22N6O (free base): 386.19; Observed: 387.25 (M+1).
N-(4-methoxyphenyl)-6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using chloro compound 1 and 4-methoxyaniline. 1H NMR (400 MHz, DMSO-d6) δ: 8.17 (d, J=19.4 Hz, 2H), 7.91 (d, J=8.4 Hz, 1H), 7.58 (d, J=8.5 Hz, 3H), 6.97 (d, J=8.4 Hz, 2H), 6.64 (s, 1H), 4.14 (s, 3H), 3.85-3.70 (m, 11H); HPLC purity: 95.75%; LCMS Calculated for C23H24N6O2 (free base): 416.20; Observed: 417.30 (M+1).
1-(4-((6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)phenyl)ethan-1-one: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using chloro compound 1 and 1-(4-aminophenyl)ethan-1-one. 1H NMR (400 MHz, DMSO-d6) δ: 10.02 (s, 1H), 8.24 (d, J=1.4 Hz, 1H), 8.11 (d, J=0.9 Hz, 1H), 8.00-7.92 (m, 2H), 7.91-7.82 (m, 3H), 7.75 (dd, J=8.5, 1.4 Hz, 1H), 6.80 (s, 1H), 4.14 (s, 3H), 3.84-3.75 (m, 8H), 2.53 (s, 3H); HPLC purity: 95.51%; LCMS Calculated for C24H24N6O2 (free base): 428.20; Observed: 429.00 (M+1).
N-(4-((6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)phenyl)acetamide: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using chloro compound 1 and N-(4-aminophenyl) acetamide. 1H NMR (400 MHz, DMSO-d6) δ: 10.57 (s, 1H), 10.06 (s, 1H), 8.25-8.14 (m, 2H), 7.93 (d, J=8.4 Hz, 1H), 7.62-7.54 (m, 5H), 6.73 (s, 1H), 4.14 (s, 3H), 3.83-3.75 (m, 8H), 2.05 (s, 3H); HPLC purity: 95.12%; LCMS Calculated for C24H25N7O2 (free base): 443.21; Observed: 444.40 (M+1).
N-(4-((6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl) amino) phenyl) methane sulfonamide: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using chloro compound 1 and N-(4-aminophenyl) methanesulfonamide. 1H NMR (400 MHz, DMSO-d6) δ: 9.49 (s, 1H), 9.43 (s, 1H), 8.22 (s, 1H), 8.09 (s, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.75 (dd, J=8.5, 1.4 Hz, 1H), 7.70-7.62 (m, 2H), 7.23-7.14 (m, 2H), 6.69 (s, 1H), 4.12 (s, 3H), 3.82-3.72 (m, 8H), 2.94 (s, 3H); HPLC purity: 98.54%; LCMS Calculated for C23H25N7O3S (free base): 479.17; Observed: 480.25 (M+1).
4-((6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)benzenesulfonamide: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using chloro compound 1 and 4-aminobenzenesulfonamide. 1H NMR (400 MHz, DMSO-d6) δ: 10.42 (s, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 7.93-7.86 (m, 3H), 7.81 (d, J=8.5 Hz, 2H), 7.69 (d, J=8.4 Hz, 1H), 7.24 (s, 2H), 6.84 (s, 1H), 4.14 (s, 3H), 3.88-3.75 (m, 8H); HPLC purity: 99.61%; LCMS Calculated for C22H23N7O3S (free base): 465.16; Observed: 466.25 (M+1).
6-(1-methyl-1H-indazol-6-yl)-N-(4-(methylsulfonyl)phenyl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using chloro compound 1 and 4-(methylsulfonyl)aniline. 1H NMR (400 MHz, DMSO-d6) δ: 10.27 (s, 1H), 8.25 (s, 1H), 8.12 (s, 1H), 7.98 (d, J=8.6 Hz, 2H), 7.88 (d, J=8.4 Hz, 3H), 7.74 (d, J=8.5 Hz, 1H), 6.83 (s, 1H), 4.14 (s, 3H), 3.84-3.75 (m, 8H), 3.17 (s, 3H); HPLC purity: 98.67%; LCMS Calculated for C23H24N6O3S (free base): 464.16; Observed: 465.30 (M+1).
6-(1-methyl-1H-indazol-6-yl)-N-(4-(methylsulfinyl)phenyl)-2-morpholinopyrimidin-4-amine:The title compound has been synthesized by following the General procedure for Buchwald Coupling described above using chloro compound 1 and 4-(methylsulfinyl)aniline. 1H NMR (400 MHz, DMSO-d6) δ: 10.05 (s, 1H), 8.24 (d, J=1.3 Hz, 1H), 8.12 (d, J=1.0 Hz, 1H), 7.96-7.85 (m, 3H), 7.70 (dd, J=23.8, 8.6 Hz, 3H), 6.78 (s, 1H), 4.14 (s, 3H), 3.84-3.75 (m, 8H), 2.73 (s, 3H); HPLC purity: 98.54%; LCMS Calculated for C23H24N6O2S (free base): 448.17; Observed: 449.30 (M+1).
To a mixture of acid 1 (1 eq) and amine 2 (1.5 eq) in DMF, DIPEA (2 eq) was added and stirred at room temperature for 10 min. HATU (1.2 eq) was added slowly and stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, water was added and extracted with ethyl acetate. Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the desired product 3.
The intermediates listed in the following table were prepared in a similar manner starting with appropriate acid 1 and compound 2.
To a stirred solution of compound 3 (1 eq) in P2O5 and methane sulfonic acid (1:10) was heated at 130° C. for 5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 4.
The intermediates 4 listed in the following table were prepared in a similar manner.
To a stirred solution of compound 4 (1 eq) in ethanol, iron powder (5 eq), water and ammonium chloride (5 eq) were added slowly. The reaction mixture was heated to reflux for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 5.
The intermediates listed in the following table were prepared in a similar manner starting with appropriate compound 4.
6-(1-methyl-1H-indazol-6-yl)-2-morpholino-N-(3-(oxazol-2-yl)phenyl)pyrimidin-4-amine:The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using chloro compound 6 and corresponding amine 5. 1H NMR (400 MHz, DMSO-d6) δ: 10.24 (s, 1H), 8.88 (s, 1H), 8.25 (d, J=8.6 Hz, 2H), 8.13 (s, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.74-7.59 (m, 3H), 7.50 (t, J=7.9 Hz, 1H), 7.41 (s, 1H), 6.77 (s, 1H), 4.14 (s, 3H), 3.91-3.78 (m, 8H); HPLC purity: 99.64%; LCMS Calculated for C25H23N7O2(free base): 453.19; Observed: 454.35 (M+1).
6-(1-methyl-1H-indazol-6-yl)-2-morpholino-N-(4-(oxazol-2-yl)phenyl)pyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using chloro compound 6 and corresponding amine 5. 1H NMR (400 MHz, DMSO-d6) δ: 9.77 (s, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 8.10 (s, 1H), 7.95 (d, J=8.5 Hz, 2H), 7.91-7.82 (m, 3H), 7.78 (d, J=8.6 Hz, 1H), 7.34 (s, 1H), 6.77 (s, 1H), 4.13 (s, 3H), 3.87-3.74 (m, 8H); HPLC purity: 99.29%; LCMS Calculated for C25H23N702:453.19; Observed: 454.30 (M+1).
To a stirred solution of compound 1 (1 g, 1 eq) in DMA (3 mL), DIPEA (0.645 g, 1 eq) and methyl hydrazine (0.276 g, 1.2 eq) were added and heated at 150° C. for 30 min in microwave. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (50 mL), washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 2. LCMS (m/z): 227.95 (M+2).
To a stirred solution of compound 2 (1 g, 1 eq) in methanol (15 mL), formaldehyde (1.66 mL, 5 eq) was added slowly at 0° C. and stirred at room temperature for 10 min. The reaction mixture was cooled to 0° C. and sodium cyanoborohydride (1.11 g, 4 eq) was added at same temperature. The reaction mixture was stirred at room temperature for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 3. LCMS (m/z): 256.00 (M+2).
The title compound has been synthesized by following the General Procedure for Boronate Ester Preparation described above using bromo compound 3 and Bis (pinacolato)diboron. LCMS (m/z): 302.15 (M+1).
The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using chloro compound 5 and Boronate ester 4. 1H NMR (400 MHz, DMSO-d6) δ: 10.47 (s, 1H), 8.04-7.95 (m, 2H), 7.74 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 3H), 6.76 (s, 1H), 3.92 (s, 3H), 3.86-3.74 (m, 8H), 3.04 (s, 6H); HPLC purity: 98.86%; LCMS Calculated for C24H26ClN7O (free base): 463.19; Observed: 464.25 (M+1).
To a stirred solution of compound 1 (2 g, 1 eq) in Conc. H2SO4 (8 mL), nitrating mixture (0.88 mL Conc. HNO3+2 mL Conc. H2SO4) was added at 0° C. and stirred at same temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured onto ice water and basified to pH 9 using 2N NaOH. The precipitated solid was filtered, washed with water and dried under reduced pressure to afford the title compound 2. LCMS (m/z): 190.00 (M+1).
To a stirred solution of compound 2 (0.5 g, 1 eq) in ethanol (12 mL), iron powder (0.5 g), water (6 mL) and ammonium chloride (0.5 g) were added slowly. The reaction mixture was heated to reflux for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 3. LCMS (m/z): 160.05 (M+1).
N-(4-(1H-imidazol-2-yl)phenyl)-6-(1-methyl-1H-indazol-6-yl)-2-morpholino pyrimidin-4-amine: The title compound has been synthesized by following the General procedure for Buchwald Coupling described above using corresponding chloro compound 4 and amine compound 3. 1H NMR (400 MHz, MeOD) δ: 8.15 (d, J=5.9 Hz, 2H), 8.00 (d, J=6.9 Hz, 5H), 7.68 (s, 2H), 7.55 (dd, J=8.4, 1.4 Hz, 1H), 6.72 (s, 1H), 4.20 (s, 3H), 3.99-3.84 (m, 8H); HPLC purity: 97.85%; LCMS Calculated for C25H24N80 (free base): 452.21; Observed: 453.40 (M+1).
N-(4-(1H-imidazol-2-yl)phenyl)-6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholino pyrimidin-4-amine:The title compound has been synthesized by following the General procedure for Buchwald Coupling described above using corresponding chloro compound 4 and amine compound 3. 1H NMR (400 MHz, DMSO-d6) δ: 12.35 (s, 1H), 9.56 (s, 1H), 8.16 (s, 1H), 7.92-7.85 (m, 2H), 7.83-7.68 (m, 4H), 7.10-7.02 (m, 2H), 6.73 (s, 1H), 4.04 (s, 3H), 3.83-3.74 (m, 8H), 2.57 (s, 3H); HPLC purity: 94.71%; LCMS Calculated for C26H26N8O: 466.22; Observed: 467.40 (M+1).
To a stirred solution of compound 1 (0.5 g, 1 eq) in DMF (10 mL), sodium hydride (0.095 g, 1.5 eq) was added at 0° C. and stirred for 15 min followed by the addition of methyl iodide (0.562 g, 1.5 eq) at 0° C. and stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice water and extracted with ethyl acetate (2×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 2. LCMS (m/z): 204.05 (M+1).
To a stirred solution of compound 2 (0.4 g, 1 eq) in ethanol (12 mL), iron powder (0.4 g), water (6 mL) and ammonium chloride (0.4 g) were added slowly. The reaction mixture was heated to reflux for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 3. LCMS (m/z): 173.10 (M+).
N-(4-(1-methyl-1H-imidazol-2-yl)phenyl)-6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine:The title compound has been synthesized by following the General procedure for Buchwald Coupling described above using corresponding chloro compound 4 and amine compound 3. 1H NMR (400 MHz, MeOD) δ: 8.15 (d, J=2.3 Hz, 2H), 8.03 (dd, J=20.5, 8.4 Hz, 3H), 7.91-7.83 (m, 2H), 7.68 (dd, J=13.8, 2.1 Hz, 2H), 7.55 (dd, J=8.4, 1.5 Hz, 1H), 6.75 (s, 1H), 4.20 (s, 3H), 4.01-3.85 (m, 11H); HPLC purity: 98.15%; LCMS Calculated for C26H26N8O (free base): 466.22; Observed: 467.45 (M+1).
6-(1,3-dimethyl-1H-indazol-6-yl)-N-(4-(1-methyl-1H-imidazol-2-yl)phenyl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the General procedure for Buchwald Coupling described above using corresponding chloro compound 4 and amine compound 3. 1H NMR (400 MHz, DMSO-d6, D2O exchange) δ: 8.15 (s, 1H), 7.84-7.71 (m, 4H), 7.65-7.58 (m, 2H), 7.21 (d, J=1.3 Hz, 1H), 6.96 (d, J=1.3 Hz, 1H), 6.72 (s, 1H), 4.00 (s, 3H), 3.81-3.72 (m, 11H), 2.48 (s, 3H); HPLC purity: 98.77%; LCMS Calculated for C27H28N8O: 480.24; Observed: 481.40 (M+1).
To a stirred solution of compound 1 (1 g, 1 eq) in Conc. H2SO4 (4 mL), nitrating mixture (0.44 mL Conc. HNO3+1 mL Conc. H2SO4) was added at 0° C. and stirred at same temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured onto ice water and basified to pH 9 using 2N NaOH. The precipitated solid was filtered, washed with water and dried under reduced pressure to afford the title compound 2. LCMS (m/z): 190.00 (M+1).
To a stirred solution of NaH (0.069 g, 1.2 eq) in dry THF (10 mL), compound 2 (0.45 g, 1 eq) was added at 0° C. and stirred for 30 min. followed by the addition of Boc anhydride (0.57 g, 1.1 eq) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford title compound 3.
To a stirred solution of compound 3 (0.4 g, 1 eq) in methanol (5 mL), 10% Pd/C (0.04 g) was added and stirred under hydrogen atmosphere (balloon pressure) at room temperature for 8 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite. The filtrate was evaporated under reduced pressure to afford title compound 4.
The title compound has been synthesized by following the General procedure for Buchwald Coupling described above using chloro compound 5 and amine compound 4. LCMS (m/z): 553.40 (M+1).
To a stirred solution of compound 6 (0.06 g, 1 eq) in methanol (5 mL), methanolic HCl (3 mL) was added and stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The crude product was purified by washing with diethyl ether to afford title compound as HCl salt. HPLC purity: 99.04%; LCMS Calculated for C25H24N80 (free base): 452.21; Observed: 453.30 (M+1).
Step 1: Synthesis of 1-methyl-4-(4-nitrophenyl)-1H-imidazole (2)
To a stirred solution of compound 1 (1 g, 1 eq) in DMF (15 mL), sodium hydride(0.315 g, 1.5 eq) was added at 0° C. and stirred for 15 min followed by the addition of methyl iodide (1.12 g, 1.5 eq) at 0° C. and stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice water and extracted with ethyl acetate (2×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 2. LCMS (m/z): 204.10 (M+1).
To a stirred solution of compound 2 (0.7 g, 1 eq) in ethanol (10 mL), iron powder (0.731 g, 4 eq), water (5 mL) and ammonium chloride (0.731 g, 4 eq) were added slowly. The reaction mixture was heated to reflux for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was dissolved in 20% methanol in dichloromethane, filtered through celite and evaporated under reduced pressure to afford the title compound 3. LCMS (m/z): 174.05 (M+1).
N-(4-(1-methyl-1H-imidazol-4-yl)phenyl)-6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the General procedure for Buchwald Coupling described above using corresponding chloro compound 4 and amine compound 3. 1H NMR (400 MHz, DMSO-d6) δ: 9.43 (s, 1H), 8.23 (s, 1H), 8.09 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.80-7.63 (m, 5H), 7.60 (s, 1H), 7.50 (s, 1H), 6.71 (s, 1H), 4.13 (s, 3H), 3.82-3.79 (m, 8H), 3.67 (s, 3H); HPLC purity: 97.07%; LCMS Calculated for C26H26N80: 466.22; Observed: 467.35 (M+1).
Synthesis of 6-(1,3-dimethyl-1H-indazol-6-yl)-N-(4-(1-methyl-1H-imidazol-4-yl)phenyl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the General procedure for Buchwald Coupling described above using corresponding chloro compound 4 and amine compound 3. Structure has been confirmed by NOE. 1H NMR (400 MHz, MeOD) δ: 9.01 (s, 1H), 8.05 (s, 1H), 7.97-7.77 (m, 6H), 7.50 (d, J=8.4 Hz, 1H), 6.68 (s, 1H), 4.11 (s, 3H), 4.01 (s, 3H), 3.97-3.83 (m, 8H), 2.60 (s, 3H); HPLC purity: 98.4%; LCMS Calculated for C27H28N80 (free base): 480.24; Observed: 481.40 (M+1).
To a stirred solution of compound 1 (0.5 g, 1 eq) in ethanol (10 mL), iron powder (0.65 g, 4 eq), water (5 mL) and ammonium chloride (0.65 g. 4 eq) were added slowly. The reaction mixture was heated to reflux for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 2. LCMS (m/z): 133.95 (M+1).
The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using chloro compound 3 and amino compound 2. 1H NMR (400 MHz, DMSO-d6) δ: 12.96 (s, 1H), 9.37 (s, 1H), 8.22 (s, 1H), 8.12-8.00 (m, 3H), 7.83 (d, J=8.5 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.60 (s, 2H), 6.68 (s, 1H), 4.12 (s, 3H), 3.82-3.72 (m, 8H); HPLC purity: 99.65%; LCMS Calculated for C23H22N8O: 426.19; Observed: 427.25 (M+1).
To a stirred solution of compound 1 (2 g, 1 eq) in ethanol (20 mL), iron powder (3.4 g, 5 eq), water (10 mL) and ammonium chloride (3.18 g. 5 eq) were added slowly. The reaction mixture was heated to reflux for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 2. LCMS (m/z): 134.05 (M+1).
N-(6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1H-indazol-6-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 3 and amine 2. 41 NMR (400 MHz, DMSO-d6) δ: 10.97 (s, 1H), 8.27-8.13 (m, 3H), 8.04 (s, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 6.90 (s, 1H), 4.15 (s, 3H), 3.83-3.75 (m, 8H); HPLC purity: 99.44%; LCMS Calculated for C23H22N8O (free base): 426.19; Observed: 427.35 (M+1).
N-(6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1H-indazol-6-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 3 and amine 2. 1H NMR (400 MHz, MeOD) δ: 8.24 (s, 1H), 8.08 (s, 1H), 8.00 (s, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.20 (d, J=8.5 Hz, 1H), 6.67 (s, 1H), 4.08 (s, 3H), 3.98-3.86 (m, 8H), 2.58 (s, 3H); HPLC purity: 97.87%; LCMS Calculated for C24H24N8O: 440.21; Observed: 441.40 (M+1).
The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 1 and 4-cyano aniline 2. LCMS (m/z): 412.30 (M+1).
The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 1 and 4-cyano aniline 2. LCMS (m/z): 426.25 (M+1).
To a stirred solution of corresponding compound 3 (0.1 g, 1 eq) in ethanol (1 mL), hydroxyl amine hydrochloride (0.037g, 2.2 eq) and triethylamine (0.056 g, 2.3 eq) were added at room temperature. The reaction mixture was heated to reflux for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate (2×25 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by recrystallization using chloroform and hexane to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 9.56 (s, 1H), 9.47 (s, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.80-7.60 (m, 5H), 6.74 (s, 1H), 5.72 (s, 2H), 4.13 (s, 3H), 3.86-3.70 (m, 8H); HPLC purity: 96.57%; LCMS Calculated for C23H24N8O2: 444.20; Observed: 445.25 (M+1).
The title compound has been synthesized by following the above procedure. LCMS (m/z): 459.0 (M+1).
N-(4-(1,2,4-oxadiazol-3-yl)phenyl)-6-(1-methyl-1H-indazol-6-yl)-2-morpholino pyrimidin-4-amine: A stirred solution of corresponding compound 4 (0.4 g, 1 eq) in triethyl orthoformate (10 mL) was heated at 150° C. for 15 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. The organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 5% methanol in dichloromethane to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 9.85 (s, 1H), 9.65 (d, J=3.0 Hz, 1H), 8.25 (s, 1H), 8.11 (d, J=2.9 Hz, 1H), 8.02 (dd, J=8.8, 3.0 Hz, 2H), 7.89 (ddd, J=22.2, 8.6, 2.9 Hz, 3H), 7.82-7.74 (m, 1H), 6.78 (d, J=2.9 Hz, 1H), 4.14 (d, J=3.1 Hz, 3H), 3.88-3.71 (m, 8H); HPLC purity: 93.32%; LCMS Calculated for C24H22N8O2: 454.19; Observed: 455.30 (M+1).
N-(4-(1,2,4-oxadiazol-3-yl)phenyl)-6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the above procedure. 1H NMR (400 MHz, DMSO-d6) δ: 10.11 (s, 1H), 9.66 (s, 1H), 8.17 (s, 1H), 8.03 (d, J=8.4 Hz, 2H), 7.92 (d, J=8.4 Hz, 2H), 7.82 (d, J=8.4 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 6.79 (s, 1H), 4.05 (s, 3H), 3.84-3.75 (m, 8H), 2.58 (s, 3H); HPLC purity: 96.64%; LCMS Calculated for C25H24N8O2 (free base): 468.20; Observed: 469.30 (M+1).
To a stirred solution of compound 1 (0.5 g, 1 eq) in ethanol (10 mL), hydroxyl amine hydrochloride (0.516 g, 2.2 eq) was added followed by the addition of triethylamine (1 mL, 2.3 eq). The reaction mixture was heated to reflux for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was diluted with water and extracted with ethyl acetate (2×25 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was crystallized using chloroform and hexane to afford the title compound 2. LCMS (m/z): 181.90 (M+1).
To a stirred solution of compound 2 (0.2 g, 1 eq) in dichloromethane (10 mL), triethylamine (0.8 mL, 2.6 eq) was added followed by the addition of acetyl chloride (0.2 mL, 1.3 eq) at 0° C. and stirred for 1 h at same temperature. The reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (2×25 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was recrystallized from ethanol to afford the title compound 3. LCMS (m/z): 224.05 (M+1).
To a stirred solution of compound 3 (0.2 g, 1 eq) in dichloromethane (10 mL), tetrabutyl ammonium fluoride (1.3 mL, 3 eq) was added at 0° C. and stirred for 2 h at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ethyl acetate: diethyl ether (1:1) and washed with water. The organic extracts were washed with aq. potassium carbonate, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was washed with hexane to afford the title compound 4. 1H NMR (400 MHz, CDC13) δ: 8.34 (d, J=9.2 Hz, 2H), 8.25 (d, J=9.2 Hz, 2H), 2.69 (s, 3H).
To a stirred solution of compound 4 (0.28 g, 1 eq) in acetic acid (10 mL), iron powder (0.7 g, 9 eq) was added slowly. The reaction mixture was stirred at room temperature for 5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was dissolved in water and ethyl acetate, filtered through celite and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 2. LCMS (m/z): 176.00 (M+1).
N-(4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-6-(1-methyl4H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the General procedure for Buchwald Coupling described above using corresponding chloro compound 6 and amino compound 5. 1H NMR (400 MHz, DMSO-d6) δ: 10.09 (s, 1H), 8.25 (s, 1H), 8.12 (s, 1H), 7.98 (d, J=8.8 Hz, 2H), 7.94-7.83 (m, 3H), 7.73 (d, J=8.6 Hz, 1H), 6.79 (s, 1H), 4.14 (s, 3H), 3.88-3.75 (m, 8H), 2.65 (s, 3H); HPLC purity: 96.06%; LCMS Calculated for C25H24N8O2 (free base): 468.20; Observed: 469.40 (M+1).
To a stirred solution of compound 1 (2 g, 1 eq) in acetonitrile (100 mL), NBS (3.23 g, 1 eq) was added followed by the addition of p-TSA (3.12 g, 1 eq). The reaction mixture was heated to 50° C. for 24 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was basified with saturated sodium bicarbonate solution and extracted with dichloromethane (3×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 2. 1H NMR (400 MHz, CDCl3) δ: 8.35 (d, J=8.4 Hz, 2H), 8.16 (d, J=9.2 Hz, 2H), 4.45 (s, 2H).
A stirred solution of compound 2 (1 g, 1 eq) in formamide 3 (2.55 g, 14.74 eq) was added at 130° C. for 1.5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (2×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 20% EtOAc-hexane to afford the title compound 4. 1H NMR (400 MHz, CDCl3) δ: 8.29 (d, J=8.8 Hz, 2H), 8.10 (s, 1H), 7.99 (s, 1H), 7.92 (d, J=8.8 Hz, 2H).
To a stirred solution of compound 4 (0.7 g, 1 eq) in acetic acid (10 mL), Iron powder (2.063 g) was added in one portion and the reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated to dryness. The residue was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate (2×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 30% EtOAc-hexane to afford the title compound 5. LCMS (m/z): 161.00 (M+1).
6-(1-methyl-1H-indazol-6-yl)-2-morpholino-N-(4-(oxazol-4-yl)phenyl)pyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 6 and amino compound 5. 1H NMR (400 MHz, DMSO-d6) δ: 9.57 (s, 1H), 8.54 (d, J=1.0 Hz, 1H), 8.44 (d, J=0.9 Hz, 1H), 8.24 (d, J=1.2 Hz, 1H), 8.10 (d, J=1.0 Hz, 1H), 7.89-7.72 (m, 6H), 6.74 (s, 1H), 4.13 (s, 3H), 3.83-3.74 (m, 8H); HPLC purity: 99.04%; LCMS Calculated for C25H23N7O2: 453.19; Observed: 454.35 (M+1).
6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholino-N-(4-(oxazol-4-yl)phenyl) pyrimidin-4-amine:The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 6 and amine 5. 1H NMR (400 MHz, DMSO-d6) δ: 9.55 (s, 1H), 8.54 (d, J=1.0 Hz, 1H), 8.43 (d, J=1.0 Hz, 1H), 8.16 (s, 1H), 7.88-7.68 (m, 6H), 6.73 (s, 1H), 4.04 (s, 3H), 3.86-3.70 (m, 8H), 2.45 (s, 3H); HPLC purity: 93.56%; LCMS Calculated for C26H25N7O2: 467.21; Observed: 468.30 (M+1).
1-(4-((6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)phenyl) ethan-1-one (3): The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 2 and amine 1. LCMS (m/z): 429.35 (M+1).
1-(4-((6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)phenyl) ethan-1-one (3): The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 2 and amine 1. LCMS (m/z): 443.35 (M+1).
(Z)-3-(dimethylamino)-1-(4-46-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl) amino) phenyl) prop-2-en-1-one (4): To a stirred solution of corresponding compound 3 (0.5 g, 1 eq) in DMF (7 mL), dimethylformamide dimethyl acetal (DMF-DMA) (0.2 mL, 1.2 eq) was added and heated at 80° C. for 1.5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with cold water and filtered. The solid was washed with water, dried under vacuum to afford title compound 4. LCMS (m/z): 484.35 (M+1).
((Z)-1-(4-((6-(1, 3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl) amino) phenyl)-3-(dimethylamino) prop-2-en-1-one (4): To a stirred solution of corresponding compound 3 (0.4 g, 1 eq) in DMF (5 mL), dimethylformamide dimethyl acetal (10 mL) was added and heated at 120° C. for 1.5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with cold water and filtered. The solid was washed with water, dried under vacuum to afford title compound 4. LCMS (m/z): 498.40 (M+1).
N-(4-(1H-pyrazol-3-yl)phenyl)-6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: To a stirred solution of corresponding compound 4 (0.3 g, 1 eq) in hydrazine hydrate (5 mL) was heated at 120° C. for 8 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was diluted with water and extracted with ethyl acetate (2×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by preparative HPLC to afford title compound. 1H NMR (400 MHz, DMSO-d6) δ: 10.12 (s, 1H), 8.23 (s, 1H), 8.14 (s, 1H), 7.91 (d, J=8.5 Hz, 2H), 7.85-7.62 (m, 6H), 6.78-6.67 (m, 2H), 4.14 (s, 3H), 3.84-3.76 (m, 8H); HPLC purity: 97.73%; LCMS Calculated for C25H24N8O (free base): 452.21; Observed: 453.35 (M+1).
N-(4-(1H-pyrazol-3-yl)phenyl)-6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholino pyrimidin-4-amine: The title compound has been synthesized by following same procedure described above. 1H NMR (400 MHz, DMSO-d6) δ: 10.45 (s, 1H), 8.15 (s, 1H), 7.91-7.80 (m, 3H), 7.80-7.73 (m, 3H), 7.57 (d, J=8.4 Hz, 1H), 6.80-6.70 (m, 2H), 4.06 (s, 3H), 3.90-3.76 (m, 8H), 2.52 (s, 3H); HPLC purity: 96.22%; LCMS Calculated for C26H26N8O: 466.22; Observed: 467.35 (M+1).
To a stirred solution of compound 1 (5 g, 1 eq) in DMF (20 mL), dimethylformamide dimethylacetal 2 (40 mL) was added and heated at 120° C. for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with cold water and filtered. The solid was washed with water, dried under vacuum to afford title compound 3. LCMS (m/z); 221.10 (M+1).
A stirred solution of compound 3 (2 g, 1 eq) in methyl hydrazine (10 mL) was heated at 100° C. for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was diluted with water and extracted with ethyl acetate (3×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford mixture of compounds 4 & 4a.
To a stirred solution of compound 4 & 4a (1 g, 1 eq) in ethanol (30 mL), iron powder (1.37 g, 5 eq), water (10 mL) and ammonium chloride (1.31 g, 5 eq) were added slowly. The reaction mixture was heated to reflux for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the mixture of compounds 5 & 5a. LCMS (m/z): 174.05 (M+1).
6-(1-methyl-1H-indazol-6-yl)-N-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 6 and amino compound 5 and 5a. The individual regioisomers were separated by Preparative HPLC. 1H NMR (400 MHz, DMSO-d6) δ: 9.89 (s, 1H), 8.24 (d, J=1.3 Hz, 1H), 8.12 (s, 1H), 7.92-7.78 (m, 3H), 7.74 (d, J=8.5 Hz, 1H), 7.56-7.48 (m, 2H), 7.46 (d, J=1.9 Hz, 1H), 6.76 (s, 1H), 6.38 (d, J=1.9 Hz, 1H), 4.14 (s, 3H), 3.87 (s, 3H), 3.84-3.75 (m, 8H); HPLC purity: 97.25%; LCMS Calculated for C26H26N8O (free base): 466.22; Observed: 467.40 (M+1).
6-(1-methyl-1H-indazol-6-yl)-N-(4-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholino pyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 9.50 (s, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.82-7.67 (m, 6H), 6.72 (s, 1H), 6.63 (d, J=2.2 Hz, 1H), 4.13 (s, 3H), 3.86 (s, 3H), 3.82-3.74 (m, 8H); HPLC purity: 98.07%; LCMS Calculated for C26H26N8O: 466.22; Observed: 467.35 (M+1).
6-(1,3-dimethyl-1H-indazol-6-yl)-N-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)-2-morpholino pyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 6 and amino compound 5 and 5a. The individual regioisomers were separated by Preparative HPLC. 1H NMR (400 MHz, DMSO-d6) δ: 10.20 (s, 1H), 8.16 (s, 1H), 7.86 (dd, J=8.5, 3.1 Hz, 3H), 7.58 (dd, J=22.3, 8.2 Hz, 3H), 7.47 (d, J=1.9 Hz, 1H), 6.81 (s, 1H), 6.40 (d, J=1.9 Hz, 1H), 4.05 (s, 3H), 3.88 (s, 3H), 3.85-3.75 (m, 8H), 2.52 (s, 3H); HPLC purity: 99.57%; LCMS Calculated for C27H28N8O (free base): 480.24; Observed: 481.30 (M+1).
6-(1,3-dimethyl-1H-indazol-6-yl)-N-(4-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholino pyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 10.36 (s, 1H), 8.14 (s, 1H), 7.90-7.69 (m, 6H), 7.58 (d, J=8.5 Hz, 1H), 6.75 (s, 1H), 6.66 (d, J=2.3 Hz, 1H), 4.05 (s, 3H), 3.87 (s, 3H), 3.85-3.76 (m, 8H), 2.52 (s, 3H); HPLC purity: 98.12%; LCMS Calculated for C27H28N8O (freebase): 480.24; Observed: 481.35 (M+1).
To a stirred solution of compound 1 (0.7 g, 1 eq) and CuI (0.045 mg, 0.05 g) in DMF: methanol (9:1; 10 mL), TMSN3 (0.821 g, 1.5 eq) was added. The reaction mixture was heated at 100° C. for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (2×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 2. LCMS (m/z): 191.10 (M+1).
To a stirred solution of compound 2 (0.8 g, 1 eq) in ethanol (30 mL), iron powder (1.11 g, 5 eq), water (15 mL) and ammonium chloride (1.17 g. 5 eq) were added slowly. The reaction mixture was heated at 90° C. for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 3. LCMS (m/z): 161.00 (M+1).
N-(4-(1H-1,2,3-triazol-5-yl)phenyl)-6-(1-methyl-1H-indazol-6-yl)-2-morpholino pyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 4 and amine 3. 1H NMR (400 MHz, DMSO-d6) δ: 8.29 (s, 1H), 8.24 (s, 1H), 8.15 (s, 1H), 7.90 (dd, J=15.1, 8.4 Hz, 3H), 7.81 (d, J=8.4 Hz, 2H), 7.67 (d, J=8.5 Hz, 1H), 6.77 (s, 1H), 4.15 (s, 3H), 3.82-3.69 (m, 8H); HPLC purity: 99.98%; LCMS Calculated for C24H23N9O (free base): 453.20; Observed: 454.25 (M+1).
N-(4-(1H-1,2,3-triazol-5-yl)phenyl)-6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholino pyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 4 and amine 3. 1H NMR (400 MHz, DMSO-d6) δ: 15.05 (s, 1H), 9.57 (s, 1H), 8.25 (s, 1H), 8.17 (s, 1H), 7.87-7.69 (m, 6H), 6.74 (s, 1H), 4.04 (s, 3H), 3.83-3.74 (m, 8H), 2.50 (s, 3H); HPLC purity: 96.37%; LCMS Calculated for C25H25N9O: 467.22; Observed: 468.25 (M+1).
To a stirred solution of compound 1 (0.5 g, 1 eq) and compound 2 (0.314 g, 1 g) in DMF (10 mL), EDCI (0.571 g, 1 eq) was added followed by the addition of HOBt (0.403 g, 1 eq). The reaction mixture was stirred at room temperature for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (2×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was dissolved in 5% NaOH solution and heated at 60° C. for 18 h. the reaction mixture was cooled to 0° C. and acidified to pH 6 using 1N HCl. The aqueous layer was saturated with sodium chloride and extracted with ethyl acetate (2×25 mL). Combined organic extracts were evaporated under reduced pressure to afford the title compound 3. 1H NMR (400 MHz, DMSO-d6) δ: 14.12 (s, 1H), 8.38 (d, J=8.4 Hz, 2H), 8.38 (d, J=8.0 Hz, 2H) 3.58 (s, 3H).
To a stirred solution of compound 3 (0.1 g, 1 eq) in dichloromethane (10 mL), H2O2 (0.032 g, 2.2 eq) was added slowly at 0° C. followed by the addition of acetic acid at same temperature. The reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was basified to pH 10 with aq. sodium hydroxide and extracted with dichloromethane (2×10 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 4. LCMS (m/z): 205.00 (M+1).
To a stirred solution of compound 4 (0.05 g, 1 eq) in ethanol (5 mL), iron powder (0.068 g, 5 eq), water (2 mL) and ammonium chloride (0.065 g. 5 eq) were added slowly. The reaction mixture was heated at 90° C. for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was diluted with water and extracted with 10% methanol in dichloromethane and evaporated under reduced pressure to afford the title compound 5. LCMS (m/z): 174.95 (M+1).
6-(1-methyl-1H-indazol-6-yl)-N-(4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 6 and amine 5. 1H NMR (400 MHz, DMSO-d6) δ: 10.32 (s, 1H), 9.32 (s, 1H), 8.26 (d, J=1.2 Hz, 1H), 8.13 (d, J=1.0 Hz, 1H), 8.08-7.99 (m, 2H), 7.92-7.82 (m, 3H), 7.76 (dd, J=8.5, 1.4 Hz, 1H), 6.89 (s, 1H), 3.92 (s, 3H), 3.86 (s, 3H), 3.84-3.76 (m, 8H); HPLC purity: 95.56%; LCMS Calculated for C25H25N9O (free base): 467.22; Observed: 468.35 (M+1).
The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using chloro compound 1 and amine 2. 1H NMR (400 MHz, CDCl3) δ: 10.60 (s, 1H),8.07-7.97 (m, 3H), 7.65 (s, 2H), 7.55 (d, J=8.2 Hz, 2H), 6.73 (s, 1H), 6.57 (s, 1H), 4.06 (s, 3H), 3.92-3.82 (m, 8H), 2.56 (s, 3H), 2.57 (s, 3H); HPLC purity: 99.08%; LCMS Calculated for C26H27N9O: 481.23; Observed: 482.40 (M+1).
To a stirred solution of compound 1 (0.7 g, 1 eq) in methanol (10 mL), 10% Pd—C (0.1 g) was added under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 18 h under hydrogen balloon pressure. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 5% MeOH-DCM to afford the title compound 2. LCMS (m/z): 160.00 (M+1).
To a stirred solution of compound 3 (0.2 g, 1 eq) and compound 2 (0.093 g, 1 eq) in 1,4-dioxane (10 mL), cesium carbonate (0.285g, 1.5 eq) was added and purged with argon for 10 min, followed by the addition of xantphos (0.033 g,0.15 eq) and purged with argon for additional 5 min. Pd2(dba)3 (0.053 g,0.1 eq) was added and stirred at 100° C. for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated to dryness. The residue was dissolved in ethyl acetate (50 mL), washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by preparative HPLC to afford the desired product. 1H NMR (400 MHz, MeOD) δ: 8.97 (d, J=1.4 Hz, 1H), 8.10 (s, 1H), 7.85 (q, J=8.5 Hz, 4H), 7.78-7.71 (m, 2H), 7.67 (dd, J=8.5, 1.4 Hz, 1H), 6.66 (s, 1H), 4.08 (s, 3H), 3.96-3.84 (m, 8H),2.58 (s, 3H); HPLC purity: 98.24%; LCMS Calculated for C26H26N8O: 466.22; Observed: 467.25 (M+1).
To a stirred solution of compound 1 (1 g, 1 eq) in THF (10 mL), NaH (0.161 g, 1.1 eq) was added under nitrogen atmosphere at 0° C. and stirred for 30 min. Boc-anhydride (1.6 g, 1.2 eq) was added at same temperature and stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice water extracted with ethyl acetate (3×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 2.
To a stirred solution of compound 2 (1 g, 1 eq) in ethyl acetate (30 mL), 10% Pd—C (0.28 g) was added under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3 h under hydrogen atmosphere (balloon pressure). The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure to afford the title compound 3.
The title compound has been synthesized by following the General procedure for Buchwald Coupling described above using chloro compound 4 and amino compound 3. LCMS (m/z): 541.45 (M+1).
To a stirred solution of compound 5 (0.09 g, 1 eq) in methanol (5 mL), methanolic HCl (3 mL) was added and stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The crude product was purified by washing with diethyl ether to afford title compound as a HCl salt. 1H NMR (400 MHz, MeOD) δ: 8.26 (s, 1H), 8.15 (s, 1H), 8.03 (s, 1H), 7.93 (d, J=8.6 Hz, 1H), 7.72-7.64 (m, 2H), 7.50 (s, 1H), 6.66-6.61 (s, 1H), 4.11 (s, 3H), 3.92-3.80 (m, 8H), 2.60 (s, 3H); HPLC purity: 95.11%; LCMS Calculated for C24H24N80 (free base): 440.21; Observed: 441.35 (M+1).
The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using chloro compound 1 and amine 2. LCMS (m/z): 444.30 (M+1).
To a stirred solution of compound 3 (0.6 g, 1 eq) in DMF (5 mL), DMFDMA (10 mL) was added and heated at 120° C. for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with cold water and filtered. The solid was washed with water, dried under vacuum to afford title compound 4. LCMS (m/z): 499.35 (M+1).
To a stirred solution of compound 4 (0.4 g, 1 eq) in 1,4-dioxane (10 mL), hydroxylamine hydrochloride (0.067 g,1.2 eq), 5N NaOH (0.19 mL) and acetic acid (5 mL) were added and heated at 90° C. for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with cold water. The precipitated solid was filtered; residue was washed with water and dried under vacuum. The crude product was purified by preparative HPLC to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 9.96 (s, 1H), 9.02 (d, J=1.0 Hz, 1H), 8.18 (s, 1H), 8.10 (d, J=8.5 Hz, 2H), 7.97 (d, J=8.5 Hz, 2H), 7.83-7.70 (m, 2H), 6.79 (s, 1H), 4.04 (s, 3H), 3.84-3.71 (m, 8H), 2.46 (s, 3H); HPLC purity: 98.24%; LCMS Calculated for C25H24N8O2: 468.20; Observed: 469.25 (M+1).
To a stirred solution of compound 1 (1.5 g, 1 eq) in DMF (15 mL), compound 2 (1.22 mL, 1.2 eq), HATU (5.1 g, 1.2 eq) and DIPEA (3 mL, 2 eq) were added and stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 3. 1H NMR (400 MHz, DMSO-d6) δ: 8.90 (t, J=5.2 Hz, 1H), 8.32 (d, J=8.8 Hz, 2H), 8.07 (d, J=8.8 Hz, 2H), 4.53 (t, J=5.2 Hz, 1H), 3.99 (t, J=5.6 Hz, 2H), 3.31 (s, 6H).
A stirred mixture of compound 3 (0.5 g, 1 eq) and P205: methane sulphonic acid (1:10; 11 mL) was heated at 130° C. for 5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford title compound 4. LCMS (m/z): 190.95 (M+1).
To a stirred solution of compound 4 (0.35 g, 1 eq) in ethanol (10 mL), iron powder (0.308 g, 4 eq), water (10 mL) and ammonium chloride (0.292 g, 4 eq) were added slowly. The reaction mixture was heated to reflux for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 5. LCMS (m/z): 160.90 (M+1).
The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using chloro compound 6 and amine compound 5. 1H NMR (400 MHz, MeOD) δ: 8.15-8.07 (m, 2H), 8.05-7.98 (m, 2H), 7.94 (d, J=8.4 Hz, 1H), 7.84 (d, J=8.5 Hz, 2H), 7.50 (dd, J=8.4, 1.4 Hz, 1H), 7.33 (d, J=0.9 Hz, 1H), 6.64 (s, 1H), 4.11 (s, 3H), 3.97-3.84 (m, 8H), 2.60 (s, 3H); HPLC purity: 97.85%; LCMS Calculated for C26H25N7O2 (free base): 467.21; Observed: 468.40 (M+1).
To a stirred solution of compound 1 (1 g, 1 eq) in t-butanol (20 mL), 2-aminoethanol (0.44 g, 1.1 eq) was added and stirred at 70° C. for 4 h. Potassium carbonate (2.74 g, 3 eq) and Iodine (2.01 g, 1.2 eq) were added to the reaction mixture and again heated at 70° C. for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was quenched with saturated sodium thiosulphate solution and extracted with ethyl acetate (3×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 30% EtOAc-hexane to afford the title compound 2. LCMS (m/z): 193.00 (M+1).
To a stirred solution of compound 2 (0.3 g, 1 eq) in ethanol (5 mL), iron powder (0.305g, 3.5 eq), water (5 mL) and ammonium chloride (0.3 g 3.5 eq) were added slowly. The reaction mixture was heated to reflux for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (25 mL), washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 3. LCMS (m/z): 163.00 (M+1).
The title compound has been synthesized by using general procedure for Buchwald coupling using the chloro compound 4 and amine compound 3. 1H NMR (400 MHz, CDCl3) δ: 8.01 (s, 1H), 7.95 (d, J=8.3 Hz, 2H), 7.67 (s, 2H), 7.53 (d, J=8.5 Hz, 2H), 6.70 (s, 1H), 6.59 (s, 1H), 4.44 (t, J=9.4 Hz, 2H), 4.08 (t, J=9.5 Hz, 2H), 4.07 (s, 3H), 3.93-3.83 (m, 8H), 2.59 (s, 3H); HPLC purity: 91.06%; LCMS Calculated for C26H27N7O2: 469.22; Observed: 470.45 (M+1).
To a stirred solution of compound 1 (1 g, 1 eq) in DMF (1.5 mL), DMF DMA (3 mL) was added and heated at 120° C. for 1.5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with cold water and filtered. The solid was washed with water, dried under vacuum to afford the title compound 2. LCMS (m/z): 222.00 (M+1).
To a stirred solution of compound 2 (1.2 g, 1 eq) in acetic acid (10 mL), hydrazine hydrate (0.3 mL, 1.1 eq) was added and heated at 90° C. for 1.5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate (3×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 3. LCMS (m/z): 191.00 (M+1).
To a stirred solution of compound 3 (0.05 g, 1 eq) in ethanol (5 mL), iron powder (0.074 g, 5 eq), water (3 mL) and ammonium chloride (0.069 g 5 eq) were added slowly. The reaction mixture was heated to reflux for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (25 mL), washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 4. LCMS (m/z): 161.00 (M+1).
The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using chloro compound 5 and amine 4. 1H NMR (400 MHz, DMSO-d6) δ: 14.14-14.03 (m, 1H), 9.64 (s, 1H), 8.42-8.25 (m, 1H), 8.17 (s, 1H), 7.97 (d, J=8.3 Hz, 2H), 7.86-7.69 (m, 4H), 6.75 (s, 1H), 4.04 (s, 3H), 3.83-3.74 (m, 8H), 2.50 (s, 3H); HPLC purity: 99.02%; LCMS Calculated for C25H25N9O: 467.22; Observed: 468.35 (M+1).
To a stirred solution of compound 1 (1.6 g, 1 eq) in aq. ammonia solution (5 mL), copper chloride (catalytic amount) was added and heated at 90° C. in a sealed tube for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was stirred with 20% methanol in dichloromethane and filtered. The filtrate was evaporated under reduced pressure to afford the title compound 2. LCMS (m/z): 148.00 (M+1).
1-methyl-N-(6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1H-benzo[d]imidazol-5-amine: The title compound has been synthesized by following the General procedure for Buchwald Coupling described above using corresponding chloro compound 3 and amine 2. 1H NMR (400 MHz, DMSO-d6) δ: 9.37 (s, 1H), 8.23 (d, J=1.2 Hz, 1H), 8.16-8.06 (m, 2H), 8.03 (s, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.75 (dd, J=8.6, 1.3 Hz, 1H), 7.56-7.45 (m, 2H), 6.69 (s, 1H), 4.12 (s, 3H), 3.82 (s, 3H),3.81-3.72 (m, 8H); HPLC purity: 97.76%; LCMS Calculated for C24H24N8O: 440.21; Observed: 441.30 (M+1).
To a stirred solution of compound 1 (0.2 g, 1 eq) in aq. ammonia solution (2 mL), copper chloride (catalytic amount) was added and heated at 100° C. for 5 h in a sealed tube. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was stirred with 20% methanol in dichloromethane and filtered. The filtrate was concentrated under reduced pressure to afford title compound 2. LCMS (m/z): 148.00 (M+1).
1-methyl-N-(6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1H-benzo[d]imidazol-6-amine: The title compound has been synthesized by following the General procedure for Buchwald Coupling described above using corresponding chloro compound 3 and amine 2. 1H NMR (400 MHz, DMSO-d6) δ: 9.54 (s, 1H), 8.32 (s, 1H), 8.24 (d, J=1.2 Hz, 1H), 8.09 (d, J=1.0 Hz, 2H), 7.85 (d, J=8.5 Hz, 1H), 7.77 (dd, J=8.5, 1.3 Hz, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.20 (dd, J=8.6, 2.0 Hz, 1H), 6.74 (s, 1H), 4.13 (s, 3H), 3.87 (s, 3H), 3.82-3.71 (m, 8H); HPLC purity: 99.42%; LCMS Calculated for C24H24N8O: 440.21; Observed: 441.35 (M +1).
N-(6-(1, 3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1-methyl-1H-benzo[d]imidazol-6-amine: The title compound has been synthesized by following the General procedure for Buchwald Coupling described above using corresponding chloro compound 3 and amine 2. 1H NMR (400 MHz, DMSO-d6) δ: 9.53 (s, 1H), 8.32 (s, 1H), 8.16 (s, 1H), 8.09 (s, 1H), 7.82-7.68 (m, 2H), 7.57 (d, J=8.6 Hz, 1H), 7.20 (dd, J=8.5, 2.0 Hz, 1H), 6.73 (s, 1H), 4.03 (s, 3H), 3.86 (s, 3H), 3.82-3.71 (m, 8H), 2.55 (s, 3H); HPLC purity: 98%; LCMS Calculated for C25H26N8O: 454.22; Observed: 455.40 (M+1).
To a stirred solution of compound 1 (0.2 g, 1 eq) in 2 N NaOH solution (10 mL), water (5 mL) was added followed by the addition of DMS (3 mL, 2.53 eq). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was cooled at 0° C. and stirred for 2 h at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was filtered. The residue was dried under reduced pressure and purified by column chromatography on silica gel 100-200 mesh using 30% EtOAc-hexane to afford the title compounds 2, 5 and 7. LCMS (m/z): 178.90 (M+1).
To a stirred solution of compound 2 (0.4 g, 1 eq) in methanol: ethyl acetate (1:1; 40 mL), 10% Pd—C (0.1 g) was added and stirred at room temperature under hydrogen atmosphere (balloon pressure) for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure to afford the title compound 3. LCMS (m/z): 149.00 (M+1).
2-methyl-N-(6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-2H-benzo[d][1,2,3]triazol-5-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 4 and amine 3. 1H NMR (400 MHz, DMSO-d6) δ: 9.69 (s, 1H), 8.50 (s, 1H), 8.25 (s, 1H), 8.10 (s, 1H), 7.89-7.75 (m, 3H), 7.47 (d, J=9.2 Hz, 1H), 6.78 (s, 1H), 4.44 (s, 3H), 4.13 (s, 3H), 3.90-3.72 (m, 8H); HPLC purity: 99.31%; LCMS Calculated for C23H23N9O: 441.20; Observed: 442.00 (M+1).
N-(6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-2-methyl-2H-benzo[d][1,2,3]triazol-5-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 4 and amine 3. 1H NMR (400 MHz, DMSO-d6) δ: 9.66 (s, 1H), 8.48 (s, 1H), 8.17 (s, 1H), 7.88-7.70 (m, 3H), 7.51-7.43 (m, 1H), 6.78 (s, 1H), 4.44 (s, 3H), 4.04 (s, 3H), 3.90-3.76 (m, 8H), 2.52 (s,3H); HPLC purity: 98.68%; LCMS Calculated for C24H25N9O: 455.22; Observed: 456.40 (M+1).
The title compound 6 has been synthesized by using the procedure described above for reduction for step 2 using the nitro compound 5 and 10% Pd—C. LCMS (m/z): 148.90 (M+1).
1-methyl-N-(6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1H-benzo[d][1,2,3]triazol-5-amine: The title compound has been synthesized by following the General procedure for Buchwald Coupling described above using corresponding chloro compound 4 and amine 6. 1H NMR (400 MHz, DMSO-d6) δ: 9.66 (s, 1H), 8.47 (d, J=1.8 Hz, 1H), 8.25 (s, 1H), 8.10 (s, 1H), 7.89-7.74 (m, 3H), 7.73-7.66 (m, 1H), 6.75 (s, 1H), 4.28 (s, 3H), 4.13 (s, 3H), 3.89-3.75 (m, 8H); HPLC purity: 96.12%; LCMS Calculated for C23H23N9O: 441.20; Observed: 442.00 (M+1).
N-(6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1-methyl-1H-benzo[d][1,2,3]triazol-5-amine: The title compound has been synthesized by following the General procedure for Buchwald Coupling described above using corresponding chloro compound 4 and amine 6. 1H NMR (400 MHz, DMSO-d6) δ: 9.65 (s, 1H), 8.47 (d, J=1.7 Hz, 1H), 8.17 (s, 1H), 7.80 (dd, J=8.8, 2.8 Hz, 2H), 7.73 (d, J=8.4 Hz, 2H), 6.74 (s, 1H), 4.28 (s, 3H), 4.04 (s, 3H), 3.89-3.75 (m, 8H), 2.45 (s, 3H); HPLC purity: 99.35%; LCMS Calculated for C24H25N9O: 455.22; Observed: 456.35 (M+1).
The title compound 8 has been synthesized by using the procedure described above for reduction for step 2 using the nitro compound 7 and 10% Pd—C. LCMS (m/z): 148.90 (M+1).
1-methyl-N-(6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1H-benzo[d][1,2,3]triazol-6-amine: The title compound has been synthesized by following the General procedure for Buchwald Coupling described above using corresponding chloro compound 4 and amine 8. 1H NMR (400 MHz, DMSO-d6) δ: 9.87 (s, 1H), 8.57 (s, 1H), 8.26 (s, 1H), 8.10 (s, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H),6.81 (s, 1H), 4.23 (s, 3H), 4.14 (s, 3H), 3.89-3.77 (m, 8H); HPLC purity: 98.33%; LCMS Calculated for C23H23N9O: 441.20; Observed: 442.30 (M+1).
N-(6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1-methyl-1H-benzo[d][1,2,3]triazol-6-amine: The title compound has been synthesized by following the General procedure for Buchwald Coupling described above using corresponding chloro compound 4 and amine 8. 1H NMR (400 MHz, DMSO-d6) δ: 9.86 (s, 1H), 8.56 (d, J=1.8 Hz, 1H), 8.18 (d, J=1.2 Hz, 1H), 7.94 (d, J=8.9 Hz, 1H), 7.84-7.71 (m, 2H), 7.36 (dd, J=9.0, 1.9 Hz, 1H), 6.80 (s, 1H), 4.23 (s, 3H), 4.04 (s, 3H), 3.93-3.77 (m, 8H), 2.52 (s, 3H); HPLC purity: 99.53%; LCMS Calculated for C24H25N9O: 455.22; Observed: 456.25 (M+1).
To a stirred solution of compound 1 (0.6 g, 1 eq) in methanol (10 mL), Raney nickel (0.1 g) was added. The reaction mixture was stirred at room temperature under hydrogen atmosphere (balloon pressure) for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure to afford the title compound 6. LCMS (m/z): 135.00 (M+1).
N-(6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)benzo[d]oxazol-6-amine: The title compound has been synthesized by following the General procedure for Buchwald Coupling described above using corresponding chloro compound 3 and amine 2. 1H NMR (400 MHz, DMSO-d6) δ: 9.73 (s, 1H), 8.63 (s, 1H), 8.38 (d, J=1.9 Hz, 1H), 8.25 (s, 1H), 8.10 (s, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.82-7.69 (m, 2H), 7.47 (dd, J=8.6, 2.0 Hz, 1H), 6.76 (s, 1H), 4.13 (s, 3H), 3.84-3.75 (m, 8H); HPLC purity: 96.64%; LCMS Calculated for C23H21N7O2: 427.18; Observed: 428.25 (M+1).
N-(6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)benzo[d]oxazol-6-amine: The title compound has been synthesized by following the General procedure for Buchwald Coupling described above using corresponding chloro compound 3 and amine 2. 1H NMR (400 MHz, DMSO-d6) δ: 9.72 (s, 1H), 8.63 (d, J=1.0 Hz, 1H), 8.41-8.35 (m, 1H), 8.17 (s, 1H), 7.83-7.69 (m, 3H), 7.47 (dt, J=8.7, 1.4 Hz, 1H), 6.75 (s, 1H), 4.04 (s, 3H), 3.84-3.75 (m, 8H), 2.52 (s, 3H); HPLC purity: 96.36%; LCMS Calculated for C24H23N7O2: 441.19; Observed: 442.20 (M+1).
To a stirred solution of compound 1 (2 g, 1 eq) in DMF (20 mL), NaH (1.47 g, 3 eq) was added slowly at 0° C. followed by the addition of methyl iodide (2.3 mL, 3 eq) at same temperature. The reaction mixture was stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 50% EtOAc-hexane to afford the title compounds 2 and 5 (confirmed by NOE). LCMS (m/z): 178.00 (M+1).
To a stirred solution of compound 2 (1 g, 1 eq) in ethanol (20 mL), iron powder (1.19 g, 4 eq), water (10 mL) and ammonium chloride (1.19 g, 4 eq) were added slowly. The reaction mixture was refluxed for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (2×25 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 60% EtOAc-hexane to afford the title compound 3. LCMS (m/z): 147.95 (M+1).
1-methyl-N-(6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1H-indazol-5-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 4 and amine 3. 1H NMR (400 MHz, DMSO-d6) δ: 10.30 (s, 1H), 8.21(s,1H), 8.16 (s, 1H), 8.06 (d, J=5.6 Hz, 2H), 7.93 (d, J=8.4 Hz, 1H), 7.63 (dt, J=26.9, 8.7 Hz, 3H), 6.72 (s, 1H), 4.15 (s, 3H), 4.05 (s, 3H), 3.88-3.71 (m, 8H); HPLC purity: 99.76%; LCMS Calculated for C24H24N80 (free base): 440.21; Observed: 441.30 (M+1).
N-(6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1-methyl-1H-indazol-5-amine: The title compound has been synthesized by following the General procedure for Buchwald Coupling described above using corresponding chloro compound 4 and amine 3. 1H NMR (400 MHz, MeOD) δ: 8.13 (d, J=1.3 Hz, 1H), 8.07 (d, J=1.9 Hz, 1H), 7.96 (d, J=1.0 Hz, 1H), 7.75 (d, J=1.1 Hz, 2H), 7.62 (dd, J=9.0, 1.9 Hz, 1H), 7.53 (d, J=9.0 Hz, 1H), 6.61 (s, 1H), 4.06 (s, 3H), 4.04 (s, 3H), 3.90-3.80 (m, 8H), 2.56 (s, 3H); HPLC purity: 98.07%; LCMS Calculated for C25H26N8O: 454.22; Observed: 455.40 (M+1).
To a stirred solution of compound 5 (0.45 g, 1 eq) in ethanol:water (20 mL), iron powder (0.538 g, 4 eq) and ammonium chloride (0.538 g, 4 eq) were added slowly. The reaction mixture was refluxed for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (2×25 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 6. LCMS (m/z): 148.00 (M+1).
2-methyl-N-(6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-2H-indazol-5-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 4 and amine 6. 1H NMR (400 MHz, DMSO-d6) δ: 10.60 (s,1H),8.34 (s, 1H), 8.24-8.15 (m, 2H), 8.08 (s, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.59 (dd, J=26.4, 8.8 Hz, 2H), 7.43 (d, J=9.3 Hz, 1H), 6.75 (s, 1H), 4.16 (s, 3H), 4.15 (s, 3H), 3.85-3.76 (m, 8H); HPLC purity: 99.31%; LCMS Calculated for C24H24N8O (free base): 440.21; Observed: 441.30 (M+1).
N-(6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-2-methyl-2H-indazol-5-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 4 and amine 6. 1H NMR (400 MHz, MeOD) δ: 8.06-7.96 (m, 3H), 7.65 (d, J=1.1 Hz, 2H), 7.46 (d, J=9.1 Hz, 1H), 7.32 (dd, J=9.2, 2.0 Hz, 1H), 6.53 (s, 1H), 4.09 (s, 3H), 3.95 (s, 3H), 3.81-3.71 (m, 8H), 2.44 (s, 3H); HPLC purity: 99.91%; LCMS Calculated for C25H26N8O: 454.22; Observed: 455.40 (M+1).
To a stirred solution of 1 (1 g, 1 eq) in DMF (10 mL), NaH (0.29 g, 2 eq) was added at 0° C. and stirred for 15 min followed by the addition of methyl iodide (1.3 g, 1.5 eq). The reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (2×30 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to the afford title compounds 2 and 3. # 2: 1H NMR (400 MHz, CDC13) δ: 8.38 (s, 1H), 8.10 (s, 1H), 8.01 (dd, J=8.8, 2.0 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H). # 3: 1H NMR (400 MHz, CDCl3) δ: 8. 67 (s, 1H), 8.02 (s, 1H), 7.88 (dd, J=9.2, 2.0 Hz, 1H), 7.74 (d, J=9.2 Hz, 1H).
The title compound has been synthesized by following the general procedure described above for reduction using the nitro compound 2 and Fe/NH4Cl. LCMS (m/z): 148.00 (M+1).
1-methyl-N-(6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1H-indazol-6-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 4 and amine 3. 1H NMR (400 MHz, DMSO-d6) δ: 9.69 (s, 1H), 8.40 (s, 1H), 8.25 (d, J=1.3 Hz, 1H), 8.10 (d, J=1.0 Hz, 1H), 7.91 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.80-7.77 (m, 1H), 7.66 (d, J=8.7 Hz, 1H), 7.12 (dd, J=8.7, 1.7 Hz, 1H), 6.79 (s, 1H), 4.14 (s, 3H), 3.97 (s, 3H), 3.89-3.77 (m, 8H); HPLC purity: 99.73%; LCMS Calculated for C24H24N8O: 440.21; Observed: 441.35 (M+1).
N-(6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1-methyl-1H-indazol-6-amine : The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 4 and amine 3. 1H NMR (400 MHz, DMSO-d6) δ: 10.09 (s, 1H), 8.33 (s, 1H), 8.16 (s, 1H), 7.96 (s, 1H), 7.85 (d, J=8.3 Hz, 1H), 7.67 (dd, J=23.8, 8.6 Hz, 2H), 7.17 (d, J=8.6 Hz, 1H), 6.80 (s, 1H), 4.05 (s, 3H), 3.99 (s, 3H), 3.90-3.78 (m, 8H), 2.52 (s, 3H); HPLC purity: 97.96%; LCMS Calculated for C25H26N8O: 454.22; Observed: 455.40 (M+1).
The title compound has been synthesized by following the general procedure described above for reduction using the nitro compound 5 and Fe/NH4Cl. LCMS (m/z): 148.00 (M+1).
2-methyl-N-(6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-2H-indazol-6-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 4 and amine 6. 1H NMR (400 MHz, DMSO-d6) δ: 10.85 (s, 1H), 8.40 (s, 1H), 8.26-8.15 (m, 3H), 7.94 (d, J=8.4 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.29 (dd, J=8.9, 1.8 Hz, 1H), 6.90 (s, 1H), 4.17 (s, 3H), 4.15 (s, 3H), 3.90-3.78 (m, 8H); HPLC purity: 95.03%; LCMS Calculated for C24H24N8O: 440.21; Observed: 441.30 (M+1).
N-(6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-2-methyl-2H-indazol-6-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 4 and amine 6. 1H NMR (400 MHz, DMSO-d6) δ: 10.97 (s, 1H), 8.39 (s, 1H), 8.17 (d, J=15.7 Hz, 2H), 7.88 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.9 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.27 (d, J=9.3 Hz, 1H), 6.87 (s, 1H), 4.17 (s, 3H), 4.06 (s, 3H), 3.89-3.78 (m, 8H), 2.53 (s, 3H); HPLC purity: 98.89%; LCMS Calculated for C25H26N8O: 454.22; Observed: 455.30 (M+1).
The title compound (crude) has been synthesized by using the general procedure described above for reduction using the nitro compound 1 and Fe/NH4Cl. LCMS (m/z): 132.95 (M+1).
N-(6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1H-indol-6-amine: The title compound has been synthesized by following the General procedure for Buchwald Coupling described above using corresponding chloro compound 3 and amine 2. ‘H NMR (400 MHz, DMSO-d6) δ: 11.02 (s, 1H), 9.31 (s, 1H), 8.22 (s, 1H), 8.09 (s, 1H), 8.03 (s, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.26 (t, J=2.7 Hz, 1H), 7.09 (dd, J=8.4, 1.9 Hz, 1H), 6.71 (s, 1H), 6.36 (t, J=2.4 Hz, 1H), 4.12 (s, 3H), 3.84-3.74 (m, 8H); HPLC purity: 94.31%; LCMS Calculated for C24H23N7O: 425.20; Observed: 426.30 (M+1).
N-(6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1H-indol-6-amine: The title compound has been synthesized by following the General procedure for Buchwald Coupling described above using corresponding chloro compound 3 and amine 2. 1H NMR (400 MHz, DMSO-d6) δ: 11.02 (s, 1H), 9.31 (s, 1H), 8.09 (s, 1H), 8.03 (s, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.26 (t, J=2.7 Hz, 1H), 7.09 (dd, J=8.4, 1.9 Hz, 1H), 6.71 (s, 1H), 6.36 (t, J=2.4 Hz, 1H), 4.12 (s, 3H), 3.83-3.74 (m, 8H), 2.50 (s, 3H); HPLC purity: 92.29%; LCMS Calculated for C25H25N7O: 439.21; Observed: 440.35 (M+1).
To a stirred solution of compound 1 (1 g, 1 eq) in DMF (10 mL), NaH (0.221 g,1.5 eq) was added at 0° C. followed by the addition of methyl iodide (2.3 mL, 3 eq) at same temperature. The reaction mixture was stirred at same temperature for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 20% EtOAc-hexane to afford the title compound 2.
The title compound (crude) has been synthesized by following the general procedure described above for reduction using the nitro compound 2 and Fe/NH4Cl. LCMS (m/z): 147.00 (M+1).
1-methyl-N-(6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1H-indol-6-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 4 and amine 3. 1H NMR (400 MHz, DMSO-d6) δ: 9.41 (s, 1H), 8.26-8.16 (m, 2H), 8.09 (d, J=1.0 Hz, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.76 (dd, J=8.5, 1.4 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.24 (d, J=3.1 Hz, 1H), 7.04 (dd, J=8.5, 1.8 Hz, 1H), 6.72 (s, 1H), 6.38-6.32 (m, 1H), 4.13 (s, 3H), 3.91-3.73 (m, 8H), 3.75 (s, 3H); HPLC purity: 95.89%; LCMS Calculated for C25H25N7O: 439.21; Observed: 440.35 (M+1).
N-(6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1-methyl-1H-indol-6-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 4 and amine 3. 1H NMR (400 MHz, DMSO-d6) δ: 9.41 (s, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.46 (d, J=8.4, 1H), 7.23 (d, J=7.2 Hz, 1H), 7.04 (dd, J=8.5, 1.6Hz, 1H), 6.71 (s, 1H), 6.35-6.34 (m, 1H), 4.13 (s, 3H), 3.91-3.75 (m, 8H), 3.73 (s, 3H), 2.51 (s, 3H); HPLC purity: 95.09%; LCMS Calculated for C26H27N7O: 453.23; Observed: 454.30 (M+1).
To a stirred solution of compound 1 (1 g, 1 eq) in DMF (5 mL), NaH (0.222 g, 1.5 eq) was added at 0° C. followed by the addition of methyl iodide (1.3 mL, 1.5 eq) at same temperature. The reaction mixture was stirred at same temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (2×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 2.
The title compound has been synthesized by following the general procedure described above for reduction using the nitro compound 2 and Fe/NH4Cl. LCMS (m/z): 147.00 (M+1).
1-methyl-N-(6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1H-indol-5-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 4 and amine 3. 1H NMR (400 MHz, DMSO-d6) δ: 9.41 (s, 1H), 8.26-8.16 (m, 2H), 8.09 (d, J=1.0 Hz, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.76 (dd, J=8.5, 1.4 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.24 (d, J=3.1 Hz, 1H), 7.04 (dd, J=8.5, 1.8 Hz, 1H), 6.72 (s, 1H), 6.38-6.32 (m, 1H), 4.13 (s, 3H), 3.91-3.73 (m, 8H), 3.75 (s, 3H); HPLC purity: 95.89%; LCMS Calculated for C25H25N7O: 439.21; Observed: 440.35 (M+1).
N-(6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1-methyl-1H-indol-5-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 4 and amine 3. 1H NMR (400 MHz, DMSO-d6) δ: 9.18 (s, 1H), 8.13 (s, 1H), 7.84-7.73 (m, 2H), 7.67 (d, J=8.6 Hz, 1H), 7.39 (d, J=2.8 Hz, 2H), 7.29 (d, J=3.0 Hz, 1H), 6.63 (s, 1H), 6.38 (d, J=3.0 Hz, 1H), 4.02 (s, 3H), 3.80-3.71 (m, 8H), 3.71 (s, 3H), 2.50 (s, 3H); HPLC purity: 96.12%; LCMS Calculated for C26H27N7O: 453.23; Observed: 454.35 (M+1).
To a stirred solution of compound 1 (1 eq) in toluene, trifluoroacetic anhydride (1.1 eq) was added and heated to reflux for 8 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was diluted with water and extracted with ethyl acetate. Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh to afford the title compound 2.
1H NMR (400 MHz, DMSO-d6) δ: 10.21 (s, 1H), 8.25 (d, J = 1.3 Hz, 1H), 8.13 (d, J = 1.0 Hz, 1H), 8.08-8.01 (m, 2H), 7.96-7.86 (m, 3H), 7.72 (d, J = 8.6 Hz, 1H), 6.81 (s, 1H), 4.14 (s, 3H), 3.85-3.76 (m, 8H); HPLC purity: 91.63%; LCMS Calculated for C25H21F3N8O2: 521.17; Observed:
6-(1-methyl-1H-indazol-6-yl)-2-morphohno-N-(4-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)phenyl)pyrimidin-4-amine: To a stirred solution of compound 2 where R is H (0.04 g, 1 eq) in methanol (2 mL), hydrazine hydrate (0.2 mL) was added and stirred at room temperature for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was diluted with water and extracted with ethyl acetate (2×10 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by preparative HPLC to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 15.20 (s, 1H), 10.21 (s, 1H), 8.25 (d, J=1.3 Hz, 1H), 8.13 (d, J=1.0 Hz, 1H), 8.08-8.01 (m, 2H), 7.96-7.86 (m, 3H), 7.72 (d, J=8.6 Hz, 1H), 6.81 (s, 1H), 4.14 (s, 3H), 3.85-3.76 (m, 8H); HPLC purity: 97.45%; LCMS Calculated for C25H22F3N9O: 521.19; Observed: 522.30 (M+1).
6-(1,3-dimethyl-1H-1-indazol-6-yl)-2-morphohno-N-(4-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)phenyl)pyrimidin-4-amine: The title compound has been synthesized by following the procedure described above for 6-(1-methyl-1H-indazol-6-yl)-2-morpholino-N-(4-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)phenyl)pyrimidin-4-amine using corresponding compound 2 where R is methyl and hydrazine hydrate. 1H NMR (400 MHz, DMSO-d6) δ: 15.14 (s, 1H), 10.02 (s, 1H), 8.17 (s, 1H), 8.03 (d, J=8.4 Hz, 2H), 7.91 (d, J=8.5 Hz, 2H), 7.82 (d, J=8.4 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 6.78 (s, 1H), 4.04 (s, 3H), 3.84-3.76 (m, 8H), 2.49 (s, 3H); HPLC purity: 96.2%; LCMS Calculated for C26H24F3N9O: 535.21; Observed: 536.25 (M+1).
The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using chloro compound 1 and amine 2. LCMS (m/z): 513.20 (M+1).
The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using compound 3 and Boronic acid 4. LCMS (m/z): 552.40 (M+1).
To a stirred solution of compound 5 (0.08 g, 1 eq) in dichloromethane (2 mL), TFA (2 mL) was added and stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate (2×20 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by preparative HPLC to afford the title compound. 1H NMR (400 MHz, MeOD) δ: 8.20 (s, 1H), 8.03 (s, 1H), 7.86-7.73 (m, 2H), 7.63 (d, J=8.7 Hz, 2H), 7.57-7.50 (m, 2H), 6.78 (q, J=2.2 Hz, 1H), 6.63 (s, 1H), 6.41 (d, J=3.3 Hz, 1H), 6.15 (q, J=2.7 Hz, 1H), 4.14 (s, 3H), 3.96-3.81 (m, 8H); HPLC purity: 98.91%; LCMS Calculated for C26H25N7O: 451.21; Observed: 452.25 (M+1).
To a stirred solution of sodium acetate (0.54g, 2 eq) in water (10 mL),compound 2(0.98 g, 1.1 eq) was added and stirred at 90° C. for 30 min. The reaction mixture was allowed to cool to room temperature, compound 1(0.5 g, 1 eq), aqueous ammonia (10 mL) and methanol (20 mL) were added. The reaction mixture was stirred at room temperature for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was evaporated under reduced pressure. The residue was dissolved in water (50 mL) and extracted with ethyl acetate (2×25 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 20% EtOAc-hexane to afford the title compound 3. LCMS (m/z): 258 (M+1).
To a stirred solution of compound 3(0.5 g, 1 eq) in ethanol (10 mL), iron powder (0.544 g, 5 eq), water (5 mL) and ammonium chloride (0.515 g, 5 eq) were added slowly. The reaction mixture was heated to reflux for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 4. LCMS (m/z): 228 (M+1).
6-(1-methyl-1H-indazol-6-yl)-2-morpholino-N-(4-(5-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)pyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for Buchwald Coupling by using corresponding chloro compound 5 and amine compound 4. 1H NMR (400 MHz, DMSO-d6)δ: 13.00 (s, 1H), 9.66 (s, 1H), 8.25 (s, 1H), 8.10 (s, 1H), 8.04 (s, 2H), 7.94 (d, J=8.4 Hz, 2H), 7.92-7.75 (m, 5H), 6.76 (s, 1H), 4.14 (s, 3H), 3.87-3.80 (m, 4H), 3.78-3.70 (m, 4H); HPLC purity: 98.06%; LCMS Calculated for C26H23F3N8O: 520.19; Observed: 521.30 (M+1).
6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholino-N-(4-(5-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)pyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for Buchwald coupling by using corresponding chloro compound 5 and amine compound 4. 1H NMR (400 MHz, DMSO-d6) δ: 12.99 (s, 1H), 9.64 (s, 1H), 8.17 (s, 1H), 8.02-7.67 (m, 7H), 6.74 (s, 1H), 4.04 (s, 3H), 3.79 (dt, J=35.9, 4.6 Hz, 8H), 2.49 (s, 3H); HPLC purity: 98.8%; LCMS Calculated for C27H25F3N8O (free base): 534.21; Observed: 535.25 (M+1).
N-(6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1H-indol-5-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 1 and amine 2. 1H NMR (400 MHz, DMSO-d6) δ: 11.16 (s, 1H), 8.11 (s, 1H), 7.87 (d, J=9.6 Hz, 1H), 7.50 (s, 1H), 7.45-7.34 (m, 2H), 7.31 (s, 1H), 6.65 (s, 1H), 6.44 (t, J=2.4 Hz, 1H), 4.05 (s, 3H),3.83-3.74 (m, 8H),2.50 (s, 3H); HPLC purity: 99.64%; LCMS Calculated for C24H23N7O: 439.21; Observed: 440.35 (M+1).
The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using compound 1 and Boronic acid 2. LCMS (m/z): 259.00 (M+1).
The title compound has been synthesized by following the General procedure for Buchwald Coupling described above using chloro compound 4 and amine 3. LCMS (m/z): 566.50 (M+1).
To a stirred solution of compound 5 (0.08 g, 1 eq) in dichloromethane (2 mL), TFA (2 mL) was added and stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate (2×20 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 60% EtOAc-hexane to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 11.14 (s, 1H), 9.42 (s, 1H), 8.15 (s, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.75-7.64 (m, 3H), 7.58 (d, J=8.5 Hz, 2H), 6.79 (s, 1H), 6.70 (s, 1H), 6.42 (s, 1H), 6.09 (q, J=2.8 Hz, 1H), 4.03 (s, 3H), 3.82-3.74 (m, 8H), 2.58 (s, 3H); HPLC purity: 95.22%; LCMS Calculated for C27H27N7O: 465.23; Observed: 466.25 (M+1).
The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using compound 1 and Boronic acid 2. LCMS (m/z): 259.00 (M+1).
To a stirred solution of compound 3 (0.8 g, 1 eq) in DMF (15 mL), NaH (0.153 g, 1.5 eq) was added at 0° C. and stirred for 30 min followed by the addition of methyl iodide (0.906 g, 1.5 eq) at same temperature. The reaction mixture was stirred at same temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 4.
The title compound has been synthesized by following the general procedure described above for reduction using the nitro compound 4 and Fe/NH4Cl.
6-(1-methyl-1H-indazol-6-yl)-N-(4-(1-methyl-1H-pyrrol-2-yl)phenyl)-2-morpholino pyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 6 and amine 5. 1H NMR (400 MHz, DMSO-d6) δ: 10.05 (s, 1H), 8.23 (s, 1H), 8.14 (s, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.72 (dd, J=22.7, 8.3 Hz, 3H), 7.43 (d, J=8.1 Hz, 2H), 6.82 (s, 1H), 6.74 (s, 1H), 6.17-6.11 (m, 1H), 6.05 (t, J=3.2 Hz, 1H), 4.14 (s, 3H), 3.84-3.75 (m, 8H), 3.66 (s, 3H); HPLC purity: 95.23%; LCMS Calculated for C27H27N7O (free base): 465.23; Observed: 466.25 (M+1).
6-(1,3-dimethyl-1H-indazol-6-yl)-N-(4-(1-methyl-1H-pyrrol-2-yl)phenyl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 6 and amine 5. 1H NMR (400 MHz, DMSO-d6) δ: 9.95 (s, 1H), 8.15 (s, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.75 (d, J=8.2 Hz, 2H), 7.63 (d, J=8.1 Hz, 1H), 7.44 (d, J=8.2 Hz, 2H), 6.82 (t, J=2.3 Hz, 1H), 6.74 (s, 1H), 6.14 (t, J=2.7 Hz, 1H), 6.05 (t, J=3.1 Hz, 1H), 4.05 (s, 3H), 3.84-3.75 (m, 8H), 3.66 (s, 3H), 2.49 (s, 3H); HPLC purity: 96.75%; LCMS Calculated for C28H29N7O (free base): 479.24; Observed: 480.50 (M+1).
To a stirred solution of compound 1 (1.3 g, 1 eq) in THF (40 mL), NaH (0.248 g, 1.5 eq) was added at 0° C. and stirred for 15 min followed by the addition of Boc anhydride (1.80 g, 1.2 eq). The reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (2×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 2.
To a stirred solution of compound 2 (0.6 g, 1 eq) in methanol (30 mL), Raney nickel (0.12 g) was added under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 18 h under hydrogen atmosphere (balloon pressure). The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure to afford the title compound 3. LCMS (m/z): 259.05 (M+1).
Step 3: Synthesis of tert-butyl 3-(4-((6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl) amino)phenyl)-1H-pyrrole-1-carboxylate (5)
The title compound has been synthesized by following the General procedure for Buchwald Coupling described above using chloro compound 4 and amine 3. LCMS (m/z): 566.55 (M+1).
To a stirred solution of compound 5 (0.15 g, 1 eq) in dichloromethane (2 mL), TFA (2 mL) was added and stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate (2×25 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 70% EtOAc-hexane to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 10.84 (s, 1H), 9.33 (s, 1H), 8.15 (s, 1H), 7.82-7.67 (m, 2H), 7.62 (d, J=8.2 Hz, 2H), 7.49 (d, J=8.2 Hz, 2H), 7.19-7.13 (m, 1H), 6.77 (d, J=2.8 Hz, 1H), 6.69 (s, 1H), 6.41 (s, 1H), 4.03 (s, 3H), 3.82-3.74 (m, 8H), 2.42 (s, 3H); HPLC purity: 96.84%; LCMS Calculated for C27H27N7O: 465.23; Observed: 466.30 (M+1).
To a stirred solution of 1 (0.6 g, 1 eq) in DMF (8 mL), NaH (0.191 g, 1.5 eq) was added at 0° C. and stirred for 15 min followed by the addition of methyl iodide (0.29 mL, 1.5 eq). The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (2×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 2.
The title compound has been synthesized by following the general procedure described above for reduction using the nitro compound 2 and Fe/NH4Cl. LCMS (m/z): 173.00 (M+1).
6-(1-methyl-1H-indazol-6-yl)-N-(4-(1-methyl-1H-pyrrol-3-yl)phenyl)-2-morpholino pyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 4 and amine 3. 1H NMR (400 MHz, DMSO-d6) δ: 9.36 (s, 1H), 8.23 (s, 1H), 8.09 (s, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.76 (dd, J=8.6, 1.3 Hz, 1H), 7.67-7.58 (m, 2H), 7.49-7.42 (m, 2H), 7.13-7.07 (m, 1H), 6.77-6.67 (m, 2H), 6.36 (s, 1H), 4.13 (s, 3H), 3.82-3.69 (m, 8H), 3.63 (s, 3H); HPLC purity: 99.22%; LCMS Calculated for C27H27N7O: 465.23; Observed: 466.30 (M+1).
6-(1,3-dimethyl-1H-indazol-6-yl)-N-(4-(1-methyl-1H-pyrrol-3-yl)phenyl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using corresponding chloro compound 4 and amine 3. 1H NMR (400 MHz, DMSO-d6) δ: 10.19 (s, 1H), 8.13 (s, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.62 (d, J=8.1 Hz, 3H), 7.52 (t, J=12.0 Hz, 2H), 7.15 (s, 1H), 6.72 (d, J=12.0 Hz, 2H), 6.39 (s, 1H), 4.05 (s, 3H), 3.85-3.75 (m, 8H), 3.64 (s, 3H), 2.60 (s, 3H); HPLC purity: 96.31%; LCMS Calculated for C28H29N7O: 479.24; Observed: 480.40 (M+1).
To a stirred solution of compound 1 (1.5 g, 1 eq) in DMF (20 mL), compound 2 (1.84 g, 1.3 eq) and K2CO3 (3.1 g, 3 eq) were added at room temperature and stirred at 80° C. for 24 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (2×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 80% EtOAc-hexane to afford the title compound 3. LCMS (m/z): 309.95 (M+1).
The title compound has been synthesized by following the General Procedure for Boronate Ester Preparation described above using bromo compound 3 and Bis (pinacolato)diboron. LCMS (m/z): 358.35 (M+1).
The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using compound 5 and Boronate ester 4. LCMS (m/z): 429.35 (M+1).
Step 4: Synthesis of N-(4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-morpholino-6-(1-(2-morpholino ethyl)-1H-indazol-6-yl)pyrimidin-4-amine
The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using chloro compound 6 and amine 7. 1H NMR (400 MHz, DMSO-d6) δ: 13.53 (s, 1H), 9.56 (s, 1H), 8.29 (s, 1H), 8.11 (s, 1H), 7.93 (d, J=8.3 Hz, 2H), 7.84 (d, J=8.4 Hz, 2H), 7.76 (d, J=8.5 Hz, 2H), 6.74 (s, 1H), 4.61 (t, J=6.4 Hz, 2H), 3.82-3.73 (m, 8H), 3.48 (t, J=4.5 Hz, 4H), 2.79 (t, J=6.5 Hz, 2H), 2.50 (s, 3H), 2.44-2.39 (m, 4H); HPLC purity: 99.93%; LCMS Calculated for C30H34N10O2: 566.29; Observed: 567.55 (M+1).
To a stirred solution of compound 1 (10 g, 1 eq) in diethyl ether (100 mL), methyl magnesium iodide (17.6 g, 3 eq) was added at 0° C. and stirred at same temperature for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (3×100 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 2. 1H NMR (400 MHz, DMSO-d6) δ: 7.49-7.39 (m, 3H), 5.38 (s, 1H), 4.95-4.89 (m, 1H), 1.31 (d, J=6.4 Hz, 3H).
To a stirred solution of compound 2 (10 g, 1 eq) in acetone (100 mL), Jones reagent (12 mL) was added at 0° C. and stirred at same temperature for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 3. 1H NMR (400 MHz, CDCl3) δ: 7.76-7.72 (m, 1H), 7.37-7.31 (m, 2H), 2.61 (s, 3H).
A stirred solution of compound 3 (9 g, 1 eq) in hydrazine hydrate (9 mL) was refluxed for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 4. LCMS (m/z): 210.95 (M+1).
To a stirred suspension of NaH (1.14 g, 3 eq) in THF (50 mL), compound 4 (2 g, 1 eq) (solution in THF) was added at 0° C. and stirred at room temperature for 1 h. Compound 5 (2.65 g, 1.5 eq) was added and the reaction mixture was heated at 70° C. for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (3×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 50% EtOAc-hexane to afford the title compound 6. LCMS (m/z): 326.15 (M+2).
The title compound (crude product) has been synthesized by following the General Procedure for Boronate Ester Preparation described above using bromo compound 6 and Bis (pinacolato)diboron. LCMS (m/z): 372.35 (M+1).
The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using chloro compound 8 and Boronate ester 7. 1H NMR (400 MHz, MeOD) δ: 8.36 (s, 1H), 8.19 (s, 1H), 7.91 (d, J=8.3 Hz, 2H), 7.83-7.70 (m, 4H), 6.66 (s, 1H), 4.55 (t, J=6.6 Hz, 2H), 3.91-3.81 (m, 8H), 3.61 (t, J=4.6 Hz, 4H), 2.87 (t, J=6.6 Hz, 2H), 2.59 (s, 3H), 2.55-2.44 (m, 4H), 2.42 (s, 3H); HPLC purity: 97.76%; LCMS Calculated for C31H36N10O2: 580.30; Observed: 581.45 (M+1).
To a stirred solution of compound 1 (10 g, 1 eq) in 1,4-dioxane (40 mL), 3N NaOH (100 mL) solution, Iodine (28.51 g, 2.2 eq) was added and stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with 20% citric acid solution, saturated sodium bicarbonate solution and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 2. LCMS (m/z): 323.00 (M+1).
To a stirred solution of compound 2 (16.3 g, 1 eq) in DMF (150 mL), NaH (1.82 g, 1.5 eq) was added and stirred at room temperature for 10 min followed by the addition of methyl iodide (14.37 g, 2 eq). The reaction mixture was stirred for 30 min at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 10% EtOAc-hexane to afford the title compound 3. LCMS (m/z): 338.85 (M+1).
The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using compound 3 and Boronate ester 4. LCMS (m/z): 236.95 (M+1).
To a stirred solution of compound 5 (2.1 g, 1 eq) in dry THF (50 mL), BH3:DMS (3.2 mL, 4 eq) was added at 0° C. and stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with 3N NaOH and 30% H2O2 solution at 0° C. The reaction mixture was stirred at room temperature for 3 h and extracted with ethyl acetate (3×50 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 60% EtOAc-hexane to afford the title compound 6. LCMS (m/z): 257.00 (M+2).
To a stirred solution of compound 6 (1.9 g, 1 eq) in dichloromethane (10 mL), TEA (0.206 g, 2 eq) was added at room temperature and stirred for 15 min. Mesyl chloride (0.175 g, 1.5 eq) was added to the reaction mixture at 0° C. and stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (3×50 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 7. LCMS (m/z): 334.05 (M+1).
To a stirred solution of morpholine (0.083 g, 1 eq) in DMF (5 mL), TEA (0.194 g, 2 eq) was added at room temperature and stirred for 15 min followed by the addition of compound 7 (0.31 g, 1 eq; as a solution in DMF). The reaction mixture was heated in a sealed tube at 90° C. for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×20 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 5% MeOH-DCM to afford the title compound 8. LCMS (m/z): 324.10 (M+1).
The title compound (crude product) has been synthesized by following the General Procedure for Boronate Ester Preparation described above using bromo compound 8 and Bis(pinacolato)diboron. LCMS (m/z): 372.40 (M+1).
The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using chloro compound 10 and Boronate ester 9. 1H NMR (400 MHz, DMSO-d6) δ: 9.61 (s, 1H), 8.17 (s, 1H), 7.93 (d, J=8.3 Hz, 2H), 7.78 (td, J=24.7, 22.5, 8.4 Hz, 4H), 6.74 (s, 1H), 4.13 (s, 1H), 4.05 (s, 3H), 3.86-3.74 (m, 8H), 3.59-3.55 (m, 4H), 3.36-3.30 (m, 4H), 3.09 (t, J=7.8 Hz, 2H), 2.70 (t, J=7.9 Hz, 2H), 2.36 (s, 3H); HPLC purity: 98.25%; LCMS Calculated for C31H36N10O2: 580.30; Observed: 581.60 (M+1).
To a stirred solution of compound 1 (10 g, 1 eq) in water (26 mL), barium chloride solution (11.97 g, 0.8 eq) in water (18 mL) was added at 100° C. and refluxed for 2 h. After completion of the reaction, the reaction mixture was filtered. The filtrate was evaporated to dryness. The residue was dissolved in solution of ethanol: acetone (1:5; 450 mL), stirred for 30 min and filtered. The solid obtained was dried under vacuum to afford the title compound 2. LCMS (m/z): 129.95 (M+1).
To a stirred solution of ethanol (200 mL), sodium metal (4.92 g, 3 eq) was added slowly under nitrogen atmosphere. After dissolution of sodium metal, compound 2 (9.2 g, 1 eq) and diethyl 2-methylmalonate (12.4 g, 1 eq) were added. The reaction mixture was refluxed for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was diluted with water, acidified to pH 2 using 1N HCl and filtered. The solid obtained was dried under vacuum to afford the title compound 3. LCMS (m/z): 212.00 (M+1).
To a stirred solution of compound 3 (7.4 g, 1 eq) in phosphorous oxychloride (60 mL), DIPEA (0.29 g, 2 eq) was added slowly and was heated to reflux for 5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, excess phosphorous oxychloride was distilled off. The residue was quenched with ice and extracted with ethyl acetate (3×100 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 10% EtOAc-hexane to afford the title compound 4. LCMS (m/z): 247.95 (M+1).
The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using chloro compound 4 and p-chloro aniline 5. LCMS (m/z): 339.10 (M+1).
The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using chloro compound 6 and Boronate ester 7. 1H NMR (400 MHz, DMSO-d6) δ: 8.46 (s, 1H), 8.09 (s, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.73 (d, J=9.1 Hz, 3H), 7.41-7.34 (m, 2H), 7.24 (dd, J=8.3, 1.3 Hz, 1H), 4.08 (s, 3H), 3.66-3.58 (m, 8H), 2.11 (s, 3H); HPLC purity: 95.05%; LCMS Calculated for C23H23ClN6O: 434.16; Observed: 435.30 (M+1).
To a stirred solution of compound 1 (1.5 g, 1 eq) in acetonitrile (15 mL), K2CO3 (3.15 g, 3 eq) was added followed by the addition of 1-bromo-2-chloroethane (0.78 mL, 1.2 eq). The reaction mixture was stirred at 90° C. for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 30% EtOAc-hexane to afford the title compound 2.
To a stirred solution of compound 2 (1.1 g, 1 eq) and compound 3 (0.57 mL, 1g) in DMF (15 mL), K2CO3 (1.47 g, 2.5 eq) was added followed by the addition of KI (0.212 g, 0.3 eq). The reaction mixture was stirred at 80° C. for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 5% MeOH-DCM to afford the title compound 4. LCMS (m/z): 323.10 (M+1).
The title compound have been synthesized by following the General Procedure for Boronate Ester Preparation described above using bromo compound 4 and Bis (pinacolato)diboron. LCMS (m/z): 371.35 (M+1).
The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using compound 6 and Boronate ester 5. 1H NMR (400 MHz, DMSO-d6) δ: 11.66 (s, 1H), 10.25 (s, 1H), 8.44 (s, 1H), 8.25 (s, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.79-7.66 (m, 3H), 7.42 (d, J=8.7 Hz, 2H), 6.80 (s, 1H), 5.00 (d, J=7.1 Hz, 2H), 3.85 (d, J=4.8 Hz, 4H), 3.78-3.62 (m, 10H), 3.44-3.29 (m, 4H), 2.82 (s, 3H); HPLC purity: 99.87%; LCMS Calculated for C28H33ClN80 (free base): 532.25; Observed: 533.40 (M+1).
To a stirred solution of compound 1 (2 g, 1 eq) in DMF (30 mL), K2CO3 (4.2 g, 3 eq) was added followed by the addition of 1-bromo-3-chloropropane (3.18 g, 2 eq). The reaction mixture was stirred at 90° C. for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 30% EtOAc-hexane to afford the title compound 2. LCMS (m/z): 274.95 (M+2).
To a stirred solution of compound 2 (0.78 g, 1 eq) and compound 3 (0.34 g, 1 g) in DMF (10 mL), K2CO3 (0.98 g, 2.5 eq) was added followed by the addition of KI (0.141 g, 0.3 eq). The reaction mixture was stirred at 90° C. for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 100% ethyl acetate to afford the title compound 4. LCMS (m/z): 337.15 (M+1).
The title compound have been synthesized by following the General Procedure for Boronate Ester Preparation described above using bromo compound 4 and Bis (pinacolato)diboron. LCMS (m/z): 385.35 (M+1).
The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using chloro compound 6 and Boronate ester 5. 1H NMR (400 MHz, DMSO-d6) δ: 9.58 (s, 1H), 8.26 (s, 1H), 8.12 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.79-7.68 (m, 3H), 7.41-7.33 (m, 2H), 6.70 (s, 1H), 4.51 (t, J=6.5 Hz, 2H), 3.84-3.69 (m, 8H), 2.56-2.40 (m, 4H), 2.36-2.18 (m, 6H), 2.02-1.98 (m, 2H); HPLC purity: 99.51%; LCMS Calculated for C29H35ClN8O (free base): 546.26; Observed: 547.40 (M+1).
Step 1: Synthesis of 4-((6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)amino) benzonitrile (3)
The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA/HCl) by using chloro compound 1 and amino compound 2. LCMS (m/z): 426.20 (M+1).
N-(4-(5-cyclopropyl-4H-1,2,4-triazol-3-yl)phenyl)-6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: To a stirred solution of compound 3 (0.2 g, 1 eq) in DMSO (5 mL), copper bromide (0.005 g, 0.05 eq), Cs2CO3 (0.458 g, 3 eq) was added and stirred for 10 min followed by the addition of cyclopropane carboximidamide hydrochloride (0.085 g,1.5 eq) at room temperature. The reaction mixture was stirred at room temperature for 48 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (3×20 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by preparative HPLC to afford the title compound. HPLC purity: 99.25%; 1H NMR (400 MHz, DMSO-d6) δ: 10.29 (s, 1H), 8.16 (s, 1H), 8.00 (d, J=8.4 Hz, 2H), 7.89-7.82 (m, 3H), 7.63 (d, J=8.4 Hz, 1H), 6.79 (s, 1H), 4.05 (s, 3H), 3.85-3.75 (m, 8H), 2.36 (s, 3H), 2.14 (td, J=8.4, 4.2 Hz, 1H), 1.15-1.07 (m, 4H); LCMS Calculated for C28H29N90 (free base): 507.25; Observed: 508.30 (M+1).
6-(1,3-dimethyl-1H-indazol-6-yl)-N-(4-(5-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the procedure described above for N-(4-(5-cyclopropyl-4H-1,2,4-triazol-3-yl)phenyl)-6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine. HPLC purity: 96.35%; 1H NMR (400 MHz, DMSO-d6) δ: 10.14 (s, 1H), 8.16 (s, 1H), 8.03 (d, J=8.4 Hz, 2H), 7.94-7.80 (m, 3H), 7.66 (d, J=8.4 Hz, 1H), 6.78 (s, 1H), 4.05 (s, 3H), 3.84 (q, J=7.9, 6.2 Hz, 4H), 3.76 (t, J=4.7 Hz, 4H), 3.20-3.16 (m, 1H), 2.60 (s, 3H), 1.35 (d, J=6.9 Hz, 6H).LCMS Calculated for C28H31N9O (free base): 509.27; Observed: 510.45 (M+1).
4-((6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)amino) benzamide: The title compound was obtained as a side product in the reaction carried out for N-(4-(5-(tert-butyl)-4H-1,2,4-triazol-3-yl)phenyl)-6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine. HPLC purity: 98.07%; 1H NMR (400 MHz, DMSO-d6) δ: 9.68 (s, 1H), 8.16 (s, 1H), 7.90-7.68 (m, 7H), 7.16 (s, 1H), 6.75 (s, 1H), 4.04 (s, 3H), 3.82 (q, J=6.7, 5.7 Hz, 4H), 3.74 (t, J=4.7 Hz, 4H), 2.52 (s, 3H); LCMS Calculated for C24H25N7O2: 443.21; Observed: 444.20 (M+1).
To a stirred solution of compound 1 (0.05 g, 1 eq) in acetonitrile (3 mL), selectfluor (0.033 g, 1 eq) was added at 0° C. The resulting reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (3×20 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by preparative HPLC to afford the title compound. HPLC purity: 97.52%; 1H NMR (400 MHz, MeOD) δ: 8.15 (s, 1H), 7.81 (s, 2H), 7.75-7.68 (m, 2H), 7.35-7.24 (m, 2H), 4.05 (s, 3H), 3.77-3.65 (m, 12H), 3.20 (dd, J=9.1, 6.8 Hz, 2H), 2.83 (t, J=8.0 Hz, 2H), 2.60 (t, J=4.6 Hz, 4H); LCMS Calculated for C28H31ClFN7O2: 551.22; Observed: 552.35 (M+1).
The title compound has been synthesized by following the General procedure for Buchwald Coupling described above using chloro compound 1 and compound 2.
The title compound has been synthesized by following the General procedure for Buchwald Coupling described above using chloro compound 1 and amino compound 2. HPLC purity: 99.78%: 1H NMR (400 MHz, DMSO-d6) δ: 11.00 (s, 1H), 9.28 (s, 1H), 8.14 (s, 1H), 8.02 (s, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.26 (t, J=2.7 Hz, 1H), 7.09 (dd, J=8.5, 1.9 Hz, 1H), 6.70 (s, 1H), 6.35 (d, J=2.9 Hz, 1H), 4.04 (s, 3H), 3.84 (t, J=4.7 Hz, 4H), 3.74 (t, J=4.7 Hz, 4H), 3.59 (t, J=4.6 Hz, 4H), 3.09 (t, J=7.8 Hz, 2H), 2.70 (t, J=7.9 Hz, 2H), 2.50-2.42 (m, 4H); LCMS Calculated for C30H34N8O2: 538.28; Observed: 539.45 (M+1).
The title compound has been synthesized by following the General procedure for Buchwald Coupling described above using chloro compound 1 and compound 2. LCMS (m/z): 640.15 (M+1).
To a stirred solution of compound 3 (0.04 g, 1 eq) in methanol (2 mL), methanolic HCl (1 mL) was added and the reaction mixture was stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was washed with diethyl ether and dried under reduced pressure to afford the title compound. HPLC purity: 99.43%; 1H NMR (400 MHz, DMSO-d6) δ: 9.59 (s, 1H), 8.29 (s, 1H), 7.94 (s, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.69 (dd, J=27.6, 8.7 Hz, 2H), 7.16 (dd, J=8.7, 1.7 Hz, 1H), 6.76 (s, 1H), 4.05 (s, 3H), 3.86 (t, J=4.6 Hz, 4H), 3.77 (t, J=4.7 Hz, 4H), 3.59 (t, J=4.6 Hz, 4H), 3.09 (t, J=7.8 Hz, 2H), 2.75-2.66 (m, 2H), 2.52-2.48 (m, 4H); LCMS Calculated for C29H33N9O2: 539.28; Observed: 540.50 (M+1).
To a stirred solution of compound 1 (3 g, 1 eq) in DMF (40 mL), K2CO3 (8.8 g, 3 eq) was added and stirred for 15 min followed by the addition of compound 2 (3.6 g, 1 eq). The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice cold water. The precipitated solid was collected by filtration, washed with water and dried under reduced pressure to afford the title compound 3. LCMS (m/z): 191.00 (M+1).
To a stirred solution of compound 3 (1.8 g, 1 eq) in methanol (10 mL), 10% Pd—C (0.5 g) was added and stirred under hydrogen atmosphere (balloon pressure) at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite. The filtrate was evaporated under reduced pressure to afford the title compound 4. LCMS (m/z): 161.00 (M+1).
The title compound has been synthesized by following the general procedure described above for Buchwald coupling by using corresponding chloro compound 5 and amine 4. HPLC purity: 95.28%; 1H NMR (400 MHz, DMSO-d6) δ: 10.80 (s, 1H), 9.29 (s, 1H), 8.25 (d, J=5.4 Hz, 2H), 8.16 (s, 1H), 7.98-7.84 (m, 5H), 7.62 (d, J=8.5 Hz, 1H), 6.85 (s, 1H), 4.15 (s, 3H), 3.87 (t, J=4.8 Hz, 4H), 3.80-3.72 (m, 4H); LCMS Calculated for C24H23N9O (free base): 453.20; Observed: 454.35 (M+1).
Step 1: Synthesis of 2-(4-nitrophenyl)-2H-1,2,3-triazole (3)
To a stirred solution of NaH (0.58 g, 1 eq)) in dry DMF (10 mL), compound 2 (1 g, 1 eq) was added at 0° C. and stirred for 15 min followed by the addition of compound 1 (2 g, 1 eq). The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice cold water. The precipitated solid was collected by filtration, washed with water and dried under reduced pressure to afford the title compound 3 as mixture of isomers. LCMS (m/z): 190.95 (M+1).
To a stirred solution of compound 3 (2 g, 1 eq) in methanol (10 mL), PtO2 (0.19 g) was added and stirred under hydrogen atmosphere (balloon pressure) at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite. The filtrate was evaporated under reduced pressure. The crude product was purified by flash column chromatography on silica gel 100-200 mesh using 20% EtOAc-hexane to afford the title compounds 4 and 4a. Both the compounds were confirmed by NOE. LCMS (m/z): 161.05 (M+1).
N-(4-(2H-1,2,3-triazol-2-yl)phenyl)-6-(1-methyl-1H-indazol-6-yl)-2-morpholino pyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA/HCl) by using corresponding chloro compound 5 and amino compound 4. HPLC purity: 99.85%; 1H NMR (400 MHz, DMSO-d6) δ: 8.24 (s, 1H), 8.12 (d, J=15.7 Hz, 3H), 8.03 (d, J=8.6 Hz, 2H), 7.90 (d, J=8.9 Hz, 4H), 7.70 (d, J=8.4 Hz, 1H), 6.78 (s, 1H), 4.15 (s, 3H), 3.85 (t, J=4.6 Hz, 4H), 3.76 (t, J=4.6 Hz, 4H); LCMS Calculated for C24H23N9O (free base): 453.20; Observed: 454.00 (M+1).
N-(4-(2H-1,2,3-triazol-2-yl)phenyl)-6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholino pyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA/HCl) by using corresponding chloro compound 5 and amino compound 4. HPLC purity: 96.63%; 1H NMR (400 MHz, DMSO-d6) δ: 10.24 (s, 1H), 8.16 (s, 1H), 8.13-8.00 (m, 3H), 7.94-7.81 (m, 4H), 7.64 (d, J=8.5 Hz, 1H), 6.77 (s, 1H), 4.05 (s, 3H), 3.85 (t, J=4.6 Hz, 4H), 3.76 (t, J=4.7 Hz, 4H); LCMS Calculated for C25H25N9O (free base): 467.22; Observed: 468.00 (M+1).
N-(4-(1H-1,2,3-triazol-1-yl)phenyl)-6-(1-methyl-1H-indazol-6-371)-2-morpholino pyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA/HCl) by using corresponding chloro compound 5 and amino compound 4a. HPLC purity: 95.37%; 1H NMR (400 MHz, DMSO-d6) δ: 9.73 (s, 1H), 8.76 (s, 1H), 8.25 (s, 1H), 8.10 (s, 1H), 7.98-7.80 (m, 6H), 7.79 (d, J=8.6 Hz, 1H), 6.76 (s, 1H), 4.14 (s, 3H), 3.84 (t, J=4.5 Hz, 4H), 3.80-3.71 (m, 4H); LCMS Calculated for C24H23N9O: 453.20; Observed: 454.30 (M+1).
N-(4-(1H-1,2,3-triazol-1-yl)phenyl)-6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholino pyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA/HCl) by using corresponding chloro compound 5 and amino compound 4a. HPLC purity: 98.66%; 1H NMR (400 MHz, DMSO-d6) δ: 9.72 (s, 1H), 8.75 (s, 1H), 8.17 (s, 1H), 7.98-7.83 (m, 5H), 7.88-7.70 (m, 2H), 6.75 (s, 1H), 4.04 (s, 3H), 3.84 (t, J=4.7 Hz, 4H), 3.74 (t, J=4.8 Hz, 4H), 2.10 (s, 3H); LCMS Calculated for C25H25N9O: 467.22; Observed: 468.25 (M+1).
The title compound (crude product) has been synthesized by following the general procedure described above for Boronate ester preparation by using bromo compound 1 and Bis (pinacolato)diboron. LCMS (m/z): 285 (M+1).
The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using compound 3 and Boronate ester 2. HPLC purity: 95.58%; 1H NMR (400 MHz, DMSO-d6) δ: 9.57 (s, 1H), 8.23 (s, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.81 (dd, J=8.5, 1.4 Hz, 1H), 7.76-7.68 (m, 2H), 7.42-7.33 (m, 2H), 7.02 (dd, J=18.0, 11.4 Hz, 1H), 6.71 (s, 1H), 6.10 (d, J=18.0 Hz, 1H), 5.49 (d, J=11.5 Hz, 1H), 4.11 (s, 3H), 3.84-3.69 (m, 8H); LCMS Calculated for C24H23ClN6O: 446.16; Observed: 447.15 (M+1).
To a stirred solution of compound 4 (0.15 g, 1 eq) in ethanol (10 mL), PtO2 (30 mg) was added and stirred under hydrogen atmosphere (balloon pressure) at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite. The filtrate was evaporated under reduced pressure. The crude product was purified by preparative HPLC to afford the desired product. HPLC purity: 99.43%; 1H NMR (400 MHz, DMSO-d6) δ: 9.54 (s, 1H), 8.15 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.71 (dd, J=8.6, 4.1 Hz, 3H), 7.37 (d, J=8.5 Hz, 2H), 6.69 (s, 1H), 4.04 (s, 3H), 3.82-3.70 (m, 8H), 2.94 (q, J=7.6 Hz, 2H), 1.33 (t, J=7.6 Hz, 3H); LCMS Calculated for C24H25ClN6O: 448.18; Observed: 449.30 (M+1).
To a stirred solution of compound 1(2.3 g, leq) in DCM (50 mL), TEA (2.52 mL, 2 eq) was added and stirred for 15 min followed by the slow addition of mesyl chloride (1.04 mL, 1.5 eq) at 0° C. The reaction mixture was stirred at rt for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford compound 2. LCMS (m/z): 334 (M+1).
6-bromo-1-methyl-3-(2-(4-methylpiperazin-1-yl) ethyl)-1H-indazole (4): To a stirred solution of compound 3 (0.45 g, 1 eq)in DMF (50 mL), TEA (0.84 mL, 2 eq) was added and stirred for 15 min followed by the addition of solution of compound 2 (1 g, 1 eq). The reaction mixture was stirred at 90° C. for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 20% EtOAc-hexane to afford title compound 4. LCMS (m/z): 339.05 (M+1).
6-bromo-1-methyl-3-(2-(piperazin-1-yl) ethyl)-1H-indazole (2): To a stirred solution of compound 3 (0.388 g, 1 eq)in DMF (50 mL), TEA (0.84 mL, 2 eq) was added and stirred for 15 min followed by the addition of solution of compound 2 (1 g, 1 eq). The reaction mixture was stirred at90° C. for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 20% EtOAc-hexane to afford title compound 4. LCMS (m/z): 324 (M+1).
1-methyl-3-(2-(4-methylpiperazin-1-yl) ethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (5):The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using bromo compound 4 and Boronate ester. LCMS (m/z): 385 (M+1).
1-methyl-3-(2-(piperazin-1-yl) ethyl)-6-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1H-indazole(5): The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using bromo compound 4 and Boronate ester. LCMS (m/z): 371 (M+1).
N-(4-chlorophenyl)-6-(1-methyl-3-(2-(4-methylpiperazin-1-yl)ethyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for Buchwald coupling by using chloro compound 6 and amine compound 5. 1H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.19 (s,1H), 7.81-7.69 (m, 1H), 7.75-7.67 (m, 3H), 7.41-7.33 (m, 2H), 6.90(s, 1H), 4.04 (s, 3H), 3.80 (t, J=4.7 Hz, 4H), 3.76-3.69 (m, 4H), 3.07 (t, J=7.9 Hz, 2H), 2.73-2.64 (m, 4H), 2.39-2.25 (m, 6H), 2.16 (s, 3H); HPLC purity: 99.57%; LCMS Calculated for C29H35ClN8O (free base): 547.09:Observed: 547.35 (M+1).
N-(4-chlorophenyl)-6-(1-methyl-3-(2-(piperazin-1-yl)ethyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for Buchwald coupling by using chloro compound 6 and amine compound 5. 1H NMR (400 MHz, DMSO-d6) δ 9.58(s,1H), 7.75-7.67 (m, 2H), 8.19(s, 1H), 7.85 (d, J=8 Hz, 1H),7.72-7.69(m, 3H), 7.41-7.38 (m, 2H), 6.85 (s, 1H), 4.04 (s, 1H), 3.83-3.76 (m, 4H), 3.72 (t, J=4.6 Hz, 4H), 3.07 (t, J=7.5 Hz, 2H), 3.00 (s, 2H), 2.73-2.61 (m, 6H), 2.35-2.30 (m, 4H); HPLC purity: 94.69%; LCMS Calculated for C28H33ClN8O (free base): 533.07; Observed: 533.55 (M+1).
N-(4-fluorophenyl)-6-(1-methyl-3-(2-morpholinoethyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for Buchwald coupling by using chloro compound 1 and amine compound 2. 1H NMR (400 MHz, CD3OD) δ 8.10 (s, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.64 (s, 2H), 7.56 (d, J=8.4 Hz, 1H), 7.20 (t, J=8.6 Hz, 2H), 6.57 (s, 1H), 4.14 (d, J=22.0 Hz, 5H), 3.90-3.81 (m, 12H), 3.76-3.64 (m, 4H), 3.55 (t, J=7.6 Hz, 2H), 3.21-3.19(m, 2H); HPLC purity: 97.32%; LCMS Calculated for C28H32FN7O2 (free base): 517.60; Observed: 518.40 (M+1).
N-(4-bromophenyl)-6-(1-methyl-3-(2-morpholinoethyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for Buchwald coupling by using chloro compound 1 and amine compound 2. 1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.18 (s, 1H), 7.75-7.63 (m, 1H),7.68-7.6 (m, 3H) 7.46-7.42 (m, 2H), 6.65 (s, 1H), 4.04 (s, 3H), 3.80 (t, J=4.6 Hz, 4H), 3.72 (t, J=4.6 Hz, 4H), 3.59-3.57(m, 4H), 3.09 (t, J=7.9 Hz, 2H), 2.75-2.66 (m, 2H), 2.42-2.39 (m, 4H); HPLC purity: 98.62%; LCMS Calculated for C28H32BrN7O2 (free base): 578.50; Observed: 580.0(M+1).
6-(1-methyl-3-(2-morpholinoethyl)-1H-indazol-6-yl)-2-morpholino-N-(p-tolyl)pyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for Buchwald coupling by using chloro compound 1 and amine compound 2. 1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.14 (s, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.55 (d, J=8.1 Hz, 3H), 7.13 (d, J=8.0 Hz, 2H), 6.66 (s, 1H), 4.04 (s, 3H), 3.79 (t, J=4.6 Hz, 4H), 3.75-3.68 (m, 4H), 3.59 (t, J=4.6 Hz, 4H), 3.08 (t, J=7.9 Hz, 2H), 2.70 (t, J=7.9 Hz, 2H), 2.48 (s, 4H), 2.26 (s, 3H); HPLC purity: 97.07%; LCMS Calculated for C29H35N7O2 (free base): 513.63; Observed: 514.35(M+1).
4-((6-(1-methyl-3-(2-morpholinoethyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl) amino) benzonitrile : The title compound has been synthesized by following the general procedure described above for Buchwald coupling by using chloro compound 1 and amine compound 2. 1H NMR (400 MHz, Methanol-d4) δ 8.14 (s, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.89 (d, J=8.4 Hz, 2H), 7.80 (d, J=8.5 Hz, 2H), 7.60 (d, J=8.6 Hz, 1H), 6.70 (s, 1H), 4.14 (d, J=24.7 Hz, 5H), 3.97-3.81 (m, 10H), 3.76-3.64 (m, 4H), 3.60-3.47 (m, 2H). HPLC purity: 97.73%; LCMS Calculated for C29H32N8O2 (free base): 524.62; Observed: 525.35 (M+1).
The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA/HCl) by using chloro compound 1 and amine 2. LCMS (m/z): 422.15 (M+1).
To a stirred solution of compound 3 (0.35 g, 1 eq) in DMSO (5 mL, 1 eq), copper bromide (0.0095 g, 0.05 eq), cesium carbonate (0.828 g, 2.55 eq) and compound 4 (0.153 g, 1.5 eq) was added and stirred at 100° C. for 2 day. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with sodium bicarbonate solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by preparative HPLC to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.24 (s, 1H), 8.15 (s, 1H), 8.03 (d, J=8.4 Hz, 2H), 7.89 (dd, J=13.2, 8.4 Hz, 3H), 7.67 (d, J=8.5 Hz, 1H), 6.84 (s, 1H),4.09(S, 3H), 3.85 (q, J=9.8, 7.1 Hz, 4H), 3.76 (t, J=4.8 Hz, 4H), 2.18 (td, J=8.1, 4.1 Hz, 1H), 1.12 (ddt, J=10.5, 5.4, 2.8 Hz, 4H); HPLC purity: 93.15%; LCMS Calculated for C27H27N9O: 493.56; Observed: 494.25 (M+1).
6-(1-methyl-3-(2-morpholinoethyl)-1H-indazol-6-yl)-2-morpholino-N-(4-(oxazol-4-yl) phenyl) pyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for Buchwald coupling by using chloro compound 1 and aniline. 1H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.16 (s, 1H), 8.56(s, 1H), 8.51(s, 1H), 8.19(s, 1H),7.88-7.76 (m, 1H), 7.79-7.68 (m, 5H), 6.73 (s, 1H), 4.05 (s, 3H), 3.82 (q, J=6.6, 5.5 Hz, 4H), 3.74 (t, J=4.7 Hz, 4H), 3.59 (t, J=4.6 Hz, 4H), 3.09 (dd, J=10.1, 5.7 Hz, 2H), 2.71 (t, J=7.9 Hz, 2H); HPLC purity: 98.86%; LCMS Calculated for C31H34N8O3 (free base): 566.65; Observed: 567.50 (M+1).
6-(1-methyl-3-(2-morpholinoethyl)-1H-indazol-6-yl)-2-morpholino-N-(4-(oxazol-2-yl) phenyl) pyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for Buchwald coupling by using chloro compound 1 and aniline. The compound was taken in methanol (3 mL), methanol HCl(1.5 mL) was added and stirred at rt for 30 min. The reaction mixture was evaporated under reduced pressure to afford title compound as HCl salt. 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.23 (s, 1H), 8.18 (s, 1H), 8.01-7.86 (m, 5H), 7.74 (d, J=8.4 Hz, 1H), 7.35 (s, 1H), 6.82 (s, 1H), 4.10 (s, 3H), 4.06-3.98 (m, 2H), 3.84 (d, J=11.9 Hz, 8H), 3.76 (q, J=7.3, 4.8 Hz, 6H), 3.62-3.54 (m, 2H), 3.18 (d, J=10.8 Hz, 2H); HPLC purity: 97.03%; LCMS Calculated for C31H34N8O3: 566.65; Observed: 567.50 (M+1).
N-(4-(1-methyl-1H-pyrazol-3-yl) phenyl)-6-(1-methyl-3-(2-morpholinoethyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for Buchwald coupling by using chloro compound 1 and aniline. 1H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.16 (d, J=3.8 Hz, 1H), 7.84 (dt, J=8.6, 4.2 Hz, 2H), 7.71 (dd, J=13.0, 4.1 Hz, 5H), 7.57-7.41 (m, 2H), 4.05 (s, 3H), 3.90-3.77 (m, 11H), 3.77-3.70 (m, 4H), 3.09 (t, J=7.8 Hz, 2H), 2.71 (dd, J=9.0, 6.7 Hz, 2H), 2.44 (s, 4H); HPLC purity: 96.83%; LCMS Calculated for C32H37N9O2 (free base): 579.70; Observed: 580.15 (M+1).
N-(4-(1-methyl-1H-imidazol-2-yl) phenyl)-6-(1-methyl-3-(2-morpholinoethyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for Buchwald coupling by using chloro compound 1 and aniline. 1H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.17 (s, 1H), 7.83 (dd, J=20.6, 8.5 Hz, 3H), 7.73 (d, J=8.4 Hz, 1H), 7.66 (d, J=8.6 Hz, 2H), 7.21 (s, 1H), 6.95 (d, J=1.2 Hz, 1H), 6.75 (s, 1H), 4.05 (s, 3H), 3.83 (t, J=4.6 Hz, 4H), 3.75 (d, J=9.2 Hz, 7H), 3.59 (t, J=4.5 Hz, 4H), 3.09 (t, J=7.8 Hz, 2H), 2.71 (t, J=7.8 Hz, 2H), 2.51 (d, J=24.0 Hz, 4H); HPLC purity: 99.84%; LCMS Calculated for C32H37N9O2 (free base): 579.70; Observed: 580.55 (M+1).
N-(4-(1-methyl-1H-pyrrol-2-yl) phenyl)-6-(1-methyl-3-(2-morpholinoethyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for Buchwald coupling by using chloro compound 1 and aniline. 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.16 (s, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.73 (td, J=8.5, 7.8, 1.8 Hz, 3H), 7.39 (d, J=8.6 Hz, 2H), 6.80 (t, J=2.2 Hz, 1H), 6.73 (s, 1H), 6.11 (dd, J=3.6, 1.9 Hz, 1H), 4.05 (s, 3H), 3.73 (t, J=4.6 Hz, 4H), 3.65 (s, 3H), 3.59 (t, J=4.6 Hz, 4H), 3.32 (s, 7H), 3.09 (dd, J=9.9, 5.9 Hz, 2H), 2.75-2.66 (m, 2H), 2.60 (s, 10H), 2.48 (s, 10H); HPLC purity: 97%; LCMS Calculated for C33H38N8O2 (free base): 578.71; Observed: 579.55 (M+1).
tert-Butyl 5-(4-((6-(1-methyl-3-(2-morpholinoethyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl) amino) phenyl)-1H-pyrazole-1-carboxylate (2): The title compound has been synthesized by following the general procedure described above for Buchwald coupling by using chloro compound 1 and aniline. LCMS (m/z): 566 (M−100).
tert-Butyl 2-(4-((6-(1-methyl-3-(2-morpholinoethyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl) amino) phenyl)-1H-imidazole-1-carboxylate (2): The title compound has been synthesized by following the general procedure described above for Buchwald coupling by using chloro compound 1 and aniline. LCMS (m/z): 566 (M−100).
N-(4-(1H-pyrazol-5-yl) phenyl)-6-(1-methyl-3-(2-morpholinoethyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: A stirred solution of corresponding compound 2 (0.06 g, 1 eq) in TFA (0.5 mL) was stirred at rt temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was quenched with saturated sodium bicarbonate solution and extracted with 10% MeOH-DCM (2×20 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 9.51-9.45 (m, 1H), 8.16 (s, 1H), 7.88-7.68 (m, 7H), 6.72 (s, 1H), 6.64 (d, J=15.3 Hz, 1H), 4.05 (s, 3H), 3.87-3.69 (m, 12H), 3.09 (t, J=7.9 Hz, 2H), 2.71 (t, J=7.9 Hz, 2H), 2.47 (d, J=4.8 Hz, 4H); HPLC purity: 96.52%; LCMS Calculated for C31H35N9O2: 565.67; Observed: 471.30 (M+1).
N-(4-(1H-imidazol-2-yl)phenyl)-6-(1-methyl-3-(2-morpholinoethyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: A stirred solution of corresponding compound 2 (0.05 g, 1 eq) in DCM (2 mL), TFA (0.2 mL) was added and stirred at rt temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was quenched with saturated sodium bicarbonate solution and extracted with 10% MeOH-DCM (2×20 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 9.56 (s, 1H), 8.20(s, 1H), 7.87 (dd, J=15.6, 8.5 Hz, 3H), 7.74 (dd, J=17.6, 8.4 Hz, 3H), 7.09 (s, 2H), 6.73 (s, 1H), 4.05 (s, 3H), 3.82 (q, J=6.9, 5.7 Hz, 4H), 3.75 (d, J=4.7 Hz, 4H), 3.59 (t, J=4.6 Hz, 4H), 3.09 (t, J=7.8 Hz, 2H), 2.71 (t, J=7.8 Hz, 2H), 2.40-2.34 (m, 4H); HPLC purity: 98.13%; LCMS Calculated for C31H35N9O2: 565.67; Observed: 566.50 (M+1).
To a stirred solution of compound 1 (1 g, 1 eq) in Conc. H2SO4 (4 mL), nitrating mixture (0.44 mL Conc. HNO3+1 mL Conc. H2SO4) was added at 0° C. and stirred at same temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured onto ice water and basified to pH 9 using 2N NaOH. The precipitated solid was filtered, washed with water and dried under reduced pressure to afford the title compound 2. LCMS (m/z): 190 (M+1).
To a stirred solution of compound 2 (0.45 g, 1 eq) in THF (10 mL), sodium hydride (0.068 g, 1.2 eq) was added at 0° C. and stirred for 30 min followed by the addition of methyl iodide (0.562 g, 1.5 eq) at 0° C. and stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice water and extracted with ethyl acetate (2×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by repeated washing with pentane to afford the title compound 3. LCMS (m/z): 290 (M+1).
To a stirred solution of compound 3 (0.4 g, 1 eq) in methanol (10 mL), 10% Pd/C (0.04 g) was added and stirred under hydrogen atmosphere (balloon pressure) at room temperature for 8 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite. The filtrate was evaporated under reduced pressure to afford title compound 4.
The title compound has been synthesized by following the general procedure described above for Buchwald coupling by using chloro compound Sand amine 4. 1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 9.43 (s, 1H), 8.16 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.71 (t, J=6.5 Hz, 6H), 7.48 (s, 1H), 6.71 (s, 1H), 4.05 (s, 3H), 3.82 (dt, J=9.8, 4.9 Hz, 4H), 3.77-3.68 (m, 4H), 3.65-3.58 (m, 4H), 3.11 (t, J=7.9 Hz, 2H), 2.82-2.73 (m, 2H), 2.44 (s, 4H) ; HPLC purity: 99.79%; LCMS Calculated for C31H35N9O2 (free base): 565.67; Observed: 566.55 (M +1).
1-ethyl-N-(6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1H-indol-6-amine: 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J=24.0 Hz, 3H), 7.92 (d, J=8.4 Hz, 1H), 7.62 (s, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.36 (d, J=3.2 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.75 (s, 1H), 6.40 (d, J=3.1 Hz, 1H), 4.16 (d, J=13.0 Hz, 5H), 3.93-3.85 (m, 8H), 1.37 (t, J=7.2 Hz, 3H); HPLC purity: 99.32%; LCMS Calculated for: C26H27N7O: 453.55; Observed: 454.40 (M+1).
N-(6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1-ethyl-1H-indol-6-amine: The title compound has been synthesized by following the general procedure described above for Buchwald Coupling by using corresponding chloro compound land amine compound 2. 1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.27 (s, 1H), 8.15 (s, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.29 (d, J=3.1 Hz, 1H), 7.00 (dd, J=8.6, 1.8 Hz, 1H), 6.73 (s, 1H), 6.36 (d, J=3.1 Hz, 1H), 4.15 (q, J=7.2 Hz, 2H), 4.03 (s, 3H), 3.87 (t, J=4.6 Hz, 8H), 2.45 (s, 3H), 1.37 (t, J=7.2 Hz, 3H); HPLC purity: 99.76%; LCMS Calculated for C27H29N7O (free base): 467.57; Observed: 468 (M+1).
1-cyclopropyl-N-(6-(1-methyl-3-(2-morpholinoethyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1H-indol-6-amine: The title compound has been synthesized by following the general procedure described above for Buchwald Coupling by using corresponding chloro compound 1 and amine compound 2. 1H NMR (400 MHz, DMSO-d6) δ 11.25 (s, 1H), 8.29 (s, 1H), 8.21 (s, 1H), 7.98 (d, J=8.6 Hz, 1H), 7.67 (d, J=6.1 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.28 (d, J=3.3 Hz, 1H), 7.12 (d, J=8.3 Hz, 1H), 6.79 (s, 1H), 6.35 (d, J=3.3 Hz, 1H), 4.10 (s, 3H), 4.06-3.97 (m, 2H), 3.94-3.73 (m, 10H), 3.55 (dd, J=24.1, 11.5 Hz, 6H), 3.44-3.37 (m, 1H), 3.18 (q, J=11.4, 11.0 Hz, 2H), 1.08-0.92 (m, 4H); HPLC purity: 99.48%; LCMS Calculated for C33H38N8O2 (free base): 578.71; Observed: 579.45 (M+1).
To a stirred solution of compound 1 (10 g, 1 eq) and compound 2 (9 mL, 1.4 eq) in DMSO (20 mL), tBuoK (19.74 g, 2.4 eq) was added. The reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 25% EtOAc-hexane to afford the title compounds 3. LCMS (m/z): 192 (M+1).
To a stirred solution of compound 3 (0.15 g, 1 eq) in DMF (5 mL), sodium hydride (0.038 g, 2 eq) was added at 0° C. and stirred for 20 min followed by the addition of methyl iodide (0.06 mL, 1.2 eq) at 0° C. and stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice water and extracted with ethyl acetate (2×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 4. LCMS (m/z): 205.1 (M+1).
To a stirred solution of compound 4 (0.15 g, 1 eq) in ethanol: water (1:1, 10 mL), iron powder (0.164 g), and ammonium chloride (0.164 g) was added. The reaction mixture was heated to reflux for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 5. LCMS (m/z): 175.05 (M+1).
N-(6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1,2,3-trimethyl-1H-indol-6-amine: The title compound has been synthesized by following the general procedure described above for Buchwald coupling by using corresponding chloro compound 6 and amine 5. 1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.14 (s, 1H), 8.00 (s, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.02 (dd, J=8.4, 1.9 Hz, 1H), 6.69 (s, 1H), 4.03 (s, 3H), 3.85 (t, J=4.6 Hz, 4H), 3.73 (t, J=4.8 Hz, 4H), 3.59 (s, 3H), 2.46 (s, 3H), 2.31 (s, 3H), 2.17 (s, 3H); HPLC purity: 94.25%; LCMS Calculated for C28H31N7O (free base): 481.59: observed : 482.40(M+1).
1, 2, 3-trimethyl-N-(6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1H-indol-6-amine: The title compound has been synthesized by following the general procedure described above for Buchwald coupling by using corresponding chloro compound 6 and amine 5. 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.14 (s, 1H), 8.00 (s, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.69 (dd, J=8.4, 1.4 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.02 (dd, J=8.4, 1.8 Hz, 1H), 6.68 (s, 1H), 4.04 (s, 3H), 3.85 (t, J=4.7 Hz, 4H), 3.73 (t, J=4.8 Hz, 4H), 3.59 (h, J=4.7, 4.0 Hz, 7H), 3.30 (s, 2H), 3.08 (dd, J=8.8, 6.8 Hz, 2H), 2.49-2.39 (m, 4H), 2.31 (s, 3H), 2.17 (s, 3H); HPLC purity: 99.16%; LCMS Calculated for C33H40N8O2 (free base): 580.72; observed: 581.50(M+1).
To a stirred solution of compound 1 (2 g, 1 eq) and compound 2 (0.35 mL, 1 eq) in TEA (16 mL, 20 eq), copper iodide (0.112 g, 0.1 eq) and Pd(PPh)3Cl2 (0.416 g, 0.1 eq)) were added and stirred at rt for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the title compound 3. LCMS (m/z): 266.05 (M+1).
To a stirred solution of compound 3 (1.44 g, 1 eq) in ethanol (25 mL), pt (O) (0.150 g) was added and stirred under hydrogen atmosphere (balloon pressure) at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite. The filtrate was evaporated under reduced pressure to obtain a crude residue. The crude product was purified by column chromatography to afford the title compound 4. LCMS (m/z): 270.15 (M+1).
To a stirred solution of compound 4(0.62 g, 1 eq) in DCM (10 mL), TEA (0.48 mL, 1.5 eq) was added and stirred for 15 min followed by the slow addition of mesyl chloride (0.21 mL, 1.2 eq) at 0° C. The reaction mixture was stirred at rt for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water, extracted with DCM (3×25 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford compound 5. LCMS (m/z): 336.1 (M+1).
To a stirred solution of compound 5 (0.6 g, 1 eq) and phthalimide (0.394 g, 1.5 eq) in DMF (10 mL), potassium carbonate (0.370 g, 1.5 eq) was added and stirred heated at 80° C. for 3h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 6. LCMS (m/z): 399.1 (M+1).
The title compound have been synthesized by following the general procedure described above for Boronate ester preparation by using bromo compound 6 and Bis (pinacolato)diboron. LCMS (m/z): 446.05 (M+1).
Step-6 : Synthesis of 2-(3-(6-(6-chloro-2-morpholinopyrimidin-4-yl)-1-methyl-1H-indazol-3-yl)propyl)isoindoline-1,3-dione (9)
The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using chloro compound 8 and Boronate ester. LCMS (m/z): 517.05 (M+1).
The title compound has been synthesized by following the general procedure described above for Buchwald coupling by using chloro compound 9 and amine compound 10. LCMS (m/z): 627.05 (M+1).
To a stirred solution of compound 1 (0.25 g, 1 eq) in ethanol (10 mL), hydrazine monohydrate (0.04 μL, 2 eq) was added and stirred at 95° C. for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (2×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the title compound 4. The compound was taken in methanol (5 mL), methanol.HCl (0.2 mL) was added and stirred at rt for 30 min. the reaction mixture was evaporated under reduced pressure and purified by washing with ether to afford title compound as HCl salt. 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 8.05 (s, 4H), 7.94 (d, J=8.5 Hz, 1H), 7.60-7.49 (m, 2H), 7.31 (d, J=3.1 Hz, 1H), 7.14 (d, J =8.8 Hz, 1H), 6.80 (s, 1H), 6.40 (d, J=3.1 Hz, 1H), 4.08 (s, 3H), 4.00-3.82 (m, 4H), 3.77 (d, J=4.8 Hz, 7H), 3.04 (t, J=7.6 Hz, 2H), 2.89 (h, J=5.9 Hz, 2H), 2.06 (p, J=7.6 Hz, 2H); HPLC purity: 96.56%; LCMS Calculated for C28H32N8O (free base): 496.61:observed: 497.45 (M+1).
To a stirred solution of compound 1 (0.6 g, 1 eq) in DMF (5 mL), sodium hydride (0.182 g, 1.5 eq) was added at 0° C. and stirred for 15 min followed by the addition of compound 2 (0.742 g, 1.5 eq) at same temperature. The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (2×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 20% EtOAc-hexane to afford title compound 3. LCMS (m/z): 310.10 (M+1).
To a stirred solution of compound 3 (0.8 g, 1 eq) in acetonitrile (10 mL), selectfluor (1.2 g, 1.4 eq) was added at room temperature. The reaction mixture was stirred at 40° C. for 36 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (2×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 30% EtOAc-hexane to afford the title compound 4. Structure has been confirmed by NOE. LCMS (m/z): 328.05 (M+1).
The title compound has been synthesized by following the general procedure described above for reduction using the nitro compound 4 and Fe/NH4Cl. LCMS (m/z): 298.15 (M+1).
N-(4-(4-fluoro-1-(4-methoxybenzyl)-1H-pyrazol-5-yl) phenyl)-6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine (7): The title compound has been synthesized by following the general procedure described above for Buchwald Coupling by using corresponding chloro compound 6 and amine 5. LCMS (m/z): 591.45 (M+1).
6-(1,3-dimethyl-1H-indazol-6-yl)-N-(4-(4-fluoro-1-(4-methoxybenzyl)-1H-pyrazol-5-yl)phenyl)-2-morpholinopyrimidin-4-amine (7): The title compound has been synthesized by following the general procedure described above for Buchwald Coupling by using corresponding chloro compound 6 and amine 5. LCMS (m/z): 605.60 (M+1).
N-(4-(4-fluoro-1H-pyrazol-5-yl)phenyl)-6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: A stirred solution of corresponding compound 7 (0.04 g, 1 eq) in TFA (5 mL) was stirred at reflux temperature for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was quenched with saturated sodium bicarbonate solution and extracted with 10% MeOH-DCM (2×20 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by preparative HPLC to afford the title compound. 41 NMR (400 MHz, CD3OD) δ: 8.23 (s, 1H), 8.03(s, 1H), 7.82-7.72 (m, 7H), 6.67 (s, 1H), 4.14 (s, 3H), 3.93-3.81 (m, 8H); HPLC purity: 98.07%; LCMS Calculated for C25H23FN8O: 470.20; Observed: 471.30 (M+1).
6-(1,3-dimethyl-1H-indazol-6-yl)-N-(4-(4-fluoro-1H-pyrazol-5-yl)phenyl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the procedure described above using corresponding compound 7 and TFA. 1H NMR (400 MHz, CD3OD) δ: 8.12 (s, 1H), 7.80-7.74 (m, 7H), 6.64 (s, 1H), 4.04 (s, 3H), 3.92-3.80 (m, 8H), 2.55 (s, 3H); HPLC purity: 97.97%; LCMS Calculated for C26H25FN8O: 484.21; Observed: 485.35 (M+1).
To a stirred solution of compound 1 (2 g, 1 eq) in DMF (40 mL), K2CO3 (5.87 g, 3 eq) was added and stirred for 15 min followed by the addition of compound 2 (1.17 g, 1 eq). The reaction mixture was stirred at 75° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice cold water and extracted with ethyl acetate (3×20 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 50% EtOAc-hexane to afford the title compounds 3 and 3a. LCMS (m/z): 205.00 (M+1).
4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (4): To a stirred solution of compound 3 (1.6 g, 1 eq) in ethanol (100 mL), iron powder (2.19 g, 5 eq), water (50 mL) and ammonium chloride (2.09 g, 5 eq) were added slowly. The reaction mixture was heated to reflux for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 4. LCMS (m/z): 175.00 (M+1).
4-(3-methyl-4H-1,2,4-triazol-4-yl)aniline (4a): To a stirred solution of compound 3a (0.6 g, 1 eq) in ethanol (40 mL), iron powder (0.823 g, 5 eq), water (20 mL) and ammonium chloride (0.78 g, 5 eq) were added slowly. The reaction mixture was heated to reflux for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 4a. LCMS (m/z): 175.00 (M+1).
N-(4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6-(1-methyl-1H-indazol-6-371)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA/HCl) by using corresponding chloro compound 5 and amino compound 4. HPLC purity: 98.48%; 1H NMR (400 MHz, DMSO-d6) δ: 9.64 (s, 1H), 9.05 (s, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.89-7.81 (m, 3H), 7.77 (dd, J=8.7, 4.6 Hz, 3H), 6.73 (s, 1H), 4.13 (s, 3H), 3.86-3.77 (m, 4H), 3.74 (t, J=4.7 Hz, 4H), 2.45 (s, 3H); LCMS Calculated for C25H25N9O: 467.22; Observed: 468.30 (M+1).
6-(1,3-dimethyl-1H-indazol-6-yl)-N-(4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for Buchwald coupling by using corresponding chloro compound 5 and amine 4. HPLC purity: 98.44%; 1H NMR (400 MHz, DMSO-d6) δ: 10.46 (s, 1H), 9.19 (s, 1H), 8.15 (s, 1H), 7.85 (q, J=8.7 Hz, 5H), 7.59 (d, J=8.5 Hz, 1H), 6.80 (s, 1H), 4.06 (s, 3H), 3.89-3.80 (m, 4H), 3.76 (t, J=4.6 Hz, 4H), 2.97 (s, 3H), 2.38 (s, 3H); LCMS Calculated for C26H27N9O (free base): 481.23; Observed: 482.30 (M+1).
6-(1-methyl-1H-indazol-6-yl)-N-(4-(3-methyl-4H-1,2,4-triazol-4-yl)phenyl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for Buchwald coupling by using corresponding chloro compound 5 and amino compound 4a. HPLC purity: 98.90%; 1H NMR (400 MHz, DMSO-d6) δ: 10.30 (s, 1H), 8.25 (s, 1H), 8.15 (d, J=7.7 Hz, 2H), 7.91 (d, J=8.4 Hz, 3H), 7.70 (d, J=8.7 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 6.81 (s, 1H), 4.14 (s, 3H), 3.88-3.81 (m, 4H), 3.75 (t, J=4.4 Hz, 4H), 2.45 (s, 3H); LCMS Calculated for C25H25N9O (free base): 467.22; Observed: 468.20 (M+1).
6-(1,3-dimethyl-1H-indazol-6-yl)-N-(4-(3-methyl-4H-1,2,4-triazol-4-yl)phenyl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for Buchwald coupling by using corresponding chloro compound 5 and amino compound 4a. HPLC purity: 99.31%; 1H NMR (400 MHz, DMSO-d6) δ: 10.44 (s, 1H), 8.17 (d, J=7.2 Hz, 2H), 7.88 (dd, J=23.1, 8.4 Hz, 3H), 7.61 (dd, J=16.5, 8.6 Hz, 3H), 6.81 (s, 1H), 4.05 (s, 3H), 3.89-3.81 (m, 4H), 3.79-3.71 (m, 4H), 2.45 (s, 6H); LCMS Calculated for C26H27N90 (free base): 481.23; Observed: 482.25 (M+1).
Step 1: Synthesis of diethyl 2-(5-bromo-3-nitropyridin-2-yl) malonate (2)
To a stirred solution of diethylmalonate (3.27 mL, 1 eq) in DMF (30 mL), NaH (0.86 g, 1.7 eq) was added portion wise at 0° C. and stirred for 15 min followed by the addition of 5-bromo-2-chloro-3-nitropyridine 1 (3 g, 1 eq).The reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with diethyl ether (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 2. LCMS (m/z): 361.05 (M+1).
A stirred solution of compound 2 (4.1 g, 1 eq) in 6 N HCl(30 mL) was heated to reflux for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed with brine. The organic extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 3. LCMS (m/z): 218.95 (M+2).
To a stirred solution of compound 3(1.73 g, 1 eq) in ethanol (10 mL), iron powder (1.78 g, 4 eq), water (10 mL) and ammonium chloride (1.7 g,4 eq) were added slowly. The reaction mixture was heated to reflux for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed with brine. The organic extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 4. LCMS (m/z): 188.90 (M+2).
To a stirred solution of compound 4 (1.15 g, 1 eq) in DCM (10 mL), acetic anhydride (0.99 mL,1.7 eq) and TEA (1 mL, 2.3 eq) were added and stirred at room temperature for 24 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (3×25 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 5. LCMS (m/z): 231.00 (M+2).
To a stirred solution of compound 5 (1.35 g,1 eq) in toluene (15 mL), potassium acetate (1.27 g, 2.2 eq), acetic anhydride (1.67 mL, 3 eq) and acetic acid (1.68 mL, 5 eq) was heated to reflux followed by the addition of isoamyl nitrite (1 mL, 1.25 eq) and refluxed for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (2×50 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 6. LCMS (m/z): 242.15 (M+2).
To a stirred solution of compound 6 (1.25 g, 1 eq) in methanol (15 mL), K2CO3 (2.15 g, 3 eq) was added and heated to reflux for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was dissolved in water and extracted with ethyl acetate (2×25 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 7. LCMS (m/z): 199.90 (M+1).
To a stirred solution of compound 7 (0.95 g,1 eq) in DMF (10 mL), NaH (0.29 g, 1.5 eq) was added and stirred at room temperature for 15 min followed by the addition of methyl iodide (0.45 mL, 1.5 eq). The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×25 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 8. LCMS (m/z): 211.90 (M+1).
The title compound has been synthesized by following the general procedure described above for Boronate ester preparation by using bromo compound 8 and Bis (pinacolato) diboron. LCMS (m/z): 259.90 (M+1).
The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using compound 10 and Boronate ester 9. 1H NMR (400 MHz, DMSO-d6) δ: 9.89 (s, 1H), 9.09 (d, J=1.8 Hz, 1H), 8.69 (t, J=1.3 Hz, 1H), 8.36 (d, J=1.0 Hz, 1H), 7.77-7.68 (m, 2H), 7.44-7.35 (m, 2H), 6.77 (s, 1H), 4.18 (s, 3H), 3.82-3.73 (m, 8H); HPLC purity: 99.46%; LCMS Calculated for C21H20ClN7O: 421.14; Observed: 422.20 (M+1).
To a stirred solution of compound 1 (0.2 g, 1 eq) in THF (3 mL),methyl magnesium iodide (0.496 g, 3 eq) was added at 0° C. and stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (2×25 mL). Combined organic extracts were washed with brine and dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 10% EtOAc-hexane to afford the title compound 3. LCMS (m/z): 217.95 (M+1).
To a stirred solution of compound 3 (0.09 g, 1 eq) in ethanol (1 mL), methyl hydrazine(0.5 mL) was added and heated at 80° C. for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (2×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 30% EtOAc-hexane to afford the title compound 4. LCMS (m/z): 227.90 (M+2).
The title compound has been synthesized by following the general procedure described above for Boronate ester preparation by using bromo compound 4 and Bis (pinacolato) diboron. LCMS (m/z): 192.00 (M+1, boronic acid).
The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using chloro compound 6 and Boronate ester 5. 1H NMR (400 MHz, DMSO-d6) δ: 10.06 (s, 1H), 9.00 (s, 1H), 8.64 (d, J=1.7 Hz, 1H), 7.73 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 6.77 (s, 1H), 4.09 (s, 3H), 3.86-3.73 (m, 8H),2.57 (s, 3H); HPLC purity: 98.62%; LCMS Calculated for C22H22ClN7O: 435.16; Observed: 436.30 (M+1).
The title compound has been synthesized by following the general procedure described above for Boronate ester preparation by using bromo compound 1 and Bis (pinacolato)diboron. LCMS (m/z): 178.00 (M +1; boronic acid).
The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using chloro compound 3 and Boronate ester 2. LCMS (m/z): 331.05 (M+1).
The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA/HCl) by using chloro compound 4 and amino compound 5. HPLC purity: 99.58%; 1H NMR (400 MHz, DMSO-d6) δ: 9.65 (s, 1H), 9.12 (d, J=1.8 Hz, 1H), 8.67 (s, 1H), 8.33 (s, 1H), 7.96-7.89 (m, 2H), 7.76 (d, J=8.3 Hz, 2H), 6.79 (s, 1H), 4.18 (d, J=1.4 Hz, 3H), 3.83 (d, J=4.9 Hz, 4H), 3.78-3.70 (m, 4H), 2.34 (s, 3H); LCMS Calculated for C24H24N10O: 468.21; Observed: 469.35 (M+1).
The title compound has been synthesized by following the general procedure described above for Buchwald coupling by using chloro compound 4 and amino compound 6. HPLC purity: 91.57%; 1H NMR (400 MHz, DMSO-d6) δ: 9.74 (s, 1H), 9.12 (d, J=1.8 Hz, 1H), 8.67 (s, 1H), 8.34 (s, 1H), 7.99 (d, J=8.3 Hz, 2H), 7.82 (d, J=8.4 Hz, 2H), 6.80 (s, 1H), 4.18 (s, 3H), 3.82-3.70 (m, 8H); LCMS Calculated for C23H22N10: 454.20; Observed: 455.30 (M+1).
To a stirred solution of compound 1 (4 g, 1 eq) in dry THF (10 mL), methyl magnesium iodide (9.91 g, 3 eq) was added at 0° C. and the resulting reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated NH4Cl solution. The residue was diluted with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 20% EtOAc-hexane to afford the title compound 2. LCMS (m/z): 217.85 (M+1).
To a stirred solution of compound 2 (1.5 g, 1 eq) in ethanol (20 mL), methyl hydrazine (2.5 g, 8 eq) was added and the resulting reaction mixture was stirred at 80° C. for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was diluted with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 10% EtOAc-hexane to afford the title compound 3. LCMS (m/z): 227.85 (M+1).
The title compound (crude product) has been synthesized by following the general procedure described above for Boronate ester preparation by using bromo compound 3 and Bis (pinacolato)diboron. LCMS (m/z): 191.00 (M+1).
The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using chloro compound 5 and Boronic acid 4. LCMS (m/z): 345.00 (M+1).
The title compound has been synthesized by following the general procedure described above for Buchwald coupling by using chloro compound 6 and amino compound 7. HPLC purity: 99.29%; 1H NMR (400 MHz, DMSO-d6) δ: 14.07 (s, 1H), 9.71 (s, 1H), 9.05 (s, 1H), 8.59 (s, 1H), 7.98 (d, J=8.3 Hz, 2H), 7.82 (d, J=8.4 Hz, 2H), 6.78 (s, 1H), 4.09 (s, 3H), 3.89-3.77 (m, 8H), 2.56 (s, 3H). LCMS Calculated for C24H24N10O: 468.21; Observed: 469.40 (M+1).
To a stirred solution of compound 1 (1.2 g, 1 eq) in dichloromethane (15 mL), N-methyl morpholine (1.36 mL, 2 eq), N, O-dimethyl hydroxyl amine hydrochloride (0.735 g, 1.2 eq) and EDCI.HCl (1.4 g, 1.2 eq) were added at −10° C. and stirred at room temperature for 15 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine and dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 50% EtOAc-hexane to afford the title compound 3. LCMS (m/z): 234.95 (M+1).
To a stirred solution of compound 3 (1 g, 1 eq) in THF (10 mL),methyl magnesium iodide (2.8 mL, 2 eq) was added at 0° C. and stirred at room temperature for 15 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (3×25 mL). Combined organic extracts were washed with brine and dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 30% EtOAc-hexane to afford the title compound 4. 1H NMR (400 MHz, CDCl3) δ: 8.61 (s, 1H), 7.45 (s, 1H), 2.68 (s, 3H).
To a stirred solution of compound 4 (0.3 g, 1 eq)in ethanol (5 mL), methyl hydrazine(0.16 mL, 2 eq)was added and heated at 50° C. for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate (2×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 20% EtOAc-hexane to afford the title compound 5. LCMS (m/z): 182.00 (M+1).
The title compound (crude product) has been synthesized by following the general procedure described above for Boronate ester preparation by using bromo compound 5 and Bis (pinacolato) diboron.
The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using chloro compound 7 and Boronate ester 6. 1H NMR (400 MHz, CDC13) δ: 8.98 (s, 1H), 8.32 (s, 1H), 7.48-7.41 (m, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.22 (s, 1H), 6.59 (s, 1H), 4.08 (s, 3H), 3.88-3.78 (m, 8H), 2.65 (s, 3H); HPLC purity: 99.02%; LCMS Calculated for C22H22ClN7O:435.16; Observed: 436.30 (M+1).
To a stirred solution of 1H-pyrazol-5-amine 1(10 g, 1 eq)in acetic acid (130 mL), methyl propiolate (11.09 g, 1.1 eq) was added and heated to reflux for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. To the oily residue ethanol, ethyl acetate and pentane were added and the obtained solid was filtered and dried to afford the title compound 2. LCMS (m/z): 136.05 (M+1).
To a stirred solution of compound 2 (6 g, 1 eq) in acetonitrile (60 mL), POBr3 (18.87 g, 1.5 eq) was added and heated to reflux for 6 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate (3×50 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 10% MeOH-DCM to afford the title compound 3.
To a stirred solution of compound 3 (6 g,1 eq) in DMF (60 mL), NaH (1.45 g, 1.2 eq) was added portion wise followed by the addition of methyl iodide (5.16 g, 1.2 eq) and stirred at room temperature for 15 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 10% EtOAc-hexane to afford the title compound 4. LCMS (m/z): 213.95 (M+2).
The title compound (crude product) has been synthesized by following the general procedure described above for Boronate ester preparation by using bromo compound 4 and Bis (pinacolato) diboron.
The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using compound 6 and Boronate ester 5. 1H NMR (400 MHz, DMSO-d6) δ: 9.86 (s, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.28-8.19 (m, 2H), 7.80-7.71 (m, 2H), 7.43-7.34 (m, 2H), 7.29 (s, 1H), 4.14 (s, 3H), 3.82-3.74 (m, 8H); HPLC purity: 96.95%; LCMS Calculated for C21H20ClN7O: 421.14; Observed: 422.25 (M+1).
To a stirred solution of compound 1 (4 g, 1 eq) in dichloromethane (50 mL), N-methyl morpholine (4.22 g, 1.2 eq), N, O-dimethyl hydroxyl amine hydrochloride (2.45 g, 1.2 eq) and EDCI.HCl (4.82 g, 1.2 eq) were added and stirred at room temperature for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine and dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 50% EtOAc-hexane to afford the title compound 3. 1H NMR (400 MHz, DMSO-d6) δ: 8.13-8.08 (m, 1H), 7.76-7.68 (m, 1H), 3.47 (s, 3H), 3.30 (s, 3H).
To a stirred solution of compound 3 (3 g, 1 eq) in THF (40 mL),methyl magnesium iodide (12.76 mL, 3 eq) was added at 0° C. and stirred at room temperature for 15 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine and dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 30% EtOAc-hexane to afford the title compound 4.
To a stirred solution of compound 4 (0.8 g, 1 eq)in ethanol (10 mL), methyl hydrazine(0.54 g, 2 eq)was added and stirred at room temperature for 15 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate (3×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 20% EtOAc-hexane to afford the title compound 5. LCMS (m/z): 181.90 (M+1).
The title compound has been synthesized by following the general procedure described above for Boronate ester preparation by using bromo compound 5 and Bis (pinacolato) diboron.
The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using chloro compound 7 and Boronate ester 6. 1H NMR (400 MHz, DMSO-d6) δ: 9.93 (s, 1H), 8.34 (d, J=8.3 Hz, 1H), 8.17 (d, J=8.3 Hz, 1H), 7.75 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 7.28 (s, 1H), 4.06 (s, 3H), 3.78-3.68 (m, 8H), 2.53 (s, 3H); HPLC purity: 98.85%; LCMS Calculated for C22H22ClN7O:435.16; Observed: 436.30 (M+1).
To a mixture of dichloro compound 1 (1 eq), boronic acid/boronate ester (1 eq) in 1,4-dioxane, 2M solution of potassium phosphate was added and purged with argon for 15 min followed by the addition of tetrakistriphenyl phosphine palladium (0.06 eq) and stirred at 90° C. for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated to dryness. The residue was taken in ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the desired product 2.
The following intermediates were prepared in a similar manner starting with appropriate boronic acid/boronate ester.
A mixture of corresponding chloro compound 2(1 eq), methyl 5-aminopicolinate3, (1 eq), cesium carbonate (1.5 eq) in 1,4-dioxane was taken and purged with argon for 10 min, followed by the addition of BINAP (0.22 eq) and purged argon for additional 5 min. Palladium acetate (0.2 eq) was added and stirred at 100° C. for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated to dryness. The residue was taken in ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the desired product 4.
The following compounds were prepared in a similar manner starting with appropriate chloro compound 2.
To a stirred solution of compound 4 (1 eq) in THF:H2O (1:1), lithium hydroxide (2 eq) in minimum amount of water was added and stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, excess of ethyl acetate was added and aqueous layer has been separated. Aqueous layer was acidified with 1N HCl, filtered off the solid obtained and dried in vacuo to afford acid 5. The crude product has been used as such for the next step without further purification.
The following compounds were prepared in a similar manner starting with appropriate ester compound.
To a mixture of Acid 5 (1 eq), HATU (1.5 eq) in DMF, DIPEA (2.5 eq) was added and stirred at room temperature for 10 min. Methyl amine hydrochloride (1.2 eq) was added slowly and stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, water was added and extracted with ethyl acetate. Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography/preparative HPLC to afford the desired product.
N-methyl-5-((6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)picolinamide: The title compound has been synthesized by following the general procedure described above for Amide coupling by using the corresponding Acid 5. 1H NMR (MeOD, 400 MHz) δ: 9.58 (s, 1H), 9.14 (s, 1H), 8.60 (s, 1H), 8.40 (d, J=8.3 Hz, 1H), 8.23 (d, J=8.8 Hz, 1H), 8.15 (d, J=8.2 Hz, 1H), 8.07 (d, J=8.6 Hz, 1H), 6.83 (s, 1H), 4.28 (s, 3H), 3.98-3.86 (m, 8H), 2.99 (s, 3H); HPLC purity: 95.35%; LCMS Calculated for C23H24N8O2 (free base): 444.20; Observed: 445.25 (M+1).
N-methyl-5-((6-(1-methyl-1H-benzo[d]imidazol-5-yl)-2-morpholinopyrimidin-4-yl)amino)picolinamide: The title compound has been synthesized by following the general procedure described above for Amide coupling by using the corresponding Acid 5. 1H NMR (DMSO-d6, 400 MHz) δ: 9.44 (s, 1H), 8.93 (s, 1H), 8.46 (d, J=4.3 Hz, 1H), 8.25 (dd, J=13.0, 8.6 Hz, 2H), 8.01 (t, J=8.9 Hz, 2H), 6.75 (s, 1H), 4.06 (s, 3H), 3.83-3.71 (m, 8H), 2.80 (s, 3H); HPLC purity: 95.82%; LCMS Calculated for C23H24N8O2 (free base): 444.20; Observed: 445.20(M+1).
N-methyl-5-((6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)picolinamide: The title compound has been synthesized by following the general procedure described above for Amide coupling by using the corresponding Acid 5. 1H NMR (DMSO-d6, 400 MHz) δ: 10.41 (s, 1H), 9.07-9.02 (m, 1H), 8.67 (q, J=5.2, 4.7 Hz, 1H), 8.32-8.23 (m, 2H), 8.15-8.01 (m, 2H), 7.89 (d, J=8.2 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 6.84 (s, 1H), 4.14 (s, 3H), 3.88-3.75 (m, 8H), 2.82 (d, J=4.9 Hz, 3H); HPLC purity: 96.23%; LCMS Calculated for C23H24N8O2 (free base): 444.20; Observed: 445.30 (M+1).
N-methyl-5-((6-(1-methyl-1H-indazol-5-yl)-2-morpholinopyrimidin-4-yl)amino)picolinamide: The title compound has been synthesized by following the general procedure described above for Amide coupling by using the corresponding Acid 5. 1H NMR (DMSO-d6, 400 MHz) δ: 10.47 (s, 1H), 9.03 (s, 1H), 8.67 (d, J=6.3 Hz, 1H), 8.45 (s, 1H), 8.32-8.19 (m, 2H), 8.05 (d, J=8.4 Hz, 1H), 7.98 (d, J=8.6 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 6.79 (s, 1H), 4.09 (s, 3H), 3.86-3.80 (m, 4H), 3.78-3.72 (m, 4H), 2.81 (d, J=4.4 Hz, 3H); HPLC purity: 97.25%; LCMS Calculated for C23H24N8O2 (free base): 444.20; Observed: 445.30 (M+1).
To a stirred solution of 4-(4,6-dichloropyrimidin-2-yl)morpholino 1(1 g, 1 eq) and 4-chloroaniline 2 (0.547 g, 1 eq) in isopropanol (10 mL), concentrated HCl (2 mL) was added and heated to reflux at 100° C. for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was taken in ethyl acetate (50 mL), washed with 1 N HCl, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 20% EtOAc-hexane to afford the title compound 3. LCMS (m/z):325.20(M+1).
N-(4-chlorophenyl)-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using chloro compound 3 and corresponding boronic acid. 1H NMR (400 MHz, DMSO-d6) δ: 9.94 (s, 1H), 9.62 (s, 1H), 8.53 (s, 1H), 8.18 (dd, J=8.8, 1.6 Hz, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.78-7.69 (m, 2H), 7.43-7.34 (m, 2H), 6.77 (s, 1H), 4.14 (s, 3H), 3.82-3.70 (m, 8H); HPLC purity: 98.73%; LCMS Calculated for C22H21ClN6O (free base): 420.15; Observed: 421.20 (M+1).
N-(4-chlorophenyl)-6-(1-methyl-1H-benzo[d]imidazol-5-yl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using chloro compound 3 and corresponding boronic acid. 1H NMR (400 MHz, DMSO-d6) δ: 10.14 (s, 1H), 9.63 (s, 1H), 8.42 (s, 1H), 8.19 (d, J=8.8 Hz, 1H), 8.08 (d, J=8.8 Hz, 1H), 7.79-7.70 (m, 2H), 7.44-7.35 (m, 2H), 6.80 (s, 1H), 4.10 (s, 3H), 3.84-3.69 (m, 8H); HPLC purity: 96.31%; LCMS Calculated for C22H21ClN6O (free base): 420.15; Observed: 421.15 (M+1).
The title compound has been synthesized by following the general procedure described above for Buchwald Coupling by using the chloro compound 1 and 4-methyl aniline 2. LCMS (m/z): 305.15 (M+1).
6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-morpholino-N-(p-tolyl)pyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using chloro compound 3 and corresponding boronic acid. 1H NMR (400 MHz, CD3OD) δ: 9.57 (s, 1H), 8.51 (s, 1H), 8.06 (s, 2H), 7.52 (d, J=7.8 Hz, 2H), 7.27 (d, J=7.9 Hz, 2H), 6.61 (s, 1H), 4.26 (s, 3H), 3.95-3.82 (m, 8H), 2.37 (s, 3H); HPLC purity: 99.17%; LCMS Calculated for C23H24N6O (free base): 400.20; Observed: 401.15 (M+1).
6-(1-methyl-1H-benzo[d]imidazol-5-yl)-2-morpholino-N-(p-tolyl)pyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using chloro compound 3 and corresponding boronic acid. 1H NMR (400 MHz, CD3OD) δ: 9.56 (s, 1H), 8.34 (s, 1H), 8.16 (d, J=8.6 Hz, 1H), 8.06 (d, J=8.7 Hz, 1H), 7.54-7.47 (m, 2H), 7.26 (d, J=8.0 Hz, 2H), 6.58 (s, 1H), 4.22 (s, 3H), 3.93-3.80 (m, 8H), 2.37 (s, 3H); HPLC purity: 95.91%; LCMS Calculated for C23H24N6O (free base): 400.20; Observed: 401.20 (M+1).
6-(1-methyl-1H-indazol-6-yl)-2-morpholino-N-(p-tolyl)pyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using chloro compound 3 and corresponding Boronate ester. 1H NMR (400 MHz, DMSO-d6) δ: 9.31 (s, 1H), 8.21 (s, 1H), 8.09 (s, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.55 (d, J=8.2 Hz, 2H), 7.13 (d, J=8.1 Hz, 2H), 6.67 (s, 1H), 4.12 (s, 3H), 3.84-3.70 (m, 8H), 2.27 (s, 3H); HPLC purity: 99.49%; LCMS Calculated for C23H24N6O: 400.16; Observed: 401.25 (M+1).
6-(1-methyl-1H-indazol-5-yl)-2-morpholino-N-(p-tolyl)pyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using chloro compound 3 and corresponding boronic acid. 1H NMR (400 MHz, DMSO-d6) δ: 8.35 (s, 1H), 8.24 (s, 1H), 7.82 (t, J=8.4 Hz, 2H), 7.56 (d, J=7.9 Hz, 2H), 7.20 (d, J=8.0 Hz, 2H), 6.66 (s, 1H), 4.10 (s, 3H), 3.85-3.70 (m, 8H), 2.29 (s, 3H); HPLC purity: 97.24%; LCMS Calculated for C23H24N6O (free base): 400.20; Observed: 401.20 (M+1).
To a stirred solution of 4-bromobenzene-1,2-diamine 1 (5 g,1 eq) and trimethylorthoformate (73 mL) in DMF (36 mL), conc. HCl (2.5 mL) was added drop wise and the reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×100 mL). Combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 60% EtOAc-hexane to afford the title compound 3. LCMS (m/z): 198.90(M+1).
To a stirred solution of 6-bromo-1H-benzo[d]imidazole 3(1 g, 1 eq) in THF (20 mL), triethylamine (0.9 mL,1.3 eq) was added and stirred for 15 min followed by the addition of Boc anhydride(1.5 mL,1.3 eq).The reaction mixture was stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (2×50 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 30% EtOAc-hexane to afford the title compound 4. LCMS (m/z): 196.85(M-Boc).
The title compound (crude product) has been synthesized by following the general procedure described above for Boronate ester preparation by using bromo compound 4 and Bis (pinacolato)diboron. LCMS (m/z): 245.10 (M-Boc).
The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using compound 6 and Boronate ester 5. 1H NMR (400 MHz, DMSO-d6) δ: 10.08 (s, 1H), 9.64 (s, 1H), 8.41 (s, 1H), 8.16 (d, J=8.6 Hz, 1H), 7.97 (d, J=8.6 Hz, 1H), 7.75 (d, J=8.6 Hz, 2H), 7.43-7.34 (m, 2H), 6.78 (s, 1H), 3.80-3.72(m, 8H); HPLC purity: 97.40%; LCMS Calculated for C21H19ClN6O: 406.13; Observed: 407 (M+1).
To a stirred solution of 4-bromo-2-fluoro-1-nitrobenzene1(2 g,1 eq), cyclopropylamine (0.518 g, 1 eq)in DMF (10 mL), DIPEA (2.34 g, 2 eq) was added and stirred at room temperature for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 2% EtOAc-hexane to afford the title compound 3. LCMS (m/z):257.00 (M+1).
To a stirred solution of 5-bromo-N-cyclopropyl-2-nitroaniline3(2.3 g,1 eq), in methanol (20 mL), Raney nickel (2.6 g) was added and stirred at room temperature for 18 h under hydrogen atmosphere. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford the title compound 4. 96%; LCMS (m/z):227.15 (M+1).
To a stirred solution of 5-bromo-N1-cyclopropylbenzene-1,2-diamine 4 (0.3 g,1 eq), in DMF (5 mL), trimethylorthoformate (4.4 mL) and Conc. HCl (0.15 mL)were added and stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (2×25 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 50% EtOAc-hexane to afford the title compound 5. LCMS (m/z):238.90 (M+1).
The title compound (crude product) has been synthesized by following the general procedure described above for Boronate ester preparation by using bromo compound 5 and Bis (pinacolato)diboron. LCMS (m/z):285.10 (M+1).
The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using compound 7 and Boronate ester 6. 1H NMR (400 MHz, DMSO-d6) δ: 9.98 (s, 1H), 9.66 (s, 1H), 8.46 (s, 1H), 8.19 (d, J=8.6 Hz, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.78-7.70 (m, 2H), 7.44-7.35 (m, 2H), 6.78 (s, 1H), 3.92 (tt, J=7.4, 4.3 Hz, 1H), 3.80-3.72 (m, 8H), 1.31-1.19 (m, 4H); HPLC purity: 96.83%; LCMS Calculated for C24H23ClN6O: 446.16; Observed: 447.20 (M+1).
To a mixture of dichloro compound 1 (1 eq), boronic acid/boronate ester (1 eq) in 1,4-dioxane, 2M solution of potassium phosphate was added and purged with argon for 15 min followed by the addition of tetrakistriphenyl phosphine palladium (0.06 eq) and stirred at 90° C. for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated to dryness. The residue was taken in ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the desired product 2.
The following intermediates were prepared in a similar manner starting with appropriate boronic acid/boronate ester.
A mixture of corresponding chloro compound 2 (1 eq), methyl 5-aminopicolinate3 (1 eq), cesium carbonate (1.5 eq) in 1,4-dioxane was taken and purged with argon for 10 min, followed by the addition of BINAP (0.22 eq) and purged with argon for additional 5 min. Palladium acetate (0.2 eq) was added and stirred at 100° C. for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated to dryness. The residue was taken in ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the desired product 4.
The following compounds were prepared in a similar manner starting with appropriate chloro compound 2.
To a stirred solution of compound 4 (1 eq) in THF:H2O (1:1), lithium hydroxide (2 eq) in minimum amount of water was added and stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, excess of ethyl acetate was added and aqueous layer has been separated. Aqueous layer was acidified with 1N HCl, filtered off the solid obtained and dried in vacuo to afford acid 5. The crude product has been used as such for the next step without further purification.
The following compounds were prepared in a similar manner starting with appropriate ester compound.
To a mixture of Acid 5(1 eq), HATU (1.5 eq) in DMF, DIPEA (2.5 eq) was added and stirred at room temperature for 10 min. Methyl amine hydrochloride (1.2 eq) was added slowly and stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, water was added and extracted with ethyl acetate. Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography/preparative HPLC to afford the desired product.
5-46-(1-cyclopropyl-1H-indazol-6-yl)-2-morphohnopyrimidin-4-yl)amino)-N-methylpicanamide: The title compound has been synthesized by following the general procedure described above for Amide coupling by using the corresponding Acid5and methyl amine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ: 10.28 (s, 1H), 9.03 (d, J=2.5 Hz, 1H), 8.66 (q, J=4.6 Hz, 1H), 8.28 (d, J=7.1 Hz, 2H), 8.11-8.01 (m, 2H), 7.88 (d, J=8.5 Hz, 1H), 7.80 (d, J=8.5 Hz, 1H), 6.83 (s, 1H), 3.89-3.72 (m, 9H), 2.81 (d, J=4.6 Hz, 3H), 1.20-1.15 (m, 4H); HPLC purity: 96.58%; LCMS Calculated for C25H26N8O2: 470.22; Observed: 471.25 (M+1).
5-((6-(1H-indazol-5-yl)-2-morphohnopyrimidin-4-yl)amino)-N-methylpicanamide: The title compound has been synthesized by following the general procedure described above for Amide coupling by using the corresponding Acid 5 and methyl amine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ: 10.50 (s, 1H), 9.03 (d, J=2.5 Hz, 1H), 8.69 (q, J=4.9 Hz, 1H), 8.45 (s, 1H), 8.32-8.22 (m, 2H), 8.06 (d, J=8.6 Hz, 1H), 7.94 (d, J=9.0 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 6.78 (s, 1H), 3.84-3.74 (m, 8H), 2.81 (d, J=4.6 Hz, 3H); HPLC purity: 93.46%; LCMS Calculated for C22H22N8O2: 430.19; Observed: 431.25 (M+1).
5-((6-(1H-benzo[d]imidazol-6-yl)-2-morphohnopyrimidin-4-yl)amino)-N-methylpicanamide: The title compound has been synthesized by following the general procedure described above for Amide coupling by using the corresponding Acid5and methyl amine hydrochloride. 1H NMR (400 MHz, Methanol-d4) δ: 8.98 (d, J=2.5 Hz, 1H), 8.35 (s, 1H), 8.32-8.23 (m, 2H), 8.01 (t, J=8.6 Hz, 2H), 7.68 (d, J=8.6 Hz, 1H), 6.68 (s, 1H), 3.95-3.82 (m, 8H), 2.96 (s, 3H); HPLC purity: 99.17%; LCMS Calculated for C22H22N8O2: 430.19; Observed: 431.25 (M+1).
5-((6-(1-(cyclopropylmethyl)-1H-benzo[d]imidazol-6-yl)-2-morphohnopyrimidin-4-yl)amino)-N-methylpicanamide: The title compound has been synthesized by following the general procedure described above for Amide coupling by using the corresponding Acid5and methyl amine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ: 9.91 (s, 1H), 8.99 (d, J=2.5 Hz, 1H), 8.60 (q, J=4.7 Hz, 1H), 8.38 (s, 1H), 8.31-8.20 (m, 2H), 8.00 (d, J=8.6 Hz, 1H), 7.92 (dd, J=8.7, 1.6 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 6.76 (s, 1H), 4.21 (d, J=7.1 Hz, 2H), 3.86-3.70 (m, 8H), 2.81 (d, J=4.7 Hz, 3H), 1.36-1.28 (m, 1H), 0.64-0.44 (m, 4H); HPLC purity: 98.07%; LCMS Calculated for C26H28N8O2: 484.23; Observed: 485.25 (M+1).
5-((6-(1-cyclopropyl-1H-benzo[d]imidazol-6-yl)-2-morphohnopyrimidin-4-yl)amino)-N-methylpicolinamide: The title compound has been synthesized by following the general procedure described above for Amide coupling by using the corresponding Acid 5 and methyl amine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ: 9.96 (s, 1H), 8.99 (d, J=2.5 Hz, 1H), 8.76 (s, 1H), 8.60 (q, J=4.8 Hz, 1H), 8.33 (s, 1H), 8.24 (dd, J=8.8, 2.5 Hz, 1H), 8.04 (dd, J=20.4, 8.5 Hz, 2H), 7.82 (d, J=8.6 Hz, 1H), 6.77 (s, 1H), 3.86-3.79 (m, 4H), 3.78-3.71 (m, 5H), 2.81 (d, J=4.8 Hz, 3H), 1.26-1.13 (m, 4H); HPLC purity: 95.47%; LCMS Calculated for C25H26N8O2: 470.22; Observed: 471.25 (M+1).
5-((6-(1-(cyclopropylmethyl)-1H-benzo[d]imidazol-5-yl)-2-morphohnopyrimidin-4-yl)amino)-N-methylpicanamide: The title compound has been synthesized by following the general procedure described above for Amide coupling by using the corresponding Acid5and methyl amine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ: 10.33 (s, 1H), 9.74 (d, J=6.5 Hz, 1H), 9.03 (t, J=2.6 Hz, 1H), 8.67-8.59 (m, 1H), 8.46 (s, 1H), 8.32-8.14 (m, 2H), 8.02 (dd, J=14.1, 8.7 Hz, 1H), 7.54 (s, 1H), 6.86 (d, J=6.6 Hz, 1H), 6.55 (s, 1H), 4.43 (dd, J=25.4, 7.3 Hz, 2H), 3.82-3.74 (m, 8H), 2.81 (d, J=4.7 Hz, 3H), 1.50-1.48 (m, 1H), 0.74-0.52 (m, 4H); HPLC purity: 95.78%; LCMS Calculated for C26H28N8O2: 484.23; Observed: 485.30 (M+1).
5-((6-(2-(cyclopropylmethyl)-2H-indazol-6-yl)-2-morphohnopyrimidin-4-yl)amino)-N-methylpicolinamide: The title compound has been synthesized by following the general procedure described above for Amide coupling by using the corresponding Acid5and methyl amine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ: 9.07 (d, J=2.4 Hz, 1H), 8.73 (q, J=4.8 Hz, 1H), 8.52 (s, 1H), 8.36-8.26 (m, 2H), 8.09 (d, J=8.6 Hz, 1H), 7.87 (d, J=8.7 Hz, 1H), 7.56 (d, J=8.9 Hz, 1H), 6.88 (s, 1H), 4.34 (d, J=7.3 Hz, 2H), 3.84-3.74 (m, 8H), 2.82 (d, J=4.5 Hz, 3H), 1.45-1.36 (m, 1H), 0.58 (dt, J=8.0, 2.9 Hz, 2H), 0.62-0.43 (m, 2H); HPLC purity: 96.85%; LCMS Calculated for C26H28N8O2: 484.23; Observed: 485.25 (M+1).
5-((6-(2-(cyclopropylmethyl)-2H-indazol-5-yl)-2-morphohnopyrimidin-4-yl)amino)-N-methylpicolinamide: The title compound has been synthesized by following the general procedure described above for Amide coupling by using the corresponding acid 5 and methyl amine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ: 10.65 (s, 1H), 9.04 (d, J=2.5 Hz, 1H), 8.70 (q, J=4.9 Hz, 1H), 8.62 (s, 1H), 8.43 (s, 1H), 8.29 (dd, J=8.7, 2.4 Hz, 1H), 8.07 (d, J=8.6 Hz, 1H), 7.77 (q, J=9.0 Hz, 2H), 6.78 (s, 1H), 4.33 (d, J=7.2 Hz, 2H), 3.86-3.72 (m, 8H), 2.81 (d, J=4.6 Hz, 3H), 1.42-1.34 (m, 1H), 0.60-0.40 (m, 4H); HPLC purity: 98.29%; LCMS Calculated for C26H28N8O2: 484.23; Observed: 485.30 (M+1).
To a mixture of dichloro compound 1 (1 eq), boronic acid/boronate ester (1 eq) in 1,4-dioxane, 2M solution of potassium phosphate was added and purged with argon for 15 min followed by the addition of tetrakistriphenyl phosphine palladium (0.06 eq) and stirred at 90° C. for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated to dryness. The residue was taken in ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the desired product 2.
The following intermediates were prepared in a similar manner starting with appropriate boronic acid/boronate ester.
A mixture of corresponding chloro compound 2(1 eq), methyl 4-aminobenzoate 3, (1 eq), cesium carbonate (1.5 eq) in 1,4-dioxane was taken and purged with argon for 10 min, followed by the addition of BINAP (0.22 eq) and purged argon for additional 5 min. Palladium acetate (0.2 eq) was added and stirred at 100° C. for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated to dryness. The residue was taken in ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the desired product 4.
The following compounds were prepared in a similar manner starting with appropriate chloro compound.
To a stirred solution of ester 3 (1 eq) in MeOH:H2O (1:1) was added sodium hydroxide (2 eq) and refluxed for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was dissolved in water, washed with ethyl acetate. Aqueous layer was acidified with 1N HCl and evaporated under reduced pressure to afford the crude product and used as such for the next step.
The crude following compounds were prepared in a similar manner starting with appropriate ester compound.
To a mixture of Acid 5 (1 eq), PYBOP (1 eq) in DMF, DIPEA (2.5 eq) was added and stirred at room temperature for 10 min. Methyl amine hydrochloride (2 eq) was added slowly and stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, water was added and extracted with ethyl acetate. Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by preparative HPLC to afford the desired product.
N-methyl-4-((6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-yl)-amino)-benzamide: The title compound has been synthesized by following the general procedure described above for Amide coupling by using the corresponding Acid 5 and methyl amine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ: 9.98 (brs, 1H), 9.61 (s, 1H), 8.51 (s, 1H), 8.40-8.30 (m, 1H), 8.20 (d, J=8.6 Hz, 1H), 7.98 (d, J=8.6 Hz, 1H), 7.88-7.75 (m, 4H), 6.82 (s, 1H), 4.15 (s, 3H), 3.87-3.74 (m, 8H), 2.77 (d, J=4.2 Hz, 3H); HPLC purity: 99.42%; LCMS Calculated for C24H25N7O2: 443.21; Observed: 444.20 (M+1).
N-methyl-4-((6-(1-methyl-1H-benzo[d]imidazol-5-yl)-2-morpholinopyrimidin-4-yl)amino) benzamide: The title compound has been synthesized by following the general procedure described above for Amide coupling by using the corresponding Acid 5 and methyl amine hydrochloride. 1H NMR (400 MHz, CD3OD) δ: 9.59 (s, 1H), 8.38 (d, J=1.4 Hz, 1H), 8.18 (d, J=8.7 Hz, 1H), 8.10 (dd, J=8.7, 1.5 Hz, 1H), 7.94-7.86 (m, 2H), 7.78 (d, J=8.3 Hz, 2H), 6.68 (s, 1H), 4.23 (s, 3H), 3.96-3.82 (m, 8H), 2.93 (s, 3H); HPLC purity: 98.44%; LCMS Calculated for C24H25N7O2: 443.21; Observed: 444.25 (M+1).
N-methyl-4-((6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl) amino)benzamide: The title compound has been synthesized by following the general procedure described above for Amide coupling by using the corresponding Acid5 and methyl amine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ: 10.05 (s, 1H), 8.36-8.29 (m, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 7.92-7.67 (m, 6H), 6.78 (s, 1H), 4.14 (s, 3H), 3.84-3.75 (m, 8H), 2.77 (d, J=4.2 Hz, 3H); HPLC purity: 99.71%; LCMS Calculated for C24H25N7O2: 443.21; Observed: 444.25 (M+1).
N-methyl-4-((6-(1-methyl-1H-indazol-5-yl)-2-morpholinopyrimidin-4-yl)amino)benzamide: The title compound has been synthesized by following the general procedure described above for Amide coupling by using the corresponding Acid5 and methyl amine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ: 10.24 (s, 1H), 8.42 (s, 1H), 8.34 (d, J=4.9 Hz, 1H), 8.22 (s, 1H), 7.95 (d, J=9.0 Hz, 1H), 7.89-7.71 (m, 5H), 6.72 (s, 1H), 4.10 (s, 3H), 3.83-3.74 (m, 8H), 2.77 (d, J=4.2 Hz, 3H); HPLC purity: 95.46%; LCMS Calculated for C24H25N7O2: 443.21; Observed: 444.25 (M+1).
The title compound has been synthesized by following the general procedure described above for Amide coupling by using the corresponding Acid 1 and cyclopropyl amine. 1H NMR (400 MHz, DMSO-d6) δ: 9.91 (s, 1H), 8.97 (d, J=2.5 Hz, 1H), 8.55 (d, J=5.0 Hz, 1H), 8.31-8.18 (m, 3H), 8.00 (d, J=8.6 Hz, 1H), 7.91 (dd, J=8.6, 1.7 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 6.75 (s, 1H), 3.92 (s, 3H), 3.82-3.74 (m, 8H), 2.90-2.85 (m, 1H), 0.74-0.63 (m, 4H); HPLC purity: 98.41%; LCMS Calculated for C25H26N8O2: 470.22; Observed: 471.35 (M+1).
To a stirred solution of 4-bromo/5-bromo-2-fluoro-1-nitrobenzene 1 (1 eq), respective amines (1 eq) in DMF (10 mL), DIPEA (2 eq) were added and stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 1% EtOAc-hexane to afford the intermediate 3.
1NMR (400 MHz, CDCl3) δ: 8.30 (d, J = 2.4 Hz, 1H), 8.09 (s, 1H), 7.47-7.44 (m, 1H), 6.62 (d, J = 9.2 Hz, 1H) 4.06-4.00 (m, 1H), 2.54-2.47 (m, 2H), 2.07-1.83 (m, 4H);
To a stirred solution of respective compound 3 (1 eq), in methanol, Raney nickel (50% w/w) was added and stirred at room temperature for 18 h under hydrogen atmosphere. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered and evaporated under reduced pressure to afford the following intermediates 4.
To a stirred solution of the respective compound 4 (1 eq), in DMF, trimethyl orthoformate (15 eq) and Conc. HCl (cat.,) were added and stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 30% EtOAc-hexane to afford the following intermediates.
The respective compound 4 (1 eq) was taken in CH3COOH and heated at 110° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was neutralized with satd. sodium bicarbonate and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 50% EtOAc-hexane to afford the following intermediates.
The following intermediates were synthesized by following the general procedure described above for Boronate ester preparation by using the respective bromo intermediates.
To a stirred solution of 6-bromo indazole/5-bromo indazole 1/2 (1 eq) and corresponding boronic acid in dichloroethane, Na2CO3 (2 eq) was added under oxygen atmosphere and stirred for 5 min followed by the addition of hot solution of copper acetate (1 eq) and pyridine (1 eq) in dichloroethane. The reaction mixture was heated to 75° C. for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution, diluted with dichloromethane and filtered through celite. The separated organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 20% EtOAc-hexane to afford compound 3a & 4a.
To a stirred solution of 6-bromo indazole/5-bromo indazole 1/2 ((1 eq) in DMF, NaH (1.3 eq) was added portion wise at 0° C. and stirred for 15 min followed by the addition of alkyl halide/trifluoroethyl trifluoromethane sulfonate (1.5 eq). The reaction mixture was stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water, extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 10% to 25% EtOAc-hexane to afford compound 3b-c & 4b-c.
To a stirred solution of 6-bromo indazole/5-bromo indazole 1/2 (1 eq) in acetonitrile, K2CO3 (3 eq) was added followed by the addition of corresponding alkyl halide (1.5 eq). The reaction mixture was heated at 100° C. for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered and washed with ethyl acetate (3×25 mL). The combined organic extracts were evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 60-120 mesh using 10% methanol in ethyl acetate to afford compound 3e-i, 3k & 4i.
To a stirred solution of 6-bromo indazole/5-bromo indazole 1/2 (1 eq) in DMF, K2CO3 (3 eq) and 3-chloro-l-bromo propane (2 eq) were added and heated at 50° C. for 13 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 60-120 mesh using 20% hexane in ethyl acetate to afford compound 7/8.
To a stirred solution of compound 7/8 (1 eq) in NMP, KI (4 eq) and morpholine/pyrrolidine (6.2 eq) were added and heated at 70° C. for 12 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 60-120 mesh using ethyl acetate/10% MeOH & DCM to afford compound 3j, 4g, and 4j.
The following intermediates were prepared using the General Procedure for the synthesis of boronate esters using the respective bromo intermediates and bispincolato diboron.
Step 1: Synthesis of 1-(4-bromo-2-fluorophenyl)ethan-1-ol (2)
A solution of compound 1 (1 eq) dissolved in dry diethyl ether was added drop wise to a stirred solution of methyl magnesium iodide (3 eq) in diethyl ether at 0° C. and stirred for 12 h at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled at 0° C. and quenched 6 N HCl solution, extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford compound 2. LCMS (m/z): 219.10 (M+).
To a stirred solution of compound 2 (1 eq) in dry acetone, Jones reagent (1.2 mL) was added drop wise at 0° C. and stirred for 30 min at same temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water, extracted with dichloromethane. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 60-120 mesh using 2% EtOAc-hexane to afford compound 3. 1H NMR (400 MHz, CDCl3) δ: 7.80-7.74 (m, 1H), 7.40-7.36 (m, 2H), 2.63 (s, 3H).
A stirred solution of compound 3 (1 eq) in hydrazine monohydrate (8 eq) was stirred at 120° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was washed with diethyl ether to afford compound 4. LCMS (m/z): 213.00 (M+2).
To a stirred solution of compound 4 (1 eq) and corresponding boronic acid in dichloroethane, Na2CO3 (2 eq) was added under oxygen atmosphere and stirred for 5 min followed by the addition of hot solution of copper acetate (1 eq) and pyridine (1 eq) in dichloroethane. The reaction mixture was heated to 75° C. for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution, diluted with dichloromethane and filtered through celite. The separated organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 20% EtOAc-hexane to afford compound 5a. LCMS (m/z): 251.05(M+1).
To a stirred solution of compound 4 (1 eq) in DMF, NaH (1.3 eq) was added portion wise at 0° C. and stirred for 5 min followed by the addition of alkyl halide/trifluoroethyl trifluoromethyl sulfonate (1.5 eq). The reaction mixture was stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water, extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 10% to 25% EtOAc-hexane to afford compounds 5b-c, 5i & 5I.
To a stirred solution of compound 4 (1 eq) in acetonitrile, K2CO3 (3 eq) was added followed by the addition of corresponding alkyl halide (1.5 eq). The reaction mixture was heated at 100° C. for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered and washed with ethyl acetate (3×25 mL). The combined organic extracts were evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 60-120 mesh using 10% methanol in ethyl acetate to afford compounds 5e & 5f.
To a stirred solution of compound 4 (1 eq) in acetonitrile, K2CO3 (3 eq) and 3-chloro-1-bromo propane/2-chloro-1-bromoethane (2 eq) were added and heated at 80° C. for 36 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 60-120 mesh using 20% hexane in ethyl acetate to afford compound 7/8.
To a stirred solution of compound 7/8 (1 eq) in NMP, KI (4 eq) and morpholine/pyrrolidine (6.2 eq) were added and heated at 80° C. for 12 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 60-120 mesh using Ethyl acetate/10% MeOH & DCM in ethyl acetate to afford compound 5g, 5h & 5j.
The following intermediates were prepared using the General Procedure for the synthesis of boronate esters using the respective bromo compounds 5a-j, 5l and bispincolato diboron to obtain comnolincis 6a-e. 6e-j & 6l.
To a stirred solution of 4-(4,6-dichloropyrimidin-2-yl)morpholine 1 (1 g, 1 eq) and 4-chloro aniline 2 (0.547 g, 1 eq) in isopropanol (10 mL), Conc. HCl (2 mL) was added and heated to reflux at 100° C. for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was taken in ethyl acetate (50 mL), washed with 1 N HCl, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 20% EtOAc-hexane to afford the title compound 3. LCMS (m/z): 325.20 (M+1).
Adopted the general procedure as described above for Suzuki reaction using the respective pinacol boronates and compound 3.
N-(4-chlorophenyl)-6-(1-(cyclopropylmethyl)-1H-benzo[d]imidazol-6-yl)-2-morpholino pyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 9.51 (s, 1H), 8.37 (s, 1H), 8.25 (d, J=1.6 Hz, 1H), 7.89 (dd, J=8.6, 1.6 Hz, 1H), 7.77-7.67 (m, 3H), 7.41-7.32 (m, 2H), 6.67 (s, 1H), 4.20 (d, J=7.1 Hz, 2H), 3.83-3.68 (m, 8H), 1.33 (ddd, J=12.4, 8.4, 4.7 Hz, 1H), 0.58 (dt, J=7.9, 2.9 Hz, 2H), 0.54-0.42 (m, 2H); HPLC purity: 99.88%; LCMS Calculated for C25H25ClN6O: 460.18; Observed: 461.25 (M+1).
N-(4-chlorophenyl)-6-(1-cyclobutyl-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-amine hydrochloride: 1H NMR (400 MHz, DMSO-d6) δ: 10.14 (s, 1H), 9.86 (s, 1H), 8.43 (s, 1H), 8.15 (d, J=8.6 Hz, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.79-7.71 (m, 2H), 7.39 (d, J=8.7 Hz, 2H), 6.80 (s, 1H), 5.32 (p, J=8.5 Hz, 1H), 3.84-3.73 (m, 8H), 2.66 (q, J=8.0 Hz, 4H), 2.06-1.92 (m, 2H); HPLC purity: 98.25%; LCMS Calculated for C25H25ClN6O: 460.18; Observed: 461.25 (M+1).
N-(4-chlorophenyl)-6-(1-(2-(dimethylamino)ethyl)-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-amine hydrochloride: 1H NMR (400 MHz, DMSO-d6) δ: 11.12 (s, 1H), 10.08 (s, 1H), 9.59 (s, 1H), 8.62 (s, 1H), 8.09 (d, J=8.7 Hz, 1H), 7.97 (d, J=8.6 Hz, 1H), 7.74 (d, J=8.6 Hz, 2H), 7.40 (d, J=8.5 Hz, 2H), 6.79 (s, 1H), 5.02 (t, J=6.5 Hz, 2H), 3.88-3.74 (m, 8H), 2.88 (s, 6H); HPLC purity: 95.89%; LCMS Calculated for C25H28ClN7O: 477.20; Observed: 478.30 (M+1).
N-(4-chlorophenyl)-6-(1-(3-(dimethylamino)propyl)-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin -4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 9.51 (s, 1H), 8.30 (s, 1H), 8.22 (d, J=1.8 Hz, 1H), 7.88 (dd, J=8.5, 1.6 Hz, 1H), 7.72 (dd, J=8.6, 4.7 Hz, 3H), 7.41-7.32 (m, 2H), 6.66 (s, 1H), 4.34 (t, J=7.0 Hz, 2H), 3.83-3.68 (m, 8H), 2.22-2.15(m, 2H), 2.13 (s, 6H), 1.96 (p, J=6.8 Hz, 2H); HPLC purity: 99.48%; LCMS Calculated for C26H30ClN7O: 491.22; Observed: 492.35 (M+1).
N-(4-chlorophenyl)-2-morpholino-6-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-benzo[d]imidazol-6-yl)pyrimidin-4-amine: 1H NMR (400 MHz, Methanol-d4) δ: 8.29 (d, J=2.0 Hz, 2H), 7.95 (dd, J=8.6, 1.6 Hz, 1H), 7.76-7.62 (m, 3H), 7.34-7.25 (m, 2H), 6.61 (s, 1H), 4.50 (t, J=6.9 Hz, 2H), 3.92-3.77 (m, 8H), 3.02 (t, J=6.8 Hz, 2H), 2.67-2.59 (m, 4H), 1.88-1.76 (m, 4H); HPLC purity: 98.19%; LCMS Calculated for C27H30ClN7O: 503.22; Observed: 504.30 (M+1).
N-(4-chlorophenyl)-2-morpholino-6-(1-(3-(pyrrolidin-1-yl)propyl)-1H-benzo[d]imidazol-6-yl)pyrimidin-4-amine hydrochloride: 1H NMR (400 MHz, DMSO-d6) δ: 10.86 (s, 1H), 9.87 (s, 1H), 9.60 (s, 1H), 8.57 (s, 1H), 8.14 (d, J=8.7 Hz, 1H), 7.97 (d, J=8.6 Hz, 1H), 7.78-7.69 (m, 2H), 7.44-7.36 (m, 2H), 6.79 (s, 1H), 4.71 (t, J=7.1 Hz, 2H), 3.85-3.73 (m, 8H), 3.54 (dq, J=10.9, 5.5 Hz, 2H), 3.24 (dd, J=9.1, 5.4 Hz, 2H), 3.04-2.86 (m, 2H), 2.38 (p, J=6.9 Hz, 2H), 2.04-1.83 (m, 4H); HPLC purity: 98.82%; LCMS Calculated for C28H32ClN7O: 517.24; Observed: 518.30 (M+1).
N-(4-chlorophenyl)-2-morpholino-6-(1-(2-morpholinoethyl)-1H-benzo[d]imidazol-6-yl)pyrimidin-4-amine hydrochloride: 1H NMR (400 MHz, DMSO-d6) δ: 11.98 (s, 1H), 10.25 (s, 1H), 9.65 (s, 1H), 8.68 (s, 1H), 8.08 (d, J=8.6 Hz, 1H), 7.99 (d, J=8.6 Hz, 1H), 7.79-7.70 (m, 2H), 7.46-7.37 (m, 2H), 6.81 (s, 1H), 5.08 (t, J=6.5 Hz, 2H), 3.98 (s, 2H), 3.93-3.69 (m, 12H), 3.67-3.57 (m, 2H), 3.20 (s, 2H); HPLC purity: 99.54%; LCMS Calculated for C27H30ClN7O2: 519.21; Observed: 520.40 (M+1).
N-(4-chlorophenyl)-2-morpholino-6-(1-(3-morpholinopropyl)-1H-benzo[d]imidazol-6-yl)pyrimidin-4-amine hydrochloride: 1H NMR (400 MHz, DMSO-d6) δ: 11.42 (s, 1H), 9.98 (s, 1H), 9.67 (s, 1H), 8.57 (s, 1H), 8.13 (d, J=8.6 Hz, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.78-7.70 (m, 2H), 7.44-7.35 (m, 2H), 6.82 (s, 1H), 4.72 (t, J=6.9 Hz, 2H), 4.00-3.69 (m, 12H), 3.44 (d, J=12.3 Hz, 2H), 3.27-3.12 (m, 2H), 3.12-2.98 (m, 2H), 2.44 (q, J=7.5, 6.9 Hz, 2H); HPLC purity: 99.2%; LCMS Calculated for C28H32ClN7O2: 533.23; Observed: 534.45 (M+1).
N-(4-chlorophenyl)-6-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 10.05 (s, 1H), 9.62 (s, 1H), 8.56 (s, 1H), 8.16 (d, J=8.6 Hz, 1H), 7.98 (d, J=8.6 Hz, 1H), 7.78-7.69 (m, 2H), 7.39 (d, J=8.7 Hz, 2H), 6.75 (s, 1H), 4.76 (t, J=4.9 Hz, 2H), 3.82 (p, J=6.1, 5.6 Hz, 6H), 3.73 (t, J=4.6 Hz, 4H), 3.29 (s, 3H); HPLC purity: 98.55%; LCMS Calculated for C24H25ClN6O2: 464.17; Observed: 465.25 (M+1).
N-(4-chlorophenyl)-6-(1-cyclopropyl-1H-benzo[d]imidazol-5-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 9.47 (s, 1H), 8.33-8.27 (m, 2H), 7.96 (dd, J=8.4, 1.7 Hz, 1H), 7.71 (d, J=8.6 Hz, 3H), 7.41-7.32 (m, 2H), 6.64 (s, 1H), 3.82-3.68 (m, 8H), 3.55 (tt, J=7.1, 3.8 Hz, 1H), 1.17-1.01 (m, 4H).; HPLC purity: 98.68%; LCMS Calculated for C24H23ClN6O: 446.16; Observed: 447.15 (M+1).
N-(4-chlorophenyl)-6-(1-(cyclopropylmethyl)-1H-benzo[d]imidazol-5-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 9.85 (s, 1H), 9.66 (d, J=11.3 Hz, 1H), 8.57 (s, 1H), 8.43 (s, 1H), 8.17 (q, J=8.6 Hz, 1H), 7.98 (d, J=8.6 Hz, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.39 (d, J=8.6 Hz, 2H), 6.75 (d, J=2.4 Hz, 1H), 4.42 (dd, J=23.6, 7.3 Hz, 2H), 3.80-3.73 (m, 8H), 1.51-1.39 (m, 1H), 0.73-0.51 (m, 4H); HPLC purity: 97.48%; LCMS Calculated for C25H25ClN6O: 460.18; Observed: 461.25 (M+1).
N-(4-chlorophenyl)-6-(1-(2-(dimethylamino)ethyl)-1H-benzo[d]imidazol-5-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 11.03 (s, 1H), 10.12 (s, 1H), 9.64 (s, 1H), 8.41 (d, J=1.5 Hz, 1H), 8.25-8.11 (m, 2H), 7.79-7.70 (m, 2H), 7.44-7.36 (m, 2H), 6.79 (s, 1H), 4.98 (t, J=6.3 Hz, 2H), 3.84-3.65 (m, 10H), 2.86 (d, J=4.1 Hz, 6H); HPLC purity: 98.94%; LCMS Calculated for C25H28ClN7O: 477.20; Observed: 478.40 (M+1).
N-(4-chlorophenyl)-6-(1-(3-(dimethylamino)propyl)-1H-benzo[d]imidazol-5-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 10.85 (s, 1H), 10.07 (s, 1H), 9.68 (s, 1H), 8.42 (s, 1H), 8.18 (s, 2H), 7.78-7.69 (m, 2H), 7.44-7.35 (m, 2H), 6.79 (s, 1H), 4.66 (t, J=6.9 Hz, 2H), 3.84-3.69 (m, 8H), 3.20-3.10 (m, 2H), 2.74 (d, J=4.8 Hz, 6H), 2.38 (q, J=7.5 Hz, 2H); HPLC purity: 99.41%; LCMS Calculated for C26H30ClN7O: 491.22; Observed: 492.30 (M+1).
N-(4-chlorophenyl)-2-morpholino-6-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-benzo[d]imidazol-5-yl)pyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 9.48 (s, 1H), 8.29 (d, J=7.1 Hz, 2H), 7.92 (d, J=8.6 Hz, 1H), 7.70 (dd, J=8.5, 5.5 Hz, 3H), 7.36 (d, J=8.6 Hz, 2H), 6.63 (s, 1H), 4.38 (t, J=6.2 Hz, 2H), 3.83-3.72 (m, 8H), 2.84 (t, J=6.3 Hz, 2H), 2.54-2.46 (m, 4H), 1.69-1.60 (m, 4H); HPLC purity: 96.31%; LCMS Calculated for C27H30ClN7O: 503.22; Observed: 504.40 (M+1).
N-(4-chlorophenyl)-2-morpholino-6-(1-(2-morpholinoethyl)-1H-benzo[d]imidazol-5-yl) pyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) 6:11.94 (s, 1H), 10.15 (s, 1H), 9.63 (s, 1H), 8.41 (s, 1H), 8.23 (d, J=8.7 Hz, 1H), 8.14 (d, J=8.8 Hz, 1H), 7.78-7.71 (m, 2H), 7.43-7.36 (m, 2H), 6.79 (s, 1H), 5.03 (t, J=6.5 Hz, 2H), 3.99 (d, J=12.8 Hz, 2H), 3.92-3.77 (m, 6H), 3.74 (d, J=5.0 Hz, 6H), 3.59 (d, J=13.0 Hz, 2H), 3.18-3.04 (m, 2H); HPLC purity: 98.24%; LCMS Calculated for C27H30ClN7O2: 519.21; Observed: 520.45 (M+1).
N-(4-chlorophenyl)-2-morpholino-6-(1-(3-morpholinopropyl)-1H-benzo[d]imidazol-5-yl)pyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 11.41 (s, 1H), 9.99 (s, 1H), 9.64 (s, 1H), 8.43 (s, 1H), 8.17 (s, 2H), 7.77-7.69 (m, 2H), 7.44-7.35 (m, 2H), 6.77 (s, 1H), 4.67 (t, J=6.9 Hz, 2H), 4.00-3.90 (m, 2H), 3.90-3.69 (m, 10H), 3.46-3.35 (m, 2H), 3.19 (dt, J=10.2, 5.6 Hz, 2H), 3.10-2.96 (m, 2H), 2.42 (p, J=7.3 Hz, 2H); HPLC purity: 97.95%; LCMS Calculated for C28H32ClN7O2: 533.23; Observed: 534.45 (M+1).
N-(4-chlorophenyl)-6-(1-cyclopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-amine hydrochloride: 1H NMR (400 MHz, DMSO-d6) δ: 9.95 (s, 1H), 8.38 (d, J=1.5 Hz, 1H), 8.19-8.11 (m, 1H), 7.90 (d, J=8.6 Hz, 1H), 7.79-7.70 (m, 2H), 7.44-7.35 (m, 2H), 6.78 (s, 1H), 3.84-3.69 (m, 8H), 3.62 (tt, J=7.1, 4.0 Hz, 1H), 2.89 (s, 3H), 1.41-1.20 (m, 4H); HPLC purity: 94.42%; LCMS Calculated for C25H25ClN6O: 460.18; Observed: 461.35 (M+1).
N-(4-chlorophenyl)-6-(1-cyclobutyl-2-methyl-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-amine1H NMR (400 MHz, DMSO-d6) δ: 10.02 (s, 1H), 8.50 (s, 1H), 8.12 (d, J=8.6 Hz, 1H), 7.91 (d, J=8.6 Hz, 1H), 7.75 (d, J=8.8 Hz, 2H), 7.39 (d, J=8.5 Hz, 2H), 6.81 (s, 1H), 5.25 (p, J=8.7 Hz, 1H), 3.84-3.67 (m, 8H), 2.96-2.82 (m, 2H),2.80 (s, 3H), 2.77-2.66 (m, 2H), 2.09-1.94 (m, 2H); HPLC purity: 98.37%; LCMS Calculated for C26H27ClN6O: 474.19; Observed: 475.35 (M+1).
N-(4-chlorophenyl)-6-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) 6:11.5 (s,1H),10.92 (s,1H), 8.50 (d, J=1.5 Hz, 1H), 8.13 (dd, J=8.6, 1.5 Hz, 1H), 7.85 (d, J=8.6 Hz, 1H), 7.73-7.65 (m, 2H), 7.42-7.33 (m, 2H), 6.78 (s, 1H), 4.85 (t, J=7.7 Hz, 2H), 3.83-3.72(m,8H), 3.61 (t, J=7.7 Hz, 2H), 2.93 (s, 6H), 2.89 (s, 3H); HPLC purity: 96.59%; LCMS Calculated for C26H30ClN7O: 491.22; Observed: 492.40 (M+1).
N-(4-chlorophenyl)-6-(1-(3-(dimethylamino)propyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, Methanol-d4) δ: 8.73 (s, 1H), 8.03 (d, J=8.7 Hz, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.48-7.41 (m, 2H), 6.71 (s, 1H), 4.83-4.66 (m, 2H), 3.94-3.86 (m, 8H), 3.47-3.38 (m, 2H), 2.96 (s, 3H), 2.94 (s, 6H), 2.46 (p, J=8.0 Hz, 2H); HPLC purity: 96.86%; LCMS Calculated for C27H32ClN7O: 505.24; Observed: 506.35 (M+1).
N-(4-chlorophenyl)-6-(2-methyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 11.73 (dd, J=12.1, 6.4 Hz, 1H), 9.89 (s, 1H), 8.63 (s, 1H), 8.10 (d, J=8.6 Hz, 1H), 7.90 (d, J=8.6 Hz, 1H), 7.78-7.68 (m, 2H), 7.46-7.32 (m, 2H), 6.78 (s, 1H), 4.97 (t, J=7.1 Hz, 2H), 3.83-3.72 (m, 10H), 3.58 (dq, J=11.0, 5.4 Hz, 2H), 3.15 (dq, J=13.7, 7.2 Hz, 2H), 2.94 (s, 3H), 2.03 (td, J=11.1, 9.7, 4.3 Hz, 2H), 2.00-1.85 (m, 2H); HPLC purity: 96.71%; LCMS Calculated for C28H32ClN7O: 517.24; Observed: 518.40 (M+1).
N-(4-chlorophenyl)-6-(2-methyl-1-(3-(pyrrolidin-l-yl)propyl)-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 9.50 (s, 1H), 8.12 (s, 1H), 7.81 (dd, J=8.4, 1.6 Hz, 1H), 7.75-7.67 (m, 2H), 7.58 (d, J=8.4 Hz, 1H), 7.40-7.32 (m, 2H), 6.63 (s, 1H), 4.30 (t, J=6.6 Hz, 2H), 3.82-3.68 (m, 8H), 2.58 (s, 3H), 2.50-2.41 (m, 6H), 1.95 (d, J=9.1 Hz, 2H), 1.69 (d, J=6.0 Hz, 4H); HPLC purity: 98.66%; LCMS Calculated for C29H34ClN7O: 531.25; Observed: 532.35 (M+1).
N-(4-chlorophenyl)-6-(2-methyl-1-(2-morpholinoethyl)-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 12.38 (s, 1H), 10.05 (s, 1H), 8.69 (s, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.92 (d, J=8.6 Hz, 1H), 7.78-7.70 (m, 2H), 7.40 (d, J=8.6 Hz, 2H), 6.81 (s, 1H), 5.04 (t, J=7.7 Hz, 2H), 4.03 (d, J=13.5 Hz, 4H), 3.85 (d, J=5.6 Hz, 4H), 3.76-3.55 (m, 8H), 3.24 (s, 2H), 2.94 (s, 3H); HPLC purity: 99.09%; LCMS Calculated for C28H32ClN7O2: 533.23; Observed: 534.45 (M+1).
N-(4-chlorophenyl)-6-(2-methyl-1-(3-morpholinopropyl)-1H-benzo[d]imidazol-6-yl)-2-morpholino pyrimidin-4-amine: 1H NMR (400 MHz, Methanol-d4) δ: 8.71 (s, 1H), 8.05-7.90 (m, 2H), 7.68 (d, J=8.5 Hz, 2H), 7.50-7.39 (m, 2H), 6.77 (s, 1H), 4.70 (t, J=7.7 Hz, 2H), 4.10-4.01 (m, 2H), 3.90 (dt, J=31.8, 4.5 Hz, 10H), 3.56 (d, J=12.1 Hz, 2H), 3.51-3.40 (m, 2H), 3.32-3.16 (m, 2H), 3.01 (s, 3H), 2.55 (d, J=15.0 Hz, 2H); HPLC purity: 98.45%; LCMS Calculated for C29H34ClN7O2: 547.25; Observed: 548.35 (M+1).
N-(4-chlorophenyl)-6-(1,2-dimethyl-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 9.80(s, 1H), 8.48 (s, 1H), 8.14 (d, J=8.6 Hz, 1H), 7.89 (d, J=8.6 Hz, 1H), 7.73 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.2 Hz, 2H), 6.75 (s, 1H), 4.18 (s, 3H), 3.81-3.73 (m,8H), 2.86 (s, 3H); HPLC purity: 98.15%; LCMS Calculated for C23H23ClN6O: 434.16; Observed: 435.25 (M+1).
N-(4-chlorophenyl)-6-(1-cyclobutyl-2-methyl-1H-benzo[d]imidazol-5-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 9.47 (s, 1H), 8.16 (s, 1H), 7.90-7.76 (m, 2H), 7.71 (d, J=8.5 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 6.61 (s, 1H), 5.01 (p, J=8.9 Hz, 1H), 3.82-3.72 (m, 8H), 2.79 (dt, J=12.6, 9.2 Hz, 2H), 2.58 (s, 3H),2.55 (d, J=7.7 Hz, 2H), 2.02-1.82 (m, 2H); HPLC purity: 98.81%; LCMS Calculated for C26H27ClN6O: 474.19; Observed: 475.40 (M+1).
N-(4-chlorophenyl)-6-(1-cyclopropyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 10.15 (s, 1H),8.24 (s, 1H),8.09(s, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.74-7.72(m, 3H), 7.41 (d, J=8.8, 2H), 6.73 (s, 1H), 3.87-3.73 (m, 9H),1.17-1.16(m,4H); HPLC purity: 92.30%; LCMS Calculated for C24H23ClN6O: 446.16; Observed: 447.20 (M+1).
N-(4-chlorophenyl)-6-(1-(cyclopropylmethyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, CD3OD) δ: 8.15 (s, 2H), 7.98 (d, J=8.8 Hz, 1H), 7.66(s, 2H), 7.51 (d, J=8.4, 1H), 7.45 (d, J=8.4 Hz, 2H), 6.61 (s, 1H),4.43 (d, J=6.8 Hz, 2H), 3.87-3.86 (m, 8H),1.46-1.40(m,1H), 0.59-0.56 (m,2H), 0.50-0.48 (m,2H) ; HPLC purity: 99.74%; LCMS Calculated for C25H25ClN6O: 460.18; Observed: 461.20 (M+1).
N-(4-chlorophenyl)-6-(2-(cyclopropylmethyl)-2H-indazol-6-yl)-2-morpholino pyrimidin-4-amine: The title compound has been synthesized by following the General Procedure for Suzuki Coupling described above using compound 7 and Boronate ester 5. 1H NMR (400 MHz, MeOD) δ: 8.54 (s, 1H),8.13 (s, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.66 (s, 2H), 7.48-7.42 (m, 3H), 6.60 (s, 1H), 4.41 (d, J=7.2 Hz, 2H), 3.90-3.84 (m, 8H), 1.52-1.46 (m, 1H),0.73-0.68 (m, 2H),0.56-0.52 (m, 2H); HPLC purity: 98.38%; LCMS Calculated for C25H25ClN6O: 460.18; Observed: 461.15 (M+1).
N-(4-chlorophenyl)-6-(1-cyclobutyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 10.31 (s, 1H), 8.24 (d, J=2.9 Hz, 2H), 7.92 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.5 Hz, 2H), 7.60 (d, J=8.4 Hz, 1H), 7.45 (d, J=8.4 Hz, 2H), 6.67 (s, 1H), 5.41 (p, J=8.2 Hz, 1H), 3.86-3.75 (m, 8H), 2.75-2.60 (m, 2H), 2.50-2.40 (m, 2H), 1.91 (td, J=9.5, 4.9 Hz, 2H); HPLC purity: 96.50%; LCMS Calculated for C25H25ClN6O: 460.18; Observed: 461.25 (M+1).
N-(4-chlorophenyl)-6-(1-(2-(dimethylamino)ethyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 9.55 (s, 1H), 8.27 (s, 1H), 8.10 (s, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.78-7.67 (m, 3H), 7.41-7.32 (m, 2H), 6.68 (s, 1H), 4.57 (t, J=6.4 Hz, 2H), 3.82-3.73 (m, 8H), 2.73 (t, J=6.4 Hz, 2H), 2.19 (s, 6H); HPLC purity: 98.51%; LCMS Calculated for C25H28ClN7O: 477.20; Observed: 478.30 (M+1).
N-(4-chlorophenyl)-6-(2-(2-(dimethylamino)ethyl)-2H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 9.52 (s, 1H), 8.42 (s, 1H), 8.27 (s, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.76-7.61 (m, 3H), 7.41-7.32 (m, 2H), 6.64 (s, 1H), 4.54 (t, J=6.3 Hz, 2H), 3.82-3.72 (m, 8H), 2.81 (t, J=6.3 Hz, 2H), 2.18 (s, 6H); HPLC purity: 97.45%; LCMS Calculated for C25H28ClN7O: 477.20; Observed: 478.25 (M+1).
N-(4-chlorophenyl)-6-(1-(3-(dimethylamino)propyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 10.21 (d, J=10.2 Hz, 1H), 8.32 (s, 1H), 8.20 (s, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.71 (dd, J=19.5, 8.4 Hz, 3H), 7.41 (d, J=8.3 Hz, 2H), 6.77 (s, 1H), 4.62 (q, J=8.3, 6.8 Hz, 3H), 3.86-3.74 (m, 8H), 3.19-3.06 (m, 2H), 2.74 (d, J=4.8 Hz, 6H), 2.28 (q, J=7.4, 6.8 Hz, 2H); HPLC purity: 97.90%; LCMS Calculated for C26H30ClN7O: 491.22; Observed: 492.30 (M+1).
N-(4-chlorophenyl)-2-morpholino-6-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazol-6-yl)pyrimidin-4-amine: 1H NMR (400 MHz, Methanol-d4) δ: 8.27 (s, 1H), 8.06 (s, 1H), 7.81 (t, J=6.5 Hz, 2H), 7.66 (d, J=8.3 Hz, 2H), 7.33-7.26 (m, 2H), 6.62 (s, 1H), 4.64 (t, J=7.0 Hz, 2H), 3.88-3.80 (m, 8H), 3.05 (t, J=7.0 Hz, 2H), 2.60 (d, J=5.7 Hz, 4H), 1.83-1.75 (m, 4H); HPLC purity: 96.53%; LCMS Calculated for C27H30ClN7O: 503.22; Observed: 504.30 (M+1).
N-(4-chlorophenyl)-2-morpholino-6-(1-(3-(pyrrolidin-1-yl)propyl)-1H-indazol-6-yl)pyrimidin-4-amine: 1H NMR (400 MHz, Methanol-d4) δ: 8.25 (s, 1H), 8.05 (s, 1H), 7.80 (q, J=8.6 Hz, 2H), 7.66 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 6.61 (s, 1H), 4.56 (t, J=6.7 Hz, 2H), 3.88-3.80 (m, 8H), 2.57-2.45 (m, 6H), 2.18 (p, J=7.2 Hz, 2H), 1.82-1.74 (m, 4H); HPLC purity: 94.04%; LCMS Calculated for C28H32ClN7O: 437.13; Observed: 438.25 (M+1).
N-(4-chlorophenyl)-2-morpholino-6-(1-(2-morpholinoethyl)-1H-indazol-6-yl)pyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 11.48 (s, 1H), 10.10-10.01 (m, 1H), 8.44 (s, 1H), 8.25 (s, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.5 Hz, 3H), 7.40 (d, J=8.4 Hz, 2H), 6.76 (s, 1H), 5.03 (t, J=7.1 Hz, 2H), 3.98 (d, J=14.0 Hz, 2H), 3.88-3.64 (m, 12H), 3.51 (d, J=12.3 Hz, 2H), 3.18 (dd, J=15.6, 7.4 Hz, 2H); HPLC purity: 97%; LCMS Calculated for C27H30ClN7O2: 519.21; Observed: 520.30 (M+1).
N-(4-chlorophenyl)-2-morpholino-6-(1-(3-morpholinopropyl)-1H-indazol-6-yl)pyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 10.03 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.72 (d, J=8.7 Hz, 3H), 7.41 (d, J=8.4 Hz, 2H), 6.74 (s, 1H), 4.82 (s, 1H), 4.61 (t, J=6.6 Hz, 2H), 3.99-3.91 (m, 2H), 3.85-3.62 (m, 8H), 3.44-3.37 (m, 4H), 3.19 (dd, J=9.9, 5.0 Hz, 2H), 3.07 (t, J=11.1 Hz, 2H), 2.32 (t, J=7.9 Hz, 2H); HPLC purity: 97.38%; LCMS Calculated for C28H32ClN7O2: 533.23; Observed: 534.40 (M+1).
N-(4-chlorophenyl)-6-(1-(2-methoxyethyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 10.40 (s, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.5 Hz, 1H), 7.43 (d, J=8.4 Hz, 2H), 6.73 (s, 1H), 4.66 (t, J=5.4 Hz, 2H), 3.81-3.66 (m,10H), 3.21(s,3H); HPLC purity: 98.66%; LCMS Calculated for C24H25ClN6O2: 464.17; Observed: 465.25 (M+1).
N-(4-chlorophenyl)-2-morpholino-6-(1-(2-morpholinoethyl)-1H-indazol-5-yl)pyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 9.50 (s, 1H), 8.44 (s, 1H), 8.19 (s, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.71 (d, J=8.3 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 6.63 (s, 1H), 4.59-4.51 (m, 2H), 3.78-3.72 (m, 8H), 3.52-3.45 (m, 4H), 2.78 (d, J=7.0 Hz, 2H), 2.42 (s, 4H); HPLC purity: 97.37%; LCMS Calculated for C27H30ClN7O2: 519.21; Observed: 520.35(M+1).
N-(4-chlorophenyl)-2-morpholino-6-(1-(3-morpholinopropyl)-1H-indazol-5-yl)pyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 9.49 (s, 1H), 8.45 (d, J=1.8 Hz, 1H), 8.20 (s, 1H), 8.00 (dd, J=8.9, 1.6 Hz, 1H), 7.79-7.66 (m, 3H), 7.41-7.32 (m, 2H), 6.62 (s, 1H), 4.47 (t, J=6.6 Hz, 2H), 3.82-3.68 (m, 8H), 3.54 (t, J=4.6 Hz, 4H), 2.22 (dt, J=28.1, 5.8 Hz, 6H), 2.00 (p, J=6.8 Hz, 2H); HPLC purity: 99.06%; LCMS Calculated for C28H32ClN7O2: 533.23; Observed: 534.40 (M+1).
N-(4-chlorophenyl)-6-(1-cyclopropyl-3-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, Methanol-d4) δ: 8.07 (d, J=1.3 Hz, 1H), 7.92 (d, J=8.3 Hz, 1H), 7.66 (d, J=8.6 Hz, 2H), 7.54-7.41 (m, 3H), 6.61 (d, J=5.1 Hz, 1H), 3.92-3.81 (m, 8H), 3.73-3.63 (m, 1H), 2.58 (s, 3H), 1.26-1.17 (m, 4H); HPLC purity: 95.02%; LCMS Calculated for C25H25ClN6O: 460.18; Observed: 461.30 (M+1).
N-(4-chlorophenyl)-6-(1-(cyclopropylmethyl)-3-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, Methanol-d4) δ: 8.04 (s, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.66-7.62(m,2H), 7.50-7.42 (m,3H), 6.56 (s, 1H), 4.33 (d, J=6.4 Hz, 2H),3.90-3.80 (m, 8H), 2.54 (s, 3H), 1.36-1.29 (m, 1H),0.58-0.46 (m, 4H); HPLC purity: 99.6%; LCMS Calculated for C26H27ClN6O: 474.19; Observed: 475.35 (M+1).
N-(4-chlorophenyl)-6-(1-cyclobutyl-3-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 9.54 (s, 1H), 8.19 (s, 1H), 7.81-7.66 (m, 4H), 7.37 (d, J=8.5 Hz, 2H), 6.68 (s, 1H), 5.30 (p, J=8.3 Hz, 1H),3.80-3.70 (m, 8H), 2.72-2.57 (m, 2H), 2.54 (s, 3H), 2.49-2.39 (m, 2H), 1.87 (tq, J=6.9, 4.0, 2.4 Hz, 2H); HPLC purity: 99.9%; LCMS Calculated for C26H27ClN6O: 474.19; Observed: 475.35 (M+1).
N-(4-chlorophenyl)-6-(1-(2-(dimethylamino)ethyl)-3-methyl4H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, Methanol-d4) δ: 8.19 (s, 1H), 7.78-7.63 (m, 4H), 7.34-7.26 (m, 2H), 6.62 (s, 1H), 4.59-4.51 (m, 2H), 3.89-3.78 (m, 8H), 2.89 (t, J=6.9 Hz, 2H), 2.57 (s, 3H), 2.34 (s, 6H); HPLC purity: 97.13%; LCMS Calculated for C26H30ClN7O: 491.22; Observed: 492.40 (M+1).
N-(4-chlorophenyl)-6-(1-(3-(dimethylamino)propyl)-3-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, Methanol-d4) δ: 8.19 (s, 1H), 7.77 (q, J=8.7 Hz, 2H), 7.66 (d, J=8.5 Hz, 2H), 7.31 (d, J=8.3 Hz, 2H), 6.61 (s, 1H), 4.54 (q, J=6.4 Hz, 2H), 3.89-3.77 (m, 8H), 3.03 (t, J=7.9 Hz, 2H), 2.76 (s,6H), 2.59 (s, 3H), 2.30 (q, J=7.4 Hz, 2H); HPLC purity: 99.55%; LCMS Calculated for C27H32ClN7O: 505.24; Observed: 506.40 (M+1).
N-(4-chlorophenyl)-6-(3-methyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, Methanol-d4) δ: 8.28 (s,1H),7.96 (d, J=7.6 Hz, 1H), 7.64-7.44 (m, 5H),6.65 (s,1H), 4.87-4.81 (m, 2H), 3.92-3.86 (m, 10H), 3.73-3.63 (m, 2H), 3.18-3.10 (m, 2H), 2.63(s, 3H), 2.14 (d, J=8.2 Hz, 2H), 2.06-1.98 (m, 2H); HPLC purity: 91.62%; LCMS Calculated for C28H32ClN7O: 517.24; Observed: 518.40 (M+1).
N-(4-chlorophenyl)-6-(3-methyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 9.55 (s, 1H), 8.18 (s, 1H), 7.81-7.66 (m, 4H), 7.37 (d, J=8.4 Hz, 2H), 6.68 (s, 1H), 4.43 (t, J=6.7 Hz, 2H), 3.82-3.72 (m, 8H),2.50 (s,3H),2.33 (dt, J=22.9, 6.1 Hz, 6H), 1.98 (dd, J=9.2, 4.5 Hz, 2H), 1.66 (q, J=4.2, 3.3 Hz, 4H); HPLC purity: 99.38%; LCMS Calculated for C29H34ClN7O: 531.25; Observed: 532.40 (M+1).
N-(4-chlorophenyl)-6-(3-methyl-1-(2-morpholinoethyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, Methanol-d4) δ: 8.18 (s, 1H), 7.74 (s, 2H), 7.66 (d, J=8.2 Hz, 2H), 7.33-7.26 (m, 2H), 6.61 (s, 1H), 4.54 (t, J=6.7 Hz, 2H), 3.87-3.76 (m,8H), 3.59 (dd, J=5.5, 3.1 Hz, 4H), 2.85 (t, J=6.6 Hz, 2H), 2.59-2.48 (m, 7H); HPLC purity: 97.74%; LCMS Calculated for C28H32ClN7O2: 533.23; Observed: 534.45 (M+1).
N-(4-chlorophenyl)-6-(3-methyl-1-(3-morpholinopropyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, D2O) δ: 7.84-7.72 (m, 2H), 7.43-7.31 (m, 5H), 6.37 (s, 1H), 4.48-4.38 (m, 2H), 4.09 (d, J=11.6Hz, 2H),3.81-3.74(m,10H), 3.47 (d, J=11.2Hz, 2H),3.18-3.04 (m,4H), 2.46 (s, 3H),2.33-2.30 (m,2H); HPLC purity: 95.26%; LCMS Calculated for C29H34ClN7O2: 547.25; Observed: 548.30 (M+1).
N-(4-chlorophenyl)-6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, Methanol-d4) δ: 8.04-7.98 (m, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.65 (d, J=8.3 Hz, 2H), 7.52-7.41 (m, 3H), 6.58 (s, 1H), 4.10 (s, 3H), 3.93-3.81 (m, 8H), 2.60 (s, 3H); HPLC purity: 99.87%; LCMS Calculated for C23H23ClN6O: 434.16; Observed: 435.20 (M+1).
The following intermediates were prepared using the general procedure for Suzuki coupling using the dichloro compound 1 and the respective boronic acid/boronate ester.
The following compounds were prepared using the general procedure as described above for Buchwald coupling using the respective chloro compound 2 and methyl-4-amino benzoate 3 to provide compound 4.
The following compounds were prepared using the general procedure as described above for ester hydrolysis using the appropriate ester compound 3 and NaOH to provide compound 5. The crude acid 5 was used as such for the next step.
The following compounds were prepared using the general procedure as described above for the peptide coupling using the appropriate acid 5 and methyl amine and PYBOP, DIPEA in DMF. The crude product was purified by preparative HPLC to afford the desired products.
4-((6-(1-cyclopropyl-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)-N-methyl benzamide: 1H NMR (400 MHz, DMSO-d6) δ: 9.68 (s, 1H), 8.34-8.20 (m, 3H), 7.95 (dd, J=8.6, 1.7 Hz, 1H), 7.86-7.70 (m, 5H), 6.73 (s, 1H), 3.85-3.56 (m, 8H),3.64-3.58 (m,1H), 2.77 (d, J=4.4 Hz, 3H), 1.19-1.04 (m, 4H); HPLC purity: 95.17%; LCMS Calculated for C26H27N7O2: 469.22; observed: 470.30 (M+1).
4-((6-(1-(cyclopropylmethyl)-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)-N-methylbenzamide: 1H NMR (400 MHz, DMSO-d6) δ: 9.65 (s, 1H), 8.37 (s, 1H), 8.27 (d, J=5.4 Hz, 2H), 7.91 (dd, J=8.4, 1.6 Hz, 1H), 7.86-7.70 (m, 5H), 6.73 (s, 1H), 4.21 (d, J=7.1 Hz, 2H), 3.86-3.74 (m, 8H), 2.77 (d, J=4.2 Hz, 3H), 1.33-1.29 (m, 1H), 0.64-0.54 (m, 2H), 0.52-0.43 (m, 2H); HPLC purity: 95.35%; LCMS Calculated for C27H29N7O2: 483.24; observed: 484.30 (M+1).
4-((6-(1-cyclobutyl-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)-N-methylbenzamide: 1H NMR (400 MHz, DMSO-d6) δ: 9.50 (s, 1H), 8.35 (d, J=1.4 Hz, 1H), 8.18-8.10 (m, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.75 (q, J=8.7 Hz, 5H), 5.21 (p, J=8.4 Hz, 1H), 3.78-3.67 (m, 8H), 2.76 (s, 3H), 2.69-2.60 (m, 4H), 1.97 (dt, J=21.8, 9.9 Hz, 2H); HPLC purity: 99.07%; LCMS Calculated for C27H29N7O2 (free base): 483.24; observed: 484.40 (M+1).
4-((6-(1-(2-(dimethylamino)ethyl)-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)-N-methylbenzamide: 1H NMR (400 MHz, CDCl3) δ: 8.13 (s, 1H), 8.07 (s, 1H), 7.90-7.74 (m, 4H), 7.60-7.53 (m, 2H), 6.79 (s, 1H), 6.57 (s, 1H), 6.11 (q, J=4.6 Hz, 1H), 4.31 (t, J=6.6 Hz, 2H), 3.94-3.82 (m, 8H), 3.03 (d, J=4.8 Hz, 3H), 2.77 (t, J=6.5 Hz, 2H), 2.32 (s, 6H); HPLC purity: 96.66%; LCMS Calculated for C27H32N8O2: 500.26; observed: 501.45 (M+1).
4-((6-(1-(3-(dimethylamino)propyl)-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)-N-methylbenzamide: 1H NMR (400 MHz, CD3OD) δ: 8.33-8.23 (m, 2H), 7.96 (dd, J=8.6, 1.7 Hz, 1H), 7.77 (d, J=16.2 Hz, 5H), 6.66 (s, 1H), 4.43 (t, J=6.9 Hz, 2H), 3.95-3.78 (m, 8H), 2.92 (s, 3H), 2.34 (q, J=6.7, 6.0 Hz, 2H), 2.24 (s, 6H), 2.13 (p, J=6.9 Hz, 2H); HPLC purity: 99.08%; LCMS Calculated for C28H34N8O2: 514.28; observed: 515.45 (M+1).
N-methyl-4-((2-morpholino-6-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-benzo[d]imidazol-6-yl)pyrimidin-4-yl)amino)benzamide: 1H NMR (400 MHz, CD3OD) δ: 8.31 (d, J=6.8 Hz, 2H), 7.97 (dd, J=8.7, 1.6 Hz, 1H), 7.77 (d, J=17.0 Hz, 5H), 6.67 (s, 1H), 4.58-4.48 (m, 2H), 3.95-3.82 (m, 8H), 3.04 (t, J=6.8 Hz, 2H), 2.92 (s, 3H), 2.65 (q, J=5.6, 4.1 Hz, 4H), 1.88-1.76 (m, 4H); HPLC purity: 93.48%; LCMS Calculated for C29H34N8O2: 526.28; observed: 527.50 (M+1).
N-methyl-4-((2-morpholino-6-(1-(2-morpholinoethyl)-1H-benzo[d]imidazol-6-yl)pyrimidin-4-yl)amino)benzamide: 1H NMR (400 MHz, DMSO-d6) δ: 11.49 (s, 1H), 10.07 (s, 1H), 9.59 (s, 1H), 8.64 (s, 1H), 8.32 (d, J=4.7 Hz, 1H), 8.14 (d, J=8.1 Hz, 1H), 7.99 (d, J=8.6 Hz, 1H), 7.88-7.75 (m, 4H), 6.86 (d, J=15.1 Hz, 1H), 5.04 (d, J=6.6 Hz, 2H), 3.99 (s, 3H), 3.89-3.71 (m, 11H), 3.64 (d, J=15.9 Hz, 4H), 2.77 (d, J=4.2 Hz, 3H); HPLC purity: 98.09%; LCMS Calculated for C29H34N8O3 (free base): 542.28; observed: 543.50 (M+1).
N-methyl-4-((2-morpholino-6-(1-(3-morpholinopropyl)-1H-benzo[d]imidazol-6-yl)pyrimidin-4-yl)amino)benzamide: 1H NMR (400 MHz, CD3OD) δ: 9.62 (s, 1H), 8.76 (s, 1H), 8.12-8.02 (m, 2H), 7.94-7.86 (m, 2H), 7.84-7.76 (m, 2H), 6.80 (s, 1H), 4.06 (d, J=13.1 Hz, 2H), 3.97 (dd, J=5.8, 3.6 Hz, 4H), 3.87 (dd, J=5.7, 3.7 Hz, 8 H), 3.56 (d, J=12.6 Hz, 2H), 3.46-3.32 (m, 2H), 3.30-3.15 (m, 2H), 2.94 (s, 3H), 2.73-2.56 (m, 2H); HPLC purity: 96.42%; LCMS Calculated for C30H36N8O3 (free base): 556.29; observed: 557.35 (M+1).
4-06-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)-N-methylbenzamide: 1H NMR (400 MHz, DMSO-d6) δ: 10.19 (s, 1H), 9.67 (s, 1H), 8.59 (s, 1H), 8.34 (d, J=5.4 Hz, 1H), 8.17 (d, J=8.7 Hz, 1H), 7.99 (d, J=8.6 Hz, 1H), 7.88-7.76 (m, 4H), 6.81 (s, 1H), 4.77 (t, J=5.1 Hz, 2H), 3.87-3.75(m, 8H), 3.28 (s, 3H), 2.77 (d, J=3.8 Hz, 3H); HPLC purity: 97.93%; LCMS Calculated for C26H29N7O3 (free base):487.23; observed: 488.35 (M+1).
4-((6-(1-cyclopropyl-1H-benzo[d]imidazol-5-yl)-2-morphohnopyrimidin-4-yl)amino)-N-methylbenzamide: 1H NMR (400 MHz, DMSO-d6) δ: 9.61 (s, 1H), 8.29 (dd, J=13.7, 5.5 Hz, 3H), 8.00-7.93 (m, 1H), 7.86-7.68 (m, 5H), 6.69 (s, 1H), 3.85-3.73 (m, 8H), 3.55 (tt, J=7.1, 3.6 Hz, 1H), 2.77 (d, J=4.4 Hz, 3H), 1.20-1.01 (m, 4H); HPLC purity: 95.52%; LCMS Calculated for C26H27N7O2:469.22; observed: 470.30 (M+1).
4-((6-(1-(cyclopropylmethyl)-1H-benzo[d]imidazol-5-yl)-2-morphohnopyrimidin-4-yl)amino)-N-methylbenzamide: 1H NMR (400 MHz, DMSO-d6) δ: 10.13 (t, J=11.4 Hz, 1H), 9.75 (d, J=8.7 Hz, 1H), 8.44 (s, 1H), 8.32 (d, J=5.2 Hz, 1H), 8.18 (t, J=6.2 Hz, 2H), 7.81 (q, J=8.5 Hz, 4H), 6.83 (d, J=6.1 Hz, 1H), 4.43 (dd, J=23.5, 7.1 Hz, 2H), 3.82-3.72 (m, 8H), 2.76 (d, J=3.8 Hz, 3H), 1.45 (d, J=8.8 Hz, 1H), 0.71-0.53 (m, 4H); HPLC purity: 98.78%; LCMS Calculated for C27H32N8O2 (free base):483.24; observed: 484.35 (M+1).
4-((6-(1-(2-(dimethylamino)ethyl)-1H-benzo[d]imidazol-5-yl)-2-morphohnopyrimidin-4-yl)amino)-N-methylbenzamide: 1H NMR (400 MHz, DMSO-d6) δ: 10.66 (s, 1H), 10.02 (s, 1H), 9.51 (s, 1H), 8.43 (s, 1H), 8.32 (q, J=4.5 Hz, 1H), 8.16 (s, 2H), 7.88-7.75 (m, 4H), 6.79 (s, 1H), 4.94 (t, J=6.3 Hz, 2H), 3.82-3.65 (m, 10H), 2.87 (d, J=4.1 Hz, 6H), 2.77 (d, J=4.2 Hz, 3H); HPLC purity: 98.94%; LCMS Calculated for C27H32N8O2 (free base): 500.26; observed: 501.45 (M+1).
N-methyl-4-((2-morphohno-6-(1-(3-(pyrradin-1-yl)propyl)-1H-benzo[d]imidazol-5-yl)pyrimidin-4-yl)amino)benzamide: 1H NMR (400 MHz, DMSO-d6) δ: 9.61 (s, 1H), 8.33-8.23 (m, 3H), 7.93 (dd, J=8.6, 1.6 Hz, 1H), 7.85-7.66 (m, 5H), 6.69 (s, 1H), 4.32 (t, J=6.9 Hz, 2H), 3.83-3.75 (m, 8H), 2.77 (d, J=4.4 Hz, 3H), 2.36 (dt, J=25.2, 6.1 Hz, 6H), 1.97 (p, J=7.1 Hz, 2H), 1.72-1.64 (m, 4H); HPLC purity: 97.36%; LCMS Calculated for C30H34N8O2:540.30; observed: 541.45 (M+1).
N-methyl-4-42-morphohno-6-(1-(2-morphohnoethyl)-1H-benzo[d]imidazol-5-yl)pyrimidin-4-yl)amino)benzamide: 1H NMR (400 MHz, CD3OD) δ: 8.36 (d, J=1.5 Hz, 1H), 8.29 (s, 1H), 8.07 (dd, J=8.5, 1.6 Hz, 1H), 7.79 (s, 4H), 7.68 (d, J=8.6 Hz, 1H), 6.65 (s, 1H), 4.45 (t, J=6.2 Hz, 2H), 3.91-3.82 (m, 8H), 3.69-3.62 (m, 4H), 2.92 (s, 3H), 2.82 (t, J=6.1 Hz, 2H), 2.52 (t, J=4.6 Hz, 4H); HPLC purity: 98.9%; LCMS Calculated for C29H34N8O3:542.28; observed: 543.45 (M+1).
N-methyl-4-((2-morpholino-6-(1-(3-morpholinopropyl)-1H-benzo[d]imidazol-5-yl)pyrimidin-4-yl)amino)benzamide: 1H NMR (400 MHz, DMSO-d6) δ: 9.60 (s, 1H), 8.33-8.22 (m, 3H), 7.93 (dd, J=8.6, 1.6 Hz, 1H), 7.85-7.67 (m, 5H), 6.69 (s, 1H), 4.32 (t, J=6.8 Hz, 2H), 3.85-3.69 (m, 8H), 3.55 (dd, J=6.3, 3.1 Hz, 4H), 2.77 (d, J=4.4 Hz, 3H), 2.29 (s, 4H), 2.21 (t, J=6.7 Hz, 2H), 1.98 (p, J=6.9 Hz, 2H); HPLC purity: 98.17%; LCMS Calculated for C30H36N8O3:556.29; observed: 557.55 (M+1).
4-((6-(1-cyclopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)-N-methylbenzamide: 1H NMR (400 MHz, DMSO-d6) δ: 9.95 (s, 1H), 8.40 (d, J=1.6 Hz, 1H), 8.31 (q, J=4.5 Hz, 1H), 8.17 (dd, J=8.5, 1.6 Hz, 1H), 7.94-7.73 (m, 5H), 6.81 (s, 1H), 3.83-3.74 (m, 8H), 3.63 (tt, J=7.3, 4.0 Hz, 1H), 2.89 (s, 3H), 2.77 (d, J=4.2 Hz, 3H), 1.41-1.21 (m, 4H); HPLC purity: 93.51%; LCMS Calculated for C27H29N7O2 (free base):483.24; observed: 484.40 (M+1).
4-((6-(1-(cyclopropylmethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)-N-methylbenzamide: 1H NMR (400 MHz, DMSO-d6) δ: 9.83 (s, 1H), 8.53 (d, J=1.5 Hz, 1H), 8.29 (q, J=4.5 Hz, 1H), 8.19 (d, J=8.6 Hz, 1H), 7.94-7.74 (m, 5H), 6.76 (s, 1H), 4.47 (d, J=7.1 Hz, 2H), 3.86-3.74 (m, 8H), 2.91 (s, 3H), 2.77 (d, J=4.4 Hz, 3H), 1.43-1.31 (m, 1H), 0.67-0.56 (m, 4H); HPLC purity: 97.2%; LCMS Calculated for C28H31N7O2 (free base):497.25; observed: 498.45 (M+1).
4-((6-(1-cyclobutyl-2-methyl-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)-N-methylbenzamide 1H NMR (400 MHz, CD3OD) δ: 8.42 (s, 1H), 8.05-7.86 (m, 4H), 7.78 (d, J=8.3 Hz, 2H), 6.69 (s, 1H), 5.33 (t, J=8.6 Hz, 1H), 3.96-3.83 (m, 8H), 3.09-2.76 (m, 10H), 2.21-2.07 (m, 2H); HPLC purity: 97.73%; LCMS Calculated for C28H31N7O2 (free base):497.25; observed: 498.45 (M+1).
4-((6-(1,2-dimethyl-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)-N-methylbenzamide: 1H NMR (400 MHz, DMSO-d6) δ: 9.62 (s,1H), 8.27 (d, J=4.0 Hz, 1H),8.11 (s,1H),7.83-7.75 (m, 5H), 7.58 (d, J=9.2 Hz, 1H), 6.70 (s,1H),3.80-3.73 (m, 11H), 2.77 (d, J=4.0 Hz, 3H), 2.56 (s, 3H); HPLC purity: 98.73%; LCMS Calculated for C25H27N7O2: 457.22; observed: 458.30 (M+1).
4-((6-(1-cyclopropyl4H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)-N-methylbenzamide: 1H NMR (400 MHz, DMSO-d6) δ: 10.03 (s, 1H), 8.30 (d, J=21.2 Hz, 2H), 8.09 (s, 1H), 7.91-7.73 (m, 6H), 6.79 (s, 1H), 3.84-3.75 (m, 9H), 2.77 (d, J=4.2 Hz, 3H), 1.17 (d, J=7.0 Hz, 4H); HPLC purity: 95.86%; LCMS Calculated for C26H27N7O2 (free base): 469.22; Observed: 470.40 (M+1).
4-((6-(1-(cyclopropylmethyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)-N-methylbenzamide: 1H NMR (400 MHz, DMSO-d6) δ: 10.35 (s, 1H), 8.35 (d, J=5.4 Hz, 1H), 8.27 (s, 1H), 8.15 (s, 1H), 7.88 (dd, J=17.3, 8.4 Hz, 3H), 7.79 (d, J=8.4 Hz, 2H), 7.67 (d, J=8.4 Hz, 1H), 6.78 (s, 1H), 4.40 (d, J=7.0 Hz, 2H), 3.83-3.75 (m, 8H), 2.77 (d, J=4.0 Hz, 3H),1.32 (p, J=6.4 Hz, 1H), 0.57-0.40 (m, 4H); HPLC purity: 96.14%; LCMS Calculated for C27H29N7O2 (free base): 483.24; Observed: 484.30 (M+1).
4-((6-(1-cyclobutyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)-N-methylbenzamide: 1H NMR (400 MHz, DMSO-d6) δ: 10.01 (s, 1H),8.36 (s, 1H), 8.31-8.18 (m, 2H), 7.87 (dd, J=14.5, 8.4 Hz, 3H), 7.77 (d, J=8.5 Hz, 3H), 6.78 (s, 1H), 5.18-5.24 (m,1H), 3.84-3.75 (m, 8H), 2.77 (d, J=4.1 Hz, 3H), 2.66 (qd, J=9.8, 2.5 Hz, 2H),2.28-2.46 (m, 2H), 1.98-1.85 (m, 2H); HPLC purity: 99.74%; LCMS Calculated for C27H29N7O2(free base): 483.24; Observed: 484.30 (M+1).
4-((6-(1-(2-(dimethylamino)ethyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)-N-methyl benzamide: 1H NMR (400 MHz, CD3OD) δ: 8.29 (d, J=1.3 Hz, 1H), 8.07 (d, J=0.9 Hz, 1H), 7.87-7.77 (m, 6H), 6.68 (s, 1H), 4.63 (t, J=6.9 Hz, 2H), 3.92-3.81 (m, 8H), 2.91 (d, J=8.0 Hz, 5H), 2.32 (s, 6H); HPLC purity: 99.9%; LCMS Calculated for C27H32N8O2: 500.26; Observed: 501.35 (M+1).
4-((6-(2-(2-(dimethylamino)ethyl)-2H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)-N-methylbenzamide: Regioisomer of the above compound obtained by chromatography after the final step. 1H NMR (400 MHz, DMSO-d6) δ: 9.64 (s, 1H), 8.43 (s, 1H), 8.28 (s, 2H), 7.79 (dt, J=11.2, 8.4 Hz, 5H), 7.66 (d, J=8.9 Hz, 1H), 6.69 (s, 1H), 4.54 (t, J=6.3 Hz, 2H), 3.85-3.73 (m, 8H), 2.87-2.74 (m, 5H), 2.18 (s, 6H); HPLC purity: 99.74%; LCMS Calculated for C27H32N8O2: 500.26; Observed: 501.35 (M+1).
N-methyl-4-42-morpholino-6-(1-(2-(pyrrolidin-l-yl)ethyl)-1H-indazol-6-yl)pyrimidin-4-yl)amino)benzamide: 1H NMR (400 MHz, DMSO-d6) δ: 9.68 (s, 1H), 8.27 (s, 2H), 8.11 (s, 1H), 7.88-7.72 (m, 6H), 6.74 (s, 1H), 4.60 (t, J=6.5 Hz, 2H), 3.82-3.73 (m, 8H), 2.91 (t, J=6.1 Hz, 2H), 2.77 (d, J=4.4 Hz, 3H),2.56-2.40 (m, 4H), 1.63 (s, 4H); HPLC purity: 99.05%; LCMS Calculated for C29H34N8O2: 526.28; Observed: 527.50 (M+1).
N-methyl-4-((2-morpholino-6-(1-(3-(pyrrolidin-1-yl)propyl)-1H-indazol-6-yl)pyrimidin-4-yl)amino)benzamide: 1H NMR (400 MHz, CD3OD) δ: 8.28 (q, J=1.0 Hz, 1H), 8.06 (d, J=0.9 Hz, 1H), 7.81 (d, J=9.9 Hz, 6H), 6.68 (s, 1H), 4.57 (t, J=6.7 Hz, 2H), 3.96-3.78 (m, 8H), 2.92 (s, 3H), 2.56-2.45 (m, 6H), 2.18 (p, J=6.8 Hz, 2H), 1.79 (p, J=3.2 Hz, 4H); HPLC purity: 98.60%; LCMS Calculated for C30H36N8O2: 540.30; Observed: 541.45 (M+1).
N-methyl-4-((2-morpholino-6-(1-(2-morpholinoethyl)-1H-indazol-6-yl)pyrimidin-4-yl)amino)benzamide: 1H NMR (400 MHz, DMSO-d6) δ: 10.98 (s, 1H), 10.06 (s, 1H), 8.42 (s, 1H), 8.33 (d, J=4.9 Hz, 1H), 8.26 (s, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.88-7.70 (m, 5H), 6.78 (s, 1H), 5.01 (t, J=6.7 Hz, 2H), 3.99 (d, J=12.7 Hz, 2H), 3.89-3.82 (m, 4H), 3.81-3.62 (m, 8H), 3.58-3.46 (m, 2H), 3.18 (d, J=9.9 Hz, 2H), 2.77 (d, J=4.3 Hz, 3H); HPLC purity: 97.56%; LCMS Calculated for C29H34N8O3 (free base): 542.28; Observed: 543.40 (M+1).
4-((6-(1-(2-methoxyethyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)-N-methylbenzamide: 1H NMR (400 MHz, DMSO-d6) δ: 10.63 (s, 1H), 8.38 (d, J=5.8 Hz, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 7.89 (dd, J=13.6, 8.4 Hz, 3H), 7.80 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.4 Hz, 1H), 6.82 (s, 1H), 6.00 (s, 1H), 4.66 (t, J=5.4 Hz, 2H), 3.89-3.72 (m, 10H), 3.21 (s, 3H), 2.78 (d, J=3.8 Hz, 3H); HPLC purity: 98.99%; LCMS Calculated for C26H29N7O3 (free base): 487.23; Observed: 488.30 (M+1).
4-((6-(1-cyclopropyl-1H-indazol-5-yl)-2-morpholinopyrimidin-4-yl)amino)-N-methylbenzamide: 1H NMR (400 MHz, CD3OD) δ: 8.34-8.27 (m, 1H), 8.17 (d, J=3.7 Hz, 1H), 7.96-7.74 (m, 6H), 6.60 (d, J=4.0 Hz, 1H), 3.95-3.82 (m, 8H), 3.77 (tq, J=7.7, 3.9 Hz, 1H), 2.93 (d, J=3.9 Hz, 3H), 1.24 (dddt, J=10.2, 6.5, 4.2, 2.0 Hz, 4H); HPLC purity: 99.02%; LCMS Calculated for C26H27N7O2 (free base): 469.22; Observed: 470.30 (M+1).
N-methyl-4-((2-morpholino-6-(1-(2-morpholinoethyl)-1H-indazol-5-yl)pyrimidin-4-yl)amino)benzamide: 1H NMR (400 MHz, DMSO-d6) δ: 11.60 (s, 1H), 10.42 (s, 1H), 8.44 (s, 1H), 8.36 (d, J=4.5 Hz, 2H), 7.98 (s, 2H), 7.90-7.76 (m, 4H), 6.80 (s, 1H), 5.00 (t, J=7.0 Hz, 2H), 3.98 (dd, J=12.1, 3.4 Hz, 2H), 3.88-3.71 (m, 10H), 3.65 (t, J=7.0 Hz, 2H), 3.52-3.46 (m, 2H), 3.17 (q, J=8.3, 6.7 Hz, 2H), 2.83 (t, 3H); HPLC purity: 97.22%; LCMS Calculated for C29H34N8O3 (free base): 542.28; Observed: 543.45 (M+1).
N-methyl-4-((2-morpholino-6-(1-(3-morpholinopropyl)-1H-indazol-5-yl)pyrimidin-4-yl)amino)benzamide: 1H NMR (400 MHz, DMSO-d6) δ: δ 9.63 (s, 1H), 8.46 (s, 1H), 8.28 (q, J=4.4 Hz, 1H), 8.21 (s, 1H), 8.01 (d, J=9.0 Hz, 1H), 7.86-7.72 (m, 5H), 6.68 (s, 1H), 4.47 (t, J=6.6 Hz, 2H), 3.85-3.77 (m, 4H), 3.77-3.68 (m, 4H), 3.54 (t, J=4.4 Hz, 4H), 2.77 (d, J=4.4 Hz, 3H), 2.29-2.15 (m, 6H), 2.00 (p, J=6.8 Hz, 2H); HPLC purity: 97.86%; LCMS Calculated for C30H36N8O3: 556.29; Observed: 557.45 (M+1).
N-methyl-4-((6-(1-methyl-1H-indazol-5-yl)-2-morpholinopyrimidin-4-yl)amino)benzamide: 1H NMR (400 MHz, DMSO-d6) δ: 10.24 (s, 1H), 8.42 (s, 1H), 8.34 (d, J=4.9 Hz, 1H), 8.22 (s, 1H), 7.95 (d, J=9.0 Hz, 1H), 7.89-7.71 (m, 5H), 6.72 (s, 1H), 4.10 (s, 3H), 3.83-3.74 (m, 8H), 2.77 (d, J=4.2 Hz, 3H); HPLC purity: 95.46%; LCMS Calculated for C24H25N7O2 (freebase): 443.21; Observed: 444.25 (M+1).
N-(4-chlorophenyl)-6-(2-methyl-1-(2-morpholinoethyl)-1H-benzo[d]imidazol-5-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, Methanol-d4) δ 8.38 (d, J=8.7 Hz, 1H), 8.28 (s, 1H), 8.05 (dd, J=8.8, 1.6 Hz, 1H), 7.65 (d, J=8.6 Hz, 2H), 7.53-7.40 (m, 2H), 6.60 (s, 1H), 5.10 (t, J=7.8 Hz, 2H), 4.05 (s, 4H), 3.93-3.66 (m, 8H), 3.64 (s, 4H), 3.47-3.32 (m, 2H), 3.06 (s, 3H)HPLC purity: 96.61%; LCMS Calculated for C28H32ClN7O:518.05:observed: 534.40(M+1).
N-methyl-4-((2-morpholino-6-(1-(3-morpholinopropyl)-1H-indazol-6-yl)pyrimidin-4-yl)amino)benzamide: 1H NMR (400 MHz, DMSO-d6) δ: 9.68 (s, 1H), 8.32-8.23 (m, 2H), 8.13 (s, 1H), 7.88-7.70 (m, 6H), 6.74 (s, 1H), 4.53 (t, J=6.3 Hz, 2H), 3.87-3.77 (m, 4H), 3.77-3.70 (m, 4H), 3.51 (t, J=4.4 Hz, 4H), 2.77 (d, J=4.4 Hz, 3H), 2.25-2.12 (m, 6H), 2.07-1.97 (m, 2H); HPLC purity: 97.44%; LCMS Calculated for C30H36N8O3: 556.29; Observed: 557.40 (M+1).
The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using compound 1 and Boronate ester 2. LCMS (m/z): 330.05 (M+1).
The title compound (crude) has been synthesized by following the general procedure described above for Buchwald Coupling by using compound3and methyl 4-aminobenzoate 4. LCMS (m/z): 445.20 (M+1).
The title compound has been synthesized by following the procedure described above for ester hydrolysis by using compound 5 and the crude product has been used as such for the next step. LCMS (m/z): 431.25 (M+1).
The following compounds were prepared using the general procedure described above for Amide coupling by using compound 6 and the appropriate amine.
N-cyclopropyl-4-((6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-yl) amino)benzamide: The title compound has been synthesized by following. 1H NMR (400 MHz, DMSO-d6) δ: 9.64 (s, 1H), 8.30-8.21 (m, 2H), 8.19 (s, 1H), 7.94-7.86 (m, 1H), 7.84-7.69 (m, 5H), 6.73 (s, 1H), 3.92 (s, 3H), 3.81-3.73 (m, 8H), 2.86-2.80 (m, 1H), 0.67 (dt, J=7.0, 3.3 Hz, 2H), 0.56 (dt, J=7.3, 4.6 Hz, 2H); HPLC purity: 95.27%; LCMS Calculated for C26H27N7O2(free base): 469.22; observed: 470.30 (M+1).
N-(cyclopropylmethyl)-4-((6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)benzamide: The title compound has been synthesized by following the general procedure described above for Amide coupling by using compound 6 and cyclopropyl methylamine. 1H NMR (400 MHz, DMSO-d6) δ: 9.66 (s, 1H), 8.40 (t, J=5.8 Hz, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 7.88 (dd, J=21.1, 8.5 Hz, 3H), 7.76 (dd, J=17.0, 8.5 Hz, 3H), 6.73 (s, 1H), 3.92 (s, 3H), 3.82-3.74 (m, 8H),3.13 (t, J=6.3 Hz, 2H), 1.07-0.97 (m, 1H), 0.47-0.38 (m, 2H), 0.22-0.20 (m, 2H); HPLC purity: 99.17%; LCMS Calculated for C27H29N7O2: 483.24; observed: 484.30(M+1).
4-((6-(1-methyl-1H-1-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)benzamide: To a stirred solution of acid 6 (150mg, 1 eq) in DMF (2 mL) CDI (67 mg, 1.2 eq) was added and the resulting mixture stirred at 60° C. for 1 h. Reaction mixture was cooled to room temperature, ammonium hydroxide (0.49 mL, 10 eq) was added and the reaction mixture was stirred for 1 h at room temperature. After completion of the reaction, water was added and extracted with ethyl acetate (2×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by preparative HPLC to afford the desired product. 1H NMR (400 MHz, DMSO-d6) δ: 9.65 (s, 1H), 8.28 (s, 1H), 8.20 (d, J=1.6 Hz, 1H), 7.94-7.70 (m, 7H), 7.15 (s, 1H), 6.73 (s, 1H), 3.92 (s, 3H), 3.86-3.70 (m, 8H); HPLC purity: 98.97%; LCMS Calculated for C23H23N7O2: 429.19; observed: 430.25 (M+1).
N-ethyl-4-((6-(1-methyl-1H-1-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-yl)amino) benzamide: The title compound has been synthesized by following the general procedure described above for Amide coupling by using compound 6 and ethyl amine. 1H NMR (400 MHz, DMSO-d6) δ: 9.83 (s, 1H), 9.45 (s, 1H), 8.49 (d, J=1.5 Hz, 1H), 8.33 (t, J=5.6 Hz, 1H), 8.18 (d, J=8.8 Hz, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.88-7.74 (m, 4H), 6.78 (s, 1H), 4.12 (s, 3H), 3.83-3.74 (m, 8H), 3.33-3.22 (m, 2H), 1.12 (t, 3H); HPLC purity: 95.41%; LCMS Calculated for C25H27N7O2 (free base): 457.22; observed: 458.40 (M+1).
N-isopropyl-4-((6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-yl) amino)benzamide: The title compound has been synthesized by following the general procedure described above for Amide coupling by using compound 6 and Isopropyl amine. 1H NMR (400 MHz, CD3OD) δ: 9.59 (s, 1H), 8.55 (s, 1H), 8.08 (s, 2H), 7.95-7.87 (m, 2H), 7.77 (d, J=8.2 Hz, 2H), 6.69 (s, 1H), 4.29-4.16 (m, 4H), 3.98-3.83 (m, 8H), 1.36-1.23 (m, 6H); HPLC purity: 95.24%; LCMS Calculated for C26H29N7O2 (free base): 471.24; observed: 472.40(M+1).
The title compound (crude product) has been synthesized by following the general procedure described above for Buchwald coupling by using chloro compound 1 and 4-cyano aniline2. LCMS (m/z): 315.90 (M+1).
The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using compound 3 and Boronate ester 4. 1H NMR (400 MHz, DMSO-d6) δ: 9.91 (s, 1H), 8.29 (s, 1H), 8.20 (d, J=1.6 Hz, 1H), 7.90 (dd, J=11.9, 8.5 Hz, 3H), 7.75 (dd, J=8.6, 6.4 Hz, 3H), 6.76 (s, 1H), 3.92 (s, 3H), 3.85-3.70 (m, 8H); HPLC purity: 97.54%; LCMS Calculated for C23H21N7O: 411.18; Observed: 412.30 (M+1).
6-(1-methyl-1H-benzo [d]imidazol-6-yl)-2-morpholino-N-phenylpyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using chloro compound 1 and aniline. 1H NMR (400 MHz, DMSO-d6) δ: 9.82 (s, 1H), 9.61 (s, 1H), 8.50 (d, J=1.5 Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.98 (d, J=8.6 Hz, 1H), 7.70 (d, J=8.0 Hz, 2H), 7.35 (t, J=7.9 Hz, 2H), 7.03 (t, J=7.4 Hz, 1H), 6.77 (s, 1H), 4.14 (s, 3H), 3.83-3.73 (m, 8H); HPLC purity: 99.08%; LCMS Calculated for C22H22N6O (free base): 386.19; Observed: 387.25 (M+1).
N-(4-bromophenyl)-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-amine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using chloro compound 1 and 4-bromo aniline. 1H NMR (400 MHz, DMSO-d6) δ: 9.95 (s, 1H), 9.61 (s, 1H), 8.48 (s, 1H), 8.15 (d, J=8.9 Hz, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.70-7.59 (m, 2H), 7.52-7.43 (m, 2H), 6.75 (s, 1H), 4.11 (s, 3H), 3.82-3.66 (m, 8H); HPLC purity: 95.60%; LCMS Calculated for C22H21BrN6O (free base): 464.10; Observed: 465.25 (M+1).
N-(4-fluorophenyl)-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 10.06 (s, 1H), 9.66 (s, 1H), 8.51 (s, 1H), 8.15 (d, J=8.7 Hz, 1H), 7.99 (d, J=8.6 Hz, 1H), 7.76-7.67 (m, 2H), 7.20 (t, J=8.8 Hz, 2H), 6.76 (s, 1H), 4.14 (s, 3H), 3.82-3.70 (m, 8H); HPLC purity: 98.81%; LCMS Calculated for C22H21FN6O (free base): 404.18; Observed: 405.25 (M+1).
N-(4-methoxyphenyl)-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-amine The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using chloro compound 1 and 4-methoxy aniline. 1H NMR (400 MHz, DMSO-d6) δ: 9.19 (s, 1H), 8.26 (s, 1H), 8.19-8.14 (m, 1H), 7.86 (dd, J=8.5, 1.6 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.61-7.53 (m, 2H), 6.96-6.87 (m, 2H), 6.60 (s, 1H), 3.91 (s, 3H), 3.82-3.67 (m, 11H); HPLC purity: 99.85%; LCMS Calculated for C23H24N6O2: 416.20; Observed: 417.30 (M+1).
N1,N1-dimethyl-N4-(6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-yl)benzene-1,4-diamine: The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using chloro compound 1 and N1,N1-dimethylbenzene-1,4-diamine 1H NMR (400 MHz, DMSO-d6) δ: 10.21 (s, 1H), 9.65 (s, 1H), 8.49 (s, 1H), 8.14 (d, J=8.8 Hz, 1H), 7.96 (d, J=8.7 Hz, 1H), 7.85 (d, J=8.6 Hz, 2H), 7.69 (d, J=8.6 Hz, 2H), 6.81 (s, 1H), 4.11 (s, 3H), 3.84-3.71 (m, 8H), 3.06 (s, 6H); HPLC purity: 99.19%; LCMS Calculated for C24H27N7O (free base): 429.23; Observed: 430.35 (M+1).
To a stirred solution of compound 2 (3 g, 1 eq) in pyridine (12 mL) and dichloromethane (30 mL), acetyl chloride(2 g, 1.2 eq)was added at 0° C. and stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 3.
To a stirred solution of compound 3 (3 g, 1 eq) in ethanol (30 mL), iron powder (4.6 g, 5 eq), water (10 mL) and ammonium chloride (4.4 g, 5 eq) were added slowly. The reaction mixture was heated to reflux for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 4. LCMS (m/z): 151.00 (M+1).
The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using chloro compound 1 and N-(4-aminophenyl)acetamide. 1H NMR (400 MHz, D20) δ: 9.18 (s, 1H), 8.08 (d, J=1.5 Hz, 1H), 7.89 (d, J=8.6 Hz, 1H), 7.78 (dd, J=8.7, 1.6 Hz, 1H), 7.41-7.33 (m, 2H), 7.23 (d, J=8.5 Hz, 2H), 6.25 (s, 1H), 4.11 (s, 3H), 3.88-3.75 (m, 8H), 1.89 (s, 3H); HPLC purity: 97.15%; LCMS Calculated for C24H25N7O2 (free base): 443.21; Observed: 444.35 (M+1).
To a stirred solution of compound 2 (2 g, 1.2 eq) in dichloromethane (20 mL), methane sulfonyl chloride (3 g, 1 eq) and pyridine were added at 0° C. and stirred at same temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (2×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude product 5.
To a stirred solution of compound 5 (0.8 g, 1 eq) in ethanol (20 mL), iron powder (1.03 g, 5 eq), water (20 mL) and ammonium chloride (0.98 g,5 eq) were added slowly. The reaction mixture was heated to reflux for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and washed with brine. The organic extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 6.
The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using chloro compound 1 and N-(4-aminophenyl) methanesulfonamide. 1H NMR (400 MHz, DMSO-d6) δ: 9.83 (s, 1H), 9.59 (d, J=3.6 Hz, 2H), 8.50 (s, 1H), 8.16 (d, J=8.7 Hz, 1H), 7.98 (d, J=8.6 Hz, 1H), 7.67 (d, J=8.6 Hz, 2H), 7.21 (d, J=8.6 Hz, 2H), 6.73 (s, 1H), 4.14 (s, 3H), 3.82-3.74 (m, 8H), 2.96 (d, J=1.2 Hz, 3H); HPLC purity: 97.02%; LCMS Calculated for C23H25N7O3S (free base): 479.17; Observed: 480.40 (M+1).
To a stirred solution of compound 7 (2 g, 1 eq) in THF (20 mL), aq. ammonia (9.3 mL) was added slowly at 0° C. and stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was dissolved in water (25 mL) and extracted with ethyl acetate (3×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude product 8. 1H NMR (400 MHz, DMSO-d6) δ: 8.42-8.40 (m, 2H), 8.07-8.05 (m, 2H), 7.73 (s, 2H).
To a stirred solution of compound 8 (0.8 g, 1 eq) in ethanol (20 mL), iron powder (1.03 g, 5 eq), water (10 mL) and ammonium chloride (0.98 g, 5 eq) were added slowly. The reaction mixture was heated to reflux for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 9. 1H NMR (400 MHz, DMSO-d6) δ: 7.42-7.40 (m, 2H), 6.90 (s, 2H), 6.60-6.58 (m, 2H), 5.80 (s, 2H).
The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using chloro compound 1 and 4-aminobenzenesulfonamide. 1H NMR (400 MHz, DMSO-d6) δ: 9.80 (s, 1H), 8.28 (s, 1H), 8.20 (d, J=1.7 Hz, 1H), 7.94-7.80 (m, 3H), 7.75 (dd, J=12.4, 8.7 Hz, 3H), 7.19 (s, 2H), 6.75 (s, 1H), 3.92 (s, 3H), 3.85-3.74 (m, 8H); HPLC purity: 98.48%; LCMS Calculated for C22H23N7O3S: 465.16; Observed: 466.30 (M+1).
To a stirred solution of compound 1 (4 g, 1 eq) in dichloromethane (60 mL), TEA (5.85 g, 2 eq) and DMAP (1.76 g, 0.5 eq) were added followed by the addition of Boc anhydride (9.48 g, 1.5 eq). The reaction mixture was stirred at room temperature for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 30% EtOAc-hexane to afford the title compound 2. 1H NMR (400 MHz, DMSO-d6) δ: 10.12 (s, 1H), 8.17 (d, J=8.8 Hz, 2H), 7.68 (d, J=8.8 Hz, 2H), 1.49 (s, 9H).
To a stirred solution of compound 2 (3 g, 1 eq) in ethyl acetate (50 mL), 10% Pd—C (0.3 g) was added and stirred at room temperature for 18 h under hydrogen atmosphere. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford the title compound 3 and used as such for the next step without further purification. LCMS (m/z): 109.05 (M−Boc).
The title compound was synthesized by following the general procedure described above for Buchwald coupling by using chloro compound 4 and amino compound 3. 1H NMR (400 MHz, DMSO-d6) δ: 9.23 (d, J=5.8 Hz, 2H), 8.26 (s, 1H), 8.17 (s, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.54 (d, J=8.6 Hz, 2H), 7.39 (d, J=8.5 Hz, 2H), 6.62 (s, 1H), 3.91 (s, 3H), 3.86-3.68 (m, 8H), 1.48 (s, 9H); HPLC purity: 99%; LCMS Calculated for C27H31N7O3: 501.25; Observed: 502.25 (M+1).
To a stirred solution of compound (3 g, 1 eq) in methanol (5 mL), methanolic HCl (3 mL) was added and stirred at room temperature for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was washed with THF, ethyl acetate and diethyl ether to afford title compound. 1H NMR (400 MHz, DMSO-d6) δ: 10.54 (s, 2H), 10.11 (s, 1H), 9.66 (s, 1H), 8.54-8.46 (m, 1H), 8.17 (dd, J=8.5, 1.5 Hz, 1H), 7.99 (d, J=8.6 Hz, 1H), 7.86-7.78 (m, 2H), 7.42-7.33 (m, 2H), 6.82 (s, 1H), 4.14 (s, 3H), 3.82-3.68 (m, 8H); HPLC purity: 98.52%; LCMS Calculated for C22H23N7O (free base): 401.20; Observed: 402.25 (M+1).
To a stirred solution of the compound 1 (2 g, 1 eq)) in DMF (20 mL), methyl amine 2 M solution in THF (9.19 mL, 2 eq) and DIPEA (3.53 g, 3 eq) were added and stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×25 mL). Combined organic extracts were washed with brine and dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude product 2 (2 g) and used as such for the next step without further purification.
To a stirred solution of compound 2 (6 g, 1 eq), in ethanol: water (2:1; 60 mL), iron powder (6 g) and ammonium chloride (5.53 g, 4 eq) were added and heated to reflux for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine and dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude compound 3. LCMS (m/z): 201.00 (M+1).
To a stirred solution of compound 3 (2 g, 1 eq) in dichloromethane (20 mL), 3-chloropropanoyl chloride (1.08 g, 1 eq) was added at 0° C. and stirred for 15 min at same temperature. The reaction mixture was evaporated to dryness. The residue was dissolved in acetic acid (10 mL) and Conc.H2SO4 (1.5 mL) and heated to reflux for 10 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure and basified to pH 8 using saturated sodium bicarbonate solution and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine and dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 30% EtOAc-hexane to afford the desired product 5 (2.05 g, impure). LCMS (m/z): 275.00 (M+2).
A stirred solution of compound 5 (1 eq) and corresponding amine (1 eq) in ethanol was heated to reflux for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was dissolved in water and extracted with 15% MeOH-DCM. Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude compound 6.
The title compound 7 was synthesized by following the general procedure described above for Boronate ester preparation by using the respective bromo compound 6 and Bis(pinacolato)diboron.
The title compounds were synthesized by general procedure described above for Suzuki coupling by using the chloro compound 8 and the respective Boronate ester 7. The crude products were purified by preparative HPLC to afford the desired products.
N-(4-chlorophenyl)-6-(2-(2-(dimethylamino)ethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-amine1H NMR (400 MHz, CD3OD) δ: 8.39 (s, 1H), 8.02-7.90 (m, 2H), 7.66 (d, J=8.1 Hz, 2H), 7.50-7.41 (m, 2H), 6.63 (s, 1H), 4.16 (s, 3H), 3.95-3.75 (m, 12H), 3.09 (s, 6H); HPLC purity: 97.01%; LCMS Calculated for C26H30ClN7O (free base): 491.22; Observed: 492.25 (M+1).
N-(4-chlorophenyl)-6-(1-methyl-2-(2-(pyrrolidin-1-yl)ethyl)-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, CD3OD) δ: 8.30-8.25 (m, 1H), 7.96-7.82 (m, 2H), 7.65 (d, J=8.4 Hz, 2H), 7.49-7.41 (m, 2H), 6.61 (s, 1H), 4.09 (s, 3H), 3.94-3.81 (m, 10H), 3.68 (t, J=7.3 Hz, 2H), 3.56-3.50 (m, 4H), 2.22-2.18 (m, 4H); HPLC purity: 98.89%; LCMS Calculated for C28H32ClN7O (free base): 517.24; Observed: 518.40 (M+1).
N-(4-chlorophenyl)-6-(1-methyl-2-(2-morpholinoethyl)-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, CD3OD) δ: 8.40 (s, 1H), 8.03-7.91 (m, 2H), 7.66 (d, J=8.2 Hz, 2H), 7.49-7.42 (m, 2H), 6.62 (d, J=2.1 Hz, 1H), 4.18 (s, 3H), 4.08-4.04 (m, 4H), 3.95-3.79 (m, 12H), 3.58-3.50 (m, 4H); HPLC purity: 96.26%; LCMS Calculated for C28H32ClN7O2 (free base): 533.23; Observed: 534.00 (M+1).
To a stirred solution of compound 1 (2 g, 1 eq) in methanol (20 mL), 2-chloroacetaldehyde (1.56 g, 2 eq) and formic acid (20 mL) were added at 0° C. and stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The crude product was washed with pentane and diethyl ether to afford the title compound 2. LCMS (m/z): 260.95 (M+2).
A stirred solution of chloro compound 2 (1 eq) and corresponding amine (1 eq) in ethanol was heated to reflux for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was dissolved in water and extracted with 15% MeOH-DCM. Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude compound 3.
The title compound 4 was synthesized by following the general procedure described above for Boronate ester preparation by using the respective bromo compound 3 and Bis(pinacolato)diboron.
The title compounds were synthesized by the general procedure described above for Suzuki coupling by using the chloro compound 5 and the respective boronate ester 4. The crude product was purified by preparative HPLC to afford the desired product.
N-(4-chlorophenyl)-6-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-amine1H NMR (400 MHz, CDCl3) δ: 8.03 (s, 1H), 7.83-7.67 (m, 2H), 7.41 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 6.54 (s, 1H), 6.49 (s, 1H), 3.97-3.77 (m, 13H), 2.62-2.54 (m, 4H), 1.82-1.76 (m 4H); HPLC purity: 97.24%; LCMS Calculated for C27H30ClN7O: 503.22; Observed: 504.40 (M+1).
N-(4-chlorophenyl)-6-(1-methyl-2-(morpholinomethyl)-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 9.51 (s, 1H), 8.14 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.68 (dd, J=24.1, 8.4 Hz, 3H), 7.36 (d, J=8.4 Hz, 2H), 6.66 (s, 1H), 3.92 (s, 3H), 3.79 (d, J=9.9 Hz, 6H), 3.75-3.68 (m, 4H), 3.58 (d, J=5.0 Hz, 4H), 2.44-2.40 (m, 4H); HPLC purity: 99.74%; LCMS Calculated for C27H30ClN7O2: 519.21; Observed: 520.40 (M+1).
To a stirred solution of compound 1 (0.1 g, 1 eq) in DMF (5 mL),TEA (0.101 g, 2 eq) and 4-chlorobutanoyl chloride (0.061 g, 1 eq) was added at 0° C. and stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure and the residue was basified using saturated sodium bicarbonate solution and extracted with ethyl acetate (2×20 mL). Combined organic extracts were washed with brine and dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was dissolved in acetic acid (5 mL) and was heated to 70° C. for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under vacuum and residue was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate (2×25 mL). Combined organic extracts were washed with brine and dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 80% EtOAc-hexane to afford the title compound 2. LCMS (m/z): 289.00 (M+1).
A stirred solution of chloro compound 2 (0.1 g, 1 eq) and morpholine (0.121 g, 4 eq) in ethanol (5 mL) was heated to reflux for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was dissolved in water and extracted with 15% MeOH-DCM (2×25 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude compound 3. LCMS (m/z): 340.15 (M+2).
The title compound was synthesized by following the general procedure described above for Boronate ester preparation by using bromo compound 3 and Bis(pinacolato)diboron.
The title compound was synthesized by the general procedure described above for Suzuki coupling by using the chloro compound 5 and boronate ester 4. The crude product was purified by preparative HPLC to afford the desired product. 1H NMR (400 MHz, DMSO-d6) δ: 9.49 (s, 1H), 8.11 (s, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.71 (d, J=8.5 Hz, 2H), 7.60 (d, J=8.4 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 6.65 (s, 1H), 3.84-3.69 (m, 11H), 3.57-3.45 (m, 4H), 2.92 (t, J=7.6 Hz, 2H), 2.37 (d, J=17.9 Hz, 6H), 2.00-1.90 (m, 2H); HPLC purity: 94.32%; LCMS Calculated for C29H34ClN7O2: 547.25; Observed: 548.35 (M+1).
To a stirred solution of compound 1 (0.7 g, 1 eq) in dichloromethane (5 mL), 3-methoxypropanoic acid (0.65 g, 1 eq) was added slowly at 0° C. and stirred at room temperature for 30 min. The reaction mixture was evaporated to dryness. The residue was dissolved in acetic acid (5 mL) and Conc.H2SO4 (1 mL) and heated to reflux for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure and basified to pH 8 using saturated sodium bicarbonate solution and extracted with ethyl acetate (2×25 mL). Combined organic extracts were washed with brine and dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude product 5 (0.81 g). LCMS (m/z): 269.00 (M+1).
The title compound (crude) was synthesized by following the general procedure described above for Boronate ester preparation by using the bromo compound 2 and Bis(pinacolato)diboron. LCMS (m/z): 317.20 (M+1).
The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using compound 4 and Boronate ester 3. 1H NMR (400 MHz, DMSO-d6) δ: 9.50 (s, 1H), 8.12 (d, J=1.7 Hz, 1H), 7.84 (dd, J=8.5, 1.7 Hz, 1H), 7.76-7.67 (m, 2H), 7.62 (d, J=8.4 Hz, 1H), 7.41-7.32 (m, 2H), 6.66 (s, 1H), 3.85-3.72 (m, 13H), 3.29 (s, 3H), 3.16 (t, J=6.7 Hz, 2H); HPLC purity: 99.77%; LCMS Calculated for C25H27ClN6O2: 478.19; Observed: 479.25 (M+1).
To a stirred solution of compound 1 (2 g, 1 eq) in THF (40 mL), CDI (2.42 g, 1.5 eq) was added and heated to reflux for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was diluted with ethyl acetate (100 mL) and washed with water. Organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude compound 2. LCMS (m/z): 226.90 (M+1).
A stirred solution of compound 2 (0.1 g, 1 eq) in POCl3 (3 mL) was heated at 110° C. for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was slowly basified to pH 8 using saturated sodium bicarbonate solution and extracted with ethyl acetate (2×25 mL). Combined organic extracts were washed with brine and dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 50% EtOAc-hexane to afford the title compound 3. LCMS (m/z): 244.95 (M+1).
A stirred solution of compound 3 (1 eq) and corresponding amine (1 eq) in ethanol was heated to reflux for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was dissolved in water and extracted with 15% MeOH-DCM. Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude compound 4.
The title compound 5 was synthesized by following the general procedure described above for Boronate ester preparation by using the respective bromo compound 4 and Bis(pinacolato)diboron.
The title compounds were synthesized by general procedure described above for Suzuki coupling by using the chloro compound 6 and the respective Boronate ester 5. The crude products were purified by preparative HPLC to afford the desired products.
N-(4-chlorophenyl)-6-(1-methyl-2-(pyrrolidin-1-yl)-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 10.04-9.95 (m, 1H), 8.12 (s, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.54 (d, J=8.3 Hz, 1H), 7.39 (d, J=8.6 Hz, 2H), 6.71 (s, 1H), 3.94 (s, 3H), 3.83-3.52 (m, 12H), 2.07-1.99 (m, 4H); HPLC purity: 96.29%; LCMS Calculated for C26H28ClN7O (free base): 489.20; Observed: 490.35 (M+1).
6-(6-((4-chlorophenyl)amino)-2-morpholinopyrimidin-4-yl)-N-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazol-2-amine: 1H NMR (400 MHz, DMSO-d6) δ: 10.10 (s, 1H), 9.31 (t, J=5.5 Hz, 1H), 8.05 (s, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.73 (d, J=8.6 Hz, 2H), 7.54 (d, J=8.2 Hz, 1H), 7.39 (d, J=8.6 Hz, 2H), 6.71 (s, 1H), 3.84-3.56 (m, 15H), 3.31 (s, 3H); HPLC purity: 95.66%; LCMS Calculated for C25H28ClN7O2 (free base): 493.20; Observed: 494.35 (M+1).
Step 1: Synthesis of 5-bromo-N-(2-morpholinoethyl)-2-nitroaniline (3)
To a stirred solution of 4-bromo-2-fluoro-1-nitrobenzene 1 (2 g, 1 eq), 2-morpholinoethanamine 2 (1.77 g, 1 eq) in DMF (20 mL), DIPEA (2.34 g, 2 eq) was added and stirred at room temperature for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 80% EtOAc-hexane to afford the title compound 3. LCMS (m/z): 330.05.90 (M+1).
To a stirred solution of compound 3 (2.8 g, 1 eq) in methanol (30 mL), Raney nickel (3 g) was added and stirred at room temperature for 18 h under hydrogen atmosphere. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered and evaporated under reduced pressure to afford the title compound 4. LCMS (m/z): 300.10 (M+1).
To a stirred solution of compound 4 (2.3 g, 1 eq) in DMF (20 mL), trimethylorthoformate (2.43 g, 3 eq) and Conc. HCl (1 mL) were added and stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (2×50 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 100% EtOAc to afford the title compound 5. LCMS (m/z): 310.10 (M+1).
The title compound was synthesized by following the general procedure described above for Boronate ester preparation by using bromo compound 5and Bis (pinacolato)diboron. LCMS (m/z): 358.30 (M+1).
The title compound was synthesized by general procedure described above for Suzuki coupling by using chloro compound 7 and Boronate ester 6. LCMS (m/z): 429.30 (M+1).
The title compound has been synthesized by following the general procedure described above for Buchwald Coupling by using chloro compound 8 and methyl 4-aminobenzoate 9. LCMS (m/z): 544.50 (M+1).
The title compound has been synthesized by following the general procedure described above for ester hydrolysis by using compound 10 and sodium hydroxide. LCMS (m/z): 530.45 (M+1).
To a stirred solution of acid 11 (0.2 g, 1 eq) in DMF (3 mL) CDI (73 mg, 1.2 eq) was added and the resulting mixture stirred at 60° C. for 1 h. Reaction mixture was cooled to room temperature, ammonium hydroxide (0.132 g, 10 eq) was added and the reaction mixture was stirred for 1 h at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (25 mL). Organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 5% MeOH-DCM to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 8.59 (s, 1H), 8.09 (d, J=8.1 Hz, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.91-7.82 (m, 3H), 7.81-7.74 (m, 2H), 7.18 (d, J=11.9 Hz, 1H), 6.80 (s, 1H), 5.03 (t, J=6.2 Hz, 2H), 3.98-3.74 (m, 18H), 3.18-3.10 (m, 2H); HPLC purity: 96.36%; LCMS Calculated for C28H32N8O3 (free base): 528.26; Observed: 529.45 (M+1).
To a stirred solution of compound 1 (0.6 g, 1 eq) in DMF (2.5 mL), K2CO3 (0.855 g, 8 eq) and 3-iodooxetane 2 (0.73 g, 1.3 eq) were added and heated at 150° C. for 5 h in microwave. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (50 mL), washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound3. 1H NMR confirms the formation of regioisomers. LCMS (m/z): 255.05 (M+2).
The title compound has been synthesized by following the general procedure described above for Boronate ester formation by using bromo compound 3 and Bis (pinacolato)diboron. LCMS (m/z): 301.15 (M+1).
The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using chloro compound 5 and boronate ester 4. Both the regioisomers were separated by chiral preparative HPLC. 1H NMR (400 MHz, DMSO-d6) δ: 9.57 (s, 1H), 8.58 (s, 1H), 8.43 (d, J=1.6 Hz, 1H), 7.94 (dd, J=8.5, 1.6 Hz, 1H), 7.82-7.67 (m, 3H), 7.41-7.32 (m, 2H), 6.66 (s, 1H), 5.85 (qd, J=7.4, 5.7 Hz, 1H), 5.18-5.01 (m, 4H), 3.83-3.68 (m, 8H); HPLC purity: 98.83%; LCMS Calculated for C24H23ClN6O2:462.16; Observed: 463.25 (M+1).
N-(4-chlorophenyl)-2-morpholino-6-(1-(oxetan-3-yl)-1H-benzo[d]imidazol-5-yl)pyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ: 9.50 (s, 1H), 8.56 (s, 1H), 8.35 (d, J=1.7 Hz, 1H), 7.97 (dd, J=8.6, 1.7 Hz, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.75-7.67 (m, 2H), 7.41-7.32 (m, 2H), 6.64 (s, 1H), 5.85-5.73 (m, 1H), 5.06 (dt, J=29.5, 7.1 Hz, 4H), 3.82-3.68 (m, 8H); HPLC purity: 99.79%; LCMS Calculated for C24H23ClN6O2:462.16; Observed: 463.25 (M+1).
N-(4-chlorophenyl)-6-(2-methyl-1-(oxetan-3-yl)-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, Chloroform-d) δ 8.71 (d, J=1.5 Hz, 1H), 7.89 (dd, J=8.5, 1.6 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.46-7.38 (m, 2H), 7.35-7.27 (m, 2H), 6.52 (d, J=18.4 Hz, 2H), 5.61-5.50 (m, 1H), 5.33 (dd, J=7.5, 5.6 Hz, 2H), 5.24 (t, J=7.7 Hz, 2H), 3.93-3.85 (m, 4H), 3.80 (dd, J=5.5, 3.9 Hz, 4H), 2.61 (s, 3H), 1.26 (d, J=12.4 Hz, 1H); HPLC purity: 99.68%; LCMS Calculated for C25H25ClN6O2: 476.96:observed: 477.30(M+1).
To a stirred solution of compound 1 (2 g, 1 eq) in DMF (20 mL), cyclopropylmethanamine (0.97 g,1.5 eq) and DIPEA (3.1 mL, 2 eq) were added at 0° C. and stirred at same temperature for 15 min. The reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (2×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 2. LCMS (m/z): 272.90 (M+2).
The title compound has been synthesized by following the general procedure described above for reduction using the nitro compound 2 and Fe/NH4Cl. LCMS (m/z): 241.00 (M+1).
A stirred solution of compound 3 (1.85 g, 1 eq) in acetic acid (15 mL) was heated to reflux for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (2×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 4. LCMS (m/z): 265.05 (M+1).
The title compound (crude product) has been synthesized by following the general procedure described above for Boronate ester preparation by using bromo compound 4 and Bis (pinacolato)diboron. LCMS (m/z): 313.25 (M+1).
The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using chloro compound 6 and Boronate ester 5. 1H NMR (400 MHz, DMSO-d6) δ: 13.53 (s, 1H), 9.55 (s, 1H), 8.21 (s, 1H), 7.92 (d, J=8.4 Hz, 3H), 7.79 (s, 2H), 7.66 (d, J=8.5 Hz, 1H), 6.70 (s, 1H), 4.25 (d, J=6.9 Hz, 2H), 3.81-3.73 (m, 8H), 2.66 (s, 3H), 2.49 (s, 3H), 1.27 (td, J=12.4, 11.4, 6.4 Hz, 1H), 0.62-0.45 (m, 4H); HPLC purity: 98.55%; LCMS Calculated for C29H31N9O: 521.27; Observed: 522.40 (M+1).
To a stirred solution of compound 1 (0.6 g, 1 eq) in isopropanol (20 mL), compound 2 (0.803 g, 1 eq) and catalytic amount of concentrated HCl was added and stirred at 120° C. for 3 h in a microwave reactor. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was basified with saturated sodium bicarbonate and extracted with ethyl acetate (2×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 5% MeOH-DCM to afford the title compound3. LCMS (m/z): 372.20 (M+1).
To a stirred solution of compound 1 (10 g, 1 eq) in DMF (50 mL), DIPEA (17.59 g, 3 eq) and methylamine (3.52 g, 2.5 eq) were added and stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 2.
To a stirred solution of compound 2 (8 g, 1 eq) in EtOH:H2O (350 mL:150 mL), Iron powder (9.69 g, 5 eq) and NH4Cl (9.26 g, 5 eq) were added. The resulting reaction mixture was refluxed for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a celite and the filtrate was evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 3. LCMS (m/z): 202.00 (M+1).
To a stirred solution of compound 3 (1 g, 1 eq) in POCl3 (2 mL), cyclopropane carboxylic acid (0.5 mL) were added. The resulting reaction mixture was heated at 120° C. for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (3×20 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 20% EtOAc-hexane to afford the title compound 4. LCMS (m/z): 250.95 (M+1).
The title compound has been synthesized by following the general procedure described above for Boronate ester preparation by using bromo compound 4 and Bis (pinacolato)diboron. LCMS (m/z): 299.15 (M+1).
The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using chloro compound 6 and Boronate ester 5. HPLC purity: 99.43%; 1NMR (400 MHz, DMSO-d6) δ: 9.76 (s, 1H), 8.44 (s, 1H), 8.12 (d, J=8.6 Hz, 1H), 7.81 (d, J=8.6 Hz, 1H), 7.76-7.69 (m, 2H), 7.42-7.35 (m, 2H), 6.73 (s, 1H), 4.12 (s, 3H), 3.84-3.77 (m, 4H), 3.76-3.69 (m, 4H), 2.60 (dd, J=14.2, 7.6 Hz, 2H), 1.42 (t, J=5.3 Hz, 3H); LCMS Calculated for C25H25ClN6O (free base): 460.18; Observed: 461.25 (M+1).
To a stirred solution of compound 1 (0.6 g, 1 eq) in DMF (6 mL), K2CO3 (0.784 g, 2 eq) and compound 2 (0.63 g, 1 eq) were added and heated at 180° C. for 5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (50 mL), washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound3.1H NMR confirms the formation of regioisomers. LCMS (m/z): 269.02 (M+2).
The title compound has been synthesized by following the general procedure described above for Boronate ester formation by using bromo compound 3 and Bis (pinacolato)diboron. LCMS (m/z): 315.05 (M+1).
The title compounds have been synthesized by following the general procedure described above for Suzuki coupling by using chloro compound 5 and boronate ester 4. Both the regioisomers were separated by preparative HPLC.
N-(4-chlorophenyl)-6-(2-methyl-1-(oxetan-3-yl)-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, Chloroform-d) δ 8.71 (d, J=1.5 Hz, 1H), 7.89 (dd, J=8.5, 1.6 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.46-7.38 (m, 2H), 7.35-7.27 (m, 2H), 6.52 (d, J=18.4 Hz, 2H), 5.61-5.50 (m, 1H), 5.33 (dd, J=7.5, 5.6 Hz, 2H), 5.24 (t, J=7.7 Hz, 2H), 3.93-3.85 (m, 4H), 3.80 (dd, J=5.5, 3.9 Hz, 4H), 2.61 (s, 3H); HPLC purity: 99.68%; LCMS Calculated for C25H25ClN6O2: 476.96; Observed: 477.30 (M+1). (4-chlorophenyl)[6-(2-methyl-1-oxetan-3-ylbenzimidazol-5-yl)-2-morpholin-4-ylpyrimidin-4-yl]amine: 1H NMR (400 MHz, Chloroform-d) δ 8.33 (s, 1H), 8.06-7.95 (m, 2H), 7.43-7.25 (m, 4H), 6.55 (s, 1H), 6.48 (s, 1H), 5.52 (q, J=6.9 Hz, 1H), 5.33-5.17 (m, 4H), 3.89 (t, J=4.7 Hz, 4H), 3.80 (t, J=4.5 Hz, 4H), 2.59 (s, 3H); HPLC purity: 99.06%; LCMS Calculated for C25H25ClN6O2: 476.96; Observed: 477.25 (M+1).
To a stirred solution of compound 1 (2 g, 1 eq) in DMF (10 mL), DIPEA (3.51 g, 3 eq) was added followed by the addition of cyclopropylmethanamine (0.774 g, 1.2 eq). The reaction mixture was stirred at rt for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 15% EtOAc-hexane to afford the title compound 2. LCMS (m/z): 272.00 (M+2).
To a stirred solution of compound 2 (2.4 g, 1 eq) in methanol (30 mL), Raney nickel (2.4 g) was added under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 18 h under hydrogen atmosphere (balloon pressure). The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure to afford the title compound 3. LCMS (m/z): 267.05 (M+2).
To a stirred solution of compound 3 (2.1 g, 1 eq) in acetic acid (20 mL) and reaction mixture was heated at 120° C. for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was basified to pH 7-8 with aq. Sodium carbonate and extracted with ethyl acetate (2×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by flash column chromatography to afford the title compound 4. LCMS (m/z): 267.00 (M+2).
The title compound has been synthesized by following the general procedure described above for Boronate ester preparation by using bromo compound 4 and Bis (pinacolato) diboron. LCMS (m/z): 313.00 (M+1).
The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using chloro compound 6 and Boronate ester 5. LCMS (m/z): 384 (M+1).
The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA/HCl) by using chloro compound 7 and amine 8. 1H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.21 (s, 1H), 8.16 (s, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.63 (d, J=6.1 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.28 (d, J=3.3 Hz, 1H), 7.08 (d, J=8.3 Hz, 1H), 6.66 (s, 1H), 6.35 (d, J=3.3 Hz, 1H), 4.18 (d, J=6.8 Hz, 2H), 3.90-3.78 (m, 4H), 3.75 (d, J=5.8 Hz, 7H), 2.57 (d, J=18.5 Hz, 3H), 1.25 (d, J=13.8 Hz, 1H), 0.59-0.52 (m, 2H), 0.47 (d, J=4.9 Hz, 2H); HPLC purity: 97.75%; LCMS Calculated for C29H31N7O (free base): 493.60; Observed: 494.50 (M+1).
To a stirred solution of compound 1 (1 g, 1 eq) in dry THF (10 mL), CDI (0.953 g, 1.1 eq) was added under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure to obtain a crude residue. The crude product was purified by column chromatography on silica gel 100-200 mesh using 40% EtOAc-hexane to afford the title compounds 2. LCMS (m/z): 214.05 (M+1).
To a stirred solution of compound 2 (0.8 g, 1 eq) in DMF (10 mL), sodium hydride (0.48 g, 3.2 eq) was added at 0° C. and stirred for 30 min followed by the addition of methyl iodide (0.58 mL, 2.5 eq) at 0° C. and stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice water and extracted with ethyl acetate (2×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 3. LCMS (m/z): 242.20 (M+1).
The title compound have been synthesized by following the general procedure described above for Boronate ester preparation by using bromo compound 3 and Bis (pinacolato)diboron. LCMS (m/z): 289.05 (M+1).
The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using chloro compound 5 and boronate ester 4 to afford title compound. The compound was taken in methanol (5 mL), methanol.HCl (0.2 mL) was added and stirred at rt for 30 min. the reaction mixture was evaporated under reduced pressure and purified by washing with ether to afford title compound as HCl salt. 1H NMR (400 MHz, DMSO-d6) δ 7.70 (dd, J=5.3, 3.5 Hz, 4H), 7.43-7.36 (m, 2H), 7.29 (d, J=8.1 Hz, 1H), 6.61 (s, 1H), 3.40 (d, J=11.1 Hz, 8H), 2.56 (s, 6H); HPLC purity: 995.59%; LCMS Calculated for C23H23ClN6O2 (free base): 450.92: Observed : 451.15(M+1).
To a stirred solution of compound 1 (3.54 g, 1.5 eq) in dry DMF (20 mL), DIPEA (6.32 mL, 2 eq) was added followed by the addition of compound 2 (4 g, 1 eq). The reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford title compound 3. LCMS (m/z): 332.05 (M+1).
To a stirred solution of compound 3 (2.8 g, 1 eq) in methanol (50 mL), Raney Ni (2 g) was added under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h under hydrogen balloon pressure. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure to afford the title compound 4. LCMS (m/z): 302.1 (M+1).
To a stirred solution of compound 4 (2.5 g, 1 eq) in dry THF (50 mL), CDI (1.48 g, 1.1 eq) was added under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure to obtain a crude residue. The crude product was purified by column chromatography on silica gel 100-200 mesh using 40% EtOAc-hexane to afford the title compounds 5. LCMS (m/z): 328 (M+1).
To a stirred solution of compound 5 (0.5 g, 1 eq) in DMF (20 mL), sodium hydride (0.061 g, 1 eq) was added at 0° C. and stirred for 30 min followed by the addition of methyl iodide (0.1 mL, 1.1 eq) at 0° C. and stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice water and extracted with ethyl acetate (2×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 6. LCMS (m/z): 342 (M+1).
The title compound have been synthesized by following the general procedure described above for Boronate ester preparation by using bromo compound 6 and Bis (pinacolato)diboron. LCMS (m/z): 342 (M+1).
The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using chloro compound 8 and boronate ester 7. 1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 7.85-7.60 (m, 4H), 7.40-7.23 (m, 3H), 6.62 (d, J=8.4 Hz,2H), 3.84-3.69 (m, 8H), 3.45 (s, 4H), 3.40 (s, 3H), 2.71-2.63 (m, 2H),2.23 (dd, J=5.3, 3.5 Hz, 4H); HPLC purity: 98.74%; LCMS Calculated for C28H32ClN7O3 (free base): 550.05:observed: 450.45(M+1).
Synthesis of 6-(1H-benzo[d]imidazol-4-yl)-N-(4-chlorophenyl)-2-morpholinopyrimidin-4-amine
The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using chloro compound 1 and Boronic acid. 1H NMR (400 MHz, Chloroform-d) δ 8.14 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.32 (dt, J=7.9, 3.6 Hz, 3H), 6.62 (s, 1H), 3.84 (s, 9H), 3.54 (s, 1H); HPLC purity: 99.68%; LCMS Calculated for C21H19ClN6O (free base): 406.87:observed: 407.20 (M+1).
To a stirred solution of compound 1 (2 g, 1 eq) in DMF (20 mL), 2 M methyl amine solution in THF (9.13 mL, 2 eq) and DIPEA (3.53 g, 2.5 eq) were added and stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 20% EtOAc-hexane to afford the title compound 2. LCMS (m/z): 231.05 (M+1).
To a stirred solution of compound 2 (1 g, 1 eq) in ethanol (40 mL), iron powder (2.31 g, 5 eq), water (20 mL) and ammonium chloride (2.18 g, 5 eq) were added slowly. The reaction mixture was heated to reflux for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 3. LCMS (m/z): 200.95 (M+1).
To a stirred solution of compound 3 (2 g, 1 eq) in THF (40 mL), CDI (2.42g, 1.5 eq) was added slowly at room temperature. The reaction mixture was heated to reflux for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (2×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 4. LCMS (m/z): 226.90 (M+1).
The title compound has been synthesized by following the general procedure described above for Boronate ester preparation by using bromo compound 4 and Bis (pinacolato)diboron. LCMS (m/z): 275.20 (M+1).
The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using chloro compound 6 and boronate ester 5. 1H NMR (400 MHz, DMSO-d6) δ: 11.21 (s, 1H),10.20 (s, 1H), 7.71 (d, J=8.5 Hz, 2H), 7.60 (d, J=17.0 Hz, 2H), 7.41 (d, J=8.5 Hz, 2H), 7.13 (d, J=8.1 Hz, 1H), 6.62 (s, 1H), 3.82-3.72 (m, 8H),3.36 (s, 3H); HPLC purity: 99.74%; LCMS Calculated for C22H21ClN6O2 (free base):436.14; Observed: 437.35 (M+1).
To a stirred solution of 6-bromo indazole 1 (3 g, 1 eq) in DMF (20 mL), K2CO3 (6.3 g, 3 eq) and 4-(2-chloroethyl)morpholine (3.4 g, 1.2 eq) were added and heated at 90° C. for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 40% EtOAc-hexane to afford the title compound 3. LCMS (m/z): 310.05 (M+1).
The title compound (crude) was synthesized by following the general procedure described above for Boronate ester preparation by using bromo compound 3 and Bis(pinacolato)diboron.
The title compound was synthesized by general procedure described above for Suzuki coupling by using chloro compound 5 and Boronate ester 4. LCMS (m/z): 429.30 (M+1).
The title compound has been synthesized by following the general procedure described above for Buchwald Coupling by using chloro compound 6 and methyl 4-aminobenzoate 7. LCMS (m/z): 544.45 (M+1).
The title compound has been synthesized by following the general procedure described above for ester hydrolysis by using compound 5 and sodium hydroxide. 1H NMR (400 MHz, DMSO-d6) δ: 12.58 (s, 1H), 9.81 (s, 1H), 8.29 (s, 1H), 8.12 (s, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.90-7.73 (m, 4H), 6.77 (s, 1H), 4.62 (t, J=6.6 Hz, 2H), 3.83-3.75 (m, 8H), 3.48 (t, J=4.5 Hz, 4H), 2.79 (t, J=6.5 Hz, 2H), 2.44 (t, J=4.7 Hz, 4H); HPLC purity: 99.14%; LCMS Calculated for C28H31N7O4: 529.24; Observed: 530.40 (M+1).
To a stirred solution of compound 1 (1 eq) in t-butanol, 2-aminoethanol (1.1 eq) was added and stirred at 70° C. for 4 h followed by the addition of K2CO3 (3 eq) and Iodine (1.2 eq). The reaction mixture was heated at 70° C. for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was diluted with sodium thiosulphate and extracted with ethyl acetate. Combined organic extracts were washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford compound 2 2-(4-nitrophenyl)-4,5-dihydrooxazole. LCMS: (m/z): 192.95 (M+1)
To a stirred solution of compound 2 (1 eq) in ethanol, iron powder (4 eq), water and ammonium chloride (4 eq) were added slowly. The reaction mixture was heated to reflux for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 3, 4-(4,5-dihydrooxazol-2-yl)aniline. LCMS: (m/z): 163.05 (M+1).
The title compound has been synthesized by following the general procedure described above for Buchwald coupling by using chloro compound 4 and compound 3. 1H NMR (400 MHz, DMSO-d6) δ: 10.09 (s, 1H), 8.63 (t, J=5.5 Hz, 1H), 8.24 (s, 1H), 8.12 (d, J=2.7 Hz, 1H), 7.92-7.77 (m, 5H), 7.72 (d, J=8.5 Hz, 1H), 6.80 (s, 1H), 4.14 (s, 3H), 3.88-3.69 (m, 10H), 3.58 (q, J=6.1 Hz, 2H); HPLC purity: 97.52%; LCMS Calculated for C25H25N7O2 (free base): 455.21; Observed: 456.30 (M+1).
To a stirred solution of compound 1 (1 g, 1 eq) in dichloromethane (50 mL), PPh3═CHCOOCH3 (3.32 g, 1 eq) was added and stirred for 18 hat room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with dichloromethane (3×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 10% EtOAc-hexane to afford the title compound 2.
To a stirred solution of NaH (0.12 g, 1.3 eq) in diethyl ether (7 mL), a solution of compound 2 (0.8 g, 1 eq) and compound 3 (0.792 g, 1.05 eq) in DMSO: diethyl ether(1:1.3; 23 mL) was added drop wise and stirred for 4 h at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (2×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 40% EtOAc-hexane to afford title compound 4.41 NMR (400 MHz, DMSO-d6) δ: 11.82 (s, 1H), 8.17 (d, J=8.8 Hz, 2H), 7.75 (d, J=8.8 Hz, 2H), 7.58 (t, J=2.4 Hz, 1H), 7.22 (t, J=2.4 Hz, 1H), 3.67 (s, 3H).
To a stirred solution of compound 4 (0.3 g, 1 eq) in ethylene glycol (5 mL), NaOH (0.121 g, 2.5 eq) was added and stirred at 160° C. in a sealed tube for 5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (2×25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 30% EtOAc-hexane to afford the title compound 5. 1H NMR (400 MHz, DMSO-d6) δ: 11.26 (s, 1H), 8.14 (d, J=9.2 Hz, 2H), 7.78 (d, J=8.8 Hz, 2H), 7.52 (s, 1H), 6.88 (s, 1H), 6.60 (s, 1H).
To a stirred solution of compound 5 (1 eq) in EtOH:H2O (1:1, 30 mL), Iron powder (4.01 eq) and NH4Cl (4.01 eq) were added. The resulting reaction mixture was refluxed for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a celite and the filtrate was evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound. LCMS (m/z): 158.95 (M+1).
The title compound has been synthesized by following the general procedure described above for displacement reaction (IPA, Conc. HCl) by using chloro compound 7 and amine 6. 1H NMR (400 MHz, DMSO-d6) δ: 10.85 (s, 1H), 9.36 (s, 1H), 8.23 (s, 1H), 8.09 (s, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.79-7.72 (m, 1H), 7.62 (d, J=8.3 Hz, 2H), 7.49 (d, J=8.6 Hz, 2H), 7.16 (d, J=2.2 Hz, 1H), 6.78 (q, J=2.4 Hz, 1H), 6.70 (s, 1H), 6.41 (t, J=2.2 Hz, 1H), 4.13 (s, 3H), 3.86-3.73 (m, 8H); HPLC purity: 90.57%; LCMS Calculated for C26H25N7O: 451.21; Observed: 452.30 (M+1).
To a stirred solution of compound 1 (8 g, 1 eq) in Conc. H2SO4 (35 mL), nitrating mixture (13.2 mL Conc. HNO3+5 mL Conc. H2SO4) was added at 0° C. and stirred at same temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured onto ice water and basified to pH 9 using 2N NaOH. The precipitated solid was filtered, washed with water and dried under reduced pressure to afford the title compound 2. LCMS (m/z): 235 (M+1).
To a stirred solution of compound 2 (7.2 g, 1 eq) in EtOH: H2O (7:3, 100 mL), Iron powder (8.1 g, 5 eq) and NH4Cl (8.5 g, 5 eq) were added. The resulting reaction mixture was refluxed for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a celite and the filtrate was evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound. LCMS (m/z): 205.15 (M+1).
To a stirred solution of compound 3 (5.5 g, 1 eq) in DCM (50 mL), acetic anhydride (3.8 mL, 1.5 eq), and TEA (8.9 mL, 2.4 eq) was added and stirred under nitrogen atmosphere at room temperature for 18 h. The reaction mixture was evaporated under reduced pressure. Residue was diluted with methanol and potassium carbonate was added, reaction was stirred at rt for 1 h. The reaction mixture was evaporated under reduced pressure and diluted with water, precipitate solid was filtered and dried to afford title compound. LCMS (m/z): 247.15 (M+1).
To a stirred solution of compound 4 (5.5 g, 1 eq) in toluene (50 mL) and glacial acetic acid (6.4 mL), acetic anhydride (6.3 mL, 3 eq) and potassium acetate (4.8g, 2.2 eq). The reaction mixture was stirred warm at refluxed, then added isopentyl nitrite(3.5 mL, 1.2 eq)and stirred for 3 h. The reaction mixture was concentrated under reduced pressure to obtain a crude compound.
To a stirred solution of compound 5 (4g, 1 eq) in methanol (50 mL), potassium carbonate (9.8 g, 3.2 eq) was added and heated to reflux for 1 h. The reaction mixture was evaporated under reduced pressure to obtain a residue. The residue was diluted with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 30% EtOAc-hexane to afford the title compound. LCMS (m/z): 216 (M+2).
To a stirred solution of compound 6 (1.7 g, 1 eq) in dioxane (30 mL), iodine (4 g, 2 eq) and 3NaOH (10 mL) was added and stirred for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with sodium bicarbonate solution and sodium thiosulfate solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure. LCMS (m/z): 343.15 (M+2).
To a stirred solution of compound 7 (2 g, 1 eq) in dry DMF (20 mL), NaH (0.388 g, 1.5 eq) was added at 0° C. and stirred for 15 min followed by the addition of methyl iodide (0.8 mL, 2 eq). The reaction mixture was stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 20% EtOAc-hexane to afford the title compound. LCMS (m/z): 356.09 (M+2).
The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using bromo compound 8 and boronic acid. LCMS (m/z): 256.1 (M+1).
To a stirred solution of compound 9 (0.48 g, 1 eq) in dry THF (30 mL), BH3:DMS (6.2 mL, 8 eq) was added at 0° C. and stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with 4N NaOH and 30% H2O2 solution at 0° C. The reaction mixture was stirred at room temperature for 3 h and extracted with ethyl acetate (3×50 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 50% EtOAc-hexane to afford the title compound. LCMS (m/z): 273 (M+1).
To a stirred solution of compound 10 (0.4 g, 1 eq) in DCM (5 mL), TEA (0.4 mL, 2 eq) was added and stirred for 15 min followed by the slow addition of mesyl chloride (0.17 mL, 1.5 eq) at 0° C. The reaction mixture was stirred at rt for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water, extracted with DCM (3×25 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to crude residue. The residue was dissolved in DMF(3 mL),triethylamine(0.27 mL) was added and stirred at 90° C. for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 30% EtOAc-hexane to afford the compound. LCMS (m/z): 273 (M+1).
The title compound has been synthesized by following the general procedure described above for boronate ester coupling by using bromo compound 11 and Boronate ester. LCMS (m/z): 390.25 (M+1).
The title compound has been synthesized by following the general procedure described above for Suzuki coupling by using chloro compound 13 and Boronate ester compound 12. 1H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.23 (s, 1H), 7.75 (d, J=8.6 Hz, 3H), 7.39 (d, J=9 Hz, 2H), 6.73 (s, 1H), 4.04 (s, 3H), 3.82-3.65 (m, 8H),3.40-3.35(m,4H), 3.08(t, J=2.6 Hz, 2H),2.78 (t, J=2.4 Hz, 2H); HPLC purity: 96.31%; LCMS Calculated for C28H31ClFN7O2: 552.05; Observed: 552.45 (M+1).
To a stirred solution of compound 1 (20 g, 1 eq) in acetone: water (4:1, 250 mL), sodium azide (11.4 g, 1.5 eq) was added and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with DCM (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure.
To a stirred solution of propargyl alcohol (2.4 mL, 1.1 eq) and copper acetate (5 mL) in tert-butanol (30 mL), compound 2 (5 g, 1 eq) was added. The reaction mixture was degassed for 30 min and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure to obtain a crude residue. The crude product was purified by column chromatography on silica gel 100-200 mesh using 20% EtOAc-hexane to afford the compound.
To a stirred solution of compound 3 (3 g, 1 eq) in DCM (120 mL), triphenyl phosphine (6.2 g, 1.5 eq) was added followed by addition of carbon tetra bromide (7.9 g, 1.5 eq) and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure to obtain a crude residue. The crude product was purified by column chromatography on silica gel 100-200 mesh using 25% EtOAc-hexane to afford the compound.
To a stirred solution of compound 4 (1.4 g, 1 eq) in ethanol: dioxane (1:1, 20 mL), 10% Pd—C (0.166 g) was added under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 12 h under hydrogen balloon pressure. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 40% ethyl acetate to afford the title compound. LCMS (m/z): 83.05(M+1).
To a stirred solution of compound 6 (0.4 mL, 1 eq) in dry DMF (3 mL), NaH (0.211 g, 1.5 eq) was added at 0° C. and stirred for 15 min followed by the addition of compound 5 (0.380 g, 1.1 eq). The reaction mixture was stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 0-5% EtOAc-hexane to afford the title compound. LCMS (m/z): 205 (M+1).
To a stirred solution of compound 5 (0.4 g, 1 eq) in ethanol: THF (7 mL), 10% Pd—C (0.2 g) was added under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 12 h under hydrogen balloon pressure. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure to afford the title compound. LCMS (m/z): 175(M+1).
The title compound has been synthesized by following the general procedure described above for Buchwald coupling by using corresponding chloro compound 9 and amine 8. 1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.18 (s, 1H), 7.98-7.81 (m, 5H), 7.73 (d, J=9.5 Hz, 1H), 6.73 (s, 1H), 4.06 (s, 3H), 3.78 (dt, J=34.8, 4.8 Hz, 12H), 3.10 (s, 2H), 2.71 (s, 2H), 2.43 (s, 4H), 2.36 (s, 3H); HPLC purity: 98%; LCMS Calculated for C34H37N7O2: 575.70:observed: 581.55 (M+1).
Synthesis of4-((6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)-N-methylbenzamide: The title compound has been synthesized by following the general procedure described above for amide coupling by using corresponding acid compound 6 and amine. 1H NMR (400 MHz, Methanol-d4) δ 8.02 (d, J=1.3 Hz, 1H), 7.97-7.86 (m, 3H), 7.77 (d, J=8.4 Hz, 2H), 7.49 (dd, J=8.4, 1.5 Hz, 1H), 6.62 (s, 1H), 4.10 (s, 3H), 3.95-3.83 (m, 8H), 2.94 (s, 3H), 2.60 (s, 3H); HPLC purity: 95.15%; LCMS Calculated for C25H27N7O2: 457.54:observed: 488.40 (M+1).
The following compounds were prepared using methods disclosed herein or known to one of ordinary skill in the art.
N-(4-chlorophenyl)-6-(2-methyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-benzo[d]imidazol-5-yl)-2-morpholinopyrimidin-4-amine): 1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.14 (d, J=1.5 Hz, 1H), 7.86 (dd, J=8.4, 1.6 Hz, 1H), 7.75-7.66 (m, 2H), 7.56 (d, J=8.5 Hz, 1H), 7.40-7.31 (m, 2H), 6.61 (s, 1H), 4.30 (t, J=6.5 Hz, 2H), 3.81-3.67 (m, 8H), 3.37-3.32 (m, 2H), 2.76 (t, J=6.5 Hz, 3H), 1.72-1.60 (m, 4H); HPLC purity: 98.41%; LCMS Calculated for C28H32ClN7O: 518.05:observed: 518.60(M+1).
Methyl 4-((6-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-yl) amino) benzoate: 1H NMR (400 MHz, DMSO-d6) δ: 9.83 (s, 1H), 8.30-8.22 (m, 2H), 7.97-7.82 (m, 5H), 7.73 (d, J=8.5 Hz, 1H), 6.74 (s, 1H), 4.50 (t, J=5.1 Hz, 2H), 3.86-3.69 (m, 13H), 3.25 (s, 3H); HPLC purity: 98.24%; LCMS Calculated for C26H28N6O4: 488.22; Observed: 489.30 (M+1).
4-((6-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)benzoic acid: 1H NMR (400 MHz, DMSO-d6) δ: 9.81 (s, 1H), 8.30-8.23 (m, 2H), 7.91 (d, J=8.6 Hz, 3H), 7.77 (dd, J=28.7, 8.5 Hz, 3H), 6.76 (s, 1H), 4.50 (t, J=5.3 Hz, 2H), 3.86-3.66 (m, 10H), 3.25 (s, 3H); HPLC purity: 99.79%; LCMS Calculated for C25H26N6O4: 474.20; Observed: 475.35 (M+1).
2-(2-(1-methyl-6-(6-((1-methyl-1H-indol-6-yl)amino)-2-morpholinopyrimidin-4-yl)-1H-indazol-3-yl)ethyl)isoindoline-1,3-dione: 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.23(d, J=8.4 Hz, 2H), 7.92-7.65 (m, 6H), 7.45 (s, 1H), 7.21(s, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.63 (s, 1H), 6.41(s, 1H),4.05-4.02 (m, 5H), 3.83 (d, J=4.9 Hz, 4H), 3.68-3.61 (m, 7H), 3.39-3.24 (m, 2H); HPLC purity: 98.59%; LCMS Calculated for C35H32N8O3: 612.69: Observed: 631 (M+1).
N-(4-chlorophenyl)-6-(3-ethyl-1-methyl-1H-pyrazolo[4,3-b]pyridin-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 9.08(s, 1H), 8.60(s,1H), 7.72 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H), 6.73 (s, 1H), 4.08 (s, 3H), 3.73 (d, J=4.9 Hz, 4H), 3.65 (s, 4H), 2.61 (s, 2H), 2.45 (s, 3H); HPLC purity: 92.32%; LCMS Calculated for C23H24ClN7O: 449.94:observed : 450.30 (M+1).
N-(4-(2H-1,2,3-triazol-2-yl)phenyl)-6-(1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ 10.09-10.02 (m, 1H), 9.03 (d, J=1.8 Hz, 1H), 8.64 (d, J=1.8 Hz, 1H), 8.09 (s, 2H), 8.06-7.97 (m, 2H), 7.94-7.86 (m, 2H), 6.80 (s, 1H), 4.10 (s, 3H), 3.85 (d, J=4.8 Hz, 4H), 3.75 (t, J=4.7 Hz, 4H), 2.57 (s, 3H); HPLC purity: 99.88%; LCMS Calculated for C24H24N10O: 468.51:observed: 469.30(M+1).
N-(4-chlorophenyl)-6-(1H-indazol-4-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.75 (d, J=8.6 Hz, 3H), 7.63 (d, J=7.1 Hz, 1H), 7.55-7.38 (m, 3H), 6.81 (s, 1H), 3.84-3.71 (m, 8H), 2.46 (d, J=11.8 Hz, 1H); HPLC purity: 98.6%; LCMS Calculated for C21H19ClN6O (free base): 406.87:observed : 407.20 (M+1).
Methyl 4-((6-(1-(2-methoxyethyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl) amino) benzoate: 1H NMR (400 MHz, DMSO-d6) δ: 9.87 (s, 1H), 8.27 (s, 1H), 8.13 (s, 1H), 7.94 (d, J=8.5 Hz, 2H), 7.89-7.74 (m, 4H), 6.76 (s, 1H), 4.65 (t, J=5.3 Hz, 2H), 3.86-3.70 (m, 13H), 3.21 (s, 3H); HPLC purity: 99.13%; LCMS Calculated for C26H28N6O4: 488.22; Observed: 489.30 (M+1).
4-((6-(1-(2-methoxyethyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)benzoic acid: 1H NMR (400 MHz, DMSO-d6-D2O) δ: 8.18 (d, J=19.4 Hz, 2H), 7.91 (dd, J=21.1, 8.5 Hz, 3H), 7.80 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.5 Hz, 1H), 4.62 (t, J=5.2 Hz, 2H), 3.79-3.69 (m, 10H), 3.17 (s, 3H); HPLC purity: 99.13%; LCMS Calculated for C25H26N6O4: 474.20; Observed: 475.25 (M+1).
2-(3-(1-methyl-6-(6-((1-methyl-1H-indol-6-yl)amino)-2-morpholinopyrimidin-4-yl)-1H-indazol-3-yl)propyl)isoindoline-1,3-dione: 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.19 (s, 1H), 8.07 (s, 1H), 7.79 (d, J=12.7 Hz, 5H), 7.68 (dd, J=8.3, 1.3 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.23 (d, J=3.1 Hz, 1H), 7.04 (dd, J=8.5, 1.8 Hz, 1H), 6.70 (s, 1H), 6.35 (d, J=3.0 Hz, 1H), 3.93 (s, 3H), 3.73 (q, J=7.3, 6.8 Hz, 9H), 3.33 (s, 4H), 2.98 (t, J=7.4 Hz, 2H), 2.49-2.42 (m, 1H), 2.13 (p, J=7.3 Hz, 2H); HPLC purity: 98.54%; LCMS Calculated for C36H34N8O3: 626.71:observed: 627.50(M+1).
N-(4-(5-cyclopropyl-4H-1,2,4-triazol-3-yl)phenyl)-6-(1-methyl-3-(2-morpholinoethyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, Chloroform-d) δ 8.04-7.97 (m, 3H), 7.75-7.63 (m, 2H), 7.53 (d, J=8.4 Hz, 2H), 6.68 (s, 1H), 6.56 (s, 1H), 4.07 (s, 3H), 3.92 (t, J=4.8 Hz, 4H), 3.81 (dt, J=11.6, 4.8 Hz, 8H), 3.28-3.18 (m, 2H), 2.92 (t, J=8.0 Hz, 2H), 2.68 (s, 4H), 2.04 (ddd, J=13.8, 8.3, 5.2 Hz, 1H), 1.19-1.04 (m, 4H); HPLC purity: 98.54%; LCMS Calculated for C33H38N10O2 (free base): 606.72:observed: 607.50(M+1).
6-(1,3-dimethyl-1H-indazol-6-yl)-N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)phenyl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.15 (s, 2H), 7.87-7.75 (m, 2H), 7.69 (dd, J=12.6, 8.4 Hz, 3H), 7.52 (d, J=8.2 Hz, 2H), 7.25 (d, J=8.3 Hz, 2H), 6.92 (d, J=8.3 Hz, 2H), 6.69 (s, 1H), 5.24 (s, 2H), 4.03 (s, 3H), 3.85-3.78 (m, 4H), 3.73 (d, J=6.9 Hz, 7H); HPLC purity: 96.20%; LCMS Calculated for C34H34N8O2 (free base): 586.69:observed: 587.50(M+1).
N-(4-chlorophenyl)-2-morpholino-6-(2-(2-morpholinoethyl)-1-(oxetan-3-yl)-1H-benzo[d] imidazol-6-yl)pyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.25 (s, 1H), 8.10 (s, 1H), 7.97-7.74 (m, 1H), 7.58 (d, J=7.7 Hz, 3H), 7.28(s, 1H),6.74 (d, J=1.9 Hz, 1H), 4.13 (d, J=2.0 Hz, 3H), 3.82 (d, J=5.0 Hz, 8H), 3.74 (t, J=4.7 Hz, 4H), 3.05 (d, J=2 Hz, 2H), 2.86 (d, J=1.9 Hz, 2H), 2.36 (d, J=1.9 Hz, 4H); HPLC purity: 98.23%; LCMS Calculated for C30H34ClN7O3: 576.10; Observed: 576.45 (M+1).
N-(6-(1-(cyclopropylmethyl)-2-(2-morpholinoethyl)-1H-benzo[d]imidazol-6-yl)-2-morpholinopyrimidin-4-yl)-1-methyl-1H-indol-6-amine: 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.17 (s, 1H), 8.12 (s, 1H), 7.83 (d, J=8.6 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.21 (d, J=3.0 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 6.65 (s, 1H), 6.33 (d, J=3.0 Hz, 1H), 4.20 (d, J=6.8 Hz, 2H), 3.84 (t, J=4.5 Hz, 4H), 3.58 (t, J=4.6 Hz, 7H), 3.30 (d, J=1.9 Hz, 4H), 3.07 (t, J=7.6 Hz, 2H), 2.84 (t, J=7.6 Hz, 2H), 2.36-2.31(m, 4H)1.27-1.19 (m, 1H), 0.54 (d, J=7.8 Hz, 2H), 0.46 (d, J=5.0 Hz, 2H); HPLC purity: 98.91%; LCMS Calculated for C34H40N8O2: 592.75; Observed: 593.55 (M+1).
6-(1-methyl-1H-indazol-6-yl)-N-(4-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl)-2-morpholino pyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.25 (s, 1H), 8.10 (s, 1H), 7.97-7.74 (m, 7H), 6.74 (d, J=1.9 Hz, 1H), 4.13 (d, J=2.0 Hz, 3H), 3.82 (d, J=5.0 Hz, 4H), 3.74 (t, J=4.7 Hz, 4H), 2.36 (d, J=1.9 Hz, 3H); HPLC purity: 93.15%; LCMS Calculated for C25H25N9O: 467.54; Observed:468.35 (M+1).
6-(1,3-dimethyl-1H-indazol-6-yl)-N-(4-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl)-2-morpholinopyrimidin-4-amine(: 1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.16 (s, 1H), 7.96-7.69 (m, 7H), 6.72 (s, 1H), 4.04 (s, 3H), 3.82 (d, J=4.6 Hz, 4H), 3.77-3.70 (m, 4H), 2.46 (s, 3H),2.35 (s, 3H); HPLC purity: 99.02%; LCMS Calculated for C26H27N9O: 481.56; Observed:482.40 (M+1).
1,3-dimethyl-N-(6-(1-methyl-3-(2-morpholinoethyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1H-indol-6-amine: 1H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.15 (s, 1H), 8.09 (s, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.74-7.66 (m, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.09-6.96 (m, 2H), 6.71 (s, 1H), 4.04 (s, 3H), 3.90-3.82 (m, 4H), 3.78-3.55 (m, 11H), 3.09 (dd, J=8.9, 6.8 Hz, 2H), 2.70 (dd, J=8.9, 6.8 Hz, 2H), 2.22 (s, 3H); HPLC purity: 96.76%; LCMS Calculated for C32H38N8O2: 566.71; Observed: 567.45 (M+1).
1,2-dimethyl-N-(6-(1-methyl-3-(2-morpholinoethyl)-1H-indazol-6-yl)-2-morpholino pyrimidin-4-yl)-1H-indol-6-amine: 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.73-7.66 (m, 1H), 7.34 (d, J=8.3 Hz, 1H), 6.99 (dd, J=8.4, 1.8 Hz, 1H), 6.69 (s, 1H), 6.14 (s, 1H), 4.04 (s, 3H), 3.90-3.78 (m, 4H), 3.74 (t, J=4.9 Hz, 4H), 3.63-3.55 (m, 7H), 3.13-3.04 (m, 2H), 2.70 (dd, J=8.9, 6.9 Hz, 2H), 2.47 (d, J=4.6 Hz, 4H), 2.39 (s, 3H); HPLC purity: 95.74%; LCMS Calculated for C32H38N8O2: 566.71; Observed: 567.40 (M+1).
N-(6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1,2-dimethyl-1H-indol-6-amine: 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.73-7.66 (m, 1H), 7.34 (d, J=8.4 Hz, 1H), 6.99 (dd, J=8.4, 1.9 Hz, 1H), 6.69 (s, 1H), 6.14 (s, 1H), 4.03 (d, J=1.5 Hz, 3H), 3.86 (t, J=4.7 Hz, 4H), 3.74 (t, J=4.5 Hz, 4H), 3.61 (d, J=1.5 Hz, 3H), 2.39 (s, 3H), 2.21 (m, 3H); HPLC purity: 96.83%; LCMS Calculated for C27H29N7O: 467.58; Observed: 468.35 (M+1).
4-chloro-N-(6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1-methyl-1H-indol-6-amine: 1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.25 (d, J=2.5 Hz, 2H), 8.16 (d, J=2.4 Hz, 2H), 7.83-7.68 (m, 2H), 7.62 (dd, J=9.1, 2.4 Hz, 1H), 6.73 (d, J=2.4 Hz, 1H), 4.03 (d, J=2.5 Hz, 3H), 3.85-3.78 (m, 4H), 3.74 (d, J=4.9 Hz, 7H), 2.50 (dd, J=3.6, 1.9 Hz, 3H); HPLC purity: 97.19%; LCMS Calculated for C26H26ClN7O: 487.99; Observed: 488.30 (M+1).
N-(6-(3-(2-aminoethyl)-1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1-methyl-1H-indol-6-amine: 1H NMR (400 MHz, Methanol-d4) δ 8.18 (t, J=1.1 Hz, 1H), 7.98 (s, 1H), 7.79 (d, J=1.0 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.13-7.04 (m, 2H), 6.64 (s, 1H), 6.39 (dd, J=3.2, 0.9 Hz, 1H), 4.11 (s, 3H), 3.94 (t, J=4.8 Hz, 4H), 3.85-3.75 (m, 8H), 3.67-3.58 (m, 3H), 3.43 (dd, J=7.2, 5.6 Hz, 2H), 3.38-3.31 (m, 2H); HPLC purity: 96.64%; LCMS Calculated for C27H30N8O: 482.59; Observed: 483.30 (M+1).
2-(2-(1-methyl-6-(6-((1-methyl-1H-indol-6-yl)amino)-2-morpholinopyrimidin-4-yl)-1H-indazol-3-yl)ethyl)isoindoline-1,3-dione: 1H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.16(d, J=2.4 Hz, 2H), 7.88-7.66 (m, 6H), 7.25(s, 1H), 7.21(s,1H), 7.08(d, J=8.4 Hz, 1H),6.72 (s, 1H), 6.51 (d, J=2.3 Hz, 1H), 4.02-3.90 (m, 4H), 3.78 (dq, J=28.9, 4.6 Hz, 4H), 3.68 (d, J=3.5 Hz, 7H),3.28 (s, 2H); HPLC purity: 98.59%; LCMS Calculated for C35H32N8O3: 612.69; Observed: 613 (M+1).
N-(6-(3-(3-(dimethylamino)propyl)-1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1-methyl-1H-indol-6-amine: 1H NMR (400 MHz, Methanol-d4) δ 8.13 (s, 1H), 7.99 (s, 1H), 7.76 (q, J=8.3 Hz, 2H), 7.47 (d, J=8.4 Hz, 1H), 7.12-7.03 (m, 2H), 6.63 (d, J=2.5 Hz, 1H), 6.38 (d, J=3.2 Hz, 1H), 4.06 (d, J=3.3 Hz, 3H), 3.85-3.74 (m, 1H), 3.02 (t, J=7.4 Hz, 2H), 2.62-2.53 (m, 2H), 2.37 (s, 6H), 2.04 (p, J=7.8 Hz, 2H); HPLC purity: 96.38%; LCMS Calculated for C30H36N8O: 524.67; Observed: 525.40 (M+1).
1-methyl-N-(6-(1-methyl-3-(3-(pyrrolidin-1-yl)propyl)-1H-indazol-6-yl)-2-morpholino pyrimidin-4-yl)-1H-indol-6-amine: 1H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.29 (d, J=1.3 Hz, 1H), 8.27-8.16 (m, 2H), 7.87 (dd, J=8.6, 1.5 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.24 (d, J=3.1 Hz, 1H), 7.05 (dd, J=8.5, 1.9 Hz, 1H), 6.75 (s, 1H), 6.35 (d, J=3.1 Hz, 1H), 4.12 (s, 3H), 3.92-3.84 (m, 4H), 3.75 (d, J=3.5 Hz, 7H), 2.98-2.95 (m, 2H), 2.46-2.41 (m, 6H), 1.91 (dp, J=32.2, 7.1 Hz, 2H), 1.65-1.6(m, 4H); HPLC purity: 94.8%; LCMS Calculated for C32H38N8O: 550.71; Observed: 551.45 (M+1).
4-(4-((6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)amino)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one: 1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 9.61 (s, 1H), 8.32 (d, J=1.4 Hz, 1H), 8.24 (s, 1H), 8.10 (d, J=1.1 Hz, 1H), 7.89-7.73 (m, 4H), 7.61 (d, J=8.7 Hz, 2H), 6.73 (s, 1H), 4.13 (d, J=1.2 Hz, 3H), 3.78 (dt, J=35.4, 4.5 Hz, 8H); HPLC purity: 97.84%; LCMS Calculated for C24H23N9O2: 469.51; Observed: 470.35 (M+1).
N-(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)-6-(1-methyl-1H-indazol-6-371)-2-morpholino pyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.42 (s, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.90-7.74 (m, 6H), 6.74 (s, 1H), 4.11 (d, J=19.2 Hz, 6H), 3.87-3.74 (m, 8H), 2.46 (d, J=8.3 Hz, 1H); HPLC purity: 99.63%; LCMS Calculated for C25H25N9O: 467.54; Observed: 468 (M+1).
1,2,3-trimethyl-N-(6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl)-1H-indol-6-amine: 1H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.31(s, 1H),8.03 (s, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.24 (d, J=8.1 Hz, 1H), 7.10-6.94 (m, 2H), 6.35 (s, 1H), 3.98 (s, 3H), 3.76-3.62 (m, 8H),3.19 (s, 3H), 2.26 (s, 3H), 1.96 (s, 3H); HPLC purity: 96.62%; LCMS Calculated for C27H29N7O: 467.58; Observed: 468.35 (M+1).
N-(4-(1H-pyrazol-1-yl)phenyl)-6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.42 (d, J=2.5 Hz, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.89-7.74 (m, 6H), 7.71 (d, J=1.8 Hz, 1H), 6.73 (s, 1H), 4.13 (s, 3H), 3.78 (dt, J=36.9, 4.6 Hz, 8H), 2H); HPLC purity: 95.07%; LCMS Calculated for C25H24N8O: 452.52; Observed: 453.30 (M+1).
6-(1-methyl-1H-indazol-6-yl)-N-(4-(4-methyl-1H-pyrazol-1-yl)phenyl)-2-morpholino pyrimidin-4-amine1H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.26-8.16 (m, 2H), 8.09 (d, J=1.0 Hz, 1H), 7.89-7.69 (m, 6H), 7.52 (s, 1H), 6.72 (s, 1H), 4.13 (s, 3H), 3.78 (dt, J=36.0, 4.7 Hz, 8H), 2.10 (s, 3H); HPLC purity: 97.08%; LCMS Calculated for C26H26N8O: 466.55; Observed: 467.30 (M+1).
6-(1-methyl-1H-indazol-6-yl)-N-(4-(3-methyl-1H-pyrazol-1-yl)phenyl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.32-8.21 (m, 2H), 8.10 (s, 1H), 7.91-7.70 (m, 6H), 7.67-7.51 (m, 1H), 6.71 (s, 1H), 6.30 (d, J=2.3 Hz, 1H), 4.13 (s, 3H), 3.78 (dt, J=35.5, 4.6 Hz, 8H), 2.27 (s, 3H); HPLC purity: 96.09%; LCMS Calculated for C26H26N8O: 466.55; Observed: 467.25 (M+1).
N-(4-(1H-pyrazol-1-yl)phenyl)-6-(1,3-dimethyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.42 (d, J=2.5 Hz, 1H), 8.24 (s, 1H), 7.89-7.74 (m, 7H), 6.73 (s, 1H), 6.52 (t, J=2.1 Hz, 1H), 4.13 (s, 3H), 3.78 (dt, J=36.9, 4.6 Hz, 8H), 2.46 (s, 3H); HPLC purity: 94.51%; LCMS Calculated for C26H26N8O: 466.55; Observed: 467.35 (M+1).
6-(1,3-dimethyl-1H-indazol-6-yl)-N-(4-(4-methyl-1H-pyrazol-1-yl)phenyl)-2-morpholino pyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.09 (d, J=1.0 Hz, 2H), 7.89-7.69 (m, 6H), 7.52 (s, 1H), 6.72 (s, 1H), 4.13 (s, 3H), 3.78 (dt, J=36.0, 4.7 Hz, 8H), 2.46(s, 3H),2.10 (s, 3H); HPLC purity: 97.06%; LCMS Calculated for C27H28N8O: 480.58; Observed: 481.35 (M+1).
6-(1,3-dimethyl-1H-indazol-6-yl)-N-(4-(3-methyl-1H-pyrazol-1-yl)phenyl)-2-morpholino pyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.29 (d, J=1.3 Hz, 1H), 8.16 (s, 1H), 7.87-7.67 (d, J=8.4 Hz, 6H), 6.75 (s, 1H), 6.35 (d, J=3.1 Hz, 1H), 4.08 (s, 3H), 3.92-3.84 (m, 8H), 2.46 (s, 3H), 2.12 (s, 3H); HPLC purity: 95%; LCMS Calculated for C27H28N8O: 480.58; Observed: 481.30 (M+1).
N-(4-(1H-pyrazol-1-yl)phenyl)-6-(1-methyl-3-(2-morpholinoethyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.42 (d, J=2.4 Hz, 1H), 8.16 (s, 1H), 7.88-7.66 (m, 7H), 6.72 (s, 1H), 6.51 (d, J=2.3 Hz, 1H), 4.05 (s, 3H), 3.78 (dq, J=28.9, 4.6 Hz, 8H), 3.58 (q, J=7.6, 6.0 Hz, 4H), 3.28 (s, 2H), 3.09 (dd, J=9.4, 6.3 Hz, 2H), 2.56 (d, J=18.9 Hz, 2H), 2.47 (d, J=5.5 Hz, 4H); HPLC purity: 97.54%; LCMS Calculated for C31H35N9O2: 565.68; Observed: 566.45 (M+1).
N-(4-(3-methyl-1H-pyrazol-1-yl)phenyl)-6-(1-methyl-3-(2-morpholinoethyl)-1H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.28 (d, J=2.4 Hz, 1H), 8.16 (s, 1H), 7.92-7.68 (m, 6H), 6.70 (s, 1H), 6.30 (d, J=2.3 Hz, 1H), 4.05 (s, 3H), 3.81 (q, J=6.0, 5.2 Hz, 4H), 3.73 (t, J=4.7 Hz, 4H), 3.63-3.56 (m, 4H), 3.14-3.04 (m, 2H), 2.72 (d, J=8.6 Hz, 2H), 2.50 (s, 4H), 2.27 (s, 3H); HPLC purity: 93.48%; LCMS Calculated for C32H37N9O2: 579.71; Observed: 580.45 (M+1).
N-(4-chlorophenyl)-6-(2-(2-(dimethylamino)ethyl)-3-methyl-2H-indazol-6-yl)-2-morpholinopyrimidin-4-amine: 1H NMR (400 MHz, MeOD) δ: 8.21 (s, 1H), 7.74-7.63 (m, 4H), 7.33-7.24 (m, 2H), 6.58 (s, 1H), 4.53 (t, J=6.9 Hz, 2H), 3.83-3.74 (m, 8H), 2.93 (t, J=6.9 Hz, 2H), 2.70 (s, 3H), 2.34 (s, 6H); HPLC purity: 97.92%; LCMS Calculated for C26H30ClN7O: 491.22; Observed: 492.40 (M+1).
Methyl 4-((6-(1-methyl-1H-indazol-6-yl)-2-morpholinopyrimidin-4-yl) amino) benzoate: 1H NMR (400 MHz, DMSO-d6) δ: 9.87 (s, 1H), 8.25 (s, 1H), 8.10 (s, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.86 (d, J=8.2 Hz, 3H), 7.78 (d, J=8.5 Hz, 1H), 6.79 (s, 1H), 4.13 (s, 3H), 3.82-3.74 (m, 11H); HPLC purity: 94.79%; LCMS Calculated for C24H24N6O3: 444.19; Observed: 445.25 (M+1).
The following describes ways in which the compounds described herein were tested to measure in vitro activity in cell-based assays. A person of ordinary skill in the art would know that variations in the assay conditions could be used to determine the activity of the compounds. See Nat. Chem Biol. 2012, 8, 197.
Dermal fibroblasts from humans with an MPS disorder and from healthy donors are grown. Cells are expanded and kept in culture for analysis. Human foreskin fibroblasts can be obtained from the American Type Culture Collection (CRL-1634). Human dermal fibroblasts derived from biopsies of individuals are purchased from Coriell Institute: clinically healthy individuals, GM00408, GM00409, GM00200 (clinically unaffected sibling of an individual with metachromatic leukodystrophy), GM05659, GM08398, and GM15871 (clinically unaffected sibling of an individual with unclassified Ehlers-Danlos syndrome); heterozygous MPS I carriers, GM01392, GM01393 and GM0003; homozygous individuals affected with MPS I, GM06214, GM11495, GM00034, GM01391 and GM01256; individuals with MPS II, GM01896, GM03181, GM00615 and GM00298; individuals with MPS IIIA, GM00879, GM00643, GM00934, GM06110 and GM00629; MPS IIIB, GM01426; MPS IIIC, GM05157; MPS IIID, GM05093; and MPS VII, GM00121. All cells are grown in DMEM containing 50 U ml-1 penicillin, 50 pg ml-1 streptomycin, 2 mM glutamine and 10% FBS. Cells are seeded on 15-cm-diameter tissue culture dishes, grown to confluence and maintained in culture for analysis. Sulfamidase activity in cell extracts is measured with 4-methylumbelliferyl-α-D-N-sulfoglucosaminide according the vendors instructions substituting Tris-acetate buffer (pH 6.5; Moscerdam).
Cells are treated with a compound of the invention at a concentration at or below 30 μM for 4 to 21 days. Cell monolayers are washed with phosphate buffered saline and detached by treatment with GIBCO trypsin-EDTA solution (Invitrogen). After centrifugation, the supernatant is removed and the cells are lysed in 0.5 mL of 0.1 N sodium hydroxide. The amount of protein is determined by bicinchoninic acid (BCA assay, Thermo Scientific). GAGs are isolated by anion exchange chromatography and digested with glycosaminoglycan lyases (heparinases I, II, and III, IBEX).
Enzymatically depolymerized GAG preparations are differentially mass labeled by reductive amination with [12C6]aniline. Briefly, heparan sulfate disaccharides (1-10 pmol) are dried down in a centrifugal evaporator and reacted with [12C6]aniline or [13C6]aniline (15 μL, 165 μmol) and 15 μL of 1 M NaCNBH3 (Sigma-Aldrich) freshly prepared in dimethylsulfoxide/acetic acid (7:3, v/v) is added to each sample. Reactions are carried out at 37° C. for 16 h and then dried in a centrifugal evaporator. Unsubstituted amines are reacted with propionic anhydride (Sigma-Aldrich). Dried samples are reconstituted in 20 μL of 50% methanol, and 3 μL of propionic anhydride (Sigma-Aldrich, 23.3 μmol) is added. Reactions are carried out at ˜23° C. for 2 h. Acylated disaccharides are subsequently aniline tagged as described above. Each sample is mixed with commercially available standard unsaturated disaccharides (Seikagaku), standard N-sulfoglucosamine, glucosamine-6-sulfate, N-acetylgalactosamine-4-sulfate and N-acetylgalactosamine-6-sulfate (Sigma-Aldrich), and/or synthesized α-L-idopyranosyluronate-(1,4)-2-N-acetyl-2-deoxy-α/β-D-glucopyranoside (I0S0). All standards are tagged with [13C6]aniline (Sigma-Aldrich). Samples are then analyzed by LC-MS using an LTQ Orbitrap Discovery electrospray ionization mass spectrometer (Thermo Scientific) equipped with quaternary HPLC pump (Finnigan Surveyor MS pump) and a reverse-phase capillary column as described in J. Biol. Chem. 2008, 283(48), 33674.
MPS II: Assay 1, as described above, was used to determine activity for MPS II using GM01896 cells. The cells were treated with a compound of the invention and the heparan sulfate disaccharide detected was [12C6]aniline-tagged I2a4, I2a6, 12S0 and/or I2S6. Extracted ion chromatograms were obtained. Cell viability was monitored using alamar blue or ATP quantification. IC50's were calculated using curve fitting within the ChemInnovation CBIS database system. Data is given in Table 2.
Assay 1 can be adapted for use in testing cellular activity of compounds of the invention for treating MPS I where the biomarker detected is I0a6, I0a4, I0a10, I0S0 and/or I0S6; MPS IIIA where the biomarker detected is S0, S0U0S6, S0U2A6, S0U2S0, S0U2S6, S6U0A6, S6U0S0, S6U0S6, S6U2A6, S6U2S0, and/or S6U2S6; MPSIIIB where the biomarker detected is A0U0A6, A0U0S6, A0U2A0, A0U2S0, and/or A0U2S6; MPS IIIC where the biomarker detected is H0U0S6, H0U2A6, H0U2S0, H0U2S6, H6U0A6, H6U0S0, H6U0S6, H6U2A6, H6U2S0, and/or H6U2S6; MPS IIID where the biomarker detected is H6; and MPS VII where the biomarker detected is G0a0, G0a4, G0a10, G0a6, G0A0, G0A6, G0S0, and/or G0S6. Saccharide structure naming code is as described in Lawrence et al. Nature Methods 2008, 5(4), 291. Certain embodiments have been evaluated in Assay I in MPSIIIA cells and demonstrated activity in the range of about 0.2 μM to about 2 μM.
The compounds of Formula I have the ability to reduce heparan sulfate accumulation as shown by Assay 1 in which the compounds reduced biomarker(s) indicative of abnormal HS accumulation in MPS II cells. Certain embodiments have also been evaluated in MPS IIIA cells and demonstrated a reduction in biomarker(s) indicative of abnormal HS accumulation. The compounds in the following table show activity in Assay 1 for MPS II, where activity “A” represents an IC50 of less than 1 to 500 nM; “B” represents an IC50 greater than 500 to 1000 nM, and “C” represents an IC50 greater than 1000 to 5000 nM. A person of ordinary skill in the art would recognize that the compounds have the ability to modulate HS biosynthesis in general which enables the degradation of the heparan sulfate polymer and therefore are useful for treating diseases associated with abnormal HS accumulation.
MPS IIIA mice (Sgsh−/−) are obtained from Jackson Laboratory (B6.Cg-Sgsh) and were housed in Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC)-approved vivaria in the School of Medicine, University of California, San Diego, following standards and procedures approved by the local Institutional Animal Care and Use Committee for the ethical use of animals in experiments. Canine samples are provided by P. Dickson (University of California, Harbor). MPS MA mice (see Bhaumik et al. Glycobiol 1999, 9, 1389) are injected with an amount (e.g., about 100 mg/kg/day) of an HS biosynthesis inhibitor. Samples of mouse urine are incubated for one hour at 37° C. with two volumes of 0.1% cetylpyridinium chloride in 0.054 M sodium citrate (pH 4.8). Samples are centrifuged for 10 minutes at 3000 rpm and pellets are resuspended in 150 μL 2 M LiCl. Following addition of 800 μL absolute ethanol, samples are incubated at −20° C. for one hour and then centrifuged for 10 minutes at 3000 rpm. Pellets are resuspended in 200 μL of water, lyophilized, and then resuspended in 20 μL water. Purified glycosaminoglycan samples (0.2 μmol creatinine equivalents) are analyzed on 40-50% linear gradient polyacrylamide gels. Samples are compared to results for a control MPS IIIA mouse (or population thereof) that was not exposed to an HS biosynthesis inhibitor.
Samples from MPS IIIB mice are provided by E. Neufeld (University of California, Los Angeles). Human urine samples without personal identifying information are obtained from donors from an MPS patient advocacy group with informed consent.
The non-specific inhibitor of sulfation, sodium chlorate, is used for validation or SRT. 30-60 mM sodium chlorate inhibits the synthesis of PAPs, the sulfate donor used in all cellular sulfation reactions including heparan sulfate biosynthesis. Cells grown in the presence of sodium chlorate produce heparan sulfate with reduced sulfation. In certain instances, in vitro MPS models are based on measuring the accumulation of GAG fragments in cultured primary human fibroblast from MPS patients. In some instances, the GAGs that accumulate in MPS patients are much smaller than normal tissue GAGs and they lack a core protein on their reducing termini. Based on these features the in vitro MPS model is based on a method of tagging reducing ends of the GAGs with a detectable label and analyzing (i.e., detecting and/or measuring) the detectable labels using a device suitable for detecting the label (e.g., an HPLC with a fluorimeter).
Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following description. It should be understood, however, that the description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the present description will become apparent from this detailed description.
All publications including patents, patent applications and published patent applications cited herein are hereby incorporated by reference for all purposes.
This application claims the benefit of priority under 35 U.S.C. § 119(e) to provisional U.S. Patent Application No. 62/062,036 filed Oct. 9, 2014, the entire contents of which are hereby incorporated by reference.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US15/54761 | 10/8/2015 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62062036 | Oct 2014 | US |
