AR075368A1 - GLICOSILCERAMIDE SINTASA INHIBITORS - Google Patents

GLICOSILCERAMIDE SINTASA INHIBITORS

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Publication number
AR075368A1
AR075368A1 ARP100100327A ARP100100327A AR075368A1 AR 075368 A1 AR075368 A1 AR 075368A1 AR P100100327 A ARP100100327 A AR P100100327A AR P100100327 A ARP100100327 A AR P100100327A AR 075368 A1 AR075368 A1 AR 075368A1
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Argentina
Prior art keywords
alkyl
heteroaryl
haloalkyl
independently
ring
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ARP100100327A
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Spanish (es)
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Exelixis Inc
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Publication of AR075368A1 publication Critical patent/AR075368A1/en

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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P3/00—Drugs for disorders of the metabolism
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/00—Antineoplastic agents
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07C2601/14—The ring being saturated

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Abstract

Moduladores de glucosilceramida sintasa (GCS) y métodos para hacer los compuesto. Comprende además composiciones que comprenden los compuestos, N-oxidos, y/o sales farmacéuticamente aceptables de los mismos. También comprende el uso de los compuestos y composiciones para la fabricacion de medicamentos, particularmente para tratar enfermedades en las cuales GCS es un mediador o está implicado. Reivindicacion 1: Un compuesto de la formula (1), o un estereoisomero sencillo o mezcla de estereoisomeros de los mismos, N-oxidos de los mismos, y de manera adicional opcionalmente como una sal farmacéuticamente aceptable de los mismos, caracterizado porque A es isopropilo, t-butilo, cicloalquilo C3-8, heterociclilo, arilo, o heteroarilo, en donde el cicloalquilo, heterociclilo, arilo, y heteroarilo están opcionalmente sustituidos por uno, dos o tres grupos RA, en donde cada RA es independientemente RA2, alquilo C1-4, haloalquilo C1-4, arilo, arilalquilo C1-4, o alquilo C1-4-RA2, en donde el arilo del grupo arilalquilo C1-4 está opcionalmente sustituido con uno, dos o tres grupos RA2, en donde, cada RA2 es independientemente halogeno, ciano, nitro, -ORA1, -SRA1, -N(RA1)2, -C(O)RA1, -S(O)RA1, -S(O)2RA1, -S(O)N(RA1)2, -S(O)2N(RA1)2, -C(O)ORA1, -C(O)N(RA1)2, -N(RA1)C(O)RA1, -N(RA1)C(O)ORA1, -N(RA1)C(O)N(RA1)2, -N(RA1)S(O)2RA1, -N(RA1)C(=NRA1)N(RA1)2, -P(O)(ORA1)2, o -OP(O)(ORA1)2, en donde cada RA1 es independientemente hidrogeno, alquilo C1-4, o haloalquilo C1-4, o dos RA enlazados a átomos de carbono adyacentes, tomados juntos, forman -O-(G)y-O-, en donde cada G es independientemente -CH2-, -C(H)(F)-, o -CF2-, e y es 1, 2, o 3; L es -[C(RL)2]p-L1-[C(RL)2]q-, en donde p es 1, 2, o 3; q es un entero seleccionado de 0 hasta (3-p); L1 es una union u -O-; y cada RL es independientemente hidrogeno, metilo, o halometilo; R1 es -N(R10)(R11) o una porcion de la formula (2), en donde R10 es hidrogeno o alquilo C1-4; R11 es -R13,-cicloalquilo C3-6-N(R12)2, -cicloalquilo C3-6-R13, alquilo C1-4-N(R12)2, o alquilo C1-6-R13, en donde cada R12 es independientemente hidrogeno o alquilo C1-4; y R13 es (a) un anillo heterociclilo monocíclico de 4-10 miembros, bicíclico fusionado de 4-10 miembros, bicíclico puenteado de 5-10 miembros, o bicíclico espiro de 5-10 miembros, donde el anillo heterociclilo comprende uno, dos o tres átomos de nitrogeno anular, y opcionalmente comprende un átomo de oxígeno o azufre anular, o (b) un heteroarilo monocíclico de 5 o 6 miembros o un heteroarilo bicíclico fusionado de 8-10 miembros, donde el anillo heteroarilo comprende uno, dos, o tres átomos de N anulares, y opcionalmente comprende un átomo de O o S anular, en donde el heterociclilo y heteroarilo están cada uno opcionalmente sustituidos con uno, dos, o tres, grupos R13A, en donde cada grupo R13A es independientemente halogeno, ciano, nitro, alquilo C1-4, haloalquilo C1-4, arilalquilo C1-4, -ORB1, -SRB1, -N(RB1)2, -C(O)RB1, -S(O)RB1, -S(O)2RB1, -S(O)N(RB1)2, -S(O)2N(RB1)2, -C(O)ORB1, -C(O)N(RB1)2, -N(RB1)C(O)RB1, -N(RB1)C(O)ORB1, -N(RB1)C(O)N(RB1)2, o -N(RB1)S(O)2RB1, en donde cada RB1 es independientemente hidrogeno, alquilo C1-4, haloalquilo C1-4,arilo, o arilalquilo C1-4, w es 0, 1, 2, o 3; el anillo B en la definicion de R1 es (a) un anillo heterocíclico monocíclico de 4-10 miembros, bicíclico fusionado de 4-10 miembros, bicíclico puenteado de 5-10 miembros, o bicíclico espiro de 5-10 miembros, donde el anillo heterociclilo opcionalmente comprende un átomo de oxígeno o azufre anular, y opcionalmente uno, dos, o tres átomos de nitrogeno anulares adicionales, o (b) un heteroarilo monocíclico de 5 o 6 miembros o un heteroarilo bicíclico fusionado de 8-10 miembros, donde el anillo heteroarilo opcionalmente comprende un átomo de oxígeno o azufre anular, y opcionalmente uno, dos, o tres átomos de nitrogeno anulares adicionales; R20 es -RB2, hidrogeno, alquilo C1-4, haloalquilo C1-4, cicloalquilo C3-8, arilalquilo C1-4, o alquilo C1-4-RB2, donde cada RB2 es independientemente ciano, nitro, -ORB3, -SRB3, -N(RB3)2, -C(O)RB3, -S(O)RB3, -S(O)2RB3, -S(O)N(RB3)2, -S(O)2N(RB3)2, -C(O)ORB3, -C(O)N(RB3)2, -N(RB3)C(O)RB3, -N(RB3)C(O)ORB3, -N(RB3)C(O)N(RB3)2 o -N(RB3)S(O)2RB3, en donde cada RB3 es independientemente hidrogeno, alquilo C1-4, haloalquilo C1-4, arilo, o arilalquilo C1-4; o dos RB3 tomados junto con el átomo de nitrogeno al cual ambos se enlazan forman un heterociclilo o heteroarilo monocíclico saturado o no saturado, en donde el heterociclilo y heteroarilo están cada uno opcionalmente sustituidos con uno, dos, o tres grupos los cuales son cada uno independientemente alquilo C1-3, halogeno, o haloalquilo C1-4; y cada R21 es independientemente halogeno o -R20; R2 es metilo opcionalmente sustituido con uno, dos o tres grupos halo, o ambos R2 tomados junto con el átomo de carbono al cual se enlazan forman un grupo ciclopropilo; m es 1, 2, 3, 4 o 5; y cada R3 es independientemente halogeno, ciano, nitro, alquilo C1-4, haloalquilo C1-4, cicloalquilo C3-6, -ORC1, -N(RC1)2, -C(O)RC1, -S(O)RC1, -S(O)2RC1, -S(O)N(RC1)2, -S(O)2N(RC1)2, -C(O)ORC1, -C(O)N(RC1)2, -N(RC1)C(O)RC1, -N(RC1)C(O)ORC1, -N(RC1)C(O)N(RC1)2 o -N(RC1)S(O)2RC1, en donde cada RC1 es independientemente hidrogeno, alquilo C1-4, haloalquilo C1-4, arilo, o arilalquilo C1-4, o dos R3 tomados junto con los átomos en el anillo a los cuales se enlazan forman un arilo, heteroarilo, un cicloalquilo monocíclico, o un heterociclilo, cada uno opcionalmente sustituido con uno, dos, o tres grupos los cuales son cada uno independientemente alquilo C1-3, halogeno, o haloalquilo C1-4.Glucosylceramide synthase (GCS) modulators and methods for making the compounds. It further comprises compositions comprising the compounds, N-oxides, and / or pharmaceutically acceptable salts thereof. It also includes the use of the compounds and compositions for the manufacture of medicaments, particularly for treating diseases in which GCS is a mediator or is involved. Claim 1: A compound of the formula (1), or a simple stereoisomer or mixture of stereoisomers thereof, N-oxides thereof, and additionally optionally as a pharmaceutically acceptable salt thereof, characterized in that A is isopropyl , t-butyl, C3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted by one, two or three RA groups, wherein each RA is independently RA2, C1 alkyl -4, C1-4 haloalkyl, aryl, C1-4 arylalkyl, or C1-4-RA2 alkyl, wherein the aryl of the C1-4 arylalkyl group is optionally substituted with one, two or three RA2 groups, wherein, each RA2 is independently halogen, cyano, nitro, -ORA1, -SRA1, -N (RA1) 2, -C (O) RA1, -S (O) RA1, -S (O) 2RA1, -S (O) N (RA1 ) 2, -S (O) 2N (RA1) 2, -C (O) ORA1, -C (O) N (RA1) 2, -N (RA1) C (O) RA1, -N (RA1) C ( O) ORA1, -N (RA1) C (O) N (RA1) 2, -N (RA1) S (O) 2RA1, -N (RA1) C (= NRA1) N (RA1) 2, -P (O ) (ORA1) 2, or -OP (O) (ORA1) 2, in where each RA1 is independently hydrogen, C1-4 alkyl, or C1-4 haloalkyl, or two RA linked to adjacent carbon atoms, taken together, form -O- (G) and O-, where each G is independently -CH2- , -C (H) (F) -, or -CF2-, and y is 1, 2, or 3; L is - [C (RL) 2] p-L1- [C (RL) 2] q-, where p is 1, 2, or 3; q is an integer selected from 0 to (3-p); L1 is a union or -O-; and each RL is independently hydrogen, methyl, or halomethyl; R1 is -N (R10) (R11) or a portion of the formula (2), wherein R10 is hydrogen or C1-4 alkyl; R11 is -R13, -C3-6-N (R12) 2 -cycloalkyl, C3-6-R13-cycloalkyl, C1-4-N (R12) 2 alkyl, or C1-6-R13 alkyl, wherein each R12 is independently hydrogen or C1-4 alkyl; and R13 is (a) a 4-10 membered monocyclic heterocyclyl ring, 4-10 membered fused bicyclic, 5-10 membered bridged bicyclic, or 5-10 membered bicyclic ring, wherein the heterocyclyl ring comprises one, two or three ring nitrogen atoms, and optionally comprises an oxygen atom or ring sulfur, or (b) a 5 or 6 membered monocyclic heteroaryl or an 8-10 membered fused bicyclic heteroaryl, wherein the heteroaryl ring comprises one, two, or three annular N atoms, and optionally comprises an annular O or S atom, wherein the heterocyclyl and heteroaryl are each optionally substituted with one, two, or three, R13A groups, wherein each R13A group is independently halogen, cyano, nitro, C1-4 alkyl, C1-4 haloalkyl, C1-4 arylalkyl, -ORB1, -SRB1, -N (RB1) 2, -C (O) RB1, -S (O) RB1, -S (O) 2RB1 , -S (O) N (RB1) 2, -S (O) 2N (RB1) 2, -C (O) ORB1, -C (O) N (RB1) 2, -N (RB1) C (O) RB1, -N (RB1) C (O) ORB1, -N (RB1) C (O) N (RB1) 2, or -N (RB1) S (O) 2RB1, where each RB1 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, aryl, or C1-4 arylalkyl, w is 0, 1, 2, or 3; Ring B in the definition of R1 is (a) a 4-10 membered monocyclic heterocyclic ring, 4-10 membered fused bicyclic, 5-10 membered bridged bicyclic, or 5-10 membered bicyclic spiro, where the ring heterocyclyl optionally comprises an annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms, or (b) a 5- or 6-membered monocyclic heteroaryl or an 8-10 membered fused bicyclic heteroaryl, wherein the heteroaryl ring optionally comprises an annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms; R20 is -RB2, hydrogen, C1-4 alkyl, C1-4 haloalkyl, C3-8 cycloalkyl, C1-4 arylalkyl, or C1-4-RB2 alkyl, where each RB2 is independently cyano, nitro, -ORB3, -SRB3, -N (RB3) 2, -C (O) RB3, -S (O) RB3, -S (O) 2RB3, -S (O) N (RB3) 2, -S (O) 2N (RB3) 2, -C (O) ORB3, -C (O) N (RB3) 2, -N (RB3) C (O) RB3, -N (RB3) C (O) ORB3, -N (RB3) C (O) N (RB3) 2 or -N (RB3) S (O) 2RB3, wherein each RB3 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, aryl, or C1-4 arylalkyl; or two RB3 taken together with the nitrogen atom to which both bind form a saturated or unsaturated monocyclic heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl are each optionally substituted with one, two, or three groups which are each independently C1-3 alkyl, halogen, or C1-4 haloalkyl; and each R21 is independently halogen or -R20; R2 is methyl optionally substituted with one, two or three halo groups, or both R2 taken together with the carbon atom to which they are attached form a cyclopropyl group; m is 1, 2, 3, 4 or 5; and each R3 is independently halogen, cyano, nitro, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, -ORC1, -N (RC1) 2, -C (O) RC1, -S (O) RC1, -S (O) 2RC1, -S (O) N (RC1) 2, -S (O) 2N (RC1) 2, -C (O) ORC1, -C (O) N (RC1) 2, -N ( RC1) C (O) RC1, -N (RC1) C (O) ORC1, -N (RC1) C (O) N (RC1) 2 or -N (RC1) S (O) 2RC1, where each RC1 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, aryl, or C1-4 arylalkyl, or two R3 taken together with the ring atoms to which they bind form an aryl, heteroaryl, a monocyclic cycloalkyl, or a heterocyclyl , each optionally substituted with one, two, or three groups which are each independently C1-3 alkyl, halogen, or C1-4 haloalkyl.

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