NZ804540B2 - Aryl- or heteroaryl-substituted benzene compounds - Google Patents

Aryl- or heteroaryl-substituted benzene compounds

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Publication number
NZ804540B2
NZ804540B2 NZ804540A NZ80454012A NZ804540B2 NZ 804540 B2 NZ804540 B2 NZ 804540B2 NZ 804540 A NZ804540 A NZ 804540A NZ 80454012 A NZ80454012 A NZ 80454012A NZ 804540 B2 NZ804540 B2 NZ 804540B2
Authority
NZ
New Zealand
Prior art keywords
formula
compound
alkyl
aryl
halo
Prior art date
Application number
NZ804540A
Other versions
NZ804540A (en
Inventor
Richard Chesworth
Kenneth William Duncan
Satoshi Kawano
Heike Keilhack
Christine Klaus
Kevin Wayne Kuntz
Masashi Seki
Syuji Shirotori
Natalie Warholic
Timothy James Nelson Wigle
Original Assignee
Epizyme Inc
Filing date
Publication date
Application filed by Epizyme Inc filed Critical Epizyme Inc
Publication of NZ804540A publication Critical patent/NZ804540A/en
Publication of NZ804540B2 publication Critical patent/NZ804540B2/en

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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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    • C07D213/60—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 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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Abstract

Disclosed are the compounds: 3-[Ethyl(oxan-4-yl)amino]-2-methyl-5-[4-(morpholin-4-ylmethyl)phenyl]benzoic acid; methyl 5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-carboxylate; Methyl 3-Amino-5-bromo-2-methylbenzoate; Methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate; and Methyl 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate. Also disclosed is their use in preparing Tazemetostat and related compounds, and in preparing further intermediates.

Claims (19)

What is claimed is:
1. A compound according to either of the following formulae:
2. A compound according to any one of the following formulae: N Br , , or .
3. A process of preparing a compound of a F sing converting a nd of Formula E into a compound of Formula F: Formula E Formula F wherein R6 is C6-C10 aryl or 5- or 6-membered heteroaryl, each of which is optionally tuted with one or more –Q2-T2, wherein Q2 is a bond or C1-C3 alkyl linker optionally substituted with halo, cyano, hydroxyl or C1-C6 alkoxy, and T2 is H, halo, cyano, -ORa, -NRaRb, -(NRaRbRc)+A–, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRbC(O)Ra, -NRbC(O)ORa, -S(O)2Ra, -S(O)2NRaRb, or RS2, in which each of Ra, Rb, and Rc, independently is H or RS3, A– is a ceutically acceptable anion, each of RS2 and RS3, ndently, is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or Ra and Rb, together with the N atom to which they are attached, form a 4 to 12- membered cycloalkyl ring having 0 or 1 additional atom, and each of RS2, RS3, and the 4 to bered heterocycloalkyl ring formed by Ra and Rb, is optionally substituted with one or more one or more –Q3-T3, wherein Q3 is a bond or C1-C3 alkyl linker each optionally tuted with halo, cyano, hydroxyl or C1-C6 alkoxy, and T3 is selected from the group consisting of halo, cyano, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12- ed heterocycloalkyl, 5- or 6-membered heteroaryl, ORd, COORd, -S(O)2Rd, -NRdRe, and –C(O)NRdRe, each of Rd and Re independently being H or C1-C6 alkyl, or –Q3-T3 is oxo; or any two neighboring –Q2-T2, together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1-4 heteroatoms selected from N, O and S and optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O-C1-C6 alkyl, cyano, C1-C6 alkoxyl, amino, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; R7 is –Q4-T4, in which Q4 is a bond, C1-C4 alkyl linker, or C2-C4 alkenyl linker, each linker optionally substituted with halo, cyano, hydroxyl or C1-C6 alkoxy, and T4 is H, halo, cyano, NRfRg, -ORf, f, -C(O)ORf, -C(O)NRfRg, -C(O)NRfORg, O)Rg, -S(O)2Rf, or RS4, in which each of Rf and Rg, independently is H or RS5, each of RS4 and RS5, independently is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered aryl, and each of RS4 and RS5 is optionally substituted with one or more –Q5-T5, wherein Q5 is a bond, C(O), C(O)NRk, NRkC(O), S(O)2, or C1-C3 alkyl linker, Rk being H or C1-C6 alkyl, and T5 is H, halo, C1-C6 alkyl, hydroxyl, cyano, C1-C6 alkoxyl, amino, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12-membered heterocycloalkyl, 5- or ered heteroaryl, or S(O)qRq in which q is 0, 1, or 2 and Rq is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 lkyl, C6-C10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6- membered heteroaryl, and T5 is optionally substituted with one or more substituents selected from the group consisting of halo, C1-C6 alkyl, hydroxyl, cyano, C1-C6 alkoxyl, amino, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12- membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T5 is H, halo, hydroxyl, or cyano; or –Q5-T5 is oxo; and each of R8 and R12, ndently, is H, halo, hydroxyl, COOH, cyano, RS6, ORS6, or COORS6, in which RS6 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4 to 12-membered heterocycloalkyl, amino, mono-C1-C6 alkylamino, or di-C1-C6 alkylamino, and RS6 is optionally substituted with one or more substituents selected from the group ting of halo, hydroxyl, COOH, C(O)O-C1-C6 alkyl, cyano, C1-C6 alkoxyl, amino, mono-C1-C6 alkylamino, and di-C1-C6 alkylamino; or R7 and R8, together with the N atom to which they are attached, form a 4 to 11-membered heterocycloalkyl ring having 0 to 2 additional heteroatoms, and the 4 to 11-membered heterocycloalkyl ring formed by R7 and R8 is optionally substituted with one or more –Q6-T6, wherein Q6 is a bond, C(O), C(O)NRm, NRmC(O), S(O)2, or C1-C3 alkyl linker, Rm being H or C1-C6 alkyl, and T6 is H, halo, C1-C6 alkyl, hydroxyl, cyano, C1-C6 alkoxyl, amino, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, or S(O)pRp in which p is 0, 1, or 2 and Rp is C1-C6 alkyl, C2-C6 l, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6- membered aryl, and T6 is optionally substituted with one or more substituents selected from the group ting of halo, C1-C6 alkyl, hydroxyl, cyano, C1-C6 alkoxyl, amino, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12- membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T6 is H, halo, hydroxyl, or cyano; or –Q6-T6 is oxo.
4. The s of claim 3, wherein the ester of the compound of Formula E is hydrolyzed to the corresponding acid, using a base in a polar solvent.
5. The process of claim 4, wherein the base is sodium hydroxide and the polar solvent is ethanol.
6. The process according to claim 4 or 5, wherein the corresponding acid is subjected to a standard amide coupling reaction, wherein the corresponding acid is reacted with an amine along with an amide ng t in a solvent to give the compound of Formula
7. The process according to claim 6, n the amide coupling reagent is (benzotriazolyloxy)tripyrrolidinophosphonium hexafluorophosphate (PYBOP), and the solvent is dimethyl sulfoxide (DMSO).
8. The process ing to any one of claims 3-7, wherein R6 is C6-C10 aryl substituted with one or more –Q2-T2 or 5- or 6-membered aryl substituted with one or more –Q2-
9. The process according to claim 8, wherein R6 is phenyl substituted with one or more –Q2-T2.
10. The process according to any one of claims 3 to 9, wherein: R7 is pyrrolidinyl, piperidinyl, tetrahydropyran, tetrahydro-2H-thiopyranyl, cyclopentyl, cyclohexyl, or cycloheptyl, each optionally substituted with one or more –Q5-T5; R8 is H, methyl, ethyl, or ethenyl; and R12 is H, , ethyl, ethenyl or halo.
11. The process according to claim 10, wherein: R7 is tetrahydropyran; R8 is ethyl; and R12 is methyl.
12. The process according to any one of claims 3 to 11, wherein: R6 is phenyl substituted with one or more –Q2-T2; Q2 is an unsubstituted C1-C3 alkyl linker; and T2 is 4 to 7-membered heterocycloalkyl.
13. The process according to claim 12, wherein: Q2 is methyl; and T2 is morpholinyl.
14. A process according to any one of claims 3 to 13; wherein the compound of Formula F is:
15. The s according to any one of claims 3 to 14, wherein the process r comprises one or more of steps (i) to (iv): (i) converting a compound of Formula A: Formula A into a compound of Formula B: Formula B; (ii) converting a compound of Formula B into a compound of Formula C: Formula C; (iii) converting a compound of Formula C into a compound of a D: Formula D; and (iv) converting a compound of Formula D into a compound of Formula E.
16. The process according to claim 15, n the process comprises two or more steps selected from steps (i) to (iv); three or more steps selected from steps (i) to (iv); or all of steps (i) to (iv).
17. A process of preparing a compound of Formula Z comprising converting a compound of Formula Y into a compound of Formula Z: Formula Y Formula Z wherein R7, R8 and R12 are each individually the same as defined in any one of claims 3, 10, or 11; Ar is an aryl ring; and X is-Q2-T2 as defined in claim 3, 12 or 13.
18. A process according to claim 9, wherein the process further comprises one or more of steps (v) to (viii): (v) converting a compound of Formula U: Formula U into a compound of Formula V: Formula V; (vi) converting a compound of Formula V into a nd of a W: (vii) converting a compound of Formula W into a compound of Formula X: Formula X; and (viii) converting a compound of Formula X into a compound of Formula Y.
19. A nd of claim 1 or 2, when used in preparing a compound of the following formula: or a pharmaceutical salt or ester thereof. ,, 00 g» \O E P <14 CD 0 ””””””””” ”””””””””””””””””””” f””””””””””””””””””””””I”””””””””””””””””””””””F f 0 Ch 00 l
NZ804540A 2012-04-13 Aryl- or heteroaryl-substituted benzene compounds NZ804540B2 (en)

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US201161474821P 2011-04-13 2011-04-13
US201161499595P 2011-06-21 2011-06-21
NZ785739A NZ785739B2 (en) 2012-04-13 Aryl- or heteroaryl-substituted benzene compounds

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