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US 2025/0026733 A1Published application
Deuterated analogs of pyrole inhibitors of erk, synthesis thereof and intermediates thereto
AssigneeBiomed Valley Discoveries, Inc.
InventorsGary DECRESCENZO, Martin TERESK
Life of this patent
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Abstract
The present disclosure provides, inter alia, deuterated analogs of ulixertinib and pharmaceutically acceptable salts thereof, which are effective inhibitors of ERK protein kinases and have surprisingly improved pharmacokinetic and metabolite formation properties. The present disclosure also provides, inter alia, methods of making and using same. Kits containing compounds and pharmaceutical compositions of such deuterated analogs are also provided.
Claims45
A compound of Formula 1:
- or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein each of X1, X2, X3, X4, X5, X6, and X7 is independently selected from the group consisting of hydrogen, deuterium, and C1-4 aliphatic, and wherein:
- R1 is hydrogen, C1-3 aliphatic, fluoro, or chloro;
- A is an optionally substituted group selected from phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- R2 is independently —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO2, —SO2R, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —NRSO2R, or N(R)2, wherein each R is independently hydrogen or C1-4 aliphatic;
- and
- m is 0, 1, or 2.
3 more elements
A compound of Formula 2A:
- or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
- each X1, X2, X3, X4, X5, X6, and X7 are independently selected from hydrogen and deuterium or C1-4 aliphatic;
- R2 is independently —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO2, —SO2R, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —NRSO2R, or N(R)2, wherein each R is independently hydrogen or C1-4 aliphatic;
- m is 0, 1, or 2;
- and A, B, C, D, E, and F are independently selected from carbon or nitrogen.
2 more elements
A compound of Formula 2B:
- or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
- each X1, X2, X3, X4, X5, X6, and X7 are independently selected from hydrogen and deuterium or C1-4 aliphatic;
- R2 is independently —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO2, —SO2R, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —NRSO2R, or N(R)2, wherein each R is independently hydrogen or C1-4 aliphatic;
- and m is 0, 1, or 2.
1 more element
A compound of Formula 3A:
- or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
- R2 is independently —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO2, —SO2R, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —NRSO2R, or N(R)2, wherein each R is independently hydrogen or C1-4 aliphatic;
- and m is 0, 1, or 2.
A compound of Formula 3B:
- or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
- R2 is independently —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO2, —SO2R, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —NRSO2R, or N(R)2, wherein each R is independently hydrogen or C1-4 aliphatic;
- and m is 0, 1, or 2.
A compound of Formula 3C:
- or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
- R2 is independently —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO2, —SO2R, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —NRSO2R, or N(R)2, wherein each R is independently hydrogen or C1-4 aliphatic;
- and m is 0, 1, or 2.
A compound of Formula 4:
- or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
- each X1, X2, X3, X4, X5, X6, and X7 is independently selected from hydrogen and deuterium or C1-4 aliphatic.
A method of synthesizing a deuterated compound according to Formula 1:
- comprising the steps of:
- (i) reacting a compound of Formula 5:
- with a compound of Formula 6:
- to produce the compound of Formula 7:
- (ii) reacting the compound of Formula 7 with the compound of Formula 8:
- to produce the compound of Formula 9:
- (iii) reacting the compound of Formula 9 with LiOH to produce the compound of Formula 10:
- (iv) reacting the compound of Formula 10 with the compound of Formula 11:
- to produce the compound of Formula 1:
- wherein each of X1, X2, X3, X4, X5, X6, and X7 is independently selected from the group consisting of hydrogen, deuterium, and C1-4 aliphatic, and wherein:
- R1 is hydrogen, C1-3 aliphatic, fluoro, or chloro;
- A is an optionally substituted group selected from phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- R2 is independently —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO2, —SO2R, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —NRSO2R, or N(R)2;
- wherein each R is independently hydrogen or C1-4 aliphatic;
- m is 0, 1, or 2,
- PG is a protecting group;
- and
- L1 and L2 are independently selected leaving groups.
15 more elements
A method of synthesizing a deuterated compound according to Formula 1:
- comprising the steps of:
- (i) reacting a compound of Formula 12:
- with a compound of Formula 8:
- to produce a compound of Formula 13:
- (ii) reacting the compound of Formula 13 with LiOH to produce the compound of Formula 14:
- (iii) reacting the compound of Formula 14 with
- to produce the compound of Formula 15:
- (iv) deprotecting the compound of Formula 15 to produce the compound of Formula 16:
- (v) reacting the compound of Formula 16 with the compound of Formula 17:
- to produce the compound of Formula 1:
- wherein each of X1, X2, X3, X4, X5, X6, and X7 is independently selected from the group consisting of hydrogen, deuterium, and C1-4 aliphatic, and wherein:
- R1 is hydrogen, C1-3 aliphatic, fluoro, or chloro;
- A is an optionally substituted group selected from phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- R2 is independently —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO2, —SO2R, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —NRSO2R, or N(R)2;
- wherein each R is independently selected from hydrogen or C1′4 aliphatic;
- m is 0, 1, or 2,
- PG is a protecting group;
- and
- L2 is a leaving group.
16 more elements
A method of synthesizing a deuterated ulixertinib of Formula 18:
- or a pharmaceutically acceptable salt thereof, comprising the steps of:
- (i) reacting a compound of Formula 7A:
- with a compound of Formula 8A:
- to provide the compound of Formula 9A:
- (ii) reacting the compound of Formula 9A with LiOH to produce the compound of Formula 10A:
- and
- (iii) reacting the compound of Formula 10A with the compound of Formula 8B:
- to produce the compound of Formula 18:
5 more elements
A method of synthesizing a deuterated ulixertinib of Formula 19, or a pharmaceutically acceptable salt thereof:
- comprising the steps of:
- (i) reacting a compound of Formula 12A:
- with a compound of Formula 8A:
- to produce a compound of Formula 13A:
- (ii) reacting the compound of Formula 13A with LiOH to produce the compound of Formula 14A:
- (iii) reacting the compound of Formula 14A with the compound of Formula 8B:
- to produce a compound of Formula 15A:
- (iv) reacting the compound of Formula 15A with TFA to produce the compound of Formula 16A:
- and
- (v) reacting the compound of Formula 16A with
- to produce the compound of Formula 19:
8 more elements
A method of synthesizing a deuterated ulixertinib of Formula 21, or a pharmaceutically acceptable salt thereof:
- comprising the steps of:
- (i) reacting a compound of Formula 7B:
- with a compound of Formula 8A:
- to produce a compound of Formula 9B:
- (ii) reacting the compound of Formula 9B with LiOH to produce a compound of Formula 10B:
- and
- (iii) reacting the compound of Formula 10B with the compound of Formula 8B:
- to produce the compound of Formula 21:
5 more elements
A method of synthesizing a deuterated ulixertinib of Formula 21A comprising the step of reacting a compound of Formula 21:
- with HCl to produce the compound of Formula 21A:
A compound selected from:
- and pharmaceutically acceptable salts, solvates, and prodrugs thereof.
Dependencies are inferred from the claim text.