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US 2023/0416228 A1Published application
Agents for the treatment of diseases by inhibition of foxo1
AssigneeForkhead Biotherapeutics Inc.
InventorsSandro Belvedere, Hua Viola Lin, Robert J. DeVita, Stephane Turcotte, Shawn Johnstone
Life of this patent
Estimating the term…
Abstract
The disclosure provides FOXO1 inhibitors having beneficial properties such as selectivity and metabolic stability. FOXO1 inhibitors are useful in the treatment of diabetes.
Claims26
A compound of formula (Ib)
- wherein:
- A is an aryl or heteroaryl of the formula:
- each is independently a single bond or a double bond;
- each of X1, X2, X3, X4, X5, X6, X7, X8, and X9 is independently CR1, N, NR1, O, or S;
- Y1 is C, N, or O wherein, (i) when Y1 is O, n is 0;
- (ii) when Y1 is N, n is 0 or 1;
- and
- (iii) when Y1 is C, n is 1;
- Y2 is C or N;
- each of Y3, Y4, Y5, and Y6 is independently CR2, N, NR2, O, or S;
- Z1 is C, N, or O;
- wherein (i) when Z1 is O, m is 0, (ii) when Z1 is N, m is 0 or 1, and (iii) wherein Z1 is C, m is 1;
- Z2 is C, N, or O;
- wherein (i) when Z2 is O, z is 0;
- (ii) when Z2 is N, z is 0 or 1;
- and (iii) when Z2 is C, z is 1;
- Z3 is C, N, or O;
- wherein (i) when Z3 is O, x is 0;
- (ii) when Z3 is N, x is 0 or 1;
- and (iii) when Z3 is C, x is 1;
- U is —C(═O)—N(R7a)—, wherein R7a is hydrogen or C1-C6 alkyl;
- each R1 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, alkylaryl, heterocyclyl, or heteroaryl, —OR7, —CN, —NH2, —NHR8, —NR9R10, —SR11, —S(O)2R12, —NHC(O)R13, —O(CH2)qR14, —NH(CH2)qR15, or —S(CH2)qR16, hydrogen, or halogen, wherein
- when (i) each of X1, X2, X3, X4, and X5 is independently CR1, or (ii) each of X1, X2, X4, and X5 is independently CR1, and X3 is N, then:
- when (i) at least one of R1 is independently Br, CN, —SCH3, —S(O)2CH3, —O(CH2)2OCH3, —O(CH2)3OCH3, —O(CH2)2morpholinyl, —OCH2COOH, —OCH2C(═O)OCH2CH3, NH(CH2)2OH, —NH(CH2)2OCH3, NH(CH2)2OCH2CH3, —O(CH2)2OH, —NHC(CH3)—CH2OH, —NHC(CH3)—CH2OCH3, —SCH2CH2OCH3;
- or
- (ii) at least one of R1 is NR9R10, wherein NR9R10 is piperidinyl, piperazinyl or pyrrolidinyl, each of which is substituted by —(CH2)tOR19, wherein R19 is hydrogen, C1-C6 alkyl, or N-, O-, or S-containing heterocyclyl, and t is 0, 1, 2, 3, 4, 5, or 6;
- each R2 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, alkylaryl, heterocyclyl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
- R3 is alkyl, arylalkyl, alkylaryl, —(CH2)qCOOR17, —(CH2)qN(R17)2, or —(CH2)qOR17, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
- R4 is alkyl, arylalkyl, alkylaryl, —(CH2)qCOOR17, —(CH2)qN(R17)2, or —(CH2)qOR17, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
- R5 is alkyl, arylalkyl, alkylaryl, —(CH2)qCOOR17, —(CH2)qN(R17)2, or —(CH2)qOR17, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
- R6 is alkyl, arylalkyl, alkylaryl, —(CH2)qCOOR17, —(CH2)qN(R17)2, or —(CH2)qOR17, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
- each R7 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, alkylaryl, heterocyclyl, or heteroaryl, each of which is independently unsubstituted or substituted, or hydrogen;
- each R8 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, alkylaryl, heterocyclyl, or heteroaryl, each of which is independently unsubstituted or substituted, or hydrogen;
- each of R9 and R10 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, alkylaryl, heterocyclyl, or heteroaryl, each of which is independently unsubstituted or substituted, or hydrogen;
- or R9 and R10 together with the nitrogen atom to which R9 and R10 are attached form a heterocyclic or heteroaromatic ring, which is unsubstituted or substituted;
- each R11, R12, R13, R14, R15, and R16 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, alkylaryl, heterocyclyl, or heteroaryl, each of which is independently unsubstituted or substituted, or —OH, —OR7, —NH2, —NHR8, —NR9R10, —(CH2)qCOOR17,—(CH2)qN(R17,—COOR18, or hydrogen;
- each of R17 and R18 is independently hydrogen or alkyl;
- and
- each q is independently 1, 2, 3, 4, 5, or 6,
- or a pharmaceutically-acceptable salt or a tautomer thereof.
37 more elements
(canceled)
(canceled)
A compound which is represented by the structure of formula (VIa):
- wherein
- G is N or CH;
- Q is N or C;
- each R2a, R2b, R2c and R2d is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, alkylaryl, heterocyclyl, or heteroaryl, each of which is independently substituted or unsubstituted, or —OR7, —CN, —NH2, —NHR8, —NR9R10, —SR11, —S(O)2R12, —NHC(O)R13, —O(CH2)qR14, —NH(CH2)qR15,—S(CH2)qR16, hydrogen or halogen;
- R3 is alkyl, arylalkyl, alkylaryl, —(CH2)qCOOR17, —(CH2)qN(R17)2, or —(CH2)qOR17, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
- R4 is alkyl, arylalkyl, alkylaryl, —(CH2)qCOOR17, —(CH2)qN(R17)2, or —(CH2)qOR17, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
- R6 is alkyl, arylalkyl, alkylaryl, —(CH2)qCOOR17, —(CH2)qN(R17)2, or —(CH2)qOR17, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
- each R7 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, alkylaryl, heterocyclyl, or heteroaryl, each of which is independently unsubstituted or substituted, or hydrogen;
- each R8 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, alkylaryl, heterocyclyl, or heteroaryl, each of which is independently unsubstituted or substituted, or hydrogen;
- each of R9 and R10 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, alkylaryl, heterocyclyl, or heteroaryl, each of which is independently unsubstituted or substituted, or hydrogen;
- or R9 and R10 together with the nitrogen atom to which R9 and R10 are attached form a heterocyclic or heteroaromatic ring, which is unsubstituted or substituted;
- each R11, R12, R13, R14, R15, and R16 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, alkylaryl, heterocyclyl, or heteroaryl, each of which is independently unsubstituted or substituted, or hydrogen;
- each of R17 and R18 is independently hydrogen or alkyl;
- each R20a and R20b is independently:
- i) —(CH2)tOR19, wherein R19 is hydrogen, a C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted, or a N, O, or S-containing heterocyclyl;
- ii) —C(O)R19a, wherein R19a is C1-C6 alkyl or —(CH2)xOR21, wherein R21 is C1-C6 alkyl that is unsubstituted or substituted with NH2 or OH, wherein x is 0 or 1;
- iii) —NR22R23, wherein R22 and R23 are independently C1-C6 alkyl, or R22 and R23, together with the nitrogen to which are R22 and R23 are attached, form an unsubstituted or substituted heterocyclic ring;
- iv) —OR24, wherein R24 is C1-C6 alkyl;
- v) an oxygen-containing heterocyclic ring;
- vi) —C1-C6 alkyl, —OH, or absent;
- or
- vii) hydrogen, provided that at least one of R20a and R20b is not hydrogen;
- or R20a and R20b together with Q form an oxygen-containing heterocyclic ring;
- c is 0 or 1;
- d is 0 or 1;
- each q is independently 1, 2, 3, 4, 5, or 6, and
- t is 0, 1, 2, 3, 4, 5 or 6;
- or a pharmaceutically-acceptable salt or a tautomer thereof.
25 more elements
26-222. (canceled)
Dependencies are inferred from the claim text.