US 11,535,660 B1 · Modulators of G-protein coupled receptors

Abstract

This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt and/or hydrate and/or prodrug of the compound) that modulate (e.g., agonize or partially agonize or antagonize) glucagon?like peptide?1 receptor (“GLP?1R”) and/or the gastric inhibitory polypeptide receptor (“GIPR”). The chemical entities are useful, e.g., for treating a subject (e.g., a human) having a disease, disorder, or condition in which modulation (e.g., agonism, partial agonism or antagonism) of GLP?1R and/or GIPR activities is beneficial for the treatment or prevention of the underlying pathology and/or symptoms and/or progression of the disease, disorder, or condition. In some embodiments, the modulation results in an enhancement of (e.g., an increase in) existing levels (e.g., normal or below normal levels) of GLP?1R and/or GIPR activity (e.g., signaling). In some embodiments, the chemical entities described herein further modulate (e.g., attenuate, uncouple)-arrestin signaling relative to what is observed with the native ligand. This disclosure also features compositions as well as other methods of using and making the said chemical entities.

A compound having formula (IAA), or a pharmaceutically acceptable salt thereof:

wherein:
ring A is:
(i) a saturated or unsaturated monocyclic ring that includes from 3-8 ring atoms (inclusive of G and the nitrogen atom labelled N*);
or
(ii) a saturated or unsaturated bicyclic or tricyclic ring that includes from 6-14 ring atoms (inclusive of G and the nitrogen atom labelled N*), wherein:
G is C(O), S(O), or SO2;
and
the dotted, circular line connecting G and N* is a divalent group that includes from 1-6 ring atoms;
wherein:
(a) from 0-2 of the divalent group's ring atoms are ring heteroatoms, which are each independently selected from the group consisting of N, N(Ra), O, S, and SO2;
and
(b) from 1-6 of the divalent group's ring atoms are ring carbon atoms, which are each independently selected from the group consisting of C, CH, CH2, CRb, C(Rb)2, and CHRb;
wherein:
(1) when ring A is a monocyclic ring, then each of the divalent group's 1-6 ring carbon atoms is independently selected from the group consisting of CH, CH2, CRb, C(Rb)2, and CHRb;
and
(2) when ring A is a bicyclic or tricyclic ring, then (A) or (B) applies:
(A) two or three adjacent ring carbon atoms of the divalent group are each independently selected from the group consisting of C, CH, CH2, CRb, C(Rb)2, and CHRb and are fused to a second ring that is selected from the group consisting of:
(a) C6-10 aryl optionally substituted with from 1-5 independently selected Rc;
(b) heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are each independently selected from the group consisting of N, N(Ra), O, and S, wherein the heteroaryl is optionally substituted with from 1-3 independently selected Rc;
(c) C3-10 cycloalkyl optionally substituted with from 1-4 independently selected Rd;
(d) heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are each independently selected from the group consisting of N(Ra), O, and S, wherein the heterocyclyl is optionally substituted with from 1-4 independently selected Rd;
or
(B) one of the divalent group's ring carbon atoms is C and is spiro-fused to a second ring that is selected from the group consisting of:
(a) C3-10 cycloalkyl optionally substituted with from 1-4 independently selected Rd;
(b) heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are each independently selected from the group consisting of N(Ra), O, and S, wherein the heterocyclyl is optionally substituted with from 1-4 independently selected Rd;
L is:
(i) —(CH2)m—X1—(CH2)n—X2—(CH2)p— (formula VIII), wherein m is from 1-6;
n is from 0-2;
and p is from 0-8;
(ii) —C(O)—(CH2)n—X3—(CH2)p— (formula IX), wherein n is from 0-2;
and p is from 0-8;
(iii) —(CH2)q—, wherein q is from 1-10;
(iv) —C(O)—;
or
(v) —(CH2)m—X1—(CH2)p— (formula VIII), wherein m is from 1-6;
and p is from 0-8;
X1 is —C(O)—;
—N(R′)C(O)—;
—C(O)N(R′)—;
or —N(R′)C(O)NR′)—;
wherein each occurrence of R′ is independently selected from the group consisting of:
H and C1-4 alkyl;
X2 is:
(i) —O—;
(ii) —S—;
(iii) —S(O)t—, wherein t is 1 or 2;
(iv) —C(Q1)(Q2)-, wherein each of Q1 and Q2 is independently selected from the group consisting of H and C1-4 alkyl;
or Q1 and Q2, together with the carbon atom to which each is attached forms C3-10 cycloalkyl that is optionally substituted with from 1-4 independently selected Rd and optionally fused to phenyl;
(v) C6-10 arylene optionally substituted with from 1-5 independently selected Rc;
(vi) heteroarylene including from 5-10 ring atoms, wherein from 1-4 ring atoms are each independently selected from the group consisting of N, N(Ra), O, and S;
and which is optionally substituted with from 1-5 independently selected Rc;
(vii) C3-10 cycloalkylene optionally substituted with from 1-4 independently selected Rd;
(viii) heterocycloalkylene including from 3-10 ring atoms, wherein from 1-3 ring atoms are each independently selected from the group consisting of N(Ra), O, and S;
and which is optionally substituted with from 1-5 independently selected Rd;
(ix) C2-C4 alkenylene optionally substituted with from 1-2 Re;
or
(x) C2-C4 alkynylene optionally substituted with from 1-2 Re;
X3 is:
—O—;
—S—;
or —S(O)t—, wherein t is 1 or 2;
each of R1, R2, and R4 is independently selected from the group consisting of H and unsubstituted C1-3 alkyl;
R2′ is as defined according to (AA) or (BB) below:
(AA)
R2′ is
wherein:
R3 is —C(O)OH, —C(O)OR31, —CH(C(O)OH)2 or a carboxylic acid isostere;
a is 0-5;
a′ is 0 or 1;
and
each of R3a and R3b is independently H or C1-3 alkyl;
(BB)
R2′ and R4 taken together with the atoms connecting them form a ring including from 5-8 ring atoms, wherein from 3-7 are ring carbon atoms each substituted with from 1-2 substituents independently selected from H, halo, hydroxy, oxo, and C1-3 alkyl;
and from 0-1 is a heteroatom (in addition to the N attached to R1) selected from O, —NH, —N(C1-3 alkyl), and S;
R31 is:
(i) C1-6 alkyl optionally substituted with from 1-2 independently selected Re;
(ii) —(C0-3 alkylene)-C3-10 cycloalkyl, wherein the cycloalkyl is optionally substituted with from 1-4 independently selected Rd;
(iii) —(C0-3 alkylene)-heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are each independently selected from the group consisting of N(Ra), O, and S, wherein the heterocyclyl is optionally substituted with from 1-4 independently selected Rd;
(iv) —(C0-3 alkylene)-C6-10 aryl, wherein the aryl is optionally substituted with from 1-5 independently selected Rc;
or
(v) —(C0-3 alkylene)-heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are each independently selected from the group consisting of N, N(Ra), O, and S, wherein the heteroaryl is optionally substituted with from 1-3 independently selected Rc;
each occurrence of Ra is independently selected from the group consisting of:
H;
C1-4 alkyl;
C3-6 cycloalkyl;
—C(═O)(C1-6 alkyl);
—C(═O)O(C1-6 alkyl);
and —S(O)1-2(C1-6 alkyl);
each occurrence of Rb is independently selected from the group consisting of:
R31;
C1-4 haloalkyl;
—OH;
oxo;
—F;
—N(Ra)(R″);
C1-4 alkoxy;
C1-4 haloalkoxy;
—C(═O)(C1-4 alkyl);
—C(═O)O(C1-6 alkyl);
—C(═O)OH, —C(═O)N(R′″)(R″″), —S(O)1-2(C1-6 alkyl);
and cyano;
each occurrence of Rc is independently selected from the group consisting of:
C1-6 alkyl optionally substituted with from 1-2 independently selected Re;
C3-6 cycloalkyl;
C1-4 haloalkyl;
—OH;
-halo;
—NO2;
N3;
—N(Ra)(R″);
C1-4 alkoxy;
C1-4 thioalkoxy;
C1-4 haloalkoxy;
—OC(═O)(C1-6 alkyl);
—C(═O)(C1-6 alkyl);
—C(═O)O(C1-6 alkyl);
—C(═O)OH, —C(═O)N(R′″)(R″″), —S(O)1-2(C1-6 alkyl);
and cyano;
each occurrence of Rd is independently selected from the group consisting of:
C1-6 alkyl optionally substituted with from 1-2 independently selected Re;
C1-4 haloalkyl;
—OH;
—F;
Cl;
—N(Ra)(R″);
oxo;
C1-4 alkoxy;
C1-4 haloalkoxy;
—OC(═O)(C1-6 alkyl);
—C(═O)(C1-6 alkyl);
—C(═O)O(C1-6 alkyl);
—C(═O)OH, —C(═O)N(R′″)(R″″), —S(O)1-2(C1-6 alkyl);
and cyano;
each occurrence of Re is independently selected from the group consisting of:
—OH;
—N(R′)(R″);
C1-4 alkoxy;
C1-4 haloalkoxy;
—OC(═O)(C1-6 alkyl);
—C(═O)O(C1-6 alkyl);
—C(═O)OH, —C(═O)N(R′″)(R″″), —S(O)1-2(C1-6 alkyl);
and cyano;
each occurrence of R″, R′″, and R″″ is independently selected from the group consisting of:
H and C1-6 alkyl;
and
—N(R4)W is a peptide having formula (XIV):
GTF(Xaa4)SD(Xaa7)S(Xaa9)(Xaa10)(Xaa11)(Xaa12)(Xaa13)QA(Xaa16)(Xaa17)(Xaa18)F-(Xaa20)(Xaa21)WL(Xaa24)(Xaa25)GGPSSGAPPPS-R5 (SEQ ID NO:
2);
wherein:
Xaa4 is T or I;
Xaa7 is Y, V, or L;
Xaa9 is I or S;
Xaa10 is Y, Q, or A;
Xaa11 is L, M, or L*;
Xaa12 is D or E;
Xaa13 is K, G, or E;
Xaa16 is A or V;
Xaa17 is (Aib) or K;
Xaa18 is E or L;
Xaa20 is V or I;
Xaa21 is N, A, or E;
Xaa24 is L or V;
and
Xaa25 is A or K;
wherein R5 is a C-terminal amino acid, amino acid ester, or amino acid amide that is optionally substituted with from 1-2 modifying groups.

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Modulators of G-protein coupled receptors

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Modulators of G-protein coupled receptors

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Abstract

Claims34