US2021196724A1PendingUtilityA1
Biaryl compositions and methods for modulating a kinase cascade
Est. expiryAug 12, 2036(~10.1 yrs left)· nominal 20-yr term from priority
C07D 213/56A61P 27/02A61K 31/5377A61K 9/0019C07D 239/34A61K 31/496C07D 413/14C07D 213/64C07D 401/12A61K 9/0053C07D 403/04C07D 413/10C07D 401/10C07C 233/22C07D 213/74A61K 9/0085A61P 35/00C07C 233/13
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Claims
Abstract
The application relates to biaryl compounds, pharmaceutical compositions comprising the compounds, and methods of use the compounds for treating cell proliferation disorders.
Claims
exact text as granted — not AI-modified1 . A method of treating or preventing a cancer, comprising administering to a subject in need thereof an effective amount of a compound of formula (A):
or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
X a is CR a or N;
X b is CR b or N;
X c is CR c or N;
X d is CR d or N;
R a is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
R b is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
R c is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
R d is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
R 1 and R 2 are each independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or O−(C 1 -C 6 alkyl);
alternatively, R 1 and R 2 , together with the carbon atom to which they are attached, form a 3-8 membered saturated, unsaturated, or partially saturated carbocycle, or a saturated, unsaturated, or partially saturated heterocycle comprising one or two 5-7 membered rings and one or more heteroatoms selected from N, O, and S;
alternatively, one of R 1 and R 2 , together with the carbon atom to which R 1 or R 2 is attached and
form a 7-12 membered saturated, unsaturated, or partially saturated carbocycle, or a 7-12 membered saturated, unsaturated, or partially saturated heterocycle comprising one or more heteroatoms selected from N, O and S;
R 3 and R 4 are each independently (a) H, (b) halogen, (c) OH, (d) COOH, (e) CONH 2 , (f) NHCOR 101 , (g) NR 101 COR 102 , (h) S(O) t R 101 , (i) C 1 -C 6 alkyl, (j) C 2 -C 6 alkenyl, (k) C 2 -C 6 alkynyl, (l) O—(C 1 -C 6 alkyl), (m) O—(C 2 -C 6 alkenyl), (n) O—(C 2 -C 6 alkynyl), (o) COO—(C 1 -C 6 alkyl), (p) COO—(C 2 -C 6 alkenyl), (q) COO—(C 2 -C 6 alkynyl), (r) CONH—(C 1 -C 6 alkyl), (s) CONH—(C 2 -C 6 alkenyl), (t) CONH—(C 2 -C 6 alkynyl), (u) CON(C 1 -C 6 alkyl) 2 , (v) CON(C 2 -C 6 alkenyl) 2 , (w) CON(C 2 -C 6 alkynyl) 2 , (x) (C 1 -C 6 alkyl)-NH 2 , (y) (C 2 -C 6 alkenyl)-NH 2 , (z) (C 2 -C 6 alkynyl) u -NH 2 , (aa1) (C 1 -C 6 alkyl) v -NH(C 1 -C 6 alkyl), (aa2) (C 1 -C 6 alkyl) v -NH(C 2 -C 6 alkenyl), (aa3) (C 1 -C 6 alkyl) v -NH(C 2 -C 6 alkynyl), (bb1) (C 2 -C 6 alkenyl) v -NH(C 1 -C 6 alkyl), (bb2) (C 2 -C 6 alkenyl) v -NH(C 2 -C 6 alkenyl), (bb3) (C 2 -C 6 alkenyl) v -NH(C 2 -C 6 alkynyl), (cc) (C 2 -C 6 alkynyl) v -NH(C 1 -C 6 alkyl), (cc2) (C 2 -C 6 alkynyl) v -NH(C 2 -C 6 alkenyl), (cc3) (C 2 -C 6 alkynyl)-NH(C 2 -C 6 alkynyl), (dd1) (C 1 -C 6 alkyl) w -N(C 1 -C 6 alkyl) 2 , (dd2) (C 1 -C 6 alkyl) w -N(C 2 -C 6 alkenyl) 2 , (dd3) (C 1 -C 6 alkyl) w -N(C 2 -C 6 alkynyl) 2 , (ee1) (C 2 -C 6 alkenyl) w -N(C 1 -C 6 alkyl) 2 , (ee2) (C 2 -C 6 alkenyl) w -N(C 2 -C 6 alkenyl) 2 , (ee3) (C 2 -C 6 alkenyl) w -N(C 2 -C 6 alkynyl) 2 , (ff1) (C 2 -C 6 alkynyl) w -N(C 1 -C 6 alkyl) 2 , (ff2) (C 2 -C 6 alkynyl) w -N(C 2 -C 6 alkenyl) 2 , (ff3) (C 2 -C 6 alkynyl) w -N(C 2 -C 6 alkynyl) 2 , (gg) 3-8 membered saturated, unsaturated, or partially saturated carbocycle, or (hh) 3-8 membered saturated, unsaturated, or partially saturated heterocycle, wherein each of (i)-(hh) is optionally substituted with one or more R 7 ;
represents a saturated, unsaturated, or partially saturated carbocycle comprising one or two 3-8 membered rings, or a saturated, unsaturated, or partially saturated heterocycle comprising one or two 5-8 membered rings and one or more heteroatoms selected from N, O and S, wherein the two 3-8 membered rings or the two 5-8 membered rings can form a fused or bridged ring structure;
represents an aromatic, saturated, unsaturated, or partially saturated carbocycle comprising one or two 3-8 membered rings, or an aromatic, saturated, unsaturated, or partially saturated heterocycle comprising one or two 5-8 membered rings and one or more heteroatoms selected from N, O and S, wherein the two 3-8 membered rings or the two 5-8 membered rings can form a fused or bridged ring structure;
each R 5 is independently (a) halogen, (b) OH, (c) CONH 2 , (d) COOH, (e) CN, (f) N 3 , (g) C 1 -C 6 alkyl, (h) C 2 -C 6 alkenyl, (i) C 2 -C 6 alkynyl, (j) O—(C 1 -C 6 alkyl), (k) O—(C 2 -C 6 alkenyl), (l) O—(C 2 -C 6 alkynyl), (m) COO—(C 1 -C 6 alkyl), (n) COO—(C 2 -C 6 alkenyl), (o) COO—(C 2 -C 6 alkynyl), (p) CONH—(C 1 -C 6 alkyl), (q) CONH—(C 2 -C 6 alkenyl), (r) CONH—(C 2 -C 6 alkynyl), (s) CON(C 1 -C 6 alkyl) 2 , (t) CON(C 2 -C 6 alkenyl) 2 , (u) CON(C 2 -C 6 alkynyl) 2 , (vi) (C 1 -C 6 alkyl) v -NH(C 1 -C 6 alkyl), (v2) (C 1 -C 6 alkyl) v -NH(C 2 -C 6 alkenyl), (v3) (C 1 -C 6 alkyl) v -NH(C 2 -C 6 alkynyl), (w1) (C 2 -C 6 alkenyl) v -NH(C 1 -C 6 alkyl), (w2) (C 2 -C 6 alkenyl)-NH(C 2 -C 6 alkenyl), (w3) (C 2 -C 6 alkenyl) v -NH(C 2 -C 6 alkynyl), (x1) (C 2 -C 6 alkynyl) v -NH(C 1 -C 6 alkyl), (x2) (C 2 -C 6 alkynyl) v -NH(C 2 -C 6 alkenyl), (x3) (C 2 -C 6 alkynyl) v -NH(C 2 -C 6 alkynyl), (y1) (C 1 -C 6 alkyl) w -N(C 1 -C 6 alkyl) 2 , (y2) (C 1 -C 6 alkyl) w -N(C 2 -C 6 alkenyl) 2 , (y3) (C 1 -C 6 alkyl) w -N(C 2 -C 6 alkynyl) 2 , (z1) (C 2 -C 6 alkenyl) w -N(C 1 -C 6 alkyl) 2 , (z2) (C 2 -C 6 alkenyl) w -N(C 2 -C 6 alkenyl) 2 , (z3) (C 2 -C 6 alkenyl) w -N(C 2 -C 6 alkynyl) 2 , (aa1) (C 2 -C 6 alkynyl) w -N(C 1 -C 6 alkyl) 2 , (aa2) (C 2 -C 6 alkynyl) w -N(C 2 -C 6 alkenyl) 2 , (aa3) (C 2 -C 6 alkynyl) w -N(C 2 -C 6 alkynyl) 2 , (bb) S—(C 1 -C 6 alkyl), (cc) S(O)—(C 1 -C 6 alkyl), (dd) S(O) 2 —(C 1 -C 6 alkyl), (ee) S—(C 2 -C 6 alkenyl), (ff) S(O)—(C 2 -C 6 alkenyl), (gg) S(O) 2 —(C 2 -C 6 alkenyl), (hh) S—(C 2 -C 6 alkynyl), (ii) S(O)—(C 2 -C 6 alkynyl), (jj) S(O) 2 —(C 2 -C 6 alkynyl), (kk) an aromatic, saturated, unsaturated, or partially saturated carbocycle comprising one or two 3-8 membered rings, or (ll) an aromatic, saturated, unsaturated, or partially saturated heterocycle comprising one or two 5-7 membered rings and one or more heteroatoms selected from N, O and S, wherein each of (g)-(ll) is optionally substituted with one or more R 8 ;
each R 6 is independently (a) halogen, (b) OH, (c) CONH 2 , (d) COOH, (e) CN, (f) N 3 , (g) C 1 -C 6 alkyl, (h) C 2 -C 6 alkenyl, (i) C 2 -C 6 alkynyl, (j) O—(C 1 -C 6 alkyl), (k) O—(C 2 -C 6 alkenyl), (l) O—(C 2 -C 6 alkynyl), (m) COO—(C 1 -C 6 alkyl), (n) COO—(C 2 -C 6 alkenyl), (o) COO—(C 2 -C 6 alkynyl), (p) CONH—(C 1 -C 6 alkyl), (q) CONH—(C 2 -C 6 alkenyl), (r) CONH—(C 2 -C 6 alkynyl), (s) CON(C 1 -C 6 alkyl) 2 , (t) CON(C 2 -C 6 alkenyl) 2 , (u) CON(C 2 -C 6 alkynyl) 2 , (v1) (C 1 -C 6 alkyl) v -NH(C 1 -C 6 alkyl), (v2) (C 1 -C 6 alkyl) v -NH(C 2 -C 6 alkenyl), (v3) (C 1 -C 6 alkyl) v -NH(C 2 -C 6 alkynyl), (w1) (C 2 -C 6 alkenyl) v -NH(C 1 -C 6 alkyl), (w2) (C 2 -C 6 alkenyl) v -NH(C 2 -C 6 alkenyl), (w3) (C 2 -C 6 alkenyl) v -NH(C 2 -C 6 alkynyl), (x1) (C 2 -C 6 alkynyl) v -NH(C 1 -C 6 alkyl), (x2) (C 2 -C 6 alkynyl) v -NH(C 2 -C 6 alkenyl), (x3) (C 2 -C 6 alkynyl) v -NH(C 2 -C 6 alkynyl), (y1) (C 1 -C 6 alkyl) w -N(C 1 -C 6 alkyl) 2 , (y2) (C 1 -C 6 alkyl) w -N(C 2 -C 6 alkenyl) 2 , (y3) (C 1 -C 6 alkyl) w -N(C 2 -C 6 alkynyl) 2 , (z1) (C 2 -C 6 alkenyl) w -N(C 1 -C 6 alkyl) 2 , (z2) (C 2 -C 6 alkenyl) w -N(C 2 -C 6 alkenyl) 2 , (z3) (C 2 -C 6 alkenyl) w -N(C 2 -C 6 alkynyl) 2 , (aa1) (C 2 -C 6 alkynyl) w -N(C 1 -C 6 alkyl) 2 , (aa2) (C 2 -C 6 alkynyl) w -N(C 2 -C 6 alkenyl) 2 , (aa3) (C 2 -C 6 alkynyl) w -N(C 2 -C 6 alkynyl) 2 , (bb) S—(C 1 -C 6 alkyl), (cc) S(O)—(C 1 -C 6 alkyl), (dd) S(O) 2 —(C 1 -C 6 alkyl), (ee) S—(C 2 -C 6 alkenyl), (ff) S(O)—(C 2 -C 6 alkenyl), (gg) S(O) 2 —(C 2 -C 6 alkenyl), (hh) S—(C 2 -C 6 alkynyl), (ii) S(O)—(C 2 -C 6 alkynyl), (jj) S(O) 2 —(C 2 -C 6 alkynyl), (kk) an aromatic, saturated, unsaturated, or partially saturated carbocycle comprising one or two 3-8 membered rings, or (ll) an aromatic, saturated, unsaturated, or partially saturated heterocycle comprising one or two 5-7 membered rings and one or more heteroatoms selected from N, O and S, wherein each of (g)-(ll) is optionally substituted with one or more R 9 ;
each R 7 is independently halogen, OH, O—(C 1 -C 6 alkyl), COO—(C 1 -C 6 alkyl), CONH—(C 1 -C 6 alkyl), CON(C 1 -C 6 alkyl) 2 , COOH, CN, N 3 , 5-6 membered saturated, unsaturated, or partially saturated carbocycle, or 5-6 membered saturated, unsaturated, or partially saturated heterocycle comprising one or more heteroatoms selected from N, O and S;
each R 8 is independently halogen, OH, O—(C 1 -C 6 alkyl), C 1 -C 6 haloalkyl, COO—(C 1 -C 6 alkyl), CONH—(C 1 -C 6 alkyl), CON(C 1 -C 6 alkyl) 2 , COOH, CN, N 3 , 5-6 membered saturated, unsaturated, or partially saturated carbocycle, or 5-6 membered saturated, unsaturated, or partially saturated heterocycle comprising one or more heteroatoms selected from N, O and S;
each R 9 is independently halogen, OH, O—(C 1 -C 6 alkyl), COO—(C 1 -C 6 alkyl), CONH—(C 1 -C 6 alkyl), CON(C 1 -C 6 alkyl) 2 , COOH, CN, N 3 , 5-6 membered saturated, unsaturated, or partially saturated carbocycle, or 5-6 membered saturated, unsaturated, or partially saturated heterocycle comprising one or more heteroatoms selected from N, O and S;
R 101 and R 102 are each independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
R 11 is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
R 12 is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
m is 1, 2, 3, 4, 5, or 6;
n is 0, 1, 2, 3, 4, 5, or 6;
t is 0, 1, or 2;
u is 0 or 1;
v is 0 or 1; and
w is 0 or 1,
provided that when m is 1,
is not
2 . The method of claim 1 , wherein the compound is of formula (I):
or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
X a is CR a or N;
X b is CR b or N;
X c is CR c or N;
X d is CR d or N;
R a is H, halogen, or C 1 -C 6 alkyl;
R b is H, halogen, or C 1 -C 6 alkyl;
R c is H, halogen, or C 1 -C 6 alkyl;
R d is H, halogen, or C 1 -C 6 alkyl;
R 1 and R 2 are each independently H, C 1 -C 6 alkyl, or O—(C 1 -C 6 alkyl);
alternatively, one of R 1 and R 2 , together with the carbon atom to which R 1 or R 2 is attached and
form a 7-12 membered saturated, unsaturated, or partially saturated carbocycle, or a 7-12 membered saturated, unsaturated, or partially saturated heterocycle containing one or more heteroatoms selected from N, O and S;
R 3 and R 4 are each independently (a) H, (b) halogen, (c) OH, (d) COOH, (e) CONH 2 , (f) NHCOR 101 , (g) NR 101 COR 102 , (h) S(O) r R 101 , (i) C 1 -C 6 alkyl, (j) O—(C 1 -C 6 alkyl), (k) COO—(C 1 -C 6 alkyl), (l) CONH—(C 1 -C 6 alkyl), (m) CON(C 1 -C 6 alkyl) 2 , (n) (C 1 -C 6 alkyl)-NH 2 , (o) (C 1 -C 6 alkyl) v -NH(C 1 -C 6 alkyl), (p) (C 1 -C 6 alkyl)-N(C 1 -C 6 alkyl) 2 , or (q) 5-6 membered saturated, unsaturated, or partially saturated carbocycle, wherein each of (i)-(q) is optionally substituted with one or more R 7 ;
represents a 5-6 membered saturated, unsaturated, or partially saturated carbocycle, or a 5-6 membered saturated, unsaturated, or partially saturated heterocycle containing one or more heteroatoms selected from N, O and S;
represents a 5-6 membered aromatic, saturated, unsaturated, or partially saturated carbocycle, or a 5-6 membered aromatic, saturated, unsaturated, or partially saturated heterocycle containing one or more heteroatoms selected from N, O and S;
each R 5 is independently (a) halogen, (b) OH, (c) C 1 -C 6 alkyl, (d) C 2 -C 6 alkenyl, (e) O—(C 1 -C 6 alkyl), (f) COO—(C 1 -C 6 alkyl), (g) CONH—(C 1 -C 6 alkyl), (h) CON(C 1 -C 6 alkyl) 2 , (i) COOH, (j) CN, or (k) N 3 , wherein each of (c)-(h) is optionally substituted with one or more R 8 ;
each R 6 is independently (a) halogen, (b) OH, (c) C 1 -C 6 alkyl, (d) C 2 -C 6 alkenyl, (e) O—(C 1 -C 6 alkyl), (f) COO—(C 1 -C 6 alkyl), (g) CONH—(C 1 -C 6 alkyl), (h) CON(C 1 -C 6 alkyl) 2 , (i) COOH, (j) CN, or (k) N 3 , wherein each of (c)-(h) is optionally substituted with one or more R 9 ;
each R 7 is independently halogen, OH, O—(C 1 -C 6 alkyl), COO—(C 1 -C 6 alkyl), CONH—(C 1 -C 6 alkyl), CON(C 1 -C 6 alkyl) 2 , COOH, CN, N 3 , 5-6 membered saturated, unsaturated, or partially saturated carbocycle, or 5-6 membered saturated, unsaturated, or partially saturated heterocycle containing one or more heteroatoms selected from N, O and S;
each R 8 is independently halogen, OH, O—(C 1 -C 6 alkyl), C 1 -C 6 haloalkyl, COO—(C 1 -C 6 alkyl), CONH—(C 1 -C 6 alkyl), CON(C 1 -C 6 alkyl) 2 , COOH, CN, N 3 , 5-6 membered saturated, unsaturated, or partially saturated carbocycle, or 5-6 membered saturated, unsaturated, or partially saturated heterocycle containing one or more heteroatoms selected from N, O and S;
each R 9 is independently halogen, OH, O—(C 1 -C 6 alkyl), COO—(C 1 -C 6 alkyl), CONH—(C 1 -C 6 alkyl), CON(C 1 -C 6 alkyl) 2 , COOH, CN, N 3 , 5-6 membered saturated, unsaturated, or partially saturated carbocycle, or 5-6 membered saturated, unsaturated, or partially saturated heterocycle containing one or more heteroatoms selected from N, O and S;
R 101 and R 102 are each independently H or C 1 -C 6 alkyl;
R 11 is H, halogen, or C 1 -C 6 alkyl;
R 12 is H, halogen, or C 1 -C 6 alkyl;
m is 1, 2, 3, 4, 5, or 6;
n is 0, 1, 2, 3, 4, 5, or 6;
t is 0, 1, or 2;
u is 0 or 1;
v is 0 or 1; and
w is 0 or 1,
provided that when m is 1,
is not
3 . The method of claim 1 , wherein the compound is of formula (II) or (III):
or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein n1 is 0, 1, 2, 3, 4, or 5.
4 . The method of claim 1 , wherein the compound is of the following formula:
or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein m1 is 0, 1, 2, 3, or 4; and R 51 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, O—(C 1 -C 6 alkyl), COO—(C 1 -C 6 alkyl), CONH—(C 1 -C 6 alkyl), CON(C 1 -C 6 alkyl) 2 , or CN, each of which is optionally substituted with one or more R 8 .
5 . The method of claim 1 , wherein the compound is of the following formula:
or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
n2 is 0, 1, 2, or 3;
n3 is 0, 1, or 2; and
A 1 , A 2 , and A 3 are each independently CR 61 or N, and wherein only one of A 1 , A 2 , and A 3 is N; and
R 61 is H or R 6 .
6 . The method of claim 1 , wherein R 5 is halogen, C 1 -C 6 alkyl, or O-C 1 -C 6 alkyl.
7 . The method of claim 1 , wherein R 6 is halogen, C 1 -C 6 alkyl, O-C 1 -C 6 alkyl, or CN.
8 . The method of claim 1 , wherein R 3 is halogen, C 1 -C 6 alkyl, or O—(C 1 -C 6 alkyl).
9 . The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
10 . The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
11 . The method of claim 1 , wherein the compound is
12 . The method of claim 1 , wherein the compound is selected from the group consisting of
or a pharmaceutically acceptable salt or solvate thereof.
13 . The method of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt or solvate thereof.
14 . The method of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt or solvate thereof.
15 . The method of claim 1 , wherein the cancer is selected from bone cancer, bladder cancer, brain cancer, breast cancer, cervix cancer, colon cancer, esophageal cancer, gastric cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, pharynx cancer, placenta cancer, prostate cancer, skin cancer, thyroid cancer, tongue cancer, uteral cancer, lymphoma, and leukemia.
16 . The method of claim 15 , wherein the cancer is skin cancer.
17 . The method of claim 16 , wherein the skin cancer is basal cell carcinoma.
18 . The method of claim 16 , wherein the skin cancer is squamous cell carcinoma.
19 . The method of claim 15 , wherein the cancer is brain cancer.
20 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.Join the waitlist — get patent alerts
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