US 2021/0230174 A1Published application

Spirocyclic tetrahydroquinazolines

AssigneesAscentage Pharma (Suzhou) Co., Ltd., Ascentage Pharma Group Corp Limited

InventorsCHAO LI, Guozhi Tang, Jianyong Chen, Lingling Jiao, Liugen Li

Life of this patent

Estimating the term…

Abstract

The present disclosure provides compounds represented by Formula I: wherein R3, A, A1, A2, A3, E, E1, E2, L, Q, Z, and are as defined in the specification, and the pharmaceutically acceptable salts and solvates thereof. Compounds of Formula I are KRAS inhibitors and are thus useful to treat cancer and other diseases.

Claims31

Dependent claims

A compound of Formula I:

wherein:
Z is
X represents a 6- to 12-membered monocyclic or bicyclic heterocyclo;
R1 is selected from the group consisting of —C(═O)R1a, —C(═O)—CR4a═CR4bR4c, —C(═O)—C≡CR5a, —S(═O)2CR4e═CR4fR4g, and —S(═O)2—C≡CR5b;
R1a is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, and C3-C6 cycloalkyl;
R4a, R4b, and R4c are independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, (amino)C1-C4 alkyl, (hydroxy)C1-C4 alkyl, (alkoxy)C1-C4 alkyl, and (heterocyclo)C1-C4 alkyl;
R5a is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, (amino)C1-C4 alkyl, (hydroxy)C1-C4 alkyl, (alkoxy)C1-C4 alkyl, and (heterocyclo)C1-C4 alkyl;
R4e, R4f, and R4g are independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, (amino)C1-C4 alkyl, (hydroxy)C1-C4 alkyl, (alkoxy)C1-C4 alkyl, and (heterocyclo)C1-C4 alkyl;
R5b is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, (amino)C1-C4 alkyl, (hydroxy)C1-C4 alkyl, (alkoxy)C1-C4 alkyl, and (heterocyclo)C1-C4 alkyl;
R2a is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, (cyano)C1-C4 alkyl, (hydroxy)C1-C4 alkyl, (alkoxy)C1-C4 alkyl, (amino)C1-C4 alkyl, (heterocyclo)C1-C4 alkyl, (aryl)C1-C4 alkyl, (hetereoaryl)C1-C4 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, —C(═O)OR5c, —C(═O)NR5dR5e, and —NR5fR5g;
R2b and R2c are independently selected from the group consisting of hydrogen and C1-C4 alkyl;
or
R2b and R2c are attached to the same carbon atom and are taken together to form a —C(═O)— group;
R5c is selected from the group consisting hydrogen and C1-C4 alkyl;
R5d and R5e are independently selected from the group consisting hydrogen and C1-C4 alkyl;
or
R5d and R5e taken together with the nitrogen atom to which they are attached form an optionally substituted 4- to 8-membered heterocyclo;
R5f and R5g are independently selected from the group consisting hydrogen and C1-C4 alkyl;
or
R5f and R5g taken together with the nitrogen atom to which they are attached form an optionally substituted 4- to 8-membered heterocyclo;
L is selected from the group consisting of —O—, —S—, and —N(R7)—;
or L is a bond;
R7 is selected from the group consisting of hydrogen and C1-C4 alkyl;
R3 is selected from the group consisting of hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, (amino)C1-C4 alkyl, (hydroxy)C1-C4 alkyl, (alkoxy)C1-C4 alkyl, (carboxamido)C1-C4 alkyl, (heterocyclo)C1-C4 alkyl, (aryl)C1-C4 alkyl, and (hetereoaryl)C1-C4 alkyl;
A is selected from the group consisting of —(CR6aR6b)m—, —O—, —S—, and —N(R7a)—;
A1 is selected from the group consisting of —(CR6cR6d)n—, —O—, —S—, and —N(R7b)—;
A2 is selected from the group consisting of —(CR6eR6f)o—, —O—, —S—, and —N(R7c)—;
A3 is selected from the group consisting of —(CR6gR6h)p—, —O—, —S—, and —N(R7d)—;
A4 is selected from the group consisting of —O—, —S—, and —N(R7e)—;
or A4 is a bond,
with the provisos that:
(1) when A is —O—, —S—, or —N(R7a)—, then A4 is a bond, A1 is —(CR6cR6d)n—, n is 1 or 2, and E is —(CR8aR8b)q;
(2) when A1 is —O—, —S—, or —N(R7b)—, then A4 is a bond, A is —(CR6aR6b)m—, and m is 1 or 2;
(3) when A2 is —O—, —S—, or —N(R7c)—, then A3 is —(CR6gR6h)p— p is 1 or 2, and E is —(CR8aR8b)q;
and
(4) when A3 is —O—, —S—, or —N(R7d)—, then A2 is —(CR6eR6f)o— and o is 1 or 2,
R6a, R6b, R6c, R6d, R6e, R6f, R6g, and R6h are each independently selected from the group consisting of hydrogen and C1-C4 alkyl;
m is 0, 1, or 2;
n is 0, 1, or 2;
o is 0, 1, or 2;
p is 0, 1, or 2;
with the proviso that the sum of m, n, o, and p is 2, 3, 4, or 5;
R7a, R7b, R7c, R7d, and R7e are independently selected from the group consisting of hydrogen and C1-C4 alkyl;
E is selected from the group consisting of —(CR8aR8b)q—, —O—, —S—, and —N(R9a)—;
E1 is selected from the group consisting of —(CR8cR8d)r—, —O—, —S—, —N(R9b)—, and —C(═O)—;
E2 is selected from the group consisting of —O—, —S—, and —N(R9c)—, or E2 is a bond
with the provisos that:
(1) when E is —O—, —S—, or —N(R9a)—, then E2 is a bond, E1 is —(CR8cR8d)q—, A is —(CR6aR6b)m—, m is 1 or 2, A2 is —(CR6eR6f)o—, and o is 1 or 2;
and
(2) when E1 is —O—, —S—, or —N(R9b)—, then E2 is a bond, E is —(CR8aR8b)r—, and r is 1 or 2,
q is 1, 2, or 3;
r is 0, 1, or 2;
with the proviso that the sum of q and r is 2, 3, 4, or 5;
R8a and R8b are each independently selected from the group consisting of hydrogen and C1-C4 alkyl;
or
R8a and R8b taken together with the carbon atom to which they are attached form a C3-C6 cycloalkyl;
R8c and R8d are each independently selected from the group consisting of hydrogen and C1-C4 alkyl;
or
R8c and R8d taken together with the carbon atom to which they are attached form a C3-C6 cycloalkyl;
R9a, R9b, and R9c are independently selected from the group consisting of hydrogen and C1-C4 alkyl;
Q is selected from the group consisting of ═C(R10)— and ═N—;
R10 is selected from the group consisting of hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl;
represents a fused optionally substituted C3-C8 cycloalkyl, a fused optionally substituted heterocylo, a fused optionally substituted C6-C10 aryl, or a fused optionally substituted 5- to 10-membered heteroaryl;
and
represents a single or double bond,
or a pharmaceutically acceptable salt or solvate thereof.

63 more elements

A compound of Formula XVI:

wherein:
Z1 is selected from the group consisting of halo and
X represents a 6- to 12-membered monocyclic or bicyclic heterocyclo;
R13 is selected from the group consisting of hydrogen, —C(═O)R14a, and —C(═O)OR14b;
R14a is C1-C6 alkyl;
R14b is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, and aralkyl;
R12 is selected from the group consisting of halo and -LR3;
L is selected from the group consisting of —O—, —S—, and —N(R7)—;
or L is a bond;
R7 is selected from the group consisting of hydrogen and C1-C4 alkyl;
R3 is selected from the group consisting of hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, (amino)C1-C4 alkyl, (hydroxy)C1-C4 alkyl, (alkoxy)C1-C4 alkyl, (carboxamido)C1-C4 alkyl, (heterocyclo)C1-C4 alkyl, (aryl)C1-C4 alkyl, and (hetereoaryl)C1-C4 alkyl;
R2a is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, (cyano)C1-C4 alkyl, (hydroxy)C1-C4 alkyl, (alkoxy)C1-C4 alkyl, (amino)C1-C4 alkyl, (heterocyclo)C1-C4 alkyl, (aryl)C1-C4 alkyl, (hetereoaryl)C1-C4 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, —C(═O)OR5c, —C(═O)NR5dR5e, and —NR5fR5g;
R2b and R2c are independently selected from the group consisting of hydrogen and C1-C4 alkyl;
or
R2b and R2c are attached to the same carbon atom and are taken together to form a —C(═O)— group;
R5c is selected from the group consisting hydrogen and C1-C4 alkyl;
R5d and R5e are independently selected from the group consisting hydrogen and C1-C4 alkyl;
or
R5d and R5e taken together with the nitrogen atom to which they are attached form an optionally substituted 4- to 8-membered heterocyclo;
R5f and R5g are independently selected from the group consisting hydrogen and C1-C4 alkyl;
or
R5f and R5g taken together with the nitrogen atom to which they are attached form an optionally substituted 4- to 8-membered heterocyclo;
A is selected from the group consisting of —(CR6aR6b)m—, —O—, —S—, and —N(R7a)—;
A1 is selected from the group consisting of —(CR6cR6d)n—, —O—, —S—, and —N(R7b)—;
A2 is selected from the group consisting of —(CR6eR6f)o—, —O—, —S—, and —N(R7c)—;
A3 is selected from the group consisting of —(CR6gR6h)p—, —O—, —S—, and —N(R7d)—;
A4 is selected from the group consisting of —O—, —S—, and —N(R7e)—;
or A4 is a bond,
with the provisos that:
(1) when A is —O—, —S—, or —N(R7a)—, then A4 is a bond, A1 is —(CR6cR6d)n—, n is 1 or 2, and E is —(CR8aR8b)q;
(2) when A1 is —O—, —S—, or —N(R7b)—, then A4 is a bond, A is —(CR6aR6b)m—, and m is 1 or 2;
(3) when A2 is —O—, —S—, or —N(R7c)—, then A3 is —(CR6gR6h)p— p is 1 or 2, and E is —(CR8aR8b)q;
and
(4) when A3 is —O—, —S—, or —N(R7d)—, then A2 is —(CR6eR6f)o— and o is 1 or 2,
R6a, R6b, R6c, R6d, R6e, R6f, R6g, and R6h are each independently selected from the group consisting of hydrogen and C1-C4 alkyl;
m is 0, 1, or 2;
n is 0, 1, or 2;
o is 0, 1, or 2;
p is 0, 1, or 2;
with the proviso that the sum of m, n, o, and p is 2, 3, 4, or 5;
R7a, R7b, R7c, R7d, and R7e are independently selected from the group consisting of hydrogen and C1-C4 alkyl;
E is selected from the group consisting of —(CR8aR8b)q—, —O—, —S—, and —N(R9a)—;
E1 is selected from the group consisting of —(CR8cR8d)r—, —O—, —S—, —N(R9b)—, and —C(═O)—;
E2 is selected from the group consisting of —O—, —S—, and —N(R9c)—, or E2 is a bond
with the provisos that:
(1) when E is —O—, —S—, or —N(R9a)—, then E2 is a bond, E1 is —(CR8cR8d)q—, A is —(CR6aR6b)m—, m is 1 or 2, A2 is —(CR6eR6f)o—, and o is 1 or 2;
and
(2) when E1 is —O—, —S—, or —N(R9b)—, then E2 is a bond, E is —(CR8aR8b)r—, and r is 1 or 2, q is 1, 2, or 3;
r is 0, 1, or 2;
with the proviso that the sum of q and r is 2, 3, 4, or 5;
R8a and R8b are each independently selected from the group consisting of hydrogen and C1-C4 alkyl;
or
R8a and R8b taken together with the carbon atom to which they are attached form a C3-C6 cycloalkyl;
R8c and R8d are each independently selected from the group consisting of hydrogen and C1-C4 alkyl;
or
R8c and R8d taken together with the carbon atom to which they are attached form a C3-C6 cycloalkyl;
R9a, R9b, and R9c are independently selected from the group consisting of hydrogen and C1-C4 alkyl;
Q is selected from the group consisting of ═C(R10)— and ═N—;
R10 is selected from the group consisting of hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl;
represents a fused optionally substituted C3-C8 cycloalkyl, a fused optionally substituted heterocylo, a fused optionally substituted C6-C10 aryl, or a fused optionally substituted 5- to 10-membered heteroaryl;
and
represents a single or double bond,
or a salt or solvate thereof.

60 more elements

A compound of Formula XXXI:

wherein:
A is selected from the group consisting of —(CR6aR6b)m—, —O—, —S—, and —N(R7a)—;
A1 selected from the group consisting of —(CR6cR6d)n—, —O—, —S—, and —N(R7b)—;
A2 is selected from the group consisting of —(CR6eR6f)o—, —O—, —S—, and —N(R7c)—;
A3 is selected from the group consisting of —(CR6gR6h)p—, —O—, —S—, and —N(R7d)—;
A4 is selected from the group consisting of —O—, —S—, and —N(R7e)—;
or A4 is a bond,
with the provisos that:
(1) when A is —O—, —S—, or —N(R7a)—, then A4 is a bond, A1 is —(CR6cR6d)n—, n is 1 or 2, and E is —(CR8aR8b)q;
(2) when A1 is —O—, —S—, or —N(R7b)—, then A4 is a bond, A is —(CR6aR6b)m—, and m is 1 or 2;
(3) when A2 is —O—, —S—, or —N(R7c)—, then A3 is —(CR6gR6h)p— p is 1 or 2, and E is —(CR8aR8b)q;
and
(4) when A3 is —O—, —S—, or —N(R7d)—, then A2 is —(CR6eR6f)o— and o is 1 or 2,
R6a, R6b, R6c, R6d, R6e, R6f, R6g, and R6h are each independently selected from the group consisting of hydrogen and C1-C4 alkyl;
m is 0, 1, or 2;
n is 0, 1, or 2;
o is 0, 1, or 2;
p is 0, 1, or 2;
with the proviso that the sum of m, n, o, and p is 2, 3, 4, or 5;
R7a, R7b, R7c, R7d, and R7e are independently selected from the group consisting of hydrogen and C1-C4 alkyl;
E is selected from the group consisting of —(CR8aR8b)q—, —O—, —S—, and —N(R9a)—;
E1 is selected from the group consisting of —(CR8cR8d)r—, —O—, —S—, —N(R9b)—, and —C(═O)—;
E2 is selected from the group consisting of —O—, —S—, and —N(R9c)—, or E2 is a bond
with the provisos that:
(1) when E is —O—, —S—, or —N(R9a)—, then E2 is a bond, E1 is —(CR8cR8d)q—, A is —(CR6aR6b)m—, m is 1 or 2, A2 is —(CR6eR6f)o—, and o is 1 or 2;
and
(2) when E1 is —O—, —S—, or —N(R9b)—, then E2 is a bond, E is —(CR8aR8b)r—, and r is 1 or 2,
q is 1, 2, or 3;
r is 0, 1, or 2;
with the proviso that the sum of q and r is 2, 3, 4, or 5;
R8a and R8b are each independently selected from the group consisting of hydrogen and C1-C4 alkyl;
or
R8a and R8b taken together with the carbon atom to which they are attached form a C3-C6 cycloalkyl;
R8c and R8d are each independently selected from the group consisting of hydrogen and C1-C4 alkyl;
or
R8c and R8d taken together with the carbon atom to which they are attached form a C3-C6 cycloalkyl;
R9a, R9b, and R9c are independently selected from the group consisting of hydrogen and C1-C4 alkyl;
represents a fused optionally substituted C3-C8 cycloalkyl, a fused optionally substituted heterocylo, a fused optionally substituted C6-C10 aryl, or a fused optionally substituted 5- to 10-membered heteroaryl;
and
represents a single or double bond,
or a salt or solvate thereof.

38 more elements

A compound of Formula XLVI

wherein:
R15 is selected from the group consisting of hydrogen and —C(═O)OR16;
R16 is C1-C6 alkyl;
A is selected from the group consisting of —(CR6aR6b)m—, —O—, —S—, and —N(R7a)—;
A1 is selected from the group consisting of —(CR6cR6d)n—, —O—, —S—, and —N(R7b)—;
A2 is selected from the group consisting of —(CR6eR6f)o—, —O—, —S—, and —N(R7c)—;
A3 is selected from the group consisting of —(CR6gR6h)p—, —O—, —S—, and —N(R7d)—;
A4 is selected from the group consisting of —O—, —S—, and —N(R7e)—;
or A4 is a bond,
with the provisos that:
(1) when A is —O—, —S—, or —N(R7a)—, then A4 is a bond, A1 is —(CR6cR6d)n—, n is 1 or 2, and E is —(CR8aR8b)q;
(2) when A1 is —O—, —S—, or —N(R7b)—, then A4 is a bond, A is —(CR6aR6b)m—, and m is 1 or 2;
(3) when A2 is —O—, —S—, or —N(R7c)—, then A3 is —(CR6gR6h)p— p is 1 or 2, and E is —(CR8aR8b)q;
and
(4) when A3 is —O—, —S—, or —N(R7d)—, then A2 is —(CR6eR6f)o— and o is 1 or 2,
R6a, R6b, R6c, R6d, R6e, R6f, R6g, and R6h are each independently selected from the group consisting of hydrogen and C1-C4 alkyl;
m is 0, 1, or 2;
n is 0, 1, or 2;
o is 0, 1, or 2;
p is 0, 1, or 2;
with the proviso that the sum of m, n, o, and p is 2, 3, 4, or 5;
R7a, R7b, R7c, R7d, and R7e are independently selected from the group consisting of hydrogen and C1-C4 alkyl;
E is selected from the group consisting of —(CR8aR8b)q—, —O—, —S—, and —N(R9a)—;
E1 is selected from the group consisting of —(CR8cR8d)r—, —O—, —S—, —N(R9b)—, and —C(═O)—;
E2 is selected from the group consisting of —O—, —S—, and —N(R9c)—, or E2 is a bond
with the provisos that:
(1) when E is —O—, —S—, or —N(R9a)—, then E2 is a bond, E1 is —(CR8cR8d)q—, A is —(CR6aR6b)m—, m is 1 or 2, A2 is —(CR6eR6f)o—, and o is 1 or 2;
and
(2) when E1 is —O—, —S—, or —N(R9b)—, then E2 is a bond, E is —(CR8aR8b)r—, and r is 1 or 2,
q is 1, 2, or 3;
r is 0, 1, or 2;
with the proviso that the sum of q and r is 2, 3, 4, or 5;
R8a and R8b are each independently selected from the group consisting of hydrogen and C1-C4 alkyl;
or
R8a and R8b taken together with the carbon atom to which they are attached form a C3-C6 cycloalkyl;
R8c and R8d are each independently selected from the group consisting of hydrogen and C1-C4 alkyl;
or
R8c and R8d taken together with the carbon atom to which they are attached form a C3-C6 cycloalkyl;
R9a, R9b, and R9c are independently selected from the group consisting of hydrogen and C1-C4 alkyl;
Q is ═N—;
represents a fused optionally substituted C3-C8 cycloalkyl, a fused optionally substituted heterocylo, a fused optionally substituted C6-C10 aryl, or a fused optionally substituted 5- to 10-membered heteroaryl;
and
represents a single or double bond,
or a salt or solvate thereof,
with the proviso that the compound is not:

42 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/200,342Filed 12 Mar 2021
Priority: CN PCT/CN2020/0710048 Jan 2020
Published: 29 Jul 2021
Term ends: Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07D 491/107
Spiro-condensed systems: with only one oxygen atom as ring hetero atom in the oxygen-containing ring
A61P 35/00
Antineoplastic agents
C07D 403/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group…
C07D 471/10
In which the condensed system contains two hetero rings: spiro-condensed systems

Family

Application17/200,342Continuation
US 11,312,724 B2Related patent
US 2021/0230174 A1This patent

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Abstract

A compound of Formula I:

wherein:
Z is
X represents a 6- to 12-membered monocyclic or bicyclic heterocyclo;
R1 is selected from the group consisting of —C(═O)R1a, —C(═O)—CR4a═CR4bR4c, —C(═O)—C≡CR5a, —S(═O)2CR4e═CR4fR4g, and —S(═O)2—C≡CR5b;
R1a is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, and C3-C6 cycloalkyl;
R4a, R4b, and R4c are independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, (amino)C1-C4 alkyl, (hydroxy)C1-C4 alkyl, (alkoxy)C1-C4 alkyl, and (heterocyclo)C1-C4 alkyl;
R5a is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, (amino)C1-C4 alkyl, (hydroxy)C1-C4 alkyl, (alkoxy)C1-C4 alkyl, and (heterocyclo)C1-C4 alkyl;
R4e, R4f, and R4g are independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, (amino)C1-C4 alkyl, (hydroxy)C1-C4 alkyl, (alkoxy)C1-C4 alkyl, and (heterocyclo)C1-C4 alkyl;
R5b is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, (amino)C1-C4 alkyl, (hydroxy)C1-C4 alkyl, (alkoxy)C1-C4 alkyl, and (heterocyclo)C1-C4 alkyl;
R2a is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, (cyano)C1-C4 alkyl, (hydroxy)C1-C4 alkyl, (alkoxy)C1-C4 alkyl, (amino)C1-C4 alkyl, (heterocyclo)C1-C4 alkyl, (aryl)C1-C4 alkyl, (hetereoaryl)C1-C4 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, —C(═O)OR5c, —C(═O)NR5dR5e, and —NR5fR5g;
R2b and R2c are independently selected from the group consisting of hydrogen and C1-C4 alkyl;
or
R2b and R2c are attached to the same carbon atom and are taken together to form a —C(═O)— group;
R5c is selected from the group consisting hydrogen and C1-C4 alkyl;
R5d and R5e are independently selected from the group consisting hydrogen and C1-C4 alkyl;
or
R5d and R5e taken together with the nitrogen atom to which they are attached form an optionally substituted 4- to 8-membered heterocyclo;
R5f and R5g are independently selected from the group consisting hydrogen and C1-C4 alkyl;
or
R5f and R5g taken together with the nitrogen atom to which they are attached form an optionally substituted 4- to 8-membered heterocyclo;
L is selected from the group consisting of —O—, —S—, and —N(R7)—;
or L is a bond;
R7 is selected from the group consisting of hydrogen and C1-C4 alkyl;
R3 is selected from the group consisting of hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, (amino)C1-C4 alkyl, (hydroxy)C1-C4 alkyl, (alkoxy)C1-C4 alkyl, (carboxamido)C1-C4 alkyl, (heterocyclo)C1-C4 alkyl, (aryl)C1-C4 alkyl, and (hetereoaryl)C1-C4 alkyl;
A is selected from the group consisting of —(CR6aR6b)m—, —O—, —S—, and —N(R7a)—;
A1 is selected from the group consisting of —(CR6cR6d)n—, —O—, —S—, and —N(R7b)—;
A2 is selected from the group consisting of —(CR6eR6f)o—, —O—, —S—, and —N(R7c)—;
A3 is selected from the group consisting of —(CR6gR6h)p—, —O—, —S—, and —N(R7d)—;
A4 is selected from the group consisting of —O—, —S—, and —N(R7e)—;
or A4 is a bond,
with the provisos that:
(1) when A is —O—, —S—, or —N(R7a)—, then A4 is a bond, A1 is —(CR6cR6d)n—, n is 1 or 2, and E is —(CR8aR8b)q;
(2) when A1 is —O—, —S—, or —N(R7b)—, then A4 is a bond, A is —(CR6aR6b)m—, and m is 1 or 2;
(3) when A2 is —O—, —S—, or —N(R7c)—, then A3 is —(CR6gR6h)p— p is 1 or 2, and E is —(CR8aR8b)q;
and
(4) when A3 is —O—, —S—, or —N(R7d)—, then A2 is —(CR6eR6f)o— and o is 1 or 2,
R6a, R6b, R6c, R6d, R6e, R6f, R6g, and R6h are each independently selected from the group consisting of hydrogen and C1-C4 alkyl;
m is 0, 1, or 2;
n is 0, 1, or 2;
o is 0, 1, or 2;
p is 0, 1, or 2;
with the proviso that the sum of m, n, o, and p is 2, 3, 4, or 5;
R7a, R7b, R7c, R7d, and R7e are independently selected from the group consisting of hydrogen and C1-C4 alkyl;
E is selected from the group consisting of —(CR8aR8b)q—, —O—, —S—, and —N(R9a)—;
E1 is selected from the group consisting of —(CR8cR8d)r—, —O—, —S—, —N(R9b)—, and —C(═O)—;
E2 is selected from the group consisting of —O—, —S—, and —N(R9c)—, or E2 is a bond
with the provisos that:
(1) when E is —O—, —S—, or —N(R9a)—, then E2 is a bond, E1 is —(CR8cR8d)q—, A is —(CR6aR6b)m—, m is 1 or 2, A2 is —(CR6eR6f)o—, and o is 1 or 2;
and
(2) when E1 is —O—, —S—, or —N(R9b)—, then E2 is a bond, E is —(CR8aR8b)r—, and r is 1 or 2,
q is 1, 2, or 3;
r is 0, 1, or 2;
with the proviso that the sum of q and r is 2, 3, 4, or 5;
R8a and R8b are each independently selected from the group consisting of hydrogen and C1-C4 alkyl;
or
R8a and R8b taken together with the carbon atom to which they are attached form a C3-C6 cycloalkyl;
R8c and R8d are each independently selected from the group consisting of hydrogen and C1-C4 alkyl;
or
R8c and R8d taken together with the carbon atom to which they are attached form a C3-C6 cycloalkyl;
R9a, R9b, and R9c are independently selected from the group consisting of hydrogen and C1-C4 alkyl;
Q is selected from the group consisting of ═C(R10)— and ═N—;
R10 is selected from the group consisting of hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl;
represents a fused optionally substituted C3-C8 cycloalkyl, a fused optionally substituted heterocylo, a fused optionally substituted C6-C10 aryl, or a fused optionally substituted 5- to 10-membered heteroaryl;
and
represents a single or double bond,
or a pharmaceutically acceptable salt or solvate thereof.

63 more elements

Facts

Application

17/200,342Filed 12 Mar 2021

Priority

CN PCT/CN2020/0710048 Jan 2020

Published

29 Jul 2021

Term ends

Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07D 491/107
Spiro-condensed systems: with only one oxygen atom as ring hetero atom in the oxygen-containing ring
A61P 35/00
Antineoplastic agents
C07D 403/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group…
C07D 471/10
In which the condensed system contains two hetero rings: spiro-condensed systems