TW202012371A - K-ras modulators with a vinyl sulfone moiety - Google Patents

Abstract

Provided herein are compounds comprising a vinyl sulfone moiety. Also provided herein are pharmaceutical compositions comprising such compounds, and methods of using such compounds and pharmaceutical compositions for inhibiting the post-translational processing of K-Ras precursors, and for treating disorders in a subject in need thereof.

Description

K-RAS Modifier with Ethylene Part

The present invention relates generally to compounds that inhibit K-Ras or post-translational treatment of RAS that will produce K-Ras protein, and more specifically to inhibitors with an ethylene ketone moiety.

KRAS is the most frequently mutated oncogene involved in human cancer. The KRAS oncogene encodes K-Ras protein, which is part of the RAS/MAPK signaling pathway. K-Ras is a GTPase that acts as a molecular switch, switching between an active GTP-bound form and an inactive GDP-bound form. K-Ras protein plays a key role in tissue signaling and is involved in cell proliferation, cell differentiation and apoptosis. Mutations in activated KRAS are common in many different human cancers. Therefore, there is a need for effective inhibitors of K-Ras, as well as effective inhibitors of post-translational processing that will produce mature and well-treated KRAS of K-Ras protein.

， 或其立體異構體或醫藥學上可接受之鹽，其中： A為4員至8員雜環烷基； B為芳基、雜芳基、環烷基或雜環烷基； W為芳基或雜芳基； X為-S(O)-、-S(O)₂ -、-S(O)NR^b53 -、-C(S)-、-C(O)-或-C(R^b13 )₂ -； 各R^b13 獨立地為氫、鹵基、烷基或鹵烷基； R^b53 為氫或烷基，其中該烷基未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、環烷基、雜環烷基、芳基、雜芳基及=O； R^b1 為氫、烷基、鹵烷基、環烷基或鹵環烷基； z為0、1或2； R^b2 、R^b3 、R^b6 、R^b7 、R^b8 、R^b9 、R^b10 及R^b11 係獨立地選自由以下組成之群：氫、鹵基、烷基、環烷基、雜環烷基、-CN、-NO₂ 、-NR^b13 R^b14 、-OR^b15 、-SO₂ R^b16 及-SO₂ NH₂ ，其中各烷基、環烷基及雜環烷基係獨立地未經取代或經一或多個鹵基取代，且其中在R^b6 及R^b7 中之一者為烷基時，z為1； 各R^b4 係獨立地選自由以下組成之群：鹵基、烷基、環烷基、雜環烷基、雜芳基、芳基、-NO₂ 、-CN、-SO₂ NH₂ 、-NR^b13 R^b14 、-OR^b15 、=O、-SR^b60 及-SO₂ R^b16 ，其中各烷基、環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個鹵基取代；及 各R^b13 、R^b14 、R^b15 、R^b16 及R^b60 獨立地為氫、烷基、鹵烷基、環烷基、鹵環烷基、雜環烷基或鹵雜環烷基； 或R^b2 及R^b3 一起形成=O； 或R^b6 及R^b1 與其所連接之原子一起形成雜環烷基，其未經取代或經一或多個鹵基取代； 或R^b10 及R^b1 與其所連接之原子一起形成雜環烷基，其未經取代或經一或多個鹵基取代； 或R^b8 及R^b1 與其所連接之原子一起形成雜環烷基，其未經取代或經一或多個鹵基取代； 或兩個至四個R^b2 、R^b3 、R^b6 及R^b7 與其所連接之原子一起形成雜環烷基或雜芳基，其中該雜環烷基或雜芳基未經取代或經一或多個鹵基取代； 或R^b1 及一個R^b4 與其所連接之原子一起形成雜環烷基，其未經取代或經一或多個鹵基取代； 或兩個至四個R^b4 與其所連接之原子一起形成芳基、雜芳基、環烷基或雜環烷基，其中該芳基、雜芳基、環烷基或雜環烷基未經取代或經一或多個鹵基取代； 各R^b5 係獨立地選自由以下組成之群：鹵基、烷基、環烷基、雜環烷基、芳基、雜芳基、炔基、-NO₂ 、-CN、-SO₂ NR^b54 R^b55 、-NR^b17 R^b18 、 -OR^b19 、-SO₂ R^b20 、=O及-SR^b21 ； 其中各環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、-OR^b22 、=O、 -NR^b23 R^b24 、-CN、-SF₅ 、-SO₂ NR^b56 R^b57 、-SR^b58 、-SO₂ R^b59 及R^b28 ，其中各R^b28 獨立地為烷基、環烷基、雜環烷基、芳基或雜芳基； 各烷基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、-OR^b25 、=O、-NR^b26 R^b27 、-CN、-SF₅ 、-SO₂ NR^b61 R^b62 、-SR^b63 、-SO₂ R^b64 及R^b65 ，其中各R^b65 獨立地為環烷基、雜環烷基、芳基或雜芳基； 各R^b17 、R^b18 、R^b19 、R^b20 、R^b21 、R^b22 、R^b23 、R^b24 、R^b25 、R^b26 、R^b27 、R^b54 、R^b55 、R^b56 、R^b57 、R^b58 、R^b59 、R^b61 、R^b62 、R^b63 及R^b64 獨立地為氫、烷基、鹵烷基、環烷基、鹵環烷基、雜環烷基、芳基、雜芳基、炔基或鹵炔基； 其中R^b17 、R^b18 、R^b19 、R^b22 、R^b23 、R^b24 、R^b25 、R^b26 、R^b27 及R^b28 之各烷基、環烷基、雜環烷基、芳基及雜芳基以及R^b65 之各環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、=O、-CN、芳基、雜芳基、烷基、炔基、環烷基、雜環烷基、-NR^b29 R^b30 、-SF₅ 及-OR^b31 ； 其中各烷基、環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：烷基、鹵烷基、炔基、鹵基、-CN、-SF₅ 、=O、-NR^b43 R^b44 、-NR^b45 C(O)R^b46 、-OR^b47 及R^b66 ，其中各R^b66 獨立地為環烷基、雜環烷基、芳基或雜芳基，且其中各R^b66 係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：=O、-NH₂ 、-SF₅ 、-OH、-O-烷基、-O-鹵烷基、鹵基、烷基及鹵烷基； 各R^b29 、R^b30 、R^b31 、R^b43 、R^b44 、R^b45 、R^b46 及R^b47 獨立地為氫、烷基或鹵烷基； 各R^b12 係獨立地選自由以下組成之群：鹵基、烷基、鹵烷基及 -OR^b32 ，其中R^b32 為氫、烷基或鹵烷基； m為0至13之整數； n為0至11之整數；及 t為0至6之整數。In one aspect, provided herein is a compound of formula (I):

, Or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: A is a 4- to 8-membered heterocycloalkyl; B is an aryl, heteroaryl, cycloalkyl or heterocycloalkyl; W is Aryl or heteroaryl; X is -S(O)-, -S(O) ₂ -, -S(O)NR ^b53 -, -C(S)-, -C(O)- or -C( R ^b13 ) ₂ -; each R ^{b13 is} independently hydrogen, halo, alkyl or haloalkyl; R ^b53 is hydrogen or alkyl, wherein the alkyl is unsubstituted or independently selected by one or more of the following Substituted by the group of substituents: halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and =O; R ^b1 is hydrogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl ; Z is 0, 1 or 2; R ^b2 , R ^b3 , R ^b6 , R ^b7 , R ^b8 , R ^b9 , R ^b10 and R ^b11 are independently selected from the group consisting of hydrogen, halo, alkyl, Cycloalkyl, heterocycloalkyl, -CN, -NO ₂ , -NR ^b13 R ^b14 , -OR ^b15 , -SO ₂ R ^b16 and -SO ₂ NH ₂ , where each alkyl, cycloalkyl and heterocycloalkane Radicals are independently unsubstituted or substituted with one or more halo groups, and when one of R ^b6 and R ^b7 is alkyl, z is 1; each R ^b4 is independently selected from the group consisting of ：Halo, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, -NO ₂ , -CN, -SO ₂ NH ₂ , -NR ^b13 R ^b14 , -OR ^b15 , =O,- SR ^b60 and -SO ₂ R ^b16 , wherein each alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group and heteroaryl group are independently unsubstituted or substituted with one or more halo groups; and each R ^b13 , R ^b14 , R ^b15 , R ^b16 and R ^{b60 are} independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl or haloheterocycloalkyl; or R ^b2 and R ^b3 together Forming =O; or R ^b6 and R ^b1 together with the atoms to which they are attached form a heterocycloalkyl group which is unsubstituted or substituted with one or more halo; or R ^b10 and R ^b1 together with the atoms to which they are attached form a hetero Cycloalkyl, which is unsubstituted or substituted with one or more halo groups; or R ^b8 and R ^b1 together with the atoms to which they are attached form a heterocycloalkyl group, which is unsubstituted or substituted with one or more halo groups; Or two to four R ^b2 , R ^b3 , R ^b6 and R ^b7 together with the atoms to which they are attached form a heterocycloalkyl or heteroaryl group, wherein the heterocycloalkyl or heteroaryl group is unsubstituted or substituted by one or Multiple halo substitutions; or R ^b1 and one R ^b4 together with the atoms to which they are attached form a heterocycloalkyl group, which is unsubstituted or substituted with one or more halo groups; or two to four R ^{b4 are} attached to it The atoms together form an aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl is not Substituted or substituted with one or more halo groups; each R ^b5 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl,- _{NO 2, -CN, -SO 2 NR} b54 R b55, -NR b17 R b18, -OR b19, -SO 2 R b20, = O and -SR ^b21; wherein each cycloalkyl, heterocycloalkyl, aryl, And heteroaryl groups are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -OR ^b22 , =O, -NR ^b23 R ^b24 , -CN, -SF ₅ , -SO ₂ NR ^b56 R ^b57 , -SR ^b58 , -SO ₂ R ^b59 and R ^b28 , where each R ^{b28 is} independently alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; The alkyl group is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, -OR ^b25 , =O, -NR ^b26 R ^b27 , -CN, ^-SF ₅ , -SO ₂ NR ^b61 R ^b62 , -SR ^b63 , -SO ₂ R ^b64 and R ^b65 , where each R ^{b65 is} independently cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each R ^b17 , R ^{b18 , R b19, R b20, R} b21, R b22, R b23, R b24, R b25, R b26, R b27, R b54, R b55, R b56, R b57, R b58, R b59, R b61, R ^b62 , R ^b63 and R ^{b64 are} independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl or haloalkynyl; wherein R ^b17 , R ^b18 , R ^b19 , R ^b22 , R ^b23 , R ^b24 , R ^b25 , R ^b26 , R ^b27 and R ^b28 each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl and R ^b65 Each cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, =O, -CN , Aryl, heteroaryl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, -NR ^b29 R ^b30 , ^-SF ₅ and -OR ^b31 ; where each alkyl, cycloalkyl, heterocycloalkyl , Aryl and heteroaryl are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SF ₅ , =O, -NR ^b43 R ^b44 , -NR ^b45 C(O)R ^b46 , -OR ^b47 and R ^b66 , of which R ^{b6 6 is} independently cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and wherein each R ^b66 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: =O, -NH ₂ , -SF ₅ , -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl; each R ^b29 , R ^b30 , R ^b31 , R ^b43 , R ^b44 , R ^b45 , R ^b46 and R ^{b47 are} independently hydrogen, alkyl or haloalkyl; each R ^b12 is independently selected from the group consisting of halo, alkyl, haloalkyl and -OR ^b32 , Where R ^b32 is hydrogen, alkyl or haloalkyl; m is an integer from 0 to 13; n is an integer from 0 to 11; and t is an integer from 0 to 6.

In some variations of the compound of formula (I), or its stereoisomer or pharmaceutically acceptable salt, A is a 5-membered or 6-membered heterocycloalkyl.

， 或其立體異構體或醫藥學上可接受之鹽，其中： A為4員至8員雜環烷基； B為芳基、雜芳基、環烷基或雜環烷基； W為芳基或雜芳基； X為-S(O)-、-S(O)₂ -、-S(O)NR^b53 -、-C(S)-、-C(O)-或-C(R^b13 )₂ -； 各R^b13 獨立地為氫、鹵基、烷基或鹵烷基； R^b53 為氫或烷基，其中該烷基未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、環烷基、雜環烷基、芳基、雜芳基及=O； R^b1 為氫、烷基、鹵烷基、環烷基或鹵環烷基； z為0或1； R^b2 、R^b3 、R^b6 、R^b7 、R^b8 、R^b9 、R^b10 及R^b11 係獨立地選自由以下組成之群：氫、鹵基、烷基、環烷基、雜環烷基、-CN、-NO₂ 、 -NR^b13 R^b14 、-OR^b15 、-SO₂ R^b16 及-SO₂ NH₂ ，其中各烷基、環烷基及雜環烷基係獨立地未經取代或經一或多個鹵基取代，且其中在R^b6 及R^b7 中之一者為烷基時，z為1； 各R^b4 係獨立地選自由以下組成之群：鹵基、烷基、環烷基、雜環烷基、雜芳基、芳基、-NO₂ 、-CN、-SO₂ NH₂ 、-NR^b13 R^b14 、-OR^b15 、=O、-SR^b60 及-SO₂ R^b16 ，其中各烷基、環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個鹵基取代；及 各R^b13 、R^b14 、R^b15 、R^b16 及R^b60 獨立地為氫、烷基、鹵烷基、環烷基、鹵環烷基、雜環烷基或鹵雜環烷基； 或R^b2 及R^b3 一起形成=O； 或R^b6 及R^b1 與其所連接之原子一起形成雜環烷基，其未經取代或經一或多個鹵基取代； 或R^b10 及R^b1 與其所連接之原子一起形成雜環烷基，其未經取代或經一或多個鹵基取代； 或R^b8 及R^b1 與其所連接之原子一起形成雜環烷基，其未經取代或經一或多個鹵基取代； 或兩個至四個R^b2 、R^b3 、R^b6 及R^b7 與其所連接之原子一起形成雜環烷基或雜芳基，其中該雜環烷基或雜芳基未經取代或經一或多個鹵基取代； 或R^b1 及一個R^b4 與其所連接之原子一起形成雜環烷基，其未經取代或經一或多個鹵基取代； 或兩個至四個R^b4 與其所連接之原子一起形成芳基、雜芳基、環烷基或雜環烷基，其中該芳基、雜芳基、環烷基或雜環烷基未經取代或經一或多個鹵基取代； 各R^b5 係獨立地選自由以下組成之群：鹵基、烷基、環烷基、雜環烷基、芳基、雜芳基、炔基、-NO₂ 、-CN、-SO₂ NR^b54 R^b55 、-NR^b17 R^b18 、 -OR^b19 、-SO₂ R^b20 、=O及-SR^b21 ； 其中各環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、-OR^b22 、=O、 -NR^b23 R^b24 、-CN、-SF₅ 、-SO₂ NR^b56 R^b57 、-SR^b58 、-SO₂ R^b59 及R^b28 ，其中各R^b28 獨立地為烷基、環烷基、雜環烷基、芳基或雜芳基； 各烷基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、-OR^b25 、=O、-NR^b26 R^b27 、-CN、-SF₅ 、 -SO₂ NR^b61 R^b62 、-SR^b63 、-SO₂ R^b64 及R^b65 ，其中各R^b65 獨立地為環烷基、雜環烷基、芳基或雜芳基； 各R^b17 、R^b18 、R^b19 、R^b20 、R^b21 、R^b22 、R^b23 、R^b24 、R^b25 、R^b26 、R^b27 、R^b54 、R^b55 、R^b56 、R^b57 、R^b58 、R^b59 、R^b61 、R^b62 、R^b63 及R^b64 獨立地為氫、烷基、鹵烷基、環烷基、鹵環烷基、雜環烷基、芳基、雜芳基、炔基或鹵炔基； 其中R^b17 、R^b18 、R^b19 、R^b22 、R^b23 、R^b24 、R^b25 、R^b26 、R^b27 及R^b28 之各烷基、環烷基、雜環烷基、芳基及雜芳基以及R^b65 之各環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、=O、-CN、芳基、雜芳基、烷基、炔基、環烷基、雜環烷基、-NR^b29 R^b30 、-SF₅ 及-OR^b31 ； 其中各烷基、環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：烷基、鹵烷基、炔基、鹵基、-CN、-SF₅ 、=O、-NR^b43 R^b44 、-NR^b45 C(O)R^b46 、-OR^b47 及R^b66 ，其中各R^b66 獨立地為環烷基、雜環烷基、芳基或雜芳基，且其中各R^b66 係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：=O、-NH₂ 、-SF₅ 、-OH、-O-烷基、-O-鹵烷基、鹵基、烷基及鹵烷基； 各R^b29 、R^b30 、R^b31 、R^b43 、R^b44 、R^b45 、R^b46 及R^b47 獨立地為氫、烷基或鹵烷基； 各R^b12 係獨立地選自由以下組成之群：鹵基、烷基、鹵烷基及-OR^b32 ，其中R^b32 為氫、烷基或鹵烷基； m為0至13之整數； n為0至11之整數；及 t為0至6之整數。In one aspect, the compound of formula (I) is a compound of formula (II):

, Or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: A is a 4- to 8-membered heterocycloalkyl; B is an aryl, heteroaryl, cycloalkyl or heterocycloalkyl; W is Aryl or heteroaryl; X is -S(O)-, -S(O) ₂ -, -S(O)NR ^b53 -, -C(S)-, -C(O)- or -C( R ^b13 ) ₂ -; each R ^{b13 is} independently hydrogen, halo, alkyl or haloalkyl; R ^b53 is hydrogen or alkyl, wherein the alkyl is unsubstituted or independently selected by one or more of the following Substituted by a group of substituents: halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and =O; R ^b1 is hydrogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl ; Z is 0 or 1; R ^b2 , R ^b3 , R ^b6 , R ^b7 , R ^b8 , R ^b9 , R ^b10 and R ^b11 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkane Group, heterocycloalkyl, -CN, -NO ₂ , -NR ^b13 R ^b14 , -OR ^b15 , -SO ₂ R ^b16 and -SO ₂ NH ₂ , where each alkyl, cycloalkyl and heterocycloalkyl Independently unsubstituted or substituted with one or more halo groups, and when one of R ^b6 and R ^b7 is alkyl, z is 1; each R ^b4 is independently selected from the group consisting of: halogen Group, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, -NO ₂ , -CN, -SO ₂ NH ₂ , -NR ^b13 R ^b14 , -OR ^b15 , =O, -SR ^b60 And -SO ₂ R ^b16 , wherein each alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group and heteroaryl group are independently unsubstituted or substituted with one or more halogen groups; and each R ^b13 and R ^b14 , R ^b15 , R ^b16 and R ^{b60 are} independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl or haloheterocycloalkyl; or R ^b2 and R ^b3 together form = O; or R ^b6 and R ^b1 together with the atoms to which they are attached form a heterocycloalkyl, which is unsubstituted or substituted with one or more halo groups; or R ^b10 and R ^b1 together with the atoms to which they are attached form a heterocycloalkane Group, which is unsubstituted or substituted with one or more halo groups; or R ^b8 and R ^b1 together with the atoms to which they are attached form a heterocycloalkyl group, which is unsubstituted or substituted with one or more halo groups; or both From four to four R ^b2 , R ^b3 , R ^b6 and R ^b7 together with the atoms to which they are attached form a heterocycloalkyl or heteroaryl group, wherein the heterocycloalkyl or heteroaryl group is unsubstituted or substituted by one or more Halo substitution; or R ^b1 and one R ^b4 together with the atoms to which they are attached form a heterocycloalkyl group which is unsubstituted or substituted with one or more halo groups; or two to four R ^b4 and the atoms to which they are attached Together form an aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl is not taken Substituted or substituted with one or more halo groups; each R ^b5 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl,- _{NO 2, -CN, -SO 2 NR} b54 R b55, -NR b17 R b18, -OR b19, -SO 2 R b20, = O and -SR ^b21; wherein each cycloalkyl, heterocycloalkyl, aryl, And heteroaryl groups are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -OR ^b22 , =O, -NR ^b23 R ^b24 , -CN, -SF ₅ , -SO ₂ NR ^b56 R ^b57 , -SR ^b58 , -SO ₂ R ^b59 and R ^b28 , where each R ^{b28 is} independently alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; The alkyl group is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, -OR ^b25 , =O, -NR ^b26 R ^b27 , -CN, ^-SF ₅ , -SO ₂ NR ^b61 R ^b62 , -SR ^b63 , -SO ₂ R ^b64 and R ^b65 , where each R ^{b65 is} independently cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each R ^b17 , R ^{b18 , R b19, R b20, R} b21, R b22, R b23, R b24, R b25, R b26, R b27, R b54, R b55, R b56, R b57, R b58, R b59, R b61, R ^b62 , R ^b63 and R ^{b64 are} independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl or haloalkynyl; wherein R ^b17 , R ^b18 , R ^b19 , R ^b22 , R ^b23 , R ^b24 , R ^b25 , R ^b26 , R ^b27 and R ^b28 each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl and R ^b65 Each cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, =O, -CN , Aryl, heteroaryl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, -NR ^b29 R ^b30 , ^-SF ₅ and -OR ^b31 ; where each alkyl, cycloalkyl, heterocycloalkyl , Aryl and heteroaryl are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SF ₅ , =O, -NR ^b43 R ^b44 , -NR ^b45 C(O)R ^b46 , -OR ^b47 and R ^b66 , of which R ^{b6 6 is} independently cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and wherein each R ^b66 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: =O, -NH ₂ , -SF ₅ , -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl; each R ^b29 , R ^b30 , R ^b31 , R ^b43 , R ^b44 , R ^b45 , R ^b46 and R ^{b47 are} independently hydrogen, alkyl or haloalkyl; each R ^b12 is independently selected from the group consisting of halo, alkyl, haloalkyl and -OR ^b32 , Where R ^b32 is hydrogen, alkyl or haloalkyl; m is an integer from 0 to 13; n is an integer from 0 to 11; and t is an integer from 0 to 6.

In some variations of the compound of formula (I) or formula (II) or its stereoisomer or pharmaceutically acceptable salt, A is a 5-membered or 6-membered heterocycloalkyl.

， 或其立體異構體或醫藥學上可接受之鹽，其中p為0至7之整數；且B、W、X、R^b4 、R^b5 、R^b10 、R^b11 、R^b12 、n及t係針對式(II)定義。In some variations, the compound of formula (II) is a compound of formula (II-A):

, Or its stereoisomer or pharmaceutically acceptable salt, where p is an integer from 0 to 7; and B, W, X, R ^b4 , R ^b5 , R ^b10 , R ^b11 , R ^b12 , n and t It is defined for formula (II).

, 或其立體異構體或醫藥學上可接受之鹽，其中p為0至7之整數；u為0至5之整數；且B、X、R^b4 、R^b5 、R^b10 、R^b11 、R^b12 及n係針對式(II)定義。In other variations, the compound of formula (II) is a compound of formula (II-A-ii):

, Or its stereoisomer or pharmaceutically acceptable salt, wherein p is an integer from 0 to 7; u is an integer from 0 to 5; and B, X, R ^b4 , R ^b5 , R ^b10 , R ^b11 , R ^b12 and n are defined for formula (II).

， 或其立體異構體或醫藥學上可接受之鹽，其中p為0至7之整數；Y為 -C(R^b52 )₂ -、-S(O)_r -、-O-或-N(R^b52 )-，其中各R^b52 獨立地為氫或R^b4 ；r為0、1或2；且B、W、X、R^b4 、R^b5 、R^b10 、R^b11 、R^b12 、n及t係針對式(II)定義。In some variations, the compound of formula (II) is a compound of formula (II-B):

, Or its stereoisomer or pharmaceutically acceptable salt, where p is an integer from 0 to 7; Y is -C(R ^b52 ) ₂ -, -S(O) _r -, -O- or -N (R ^b52 )-, wherein each R ^{b52 is} independently hydrogen or R ^b4 ; r is 0, 1 or 2; and B, W, X, R ^b4 , R ^b5 , R ^b10 , R ^b11 , R ^b12 , n and t is defined for formula (II).

， 或其立體異構體或醫藥學上可接受之鹽，其中：p為0至7之整數；Y為-C(R^b52 )₂ -、-S(O)_r -、-O-或-N(R^b52 )-，其中各R^b52 獨立地為氫或R^b4 ；r為0、1或2；u為0至5之整數；且B、X、R^b4 、R^b5 、R^b10 、R^b11 、R^b12 及n係針對式(II)定義。In some variations, the compound of formula (II) is a compound of formula (II-B-ii):

, Or its stereoisomer or pharmaceutically acceptable salt, wherein: p is an integer from 0 to 7; Y is -C(R ^b52 ) ₂ -, -S(O) _r -, -O- or- N(R ^b52 )-, wherein each R ^{b52 is} independently hydrogen or R ^b4 ; r is 0, 1 or 2; u is an integer from 0 to 5; and B, X, R ^b4 , R ^b5 , R ^b10 , R ^b11 , R ^b12 and n are defined for formula (II).

In certain variations of the compound of formula (II-B) or formula (II-B-ii) or its stereoisomer or pharmaceutically acceptable salt, Y is -CH ₂ -. Compounds of formula (I), formula (II), formula (II-A), formula (II-A-ii), formula (II-B) or formula (II-B-ii) or their stereoisomers Or in some variations of pharmaceutically acceptable salts, B is 5 or 6 membered heterocycloalkyl, or 5 or 6 membered heteroaryl, wherein the heterocycloalkyl or heteroaryl contains one to three Ring heteroatoms independently selected from the group consisting of O, N and S. In other variations, B is a 9-membered or 10-membered bicyclic heteroaryl group, which contains one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In another variation, B is (C ₉ -C ₁₀ ) bicyclic aryl. In some variations, B is (C ₅ -C ₁₀ )cycloalkyl.

， 或其立體異構體或醫藥學上可接受之鹽，其中p為0至7之整數；u為0至5之整數；且X、R^b4 、R^b5 、R^b10 、R^b11 及R^b12 係針對式(II)定義。In some variations, the compound of formula (II-B) is a compound of formula (II-Ai):

, Or its stereoisomers or pharmaceutically acceptable salts, where p is an integer from 0 to 7; u is an integer from 0 to 5; and X, R ^b4 , R ^b5 , R ^b10 , R ^b11 and R ^b12 It is defined for formula (II).

， 或其立體異構體或醫藥學上可接受之鹽，其中p為0至7之整數；Y為 -C(R^b52 )₂ -、-S(O)_r -、-O-或-N(R^b52 )-，其中各R^b52 獨立地為氫或R^b4 ；r為0、1或2；u為0至5之整數；且X、R^b4 、R^b5 、R^b10 、R^b11 及R^b12 係針對式(II)定義。In some variations, the compound of formula (II-B) is a compound of formula (II-Bi):

, Or its stereoisomer or pharmaceutically acceptable salt, where p is an integer from 0 to 7; Y is -C(R ^b52 ) ₂ -, -S(O) _r -, -O- or -N (R ^b52 )-, wherein each R ^{b52 is} independently hydrogen or R ^b4 ; r is 0, 1 or 2; u is an integer from 0 to 5; and X, R ^b4 , R ^b5 , R ^b10 , R ^b11 and R ^b12 is defined for formula (II).

， 其中： R^b33 為氫、烷基、炔基、環烷基、雜環烷基、雜芳基或芳基； 其中該烷基、環烷基、雜環烷基、雜芳基或芳基未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、烷基、環烷基、芳基、雜芳基、雜環烷基、=O、-OR^b36 、-SF₅ 及-NR^b37 R^b38 ； 其中各烷基、環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：烷基、鹵烷基、炔基、鹵基、-SF₅ 、=O、-OR^b39 、-NR^b48 R^b49 、-NR^b50 C(O)R^b51 、環烷基及雜環烷基，其中各環烷基及雜環烷基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：=O、鹵基、-OH及-SF₅ ； 各R^b34 及R^b35 獨立地為氫、鹵基或烷基； 其中各烷基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、環烷基、雜環烷基、芳基、雜芳基、-OR^b40 及-NR^b41 R^b42 ； 其中各環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、鹵烷基、烷基、-OH、=O及-SF₅ ； 或連接至同一原子之一個R^b34 及一個R^b35 與其所連接之原子一起形成環烷基或雜環烷基，其中該環烷基或雜環烷基未經取代或經一或多個鹵基取代； 各R^b36 、R^b37 、R^b38 、R^b39 、R^b40 、R^b41 、R^b42 、R^b48 、R^b49 、R^b50 及R^b51 獨立地為氫、烷基或鹵烷基； 且q為1或2。In formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula ( In some variations of compounds of II-B-ii) or their stereoisomers or pharmaceutically acceptable salts, at least one R ^b5 is:

, Where: R ^b33 is hydrogen, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl Unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, =O, -OR ^b36 , -SF ₅ and -NR ^b37 R ^b38 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently unsubstituted or independently selected by one or more of the following Group substituent substitution: alkyl, haloalkyl, alkynyl, halo, -SF ₅ , =O, -OR ^b39 , -NR ^b48 R ^b49 , -NR ^b50 C(O)R ^b51 , cycloalkyl and Heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: =O, halo, -OH, and- SF ₅ ; each R ^b34 and R ^{b35 are} independently hydrogen, halo or alkyl; wherein each alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen Radical, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR ^b40 and -NR ^b41 R ^b42 ; wherein each cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently Substitution or substitution by one or more substituents independently selected from the group consisting of halo, haloalkyl, alkyl, -OH, =O, and -SF ₅ ; or one R ^b34 connected to the same atom and One R ^b35 and the atom to which it is connected form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group is unsubstituted or substituted with one or more halo groups; each R ^b36 , R ^b37 , R ^b38 , R ^b39 , R ^b40 , R ^b41 , R ^b42 , R ^b48 , R ^b49 , R ^b50 and R ^{b51 are} independently hydrogen, alkyl or haloalkyl; and q is 1 or 2.

In formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula ( In some variations of compounds of II-B-ii) or their stereoisomers or pharmaceutically acceptable salts, at least one R ^b5 is heteroaryl or heterocycloalkyl, wherein the heteroaryl or heterocycle The alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: =O, -SF ₅ and R ^b28 .

In formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula ( In some variations of the compound of II-B-ii) or its stereoisomer or pharmaceutically acceptable salt, X is -S(O) ₂ -. In other variations, X is -C(O)-. In some variations, X is -CH ₂ -. In some variations, n is 1 or 2. In other variations, m is 0. In some variations, p is 0.

In formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula ( In some variations of the compound of II-B-ii) or its stereoisomer or pharmaceutically acceptable salt, at least one R ^b12 is chlorine.

In another aspect, provided herein is a pharmaceutical composition comprising a compound of formula (I) or formula (II) or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable endowment Form agent. In some variations, the compound of formula (I) or formula (II) is formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula ( II-Bi) or the compound of formula (II-B-ii) or its stereoisomer or pharmaceutically acceptable salt.

In another aspect, provided herein is a method of reducing the content of K-Ras protein in an individual by administering a pharmaceutical composition to the individual in need, the pharmaceutical composition comprising a therapeutically effective amount of formula (I) Or a compound of formula (II) or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some variations, the compound of formula (I) or formula (II) is formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula ( II-Bi) or the compound of formula (II-B-ii) or its stereoisomer or pharmaceutically acceptable salt.

In yet another aspect, the present invention provides a method for treating a disorder in an individual by administering a pharmaceutical composition to the individual in need thereof, the pharmaceutical composition comprising a therapeutically effective amount of formula (I) or formula (II) Compounds or their stereoisomers or pharmaceutically acceptable salts, and pharmaceutically acceptable excipients. In some variations, the compound of formula (I) or formula (II) is formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula ( II-Bi) or the compound of formula (II-B-ii) or its stereoisomer or pharmaceutically acceptable salt.

In yet another aspect, provided herein is the use of a compound of formula (I) or formula (II) or a stereoisomer or pharmaceutically acceptable salt thereof for reducing K-Ras in an individual in need Manufacture and use of protein content medicines. In some variations, the compound of formula (I) or formula (II) is formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula ( II-Bi) or the compound of formula (II-B-ii) or its stereoisomer or pharmaceutically acceptable salt.

In another aspect, provided herein is the use of a compound of formula (I) or formula (II) or a stereoisomer or a pharmaceutically acceptable salt thereof, which is an agent for treating a disorder in an individual in need Manufacturing use. In some variations, the compound of formula (I) or formula (II) is formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula ( II-Bi) or the compound of formula (II-B-ii) or its stereoisomer or pharmaceutically acceptable salt.

In yet another aspect, provided herein is a compound of formula (I) or formula (II) or a stereoisomer or pharmaceutically acceptable salt thereof, which is used to reduce K-Ras protein in an individual in need Content method. In some variations, the compound of formula (I) or formula (II) is formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula ( II-Bi) or the compound of formula (II-B-ii) or its stereoisomer or pharmaceutically acceptable salt.

In yet another aspect, provided herein is a compound of formula (I) or formula (II) or a stereoisomer or pharmaceutically acceptable salt thereof, which is used in a method of treating a disorder in an individual in need . In some variations, the compound of formula (I) or formula (II) is formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula ( II-Bi) or the compound of formula (II-B-ii) or its stereoisomer or pharmaceutically acceptable salt.

In some variations of the aspects described herein, the disorder is cancer. In some embodiments, the cancer is a hematological cancer or a solid tumor. In some variations, the cancer is pancreatic cancer, lung cancer, colorectal cancer, optic nerve path glioma, rhabdomyosarcoma, neuroblastoma, juvenile myelomonocytic leukemia, malignant peripheral schwannoma, gastrointestinal stromal tumor, Somatostatin tumor, pheochromocytoma or breast cancer. In other variations of the aspects described herein, the condition is type I neurofibromatosis, Noonan syndrome, heart-face-skin syndrome, or Legius syndrome. In certain variations of the aspects described herein (such as the treatment of disorders including cancer), the disorder is associated with mutations in K-Ras.

Cross-reference of related applications

This application claims the rights and interests of US Provisional Application No. 62/659,602 filed on April 18, 2018, the disclosure of which is incorporated herein by reference in its entirety. Statement on Federally Funded Research

The present invention was carried out with government support under the contract number HHSN261200800001E awarded by the National Institutes of Health. The government has certain rights in the invention.

The following description sets forth a large number of exemplary configurations, methods, parameters and the like. However, it should be appreciated that such description is not intended as a limitation of the scope of the present invention, but is instead provided as a description of exemplary embodiments.

Provided herein is a compound, such as formula (I), (II), (II-A), (II-Ai), (II-A-ii), (II-B), (II-Bi) or (II-A The compound of B-ii) or the stereoisomer or pharmaceutically acceptable salt of any of the foregoing is as follows. In some embodiments, the compound can inhibit K-Ras, or can inhibit post-translational processing of KRAS , which produces K-Ras protein, such as K-Ras4b. For example, in some embodiments, this compound can block the farnesylation of newly synthesized K-Ras, thereby preventing its C-terminal processing. In other embodiments, the compound or its stereoisomer or pharmaceutically acceptable salt can be administered to an individual in need, for example, in the form of a pharmaceutical composition further comprising pharmaceutically acceptable excipients. In some embodiments, in a method of treating a disorder in an individual, the compound as described herein can be administered to the individual in need in a therapeutically effective amount. The disorder may be, for example, a disorder associated with KRAS mutation. The disorder may be, for example, a disorder associated with mutations in K-Ras protein. In some embodiments, the compound inhibits K-Ras, or reduces the content of K-Ras, or inhibits the post-translational processing of KRAS that produces K-Ras proteins (such as K-Ras4b). The compounds of the present invention, compositions containing the compounds, and methods of using the compounds and compositions are described in more detail below. I. Compound of formula (I)

， 或其立體異構體或醫藥學上可接受之鹽，其中： A為4員至8員雜環烷基； B為芳基、雜芳基、環烷基或雜環烷基； W為芳基或雜芳基； X為-S(O)-、-S(O)₂ -、-S(O)NR^b53 -、-C(S)-、-C(O)-或-C(R^b13 )₂ -； 各R^b13 獨立地為氫、鹵基、烷基或鹵烷基； R^b53 為氫或烷基，其中該烷基未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、環烷基、雜環烷基、芳基、雜芳基及=O； R^b1 為氫、烷基、鹵烷基、環烷基或鹵環烷基； z為0、1或2； R^b2 、R^b3 、R^b6 、R^b7 、R^b8 、R^b9 、R^b10 及R^b11 係獨立地選自由以下組成之群：氫、鹵基、烷基、鹵烷基、-NO₂ 、-CN、-OH、-NH₂ 及 -SO₂ NH₂ ，其中在R^b6 及R^b7 中之一者為烷基時，z為1； R^b2 、R^b3 、R^b6 、R^b7 、R^b8 、R^b9 、R^b10 及R^b11 係獨立地選自由以下組成之群：氫、鹵基、烷基、環烷基、雜環烷基、-CN、-NO₂ 、 -NR^b13 R^b14 、-OR^b15 、-SO₂ R^b16 及-SO₂ NH₂ ，其中各烷基、環烷基及雜環烷基係獨立地未經取代或經一或多個鹵基取代，且其中在R^b6 及R^b7 中之一者為烷基時，z為1； 各R^b4 係獨立地選自由以下組成之群：鹵基、烷基、環烷基、雜環烷基、芳基、雜芳基、-NO₂ 、-CN、-SO₂ NH₂ 、-NR^b13 R^b14 、-OR^b15 、=O、-SR^b60 及-SO₂ R^b16 ； 其中各烷基、環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、-CN、 -NH₂ 、-NH(烷基)、-COOH、-C(O)O-烷基、-CONH₂ 、-NO₂ 、-SH、-S-烷基、-SO₃ H、-SO₄ H、-SO₂ NH₂ 、-NHNH₂ 、-ONH₂ 、-NHC(O)NHNH₂ 、-NHC(O)NH₂ 、-NHSO₂ H、-NHC(O)H、-NHC(O)-烷基、-NHC(O)O-烷基、-NHC(O)OH、-NHOH、-OH、-O-烷基、-O-鹵烷基、烷基、鹵烷基、環烷基、雜環烷基、芳基及雜芳基； 各R^b13 、R^b14 、R^b15 、R^b16 及R^b60 獨立地為氫、烷基、鹵烷基、環烷基、鹵環烷基、雜環烷基或鹵雜環烷基； 或R^b2 及R^b3 一起形成=O； 或R^b6 及R^b1 與其所連接之原子一起形成雜環烷基，其未經取代或經一或多個鹵基取代； 或R^b10 及R^b1 與其所連接之原子一起形成雜環烷基，其未經取代或經一或多個鹵基取代； 或R^b8 及R^b1 與其所連接之原子一起形成雜環烷基，其未經取代或經一或多個鹵基取代； 或兩個至四個R^b2 、R^b3 、R^b6 及R^b7 與其所連接之原子一起形成雜環烷基或雜芳基，其中該雜環烷基或雜芳基係獨立地未經取代或經一或多個鹵基取代； 或R^b1 及一個R^b4 與其所連接之原子一起形成雜環烷基，其未經取代或經一或多個鹵基取代； 或兩個至四個R^b4 與其所連接之原子一起形成芳基、雜芳基、環烷基或雜環烷基，其中該芳基、雜芳基、環烷基或雜環烷基未經取代或經一或多個鹵基取代； 各R^b5 係獨立地選自由以下組成之群：鹵基、烷基、環烷基、雜環烷基、芳基、雜芳基、炔基、-NO₂ 、-CN、-SO₂ NR^b54 R^b55 、-NR^b17 R^b18 、 -OR^b19 、-SO₂ R^b20 、=O及-SR^b21 ； 其中各環烷基、芳基、雜芳基及雜環烷基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、-OR^b22 、=O、 -NR^b23 R^b24 、-CN、-SF₅ 、-SO₂ NR^b56 R^b57 、-SR^b58 、-SO₂ R^b59 及R^b28 ，其中各R^b28 獨立地為烷基、環烷基、雜環烷基、芳基或雜芳基； 各烷基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、-OR^b25 、=O、-NR^b26 R^b27 、-CN、-SF₅ 、 -SO₂ NR^b61 R^b62 、-SR^b63 、-SO₂ R^b64 及R^b65 ，其中各R^b65 獨立地為環烷基、雜環烷基、芳基或雜芳基； 各R^b17 、R^b18 、R^b19 、R^b20 、R^b21 、R^b22 、R^b23 、R^b24 、R^b25 、R^b26 、R^b27 、R^b54 、R^b55 、R^b56 、R^b57 、R^b58 、R^b59 、R^b61 、R^b62 、R^b63 及R^b64 獨立地為氫、烷基、鹵烷基、環烷基、鹵環烷基、雜環烷基、芳基、雜芳基、炔基或鹵炔基； 其中R^b17 、R^b18 、R^b19 、R^b22 、R^b23 、R^b24 、R^b25 、R^b26 、R^b27 及R^b28 之各烷基、環烷基、雜環烷基、芳基及雜芳基以及R^b65 之各環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、=O、-CN、芳基、雜芳基、烷基、炔基、環烷基、雜環烷基、-NR^b29 R^b30 、-SF₅ 及-OR^b31 ； 其中各烷基、環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：烷基、鹵烷基、炔基、鹵基、-CN、-SF₅ 、=O、-NR^b43 R^b44 、-NR^b45 C(O)R^b46 、-OR^b47 及R^b66 ，其中各R^b66 獨立地為環烷基、雜環烷基、芳基或雜芳基，且其中各R^b66 係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：=O、-NH₂ 、-SF₅ 、-OH、-O-烷基、-O-鹵烷基、鹵基、烷基及鹵烷基； 各R^b29 、R^b30 、R^b31 、R^b43 、R^b44 、R^b45 、R^b46 及R^b47 獨立地為氫、烷基或鹵烷基； 各R^b12 係獨立地選自由以下組成之群：-CN、-NH₂ 、-NH(烷基)、 -COOH、-C(O)O-烷基、-CONH₂ 、-NO₂ 、-SH、-S-烷基、-SO₃ H、 -SO₄ H、-SO₂ NH₂ 、-NHNH₂ 、-ONH₂ 、-NHC(O)NHNH₂ 、-NHC(O)NH₂ 、-NHSO₂ H、-NHC(O)H、-NHC(O)-烷基、-NHC(O)O-烷基、-NHC(O)OH、-NHOH、環烷基、雜環烷基、芳基、雜芳基、鹵基、烷基、鹵烷基及 -OR^b32 ，其中R^b32 為氫、烷基或鹵烷基； m為0至13之整數； n為0至11之整數；及 t為0至6之整數。This article provides a compound of formula (I):

, Or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: A is a 4- to 8-membered heterocycloalkyl; B is an aryl, heteroaryl, cycloalkyl or heterocycloalkyl; W is Aryl or heteroaryl; X is -S(O)-, -S(O) ₂ -, -S(O)NR ^b53 -, -C(S)-, -C(O)- or -C( R ^b13 ) ₂ -; each R ^{b13 is} independently hydrogen, halo, alkyl or haloalkyl; R ^b53 is hydrogen or alkyl, wherein the alkyl is unsubstituted or independently selected by one or more of the following Substituted by the group of substituents: halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and =O; R ^b1 is hydrogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl ; Z is 0, 1 or 2; R ^b2 , R ^b3 , R ^b6 , R ^b7 , R ^b8 , R ^b9 , R ^b10 and R ^b11 are independently selected from the group consisting of hydrogen, halo, alkyl, Haloalkyl, -NO ₂ , -CN, -OH, -NH ₂ and -SO ₂ NH ₂ , where one of R ^b6 and R ^b7 is alkyl, z is 1; R ^b2 , R ^b3 , R ^b6 , R ^b7 , R ^b8 , R ^b9 , R ^b10 and R ^b11 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -CN, -NO ₂ , -NR ^b13 R ^b14 , -OR ^b15 , -SO ₂ R ^b16 and -SO ₂ NH ₂ , where each alkyl, cycloalkyl, and heterocycloalkyl are independently unsubstituted or substituted by one or more halo groups Substitution, and where one of R ^b6 and R ^b7 is alkyl, z is 1; each R ^b4 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl , Aryl, heteroaryl, -NO ₂ , -CN, -SO ₂ NH ₂ , -NR ^b13 R ^b14 , -OR ^b15 , =O, -SR ^b60, and -SO ₂ R ^b16 ; where each alkyl, ring Alkyl, heterocycloalkyl, aryl and heteroaryl are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -CN, -NH ₂ ,- NH(alkyl), -COOH, -C(O)O-alkyl, -CONH ₂ , -NO ₂ , -SH, -S-alkyl, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(O)NHNH ₂ , -NHC(O)NH ₂ , -NHSO ₂ H, -NHC(O)H, -NHC(O)-alkyl, -NHC( O)O-alkyl, -NHC(O)OH, -NHOH, -OH, -O-alkyl, -O-haloalkyl, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aromatic Radical and heteroaryl; each R ^b13 , R ^b14 , R ^b15 , R ^b16 and R ^{b60 are} independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl or haloheterocycloalkyl; or R ^b2 and R ^b3 together form = O; or R ^b6 and R ^b1 together with the atoms to which they are attached form a heterocycloalkyl group which is unsubstituted or substituted with one or more halo groups; or R ^b10 and R ^b1 together with the atoms to which they are attached form a heterocycloalkyl Group, which is unsubstituted or substituted with one or more halo groups; or R ^b8 and R ^b1 together with the atoms to which they are attached form a heterocycloalkyl group, which is unsubstituted or substituted with one or more halo groups; or both From four to four R ^b2 , R ^b3 , R ^b6 and R ^b7 together with the atoms to which they are attached form a heterocycloalkyl or heteroaryl group, wherein the heterocycloalkyl or heteroaryl group is independently unsubstituted or Or multiple halo groups; or R ^b1 and one R ^b4 together with the atoms to which they are attached form a heterocycloalkyl group, which is unsubstituted or substituted with one or more halo groups; or two to four R ^b4 and The linked atoms together form an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl group is unsubstituted or substituted with one or more halo groups ; Each R ^b5 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO ₂ , -CN, -SO ₂ NR ^{b54 R b55, -NR b17 R b18} , -OR b19, -SO 2 R b20, = O and -SR ^b21; wherein each cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are independently unsubstituted based Or substituted by one or more substituents independently selected from the group consisting of: halo, -OR ^b22 , =O, -NR ^b23 R ^b24 , -CN, -SF ₅ , -SO ₂ NR ^b56 R ^b57 , -SR ^b58 , -SO ₂ R ^b59 and R ^b28 , wherein each R ^{b28 is} independently alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each alkyl group is independently unsubstituted or One or more substituents independently selected from the group consisting of halo, -OR ^b25 , =O, -NR ^b26 R ^b27 , -CN, ^-SF ₅ , -SO ₂ NR ^b61 R ^b62 , -SR ^b63 , -SO ₂ R ^b64 and R ^b65 , wherein each R ^{b65 is} independently cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each R ^b17 , R ^b18 , R ^b19 , R ^b20 , R ^b21 , ^{R b22, R b23, R b24} , R b25, R b26, R b27, R b54, R b55, R b56, R b57, R b58, R b59, R b61, R b62, R b63 and R ^{b6 4 is} independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl or haloalkynyl; wherein R ^b17 , R ^b18 , R ^b19 , R ^b22 , R ^b23 , R ^b24 , R ^b25 , R ^b26 , R ^b27 and R ^b28 each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and R ^b65 each cycloalkyl, Heterocycloalkyl, aryl and heteroaryl are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, =O, -CN, aryl, heteroaryl ^Radical , alkyl, alkynyl, cycloalkyl, heterocycloalkyl, -NR ^b29 R ^b30 , ^-SF ₅ and -OR ^b31 ; where each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl The radical is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SF ₅ , =O,- NR ^b43 R ^b44 , -NR ^b45 C(O)R ^b46 , -OR ^b47 and R ^b66 , wherein each R ^{b66 is} independently cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and each R ^b66 Is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: =O, -NH ₂ , -SF ₅ , -OH, -O-alkyl, -O-haloalkane ^Radical , halo, alkyl and haloalkyl; each R ^b29 , R ^b30 , R ^b31 , R ^b43 , R ^b44 , R ^b45 , R ^b46 and R ^{b47 are} independently hydrogen, alkyl or haloalkyl; each R ^b12 based independently selected from the group consisting of: -CN, -NH _2, -NH (alkyl), -COOH, -C (O) O- _{alkyl, -CONH 2, -NO 2, -SH} , - S-alkyl, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(O)NHNH ₂ , -NHC(O)NH ₂ , -NHSO ₂ H, -NHC(O)H, -NHC(O)-alkyl, -NHC(O)O-alkyl, -NHC(O)OH, -NHOH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl Radical, halo, alkyl, haloalkyl and -OR ^b32 , wherein R ^b32 is hydrogen, alkyl or haloalkyl; m is an integer from 0 to 13; n is an integer from 0 to 11; and t is from 0 to An integer of 6.

， 或其立體異構體或醫藥學上可接受之鹽，其中： A為4員至8員雜環烷基； B為芳基、雜芳基、環烷基或雜環烷基； W為芳基或雜芳基； X為-S(O)-、-S(O)₂ -、-S(O)NR^b53 -、-C(S)-、-C(O)-或-C(R^b13 )₂ -； 各R^b13 獨立地為氫、鹵基、烷基或鹵烷基； R^b53 為氫或烷基，其中該烷基未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、環烷基、雜環烷基、芳基、雜芳基及=O； R^b1 為氫、烷基、鹵烷基、環烷基或鹵環烷基； z為0或1； R^b2 、R^b3 、R^b6 、R^b7 、R^b8 、R^b9 、R^b10 及R^b11 係獨立地選自由以下組成之群：氫、鹵基、烷基、鹵烷基、-NO₂ 、-CN、-OH、-NH₂ 及 -SO₂ NH₂ ，其中在R^b6 及R^b7 中之一者為烷基時，z為1； R^b2 、R^b3 、R^b6 、R^b7 、R^b8 、R^b9 、R^b10 及R^b11 係獨立地選自由以下組成之群：氫、鹵基、烷基、環烷基、雜環烷基、-CN、-NO₂ 、-NR^b13 R^b14 、-OR^b15 、-SO₂ R^b16 及-SO₂ NH₂ ，其中各烷基、環烷基及雜環烷基係獨立地未經取代或經一或多個鹵基取代，且其中在R^b6 及R^b7 中之一者為烷基時，z為1； 各R^b4 係獨立地選自由以下組成之群：鹵基、烷基、環烷基、雜環烷基、芳基、雜芳基、-NO₂ 、-CN、-SO₂ NH₂ 、-NR^b13 R^b14 、-OR^b15 、=O、-SR^b60 及-SO₂ R^b16 ； 其中各烷基、環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、-CN、 -NH₂ 、-NH(烷基)、-COOH、-C(O)O-烷基、-CONH₂ 、-NO₂ 、-SH、-S-烷基、-SO₃ H、-SO₄ H、-SO₂ NH₂ 、-NHNH₂ 、-ONH₂ 、-NHC(O)NHNH₂ 、-NHC(O)NH₂ 、-NHSO₂ H、-NHC(O)H、-NHC(O)-烷基、-NHC(O)O-烷基、-NHC(O)OH、-NHOH、-OH、-O-烷基、-O-鹵烷基、烷基、鹵烷基、環烷基、雜環烷基、芳基及雜芳基； 各R^b13 、R^b14 、R^b15 、R^b16 及R^b60 獨立地為氫、烷基、鹵烷基、環烷基、鹵環烷基、雜環烷基或鹵雜環烷基； 或R^b2 及R^b3 一起形成=O； 或R^b6 及R^b1 與其所連接之原子一起形成雜環烷基，其未經取代或經一或多個鹵基取代； 或R^b10 及R^b1 與其所連接之原子一起形成雜環烷基，其未經取代或經一或多個鹵基取代； 或R^b8 及R^b1 與其所連接之原子一起形成雜環烷基，其未經取代或經一或多個鹵基取代； 或兩個至四個R^b2 、R^b3 、R^b6 及R^b7 與其所連接之原子一起形成雜環烷基或雜芳基，其中該雜環烷基或雜芳基係獨立地未經取代或經一或多個鹵基取代； 或R^b1 及一個R^b4 與其所連接之原子一起形成雜環烷基，其未經取代或經一或多個鹵基取代； 或兩個至四個R^b4 與其所連接之原子一起形成芳基、雜芳基、環烷基或雜環烷基，其中該芳基、雜芳基、環烷基或雜環烷基未經取代或經一或多個鹵基取代； 各R^b5 係獨立地選自由以下組成之群：鹵基、烷基、環烷基、雜環烷基、芳基、雜芳基、炔基、-NO₂ 、-CN、-SO₂ NR^b54 R^b55 、-NR^b17 R^b18 、 -OR^b19 、-SO₂ R^b20 、=O及-SR^b21 ； 其中各環烷基、芳基、雜芳基及雜環烷基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、-OR^b22 、=O、 -NR^b23 R^b24 、-CN、-SF₅ 、-SO₂ NR^b56 R^b57 、-SR^b58 、-SO₂ R^b59 及R^b28 ，其中各R^b28 獨立地為烷基、環烷基、雜環烷基、芳基或雜芳基； 各烷基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、-OR^b25 、=O、-NR^b26 R^b27 、-CN、-SF₅ 、 -SO₂ NR^b61 R^b62 、-SR^b63 、-SO₂ R^b64 及R^b65 ，其中各R^b65 獨立地為環烷基、雜環烷基、芳基或雜芳基； 各R^b17 、R^b18 、R^b19 、R^b20 、R^b21 、R^b22 、R^b23 、R^b24 、R^b25 、R^b26 、R^b27 、R^b54 、R^b55 、R^b56 、R^b57 、R^b58 、R^b59 、R^b61 、R^b62 、R^b63 及R^b64 獨立地為氫、烷基、鹵烷基、環烷基、鹵環烷基、雜環烷基、芳基、雜芳基、炔基或鹵炔基； 其中R^b17 、R^b18 、R^b19 、R^b22 、R^b23 、R^b24 、R^b25 、R^b26 、R^b27 及R^b28 之各烷基、環烷基、雜環烷基、芳基及雜芳基以及R^b65 之各環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、=O、-CN、芳基、雜芳基、烷基、炔基、環烷基、雜環烷基、-NR^b29 R^b30 、-SF₅ 及-OR^b31 ； 其中各烷基、環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：烷基、鹵烷基、炔基、鹵基、-CN、-SF₅ 、=O、-NR^b43 R^b44 、-NR^b45 C(O)R^b46 、-OR^b47 及R^b66 ，其中各R^b66 獨立地為環烷基、雜環烷基、芳基或雜芳基，且其中各R^b66 係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：=O、-NH₂ 、-SF₅ 、-OH、-O-烷基、-O-鹵烷基、鹵基、烷基及鹵烷基； 各R^b29 、R^b30 、R^b31 、R^b43 、R^b44 、R^b45 、R^b46 及R^b47 獨立地為氫、烷基或鹵烷基； 各R^b12 係獨立地選自由以下組成之群：-CN、-NH₂ 、-NH(烷基)、 -COOH、-C(O)O-烷基、-CONH₂ 、-NO₂ 、-SH、-S-烷基、-SO₃ H、-SO₄ H、-SO₂ NH₂ 、-NHNH₂ 、-ONH₂ 、-NHC(O)NHNH₂ 、-NHC(O)NH₂ 、-NHSO₂ H、-NHC(O)H、-NHC(O)-烷基、-NHC(O)O-烷基、-NHC(O)OH、-NHOH、環烷基、雜環烷基、芳基、雜芳基、鹵基、烷基、鹵烷基及-OR^b32 ，其中R^b32 為氫、烷基或鹵烷基； m為0至13之整數； n為0至11之整數；及 t為0至6之整數。In some embodiments, the compound of formula (I) is a compound of formula (II):

, Or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: A is a 4- to 8-membered heterocycloalkyl; B is an aryl, heteroaryl, cycloalkyl or heterocycloalkyl; W is Aryl or heteroaryl; X is -S(O)-, -S(O) ₂ -, -S(O)NR ^b53 -, -C(S)-, -C(O)- or -C( R ^b13 ) ₂ -; each R ^{b13 is} independently hydrogen, halo, alkyl or haloalkyl; R ^b53 is hydrogen or alkyl, wherein the alkyl is unsubstituted or independently selected by one or more of the following Substituted by the group of substituents: halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and =O; R ^b1 is hydrogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl ; Z is 0 or 1; R ^b2 , R ^b3 , R ^b6 , R ^b7 , R ^b8 , R ^b9 , R ^b10 and R ^b11 are independently selected from the group consisting of hydrogen, halo, alkyl, haloalkane Radical, -NO ₂ , -CN, -OH, -NH ₂ and -SO ₂ NH ₂ , where one of R ^b6 and R ^b7 is alkyl, z is 1; R ^b2 , R ^b3 , R ^b6 , R ^b7 , R ^b8 , R ^b9 , R ^b10 and R ^b11 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -CN, -NO ₂ ,- NR ^b13 R ^b14 , -OR ^b15 , -SO ₂ R ^b16 and -SO ₂ NH ₂ , wherein each alkyl group, cycloalkyl group and heterocycloalkyl group are independently unsubstituted or substituted with one or more halo groups, And where one of R ^b6 and R ^b7 is alkyl, z is 1; each R ^b4 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl ^Group , heteroaryl, -NO ₂ , -CN, -SO ₂ NH ₂ , -NR ^b13 R ^b14 , -OR ^b15 , =O, -SR ^b60, and -SO ₂ R ^b16 ; where each alkyl, cycloalkyl , Heterocycloalkyl, aryl and heteroaryl are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, -CN, -NH ₂ , -NH( Alkyl), -COOH, -C(O)O-alkyl, -CONH ₂ , -NO ₂ , -SH, -S-alkyl, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(O)NHNH ₂ , -NHC(O)NH ₂ , -NHSO ₂ H, -NHC(O)H, -NHC(O)-alkyl, -NHC(O) O-alkyl, -NHC(O)OH, -NHOH, -OH, -O-alkyl, -O-haloalkyl, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and Heteroaryl; each R ^b13 , R ^b14 , R ^b15 , R ^b16 and R ^{b60 are} independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl or haloheterocycloalkyl; or R ^b2 and R ^b3 together form =O; Or R ^b6 and R ^b1 together with the atoms to which they are attached form a heterocycloalkyl, which is unsubstituted or substituted with one or more halo groups; or R ^b10 and R ^b1 together with the atoms to which they are attached form a heterocycloalkyl, It is unsubstituted or substituted with one or more halo groups; or R ^b8 and R ^b1 together with the atoms to which they are attached form a heterocycloalkyl group, which is unsubstituted or substituted with one or more halo groups; or two to The four R ^b2 , R ^b3 , R ^b6 and R ^b7 together with the atoms to which they are attached form a heterocycloalkyl or heteroaryl group, wherein the heterocycloalkyl or heteroaryl group is independently unsubstituted or substituted by one or more Substituted with one halo group; or R ^b1 and one R ^b4 together with the atom to which they are attached form a heterocycloalkyl group which is unsubstituted or substituted with one or more halo groups; or two to four R ^b4 and the one to which they are connected The atoms together form an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl group is unsubstituted or substituted with one or more halo groups; R ^b5 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO ₂ , -CN, -SO ₂ NR ^b54 R ^{b55, -NR b17 R b18, -OR} b19, -SO 2 R b20, = O and -SR ^b21; wherein each cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are independently based unsubstituted or One or more substituents independently selected from the group consisting of halo, -OR ^b22 , =O, -NR ^b23 R ^b24 , -CN, -SF ₅ , -SO ₂ NR ^b56 R ^b57 , -SR ^b58 , -SO ₂ R ^b59 and R ^b28 , wherein each R ^{b28 is} independently alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each alkyl group is independently unsubstituted or Multiple substituents independently selected from the group consisting of halo, -OR ^b25 , =O, -NR ^b26 R ^b27 , -CN, ^-SF ₅ , -SO ₂ NR ^b61 R ^b62 , -SR ^b63 , -SO ₂ R ^b64 and R ^b65 , wherein each R ^{b65 is} independently cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each R ^b17 , R ^b18 , R ^b19 , R ^b20 , R ^b21 , R ^{b22 , R b23, R b24, R} b25, R b26, R b27, R b54, R b55, R b56, R b57, R b58, R b59, R b61, R b62, R b63 and R ^b64 independently Ground is hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl or haloalkynyl; where R ^b17 , R ^b18 , R ^b19 , R ^b22 , R ^b23 , R ^b24 , R ^b25 , R ^b26 , R ^b27 and R ^b28 each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and R ^b65 each cycloalkyl, heterocyclic Alkyl, aryl and heteroaryl are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, =O, -CN, aryl, heteroaryl, Alkyl, alkynyl, cycloalkyl, heterocycloalkyl, -NR ^b29 R ^b30 , ^-SF ₅ and -OR ^b31 ; where each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are Independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SF ₅ , =O, -NR ^b43 R ^b44 , -NR ^b45 C(O)R ^b46 , -OR ^b47 and R ^b66 , wherein each R ^{b66 is} independently cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and each R ^b66 is independent It is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: =O, -NH ₂ , -SF ₅ , -OH, -O-alkyl, -O-haloalkyl, ^Halo , alkyl and haloalkyl; each R ^b29 , R ^b30 , R ^b31 , R ^b43 , R ^b44 , R ^b45 , R ^b46 and R ^{b47 are} independently hydrogen, alkyl or haloalkyl; each R ^b12 is Independently selected from the group consisting of -CN, -NH ₂ , -NH(alkyl), -COOH, -C(O)O-alkyl, -CONH ₂ , -NO ₂ , -SH, -S- Alkyl, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(O)NHNH ₂ , -NHC(O)NH ₂ , -NHSO ₂ H, -NHC (O)H, -NHC(O)-alkyl, -NHC(O)O-alkyl, -NHC(O)OH, -NHOH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Halo, alkyl, haloalkyl and -OR ^b32 , where R ^b32 is hydrogen, alkyl or haloalkyl; m is an integer from 0 to 13; n is an integer from 0 to 11; and t is from 0 to 6 Integer.

In some embodiments of the compound of formula (I) or formula (II) or its stereoisomer or pharmaceutically acceptable salt, each R ^b4 is independently selected from the group consisting of halo, alkyl , Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO ₂ , -CN, -SO ₂ NH ₂ , -NR ^b13 R ^b14 , -OR ^b15 , =O, -SR ^b60 and -SO ₂ R ^b16 , wherein each alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group and heteroaryl group is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo _{, -CN, -NH 2, -CCl 3} , -CBr 3, -CF 3, -CI 3, -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2, -CHBr ₂ , -CHF ₂ , -CHI ₂ , -OH, -COOH, -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(O)NHNH ₂ , -NHC(O)NH ₂ , -NHSO ₂ H, -NHC(O)H, -NHC(O)OH, -NHC(O)-alkyl, -NHC(O)O-alkyl, -NHOH, -OCCl ₃ , -OCBr ₃ , -OCF ₃ , -OCI ₃ , -OCH ₂ Cl, -OCH ₂ Br, -OCH ₂ F, -OCH ₂ I, -OCHCl ₂ , -OCHBr ₂ , -OCHF ₂ , -OCHI ₂ , -CONH ₂ , -NO ₂ , -NH(alkyl), -C(O)O-alkyl, -O-alkyl, alkyl (such as (C ₁ -C ₈ )alkyl, (C ₁ -C ₆ )alkyl or (C ₁ -C ₄ )alkyl), cycloalkyl (such as (C ₃ -C ₈ )cycloalkyl, (C ₃ -C ₆ )cycloalkyl or (C ₅ -C ₆ ) cycloalkyl), heterocycloalkyl (such as 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (such as ( C ₆ -C ₁₀ ) aryl, (C ₁₀ ) aryl or phenyl), and heteroaryl (such as 5 to 10 member heteroaryl, 5 to 9 member heteroaryl, or 5 to 6 member Heteroaryl).

In some embodiments of the compound of formula (I) or formula (II) or its stereoisomer or pharmaceutically acceptable salt, each R ^b12 is independently selected from the group consisting of: -CN, -NH ₂ , -NH(alkyl), -COOH, -C(O)O-alkyl, -CONH ₂ , -NO ₂ , -SH, -S-alkyl, -SO ₃ H, -SO ₄ H,- SO ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(O)NHNH ₂ , -NHC(O)NH ₂ , -NHSO ₂ H, -NHC(O)H, -NHC(O)-alkyl, -NHC(O)O-alkyl, -NHC(O)OH, -NHOH, -CCl ₃ , -CBr ₃ , -CF ₃ , -CI ₃ , -CH ₂ Cl, -CH ₂ Br, -CH ₂ F _{, -CH 2 I, -CHCl 2,} -CHBr 2, -CHF 2, -CHI 2, -OCCl 3, -OCBr 3, -OCF 3, -OCI 3, -OCH 2 Cl, -OCH 2 Br, -OCH ₂ F, -OCH ₂ I, -OCHCl ₂ , -OCHBr ₂ , -OCHF ₂ , -OCHI ₂ , -CONH ₂ , halo, -O-alkyl, -OH, alkyl (such as (C ₁ -C ₈ ) Alkyl, (C ₁ -C ₆ )alkyl or (C ₁ -C ₄ )alkyl), cycloalkyl (such as (C ₃ -C ₈ )cycloalkyl, (C ₃ -C ₆ )cycloalkane Group or (C ₅ -C ₆ )cycloalkyl), heterocycloalkyl (such as 3 member to 8 member heterocycloalkyl, 3 member to 6 member heterocycloalkyl, or 5 member to 6 member heterocycloalkyl ), aryl (such as (C ₆ -C ₁₀ ) aryl, (C ₁₀ ) aryl or phenyl), and heteroaryl (such as 5 to 10 member heteroaryl, 5 to 9 member heteroaryl , Or 5 to 6 member heteroaryl).

， 或其立體異構體或醫藥學上可接受之鹽： A為4員至8員雜環烷基； B為芳基、雜芳基、環烷基或雜環烷基； W為芳基或雜芳基； X為-S(O)-、-S(O)₂ -、-S(O)NR^b53 -、-C(S)-、-C(O)-或-C(R^b13 )₂ -； 各R^b13 獨立地為氫、鹵基、烷基或鹵烷基； R^b53 為氫或烷基，其中該烷基未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、環烷基、雜環烷基、芳基、雜芳基及=O； R^b1 為氫、烷基、鹵烷基、環烷基或鹵環烷基； z為0或1； R^b2 、R^b3 、R^b6 、R^b7 、R^b8 、R^b9 、R^b10 及R^b11 係獨立地選自由以下組成之群：氫、鹵基、烷基、環烷基、雜環烷基、-CN、-NO₂ 、 -NR^b13 R^b14 、-OR^b15 、-SO₂ R^b16 及-SO₂ NH₂ ，其中各烷基、環烷基及雜環烷基係獨立地未經取代或經一或多個鹵基取代，且其中在R^b6 及R^b7 中之一者為烷基時，z為1； 各R^b4 獨立地選自由以下組成之群：鹵基、烷基、環烷基、雜環烷基、雜芳基、芳基、-NO₂ 、-CN、-SO₂ NH₂ 、-NR^b13 R^b14 、-OR^b15 、=O、-SR^b60 及-SO₂ R^b16 ，其中各烷基、環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個鹵基取代； 各R^b13 、R^b14 、R^b15 、R^b16 及R^b60 獨立地為氫、烷基、鹵烷基、環烷基、鹵環烷基、雜環烷基或鹵雜環烷基； 或R^b2 及R^b3 一起形成=O； 或R^b6 及R^b1 與其所連接之原子一起形成雜環烷基，其未經取代或經一或多個鹵基取代； 或R^b10 及R^b1 與其所連接之原子一起形成雜環烷基，其未經取代或經一或多個鹵基取代； 或R^b8 及R^b1 與其所連接之原子一起形成雜環烷基，其未經取代或經一或多個鹵基取代； 或兩個至四個R^b2 、R^b3 、R^b6 及R^b7 與其所連接之原子一起形成雜環烷基或雜芳基，其中該雜環烷基或雜芳基未經取代或經一或多個鹵基取代； 或R^b1 及一個R^b4 與其所連接之原子一起形成雜環烷基，其未經取代或經一或多個鹵基取代； 或兩個至四個R^b4 與其所連接之原子一起形成芳基、雜芳基、環烷基或雜環烷基，其中該芳基、雜芳基、環烷基或雜環烷基未經取代或經一或多個鹵基取代； 各R^b5 係獨立地選自由以下組成之群：鹵基、烷基、環烷基、雜環烷基、芳基、雜芳基、炔基、-NO₂ 、-CN、-SO₂ NR^b54 R^b55 、-NR^b17 R^b18 、 -OR^b19 、-SO₂ R^b20 、=O及-SR^b21 ； 其中各環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、-OR^b22 、=O、 -NR^b23 R^b24 、-CN、-SF₅ 、-SO₂ NR^b56 R^b57 、-SR^b58 、-SO₂ R^b59 及R^b28 ，其中各R^b28 獨立地為烷基、環烷基、雜環烷基、芳基或雜芳基； 各烷基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、-OR^b25 、=O、-NR^b26 R^b27 、-CN、-SF₅ 、 -SO₂ NR^b61 R^b62 、-SR^b63 、-SO₂ R^b64 及R^b65 ，其中各R^b65 獨立地為環烷基、雜環烷基、芳基或雜芳基； 各R^b17 、R^b18 、R^b19 、R^b20 、R^b21 、R^b22 、R^b23 、R^b24 、R^b25 、R^b26 、R^b27 、R^b54 、R^b55 、R^b56 、R^b57 、R^b58 、R^b59 、R^b61 、R^b62 、R^b63 及R^b64 獨立地為氫、烷基、鹵烷基、環烷基、鹵環烷基、雜環烷基、芳基、雜芳基、炔基或鹵炔基； 其中R^b17 、R^b18 、R^b19 、R^b22 、R^b23 、R^b24 、R^b25 、R^b26 、R^b27 及R^b28 之各烷基、環烷基、雜環烷基、芳基及雜芳基以及R^b65 之各環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、=O、-CN、芳基、雜芳基、烷基、炔基、環烷基、雜環烷基、-NR^b29 R^b30 、-SF₅ 及-OR^b31 ； 其中各芳基、雜芳基、烷基、環烷基及雜環烷基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：烷基、鹵烷基、炔基、鹵基、-CN、-SF₅ 、=O、-NR^b43 R^b44 、-NR^b45 C(O)R^b46 、-OR^b47 及R^b66 ，其中各R^b66 獨立地為環烷基、雜環烷基、芳基或雜芳基，且其中各R^b66 係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：=O、-NH₂ 、-SF₅ 、-OH、-O-烷基、-O-鹵烷基、鹵基、烷基及鹵烷基； 各R^b29 、R^b30 、R^b31 、R^b43 、R^b44 、R^b45 、R^b46 及R^b47 獨立地為氫、烷基或鹵烷基； 各R^b12 係獨立地選自由以下組成之群：鹵基、烷基、鹵烷基及 -OR^b32 ，其中R^b32 為氫、烷基或鹵烷基； m為0至13之整數； n為0至11之整數；及 t為0至6之整數。In some embodiments of the compound of formula (II):

, Or its stereoisomer or pharmaceutically acceptable salt: A is a 4- to 8-membered heterocycloalkyl; B is an aryl, heteroaryl, cycloalkyl or heterocycloalkyl; W is an aryl Or heteroaryl; X is -S(O)-, -S(O) ₂ -, -S(O)NR ^b53 -, -C(S)-, -C(O)- or -C(R ^b13 ) ₂ -; each R ^{b13 is} independently hydrogen, halo, alkyl or haloalkyl; R ^b53 is hydrogen or alkyl, wherein the alkyl is unsubstituted or independently selected from the group consisting of one or more Substituent group substitution: halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and =O; R ^b1 is hydrogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; z Is 0 or 1; R ^b2 , R ^b3 , R ^b6 , R ^b7 , R ^b8 , R ^b9 , R ^b10 and R ^b11 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, Heterocycloalkyl, -CN, -NO ₂ , -NR ^b13 R ^b14 , -OR ^b15 , -SO ₂ R ^b16 and -SO ₂ NH ₂ , where each alkyl, cycloalkyl, and heterocycloalkyl are independently When unsubstituted or substituted with one or more halo groups, and wherein one of R ^b6 and R ^b7 is alkyl, z is 1; each R ^{b4 is} independently selected from the group consisting of halo, alkyl Group, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, -NO ₂ , -CN, -SO ₂ NH ₂ , -NR ^b13 R ^b14 , -OR ^b15 , =O, -SR ^b60 and -SO ₂ R ^b16 , wherein each alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group and heteroaryl group are independently unsubstituted or substituted with one or more halo groups; each R ^b13 , R ^b14 , R ^b15 , R ^b16 and R ^{b60 are} independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl or haloheterocycloalkyl; or R ^b2 and R ^b3 together form =O; or R ^b6 and R ^b1 together with the atoms to which they are attached form a heterocycloalkyl, which is unsubstituted or substituted with one or more halo groups; or R ^b10 and R ^b1 together with the atoms to which they are attached form a heterocycloalkyl, which does not Substituted or substituted with one or more halo groups; or R ^b8 and R ^b1 together with the atoms to which they are attached form a heterocycloalkyl group which is unsubstituted or substituted with one or more halo groups; or two to four R ^b2 , R ^b3 , R ^b6 and R ^b7 together with the atoms to which they are attached form a heterocycloalkyl or heteroaryl group, wherein the heterocycloalkyl or heteroaryl group is unsubstituted or substituted with one or more halo groups; Or R ^b1 and one R ^b4 together with the atoms to which they are attached form a heterocycloalkyl group which is unsubstituted or substituted with one or more halo groups; or two to four R ^b4 together with the atoms to which they are attached form an aryl group , Heteroaryl, cycloalkyl or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl is unsubstituted or Or substituted with multiple halo groups; each R ^b5 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO ₂ ,- ^{_{CN, -SO 2 NR b54 R b55}} , -NR b17 R b18, -OR b19, -SO 2 R b20, = O and -SR ^b21; wherein each cycloalkyl, heterocycloalkyl, aryl and heteroaryl Is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, -OR ^b22 , =O, -NR ^b23 R ^b24 , -CN, -SF ₅ , -SO ₂ NR ^b56 R ^b57 , -SR ^b58 , -SO ₂ R ^b59 and R ^b28 , where each R ^{b28 is} independently alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each alkyl group is independent It is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -OR ^b25 , =O, -NR ^b26 R ^b27 , -CN, ^-SF ₅ , -SO ₂ NR ^b61 R ^b62 , -SR ^b63 , -SO ₂ R ^b64 and R ^b65 , where each R ^{b65 is} independently cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each R ^b17 , R ^b18 , R ^b19 , ^{R b20, R b21, R b22} , R b23, R b24, R b25, R b26, R b27, R b54, R b55, R b56, R b57, R b58, R b59, R b61, R b62, R b63 And R ^{b64 is} independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl or haloalkynyl; wherein R ^b17 , R ^b18 , R ^b19, each alkyl ^{R b22, R b23, R b24} , R b25, R b26, R b27 and R ^b28, the cycloalkyl, heterocycloalkyl, aryl and heteroaryl and cycloalkyl each of R ^b65 The radicals, heterocycloalkyl, aryl and heteroaryl are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, =O, -CN, aryl, Heteroaryl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, -NR ^b29 R ^b30 , ^-SF ₅ and -OR ^b31 ; where each aryl, heteroaryl, alkyl, cycloalkyl and hetero Cycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SF ₅ , =O , -NR ^b43 R ^b44 , -NR ^b45 C(O)R ^b46 , -OR ^b47 and R ^b66 , where each R ^{b66 is} independently Is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and wherein each R ^b66 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: =O, -NH ₂ , -SF ₅ , -OH, -O-alkyl, -O-haloalkyl, halo, alkyl and haloalkyl; each R ^b29 , R ^b30 , R ^b31 , R ^b43 , R ^b44 , R ^b45 , R ^b46 and R ^{b47 are} independently hydrogen, alkyl or haloalkyl; each R ^b12 is independently selected from the group consisting of halo, alkyl, haloalkyl and -OR ^b32 , where R ^b32 Is hydrogen, alkyl or haloalkyl; m is an integer from 0 to 13; n is an integer from 0 to 11; and t is an integer from 0 to 6.

， 或其立體異構體或醫藥學上可接受之鹽： A為4員至8員雜環烷基； B為芳基、雜芳基、環烷基或雜環烷基； W為芳基或雜芳基； X為-S(O)-、-S(O)₂ -、-S(O)NR^b53 -、-C(S)-、-C(O)-或-C(R^b13 )₂ -； 各R^b13 獨立地為氫、鹵基、烷基或鹵烷基； R^b53 為氫或烷基，其中該烷基未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、環烷基、雜環烷基、芳基、雜芳基及=O； R^b1 為氫、烷基或環烷基； z為0或1； R^b2 、R^b3 、R^b6 、R^b7 、R^b8 、R^b9 、R^b10 及R^b11 係獨立地選自由以下組成之群：氫、鹵基、烷基、鹵烷基、-CN、-OH、-NO₂ 、-NH₂ 及 -SO₂ NH₂ ，其中在R^b6 及R^b7 中之一者為烷基時，z為1； 各R^b4 係獨立地選自由以下組成之群：鹵基、烷基、環烷基、雜環烷基、芳基、雜芳基、-NO₂ 、-CN、-SO₂ NH₂ 、-NR^b13 R^b14 、-OR^b15 、=O、-SR^b60 及-SO₂ R^b16 ； 其中各烷基、環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個鹵基取代；及 各R^b13 、R^b14 、R^b15 、R^b16 及R^b60 獨立地為氫、烷基、鹵烷基、環烷基或鹵環烷基； 或R^b2 及R^b3 一起形成=O； 或R^b6 及R^b1 與其所連接之原子一起形成雜環烷基 或R^b10 及R^b1 與其所連接之原子一起形成雜環烷基； 或R^b8 及R^b1 與其所連接之原子一起形成雜環烷基； 或兩個至四個R^b2 、R^b3 、R^b6 及R^b7 與其所連接之原子一起形成雜環烷基或雜芳基； 或R^b1 及一個R^b4 與其所連接之原子一起形成雜環烷基； 或兩個至四個R^b4 與其所連接之原子一起形成芳基、雜芳基、環烷基或雜環烷基； 各R^b5 係獨立地選自由以下組成之群：鹵基、烷基、環烷基、雜環烷基、芳基、雜芳基、炔基、-NO₂ 、-CN、-SO₂ NR^b54 R^b55 、-NR^b17 R^b18 、 -OR^b19 、-SO₂ R^b20 、=O及-SR^b21 ； 其中各環烷基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、-OR^b22 、=O、-NR^b23 R^b24 、-CN、-SF₅ 、 -SO₂ NR^b56 R^b57 、-SR^b58 、-SO₂ R^b59 及R^b28 ，其中各R^b28 獨立地為烷基、環烷基、雜環烷基、芳基或雜芳基； 各芳基、雜芳基及雜環烷基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、=O、-SF₅ 及R^b28 ，其中各R^b28 獨立地為烷基、環烷基、雜環烷基、芳基或雜芳基； 各烷基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、-OR^b25 、=O、-NR^b26 R^b27 、-CN、-SF₅ 、 -SO₂ NR^b61 R^b62 、-SR^b63 、-SO₂ R^b64 及R^b65 ，其中各R^b65 獨立地為環烷基、雜環烷基、芳基或雜芳基； 各R^b20 、R^b21 、R^b22 、R^b23 、R^b24 、R^b54 、R^b55 、R^b56 、R^b57 、R^b58 、R^b59 、R^b61 、R^b62 、R^b63 及R^b64 獨立地為氫、烷基、鹵烷基、環烷基或鹵環烷基； 各R^b17 、R^b18 、R^b25 、R^b26 及R^b27 獨立地為氫、烷基、環烷基、雜環烷基、芳基或雜芳基； 各R^b19 獨立地為氫、烷基、環烷基、雜環烷基、芳基、雜芳基或炔基； 其中R^b17 、R^b18 、R^b19 、R^b25 、R^b26 、R^b27 及R^b28 之各烷基、環烷基、雜環烷基、芳基及雜芳基以及R^b65 之各環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、=O、-CN、芳基、雜芳基、烷基、炔基、環烷基、雜環烷基、-NR^b29 R^b30 、-SF₅ 及-OR^b31 ； 其中各烷基、環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：烷基、鹵烷基、炔基、鹵基、-CN、-SF₅ 、=O、-NR^b43 R^b44 、-NR^b45 C(O)R^b46 、-OR^b47 及R^b66 ，其中各R^b66 獨立地為環烷基、雜環烷基、芳基或雜芳基，且其中各R^b66 係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：=O、-NH₂ 、-SF₅ 、-OH、-O-烷基、-O-鹵烷基、鹵基、烷基及鹵烷基； 各R^b29 、R^b30 、R^b31 、R^b43 、R^b44 、R^b45 、R^b46 及R^b47 獨立地為氫、烷基或鹵烷基； 各R^b12 係獨立地選自由以下組成之群：鹵基、烷基、鹵烷基及 -OR^b32 ，其中R^b32 為氫、烷基或鹵烷基； m為0至13之整數； n為0至11之整數；及 t為0至6之整數。In certain embodiments of the compound of formula (II):

, Or its stereoisomer or pharmaceutically acceptable salt: A is a 4- to 8-membered heterocycloalkyl; B is an aryl, heteroaryl, cycloalkyl or heterocycloalkyl; W is an aryl Or heteroaryl; X is -S(O)-, -S(O) ₂ -, -S(O)NR ^b53 -, -C(S)-, -C(O)- or -C(R ^b13 ) ₂ -; each R ^{b13 is} independently hydrogen, halo, alkyl or haloalkyl; R ^b53 is hydrogen or alkyl, wherein the alkyl is unsubstituted or independently selected from the group consisting of one or more Substituent group substitution: halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and =O; R ^b1 is hydrogen, alkyl or cycloalkyl; z is 0 or 1; R ^b2 , R ^b3 , R ^b6 , R ^b7 , R ^b8 , R ^b9 , R ^b10 and R ^b11 are independently selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, -CN, -OH, -NO ₂ , -NH ₂ and -SO ₂ NH ₂ , where when one of R ^b6 and R ^b7 is alkyl, z is 1; each R ^b4 is independently selected from the group consisting of halo, alkyl, Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO ₂ , -CN, -SO ₂ NH ₂ , -NR ^b13 R ^b14 , -OR ^b15 , =O, -SR ^b60, and -SO ₂ R ^b16 ; wherein each alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group and heteroaryl group are independently unsubstituted or substituted with one or more halo groups; and each R ^b13 , R ^b14 , R ^b15 , R ^b16 and R ^{b60 are} independently hydrogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; or R ^b2 and R ^b3 together form =O; or R ^b6 and R ^b1 together with the atoms to which they are connected form a hetero Cycloalkyl or R ^b10 and R ^b1 together with the atoms to which they are attached form a heterocycloalkyl; or R ^b8 and R ^b1 together with the atoms to which they are attached form a heterocycloalkyl; or two to four R ^b2 and R ^b3 , R ^b6 and R ^b7 together with the atoms to which they are attached form heterocycloalkyl or heteroaryl; or R ^b1 and one R ^b4 together with the atoms to which they are attached form heterocycloalkyl; or two to four R ^b4 and The connected atoms together form aryl, heteroaryl, cycloalkyl or heterocycloalkyl; each R ^b5 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, an aryl group, a heteroaryl group, an alkynyl _{group, -NO 2, -CN, -SO 2} NR b54 R b55, -NR b17 R b18, -OR b19, -SO 2 R b20, = O and -SR ^b21; wherein each Cycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, -OR ^b22 , =O, -NR ^b23 R ^b24 , -CN,- SF ₅ , -SO ₂ NR ^b56 R ^b57 , -SR ^b58 , -SO ₂ R ^b59 and R ^b28 , where each R ^{b28 is} independently alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; Each aryl, heteroaryl and heterocycloalkyl group is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, =O, -SF ₅ and R ^b28 , Wherein each R ^{b28 is} independently alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each alkyl group is independently unsubstituted or independently selected by one or more groups from the group consisting of Substituent substitutions: halogen, -OR ^b25 , =O, -NR ^b26 R ^b27 , -CN, ^-SF ₅ , -SO ₂ NR ^b61 R ^b62 , -SR ^b63 , -SO ₂ R ^b64 and R ^b65 , each of which R ^b65 independently is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each ^{R b20, R b21, R b22} , R b23, R b24, R b54, R b55, R b56, R b57, R ^{b58, R b59, R b61,} R b62, R b63 and R ^b64 are independently hydrogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl group; each ^{R b17, R b18, R b25} , R b26 and R ^{b27 is} independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each R ^{b19 is} independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, hetero an aryl group or alkynyl; wherein each alkyl ^{R b17, R b18, R b19} , R b25, R b26, R b27 and R ^b28, the cycloalkyl, heterocycloalkyl, aryl and heteroaryl and R ^b65 Each cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, =O, -CN , Aryl, heteroaryl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, -NR ^b29 R ^b30 , ^-SF ₅ and -OR ^b31 ; where each alkyl, cycloalkyl, heterocycloalkyl , Aryl and heteroaryl are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SF ₅ , =O, -NR ^b43 R ^b44 , -NR ^b45 C(O)R ^b46 , -OR ^b47 and R ^b66 , where each R ^{b66 is} independently cycloalkyl, heterocycloalkyl, aryl or heteroaryl , And wherein each R ^b66 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: =O, -NH ₂ , -SF ₅ , -OH, -O-alkyl , -O-haloalkyl, halo, alkyl and haloalkyl; each R ^b29 , R ^b30 , R ^b31 , R ^b43 , R ^b44 , R ^b45 , R ^b46 and R ^{b47 are} independently hydrogen, alkyl or haloalkyl; each R ^b12 is independently selected from the group consisting of halo, alkyl, Haloalkyl and -OR ^b32 , where R ^b32 is hydrogen, alkyl or haloalkyl; m is an integer from 0 to 13; n is an integer from 0 to 11; and t is an integer from 0 to 6.

In certain embodiments of the compound of formula (I) or formula (II) or its stereoisomer or pharmaceutically acceptable salt, A is a 4-membered, 5-membered, 6-membered, or 7-membered heterocycloalkyl . In some embodiments, A is 5, 6 or 7 membered heterocycloalkyl. In some embodiments, A is a 5-, 6-, or 7-membered heterocycloalkyl, which contains one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In some embodiments, A is 5- or 6-membered heterocycloalkyl. In certain embodiments, A is a 5- or 6-membered heterocycloalkyl, which contains one to three ring heteroatoms independently selected from the group consisting of O, N, and S. For example, in some embodiments, A is pyrrolidinyl, thiazolidinyl, oxazolidinyl, imidazolidinyl, piperidinyl, thiomorpholinyl, morpholinyl, or piperazinyl. In some embodiments, A is piperidinyl. In other embodiments, A is pyrrolidinyl. In some embodiments, A is a 4-membered heterocycloalkyl.

為

，且m為0至12之整數。在其他實施例中，

為

，且m為0至12之整數。In some embodiments of the compound of formula (I) or formula (II) or its stereoisomer or pharmaceutically acceptable salt,

for

, And m is an integer from 0 to 12. In other embodiments,

for

, And m is an integer from 0 to 12.

In some embodiments of the compound of formula (I) or formula (II) or its stereoisomer or pharmaceutically acceptable salt, R ^b1 is hydrogen, alkyl, haloalkyl, cycloalkyl or halo ring alkyl. In some embodiments, R ^b1 is hydrogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₃ -C ₆ )cycloalkyl, or (C ₃ -C ₆ ) Halocycloalkyl. In certain embodiments, R ^b1 is hydrogen, (C ₁ -C ₆ )alkyl, or (C ₃ -C ₆ )cycloalkyl. In some embodiments, R ^b1 is hydrogen. In other embodiments, R ^b1 is (C ₁ -C ₆ )alkyl. For example, in some embodiments, R ^b1 is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In other embodiments, R ^b1 is (C ₃ -C ₆ )cycloalkyl. For example, in some embodiments, R ^b1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In some embodiments of the compound of formula (I) or formula (II) or its stereoisomer or pharmaceutically acceptable salt, R ^b2 , R ^b3 , R ^b6 , R ^b7 , R ^b8 , R ^b9 , R ^b10 and R ^b11 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -CN, -NO ₂ , -NR ^b13 R ^b14 , -OR ^b15 ,- SO ₂ R ^b16 and -SO ₂ NH ₂ ; wherein each alkyl group, cycloalkyl group and heterocycloalkyl group are independently unsubstituted or substituted with one or more halo groups, and wherein among R ^b6 and R ^b7 When one is alkyl, z is 1. In some embodiments, when one of R ^b6 and R ^b7 is alkyl or haloalkyl, z is 1. In certain embodiments, when one or both of R ^b6 and R ^b7 are independently alkyl or haloalkyl, z is 1. In some embodiments, when R ^b6 and R ^b7 are independently alkyl, z is 0 or 1. In certain embodiments, when both R ^b6 and R ^b7 are independently alkyl or haloalkyl, z is 0 or 1. In some embodiments, each R ^b13 , R ^b14 , R ^b15 and R ^{b16 is} independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl or haloheterocycloalkyl. In certain embodiments, each R ^b13 , R ^b14 , R ^b15 and R ^{b16 is} independently hydrogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl. In certain embodiments, each R ^b13 , R ^b14 , R ^b15 and R ^{b16 is} independently hydrogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₃ -C ₆ ) Cycloalkyl, (C ₃ -C ₆ )halocycloalkyl, 3- to 8-membered heterocycloalkyl, or 3- to 8-membered heterocycloalkyl. In some embodiments, each R ^b13 , R ^b14 , R ^b15 and R ^{b16 is} independently hydrogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₃ -C ₆ ) Cycloalkyl and (C ₃ -C ₆ )halocycloalkyl.

In some embodiments, R ^b2 , R ^b3 , R ^b6 , R ^b7 , R ^b8 , R ^b9 , R ^b10 and R ^b11 are independently selected from the group consisting of hydrogen, halo, alkyl, haloalkyl , -NO ₂ , -CN, -OH, -NH ₂ and -SO ₂ NH ₂ , wherein when one of R ^b6 and R ^b7 is alkyl, z is 1; or R ^b2 and R ^b3 together form = O. In some embodiments, R ^b2 , R ^b3 , R ^b6 , R ^b7 , R ^b8 , R ^b9 , R ^b10 and R ^b11 are independently selected from the group consisting of hydrogen, halo, (C ₁ -C ₆ ) Alkyl, (C ₁ -C ₆ ) haloalkyl, -NO ₂ , -CN, -OH, -NH ₂ and -SO ₂ NH ₂ , where one of R ^b6 and R ^b7 is alkyl , Z is 1; or R ^b2 and R ^b3 together form =O. In certain embodiments, R ^b2 , R ^b3 , R ^b6 , R ^b7 , R ^b8 , R ^b9 , R ^b10 and R ^b11 are independently selected from the group consisting of hydrogen, chlorine, fluorine, (C _1- C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl and -OH, wherein when one of R ^b6 and R ^b7 is alkyl, z is 1; or R ^b2 and R ^b3 together form =O . In certain embodiments of formula (I) or formula (II) or stereoisomers or pharmaceutically acceptable salts thereof, R ^b2 and R ^b3 together form =O, and R ^b6 , R ^b7 , R ^b8 , R ^b9 , R ^b10 and R ^b11 are independently selected from the group consisting of hydrogen, halo, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, -NO ₂ ,- CN, -OH, -NH ₂ and -SO ₂ NH ₂ , wherein when one of R ^b6 and R ^b7 is an alkyl group, z is 1. In certain embodiments, R ^b2 and R ^b3 together form =O, and R ^b6 , R ^b7 , R ^b8 , R ^b9 , R ^b10 and R ^b11 are independently selected from the group consisting of hydrogen, chlorine, fluorine , (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, and -OH, wherein when one of R ^b6 and R ^b7 is an alkyl group, z is 1. In another embodiment, R ^b2 and R ^b3 together form =O; R ^b6 , R ^b7 , R ^b8 and R ^b9 are each hydrogen; and R ^b10 and R ^b11 are independently selected from the group consisting of: hydrogen, Halo, alkyl, haloalkyl, -NO ₂ , -CN, -OH, -NH ₂ and -SO ₂ NH ₂ . In certain embodiments, R ^b2 and R ^b3 together form =O; R ^b6 , R ^b7 , R ^b8 and R ^b9 are each hydrogen; and R ^b10 and R ^b11 are independently selected from the group consisting of: hydrogen, Halo, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, -NO ₂ , -CN, -OH, -NH ₂ and -SO ₂ NH ₂ . In some embodiments, R ^b2 and R ^b3 together form =O; R ^b6 , R ^b7 , R ^b8 and R ^b9 are each hydrogen; and R ^b10 and R ^b11 are independently selected from the group consisting of hydrogen, fluorine , Chlorine, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl and -OH. In some embodiments, one of R ^b10 and R ^b11 is hydrogen. In some embodiments, both R ^b10 and R ^b11 are hydrogen. In some embodiments, both R ^b6 and R ^b7 are alkyl groups, and z is 0 or 1. In some embodiments, R ^b6 and R ^{b7 are} independently alkyl or haloalkyl, and z is 0 or 1.

為

。In some embodiments of the compound of formula (I) or formula (II) or its stereoisomer or pharmaceutically acceptable salt, R ^b6 and R ^b1 together with the atom to which they are attached form a heterocycloalkyl group, wherein The heterocycloalkyl group is unsubstituted or substituted with one or more halo groups. In certain embodiments, R ^b6 and R ^b1 together with the atoms to which they are attached form a 3- to 6-membered heterocycloalkyl group, wherein the heterocycloalkyl group is unsubstituted or substituted with one or more halo groups. In some embodiments, the heterocycloalkyl group is unsubstituted. For example, in some embodiments,

for

.

In some embodiments of the compound of formula (I) or formula (II) or its stereoisomer or pharmaceutically acceptable salt, R ^b10 and R ^b1 together with the atom to which they are attached form a heterocycloalkyl group, wherein The heterocycloalkyl group is unsubstituted or substituted with one or more halo groups. In certain embodiments, R ^b10 and R ^b1 together with the atoms to which they are attached form 3 to 10 membered heterocycloalkyl, or 3 to 8 membered heterocycloalkyl, or 3 to 6 membered heterocycloalkyl , Or a 4- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more halo groups. In some embodiments, the heterocycloalkyl group is unsubstituted.

In some embodiments of the compound of formula (I) or formula (II) or its stereoisomer or pharmaceutically acceptable salt, R ^b8 and R ^b1 together with the atom to which they are attached form a heterocycloalkyl group, wherein The heterocycloalkyl group is unsubstituted or substituted with one or more halo groups. In certain embodiments, R ^b8 and R ^b1 together with the atoms to which they are attached form 3 to 10 membered heterocycloalkyl, or 3 to 8 membered heterocycloalkyl, or 3 to 6 membered heterocycloalkyl , Or a 4- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more halo groups. In some embodiments, the heterocycloalkyl group is unsubstituted.

In some embodiments of the compound of formula (I) or formula (II) or its stereoisomer or pharmaceutically acceptable salt, two to four of R ^b2 , R ^b3 , R ^b6 and R ^b7 Together with the atoms to which it is attached, a heterocycloalkyl or heteroaryl group is formed, wherein the heterocycloalkyl or heteroaryl group is unsubstituted or substituted with one or more halo groups. In some embodiments, two to four of R ^b2 , R ^b3 , R ^b6 and R ^b7 together with the atoms to which they are attached form a 3-membered to 10-membered heterocycloalkyl, or 3-membered to 8-membered heterocycloalkane Group, or a 3-membered to 6-membered heterocycloalkyl group, or a 4-membered to 6-membered heterocycloalkyl group, wherein the heterocycloalkyl group is unsubstituted or substituted with one or more halo groups. In some embodiments, the heterocycloalkyl group is unsubstituted. In certain embodiments, two to four of R ^b2 , R ^b3 , R ^b6 and R ^b7 together with the atoms to which they are attached form a 5 to 10 membered heteroaryl group, or 5 to 8 membered heteroaryl group , Or a 5- to 6-membered heteroaryl group, wherein the heteroaryl group is unsubstituted or substituted with one or more halo groups. In some embodiments, the heteroaryl group is unsubstituted. ^Two or three of R ^b2 , R ^b3 , R ^b6 and R ^b7 together with the atoms to which they are attached form a heterocycloalkyl or heteroaryl group (wherein the heterocycloalkyl or heteroaryl group is unsubstituted or When one or more halo groups are substituted), the remaining one or two of R ^b2 , R ^b3 , R ^b6 and R ^b7 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, Heterocycloalkyl, -CN, -NO ₂ , -NR ^b13 R ^b14 , -OR ^b15 , -SO ₂ R ^b16, and -SO ₂ NH ₂ ; wherein each alkyl, cycloalkyl, and heterocycloalkyl are independently When unsubstituted or substituted by one or more halo groups, and wherein one of R ^b6 and R ^b7 is an alkyl group, z is 1.

As used herein, "alkyl" refers to an unbranched or branched saturated hydrocarbon chain. In some embodiments, an alkyl group as used herein has 1 to 50 carbon atoms ((C ₁ -C ₅₀ )alkyl), 1 to 20 carbon atoms ((C ₁ -C ₂₀ )alkyl), 1 to 12 carbon atoms ((C ₁ -C ₁₂ )alkyl), 1 to 8 carbon atoms ((C ₁ -C ₈ )alkyl), 1 to 6 carbon atoms ((C ₁ -C ₆ ) Alkyl), or 1 to 4 carbon atoms ((C ₁ -C ₄ )alkyl). Examples of alkyl groups may include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, second butyl, third butyl, n-pentyl, 2-pentyl, isopentyl, neopentyl Group, n-hexyl group, 2-hexyl group, 3-hexyl group, and 3-methylpentyl group. When naming alkyl residues with a specific carbon number, all geometric isomers with that carbon number can be covered. Thus, for example, "butyl" may include n-butyl, second butyl, isobutyl, and third butyl, and "propyl" may include n-propyl and isopropyl.

As used herein, "haloalkyl" refers to an alkyl group substituted with one or more independently selectable halo groups. Thus, haloalkyl includes alkyl substituted with one or more halo groups independently selected from the group consisting of fluorine, chlorine, iodine, and bromine. Haloalkyl groups may include, for example, -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ Cl, -CHCl ₂ , -CCl ₃ , -CH ₂ CHFCl, -CHFCH ₃ , -CH ₂ Br, and -CH ₂ CHFCH ₂ CH ₂ Br.

"Alkenyl" as used herein refers to an unbranched or branched hydrocarbon chain containing at least one carbon-carbon double bond. In some embodiments, an alkenyl group as used herein has 2 to 50 carbon atoms ((C ₂ -C ₅₀ ) alkenyl group), 2 to 20 carbon atoms ((C ₂ -C ₂₀ ) alkenyl group), 2 to 12 carbon atoms ((C ₂ -C ₁₂ )alkenyl), 2 to 10 carbon atoms ((C ₂ -C ₁₀ )alkenyl), 2 to 8 carbon atoms ((C ₂ -C ₈ ) Alkenyl), 2 to 6 carbon atoms ((C ₂ -C ₆ )alkenyl), or 2 to 4 carbon atoms ((C ₂ -C ₄ )alkenyl). When the valence permits, the alkenyl group may have one, two, three, four, five, or more carbon-carbon double bonds. When naming alkenyl residues with a specific carbon number, all geometric isomers with that carbon number can be covered.

As used herein, "alkynyl" refers to an unbranched or branched hydrocarbon chain containing at least one carbon-carbon reference bond. In some embodiments, an alkynyl group as used herein has 2 to 50 carbon atoms ((C ₂ -C ₅₀ ) alkynyl group), 2 to 20 carbon atoms ((C ₂ -C ₂₀ ) alkynyl group), 2 to 12 carbon atoms ((C ₂ -C ₁₂ ) alkynyl), 2 to 10 carbon atoms ((C ₂ -C ₁₀ ) alkynyl), 2 to 8 carbon atoms ((C ₂ -C ₈ ) Alkynyl), 2 to 6 carbon atoms ((C ₂ -C ₆ ) alkynyl), or 2 to 4 carbon atoms ((C ₂ -C ₄ ) alkynyl). When the valence permits, the alkynyl group may have one, two, three, four, five, or more carbon-carbon reference bonds. When naming alkynyl residues with a specific carbon number, all geometric isomers with that carbon number can be covered.

As used herein, "alkynyloxy" refers to an -O-alkynyl moiety, where alkynyl is as described above.

As used herein, "cycloalkyl" refers to a monocyclic or polycyclic saturated hydrocarbon. In some embodiments, the cycloalkyl group has 3 to 50 carbon atoms ((C ₃ -C ₅₀ )cycloalkyl), 3 to 20 carbon atoms ((C ₃ -C ₂₀ )cycloalkyl), 3 to 12 carbon atoms ((C ₃ -C ₁₂ )cycloalkyl), 3 to 8 carbon atoms ((C ₃ -C ₈ )cycloalkyl), 3 to 6 carbon atoms ((C ₃ -C ₆ ) Cycloalkyl), or 3 to 5 carbon atoms ((C ₃ -C ₅ )cycloalkyl). Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydrocyclopentadienyl, octahydro-1 H -indene, decahydronaphthalene, cubane, bicyclo[3.1.0 ] Hexane and bicyclo [1.1.1] pentane.

As used herein, "halocycloalkyl" refers to a cycloalkyl substituted with one or more independently selectable halo groups. Thus, halocycloalkyl includes cycloalkyl substituted with one or more halo groups independently selected from the group consisting of fluorine, chlorine, iodine, and bromine. Halocycloalkyl may include, for example, cyclopropyl substituted with two fluorines, cyclopropyl substituted with one fluorine and one chlorine, cyclopentyl substituted with one fluorine, and cyclohexyl substituted with one bromine.

"Aryl" as used herein refers to a monocyclic or polycyclic group having at least one hydrocarbon aromatic ring, wherein all ring atoms of at least one hydrocarbon aromatic ring are carbon. Among them, aryl groups include polycyclic systems, and aromatic heteroatoms do not exist. The aryl group may include a group having a single aromatic ring (eg phenyl) and a group having multiple fused aromatic rings (eg naphthyl, anthracenyl). The aryl group may further include a group having one or more aromatic hydrocarbon rings fused to one or more non-aromatic hydrocarbon rings (eg, fluorenyl; 2,3-dihydro-1H-indene; 1, 2, 3,4-tetrahydronaphthalene). In certain embodiments, the aryl group includes a group having an aromatic hydrocarbon ring fused to a non-aromatic ring, wherein the non-aromatic ring contains at least one ring heteroatom independently selected from the group consisting of N, O, and S. For example, in some embodiments, the aryl group includes a group having a phenyl ring fused to a non-aromatic ring, wherein the non-aromatic ring contains at least one ring hetero independently selected from the group consisting of N, O, and S Atom (for example, alkane; thiol alkane; 2,3-dihydrobenzofuran; indoline). In some embodiments, an aryl group as used herein has 6 to 14 carbon atoms ((C ₆ -C ₁₄ )aryl) or 6 to 10 carbon atoms ((C ₆ -C ₁₀ )aryl). Where the aryl group includes a fused ring, the aryl group may be connected to one or more substituents or moieties of the chemical formula described herein via any atom of the fused ring whose valency permits.

"Heteroaryl" as used herein refers to a monocyclic or polycyclic group containing at least one aromatic ring, wherein the aromatic ring contains at least one ring heteroatom independently selected from the group consisting of N, O, and S. Heteroaryl groups may contain 5, 6, 7, 8, 9, 10, 11, 12 or more ring atoms, where ring atoms refer to the sum of carbon and heteroatoms in the one or more rings (eg, (5 members, 6 members, 7 members, 8 members, 9 members, 10 members, 11 members or 12 members heteroaryl). In some embodiments, heteroaryl groups include groups having an aromatic ring containing at least one ring heteroatom independently selected from the group consisting of N, O, and S (eg, pyridyl, pyrazinyl, furyl, thienyl) ). In certain embodiments, heteroaryl groups include polycyclic groups having an aromatic ring containing at least one ring heteroatom fused to a non-aromatic hydrocarbon ring (eg, 5,6,7,8-tetrahydroquinolinyl ; 4,5,6,7-tetrahydroisobenzofuranyl). In some embodiments, heteroaryl groups include polycyclic groups having an aromatic ring containing at least one ring heteroatom fused to an aromatic hydrocarbon ring (eg, quinolinyl, quinolinyl, benzothiazolyl). In additional embodiments, heteroaryl groups include polycyclic groups having two fused aromatic rings, where each ring contains at least one ring heteroatom (eg, naphthyridinyl). Heteroaryl groups may include groups containing 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom, each of which The ring heteroatoms are independently selected from the group consisting of N, O and S. In one example, the heteroaryl group has 3 to 8 ring carbon atoms, wherein 1 to 3 ring carbon atoms are independently selected from N, O, and S. Examples of heteroaryl groups include pyridyl, pyridazinyl, pyrimidinyl, benzothiazolyl and pyrazolyl.

烷基。"Heterocycloalkyl" as used herein refers to a non-aromatic monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from the group consisting of O, N, and S. Heterocycloalkyl can be saturated or unsaturated, and can contain 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more ring atoms, wherein ring atoms refer to the one or The sum of carbons and heteroatoms in multiple rings (eg, 3 members, 4 members, 5 members, 6 members, 7 members, 8 members, 9 members, 10 members, 11 members, or 12 members heterocycloalkyl). Heterocycloalkyl can include groups containing 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom, wherein Each ring heteroatom is independently selected from the group consisting of N, O, and S. In one example, the heterocycloalkyl group has 2 to 8 ring carbon atoms and 1 to 3 ring heteroatoms independently selected from N, O, and S. Examples of heterocycloalkyl include (but are not limited to): propylene oxide, azetidinyl, tetrahydrofuranyl, tetrahydropiperanyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidine Group, piperanyl group, thiopiperanyl group, tetrahydropiperanyl group, dioxehexenyl group, piperidinyl group, morpholinyl group, thiomorpholinyl group, piperazinyl group, aza-phenyl group, oxy-phenyl group Base, diazoxide and

alkyl.

"Haloheterocycloalkyl" as used herein refers to a heterocycloalkyl substituted with one or more independently selectable halo groups. Thus, haloheterocycloalkyl includes heterocycloalkyl substituted with one or more halo groups independently selected from the group consisting of fluorine, chlorine, iodine, and bromine.

"Halo" or "halogen" includes bromine, chlorine, fluorine and iodine.

The term "substituted" as used herein means a group in which at least one hydrogen atom or electron pair is replaced by a bond with a non-hydrogen atom. It may include, for example, halogen atoms such as F, Cl, Br, or I; oxygen atoms in hydroxyl groups; nitrogen atoms in amine groups; or oxygen atoms in sulfur dioxide groups.

It should be understood that when a range of values is listed, it is intended to cover each value and sub-range within the range. For example, "(C ₁ -C ₆ )alkyl" (which may also be referred to as C1-C6 alkyl, C _1-6 alkyl, or C1-6 alkyl) is intended to cover C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C _1-6 , C _1-5 , C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-5 , C _2-4 , C _2-3 , C _3-6 , C _3-5 , C _3-4 , C _4-6 , C _4-5 and C _5-6 alkyl.

， 或其立體異構體或醫藥學上可接受之鹽，其中： p為0至7之整數；及 B、W、X、R^b4 、R^b5 、R^b10 、R^b11 、R^b12 、n及t係針對式(II)所定義。In some embodiments, the compound of formula (II) is a compound of formula (II-A):

, Or its stereoisomer or pharmaceutically acceptable salt, wherein: p is an integer from 0 to 7; and B, W, X, R ^b4 , R ^b5 , R ^b10 , R ^b11 , R ^b12 , n and t is defined for formula (II).

In some embodiments of the compound of formula (II-A) or its stereoisomer or pharmaceutically acceptable salt, p is an integer of 0 to 6, or an integer of 0 to 5, or an integer of 0 to 4. , Or an integer from 0 to 3, or an integer from 0 to 2, or an integer from 3 to 5. In some embodiments, p is 0. In other embodiments, p is 1. In another embodiment, p is 2. In some embodiments, p is 3. In other embodiments, p is an integer from 4 to 7.

， 或其立體異構體或醫藥學上可接受之鹽，其中： p為0至7之整數； Y為-C(R^b52 )₂ -、-S(O)_r -、-O-或-N(R^b52 )-，其中各R^b52 獨立地為氫或R^b4 ； r為0、1或2；及 B、W、X、R^b4 、R^b5 、R^b10 、R^b11 、R^b12 、n及t係針對式(II)所定義。In some embodiments, the compound of formula (II) is a compound of formula (II-B):

, Or its stereoisomer or pharmaceutically acceptable salt, wherein: p is an integer from 0 to 7; Y is -C(R ^b52 ) ₂ -, -S(O) _r -, -O- or- N(R ^b52 )-, wherein each R ^{b52 is} independently hydrogen or R ^b4 ; r is 0, 1 or 2; and B, W, X, R ^b4 , R ^b5 , R ^b10 , R ^b11 , R ^b12 , n And t are defined for formula (II).

In some embodiments of the compound of formula (II-B) or its stereoisomer or pharmaceutically acceptable salt, p is an integer of 0 to 6, or an integer of 0 to 5, or an integer of 0 to 4. , Or an integer from 0 to 3, or an integer from 0 to 2, or an integer from 3 to 5. In some embodiments, p is 0. In other embodiments, p is 1. In another embodiment, p is 2. In some embodiments, p is 3. In other embodiments, p is an integer from 4 to 7.

In some embodiments of the compound of formula (I), formula (II), formula (II-A) or formula (II-B), or a stereoisomer or pharmaceutically acceptable salt thereof, W is aryl Or heteroaryl. In some embodiments, W is (C ₆ -C ₁₀ )aryl. In certain embodiments, W is 5 to 8 membered heteroaryl. In certain embodiments, W is 5 to 7 membered heteroaryl. In some embodiments, W is 5, 6 or 7 membered heteroaryl. In some embodiments of the compound of formula (I), formula (II), formula (II-A) or formula (II-B), or its stereoisomer or pharmaceutically acceptable salt, W is 5 members Up to 10 membered heteroaryl groups, wherein the heteroaryl group contains one to five ring heteroatoms independently selected from the group consisting of O, N and S. In certain embodiments, W is a 5- or 6-membered heteroaryl group, wherein the heteroaryl group contains one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In other embodiments, W is a 9- or 10-membered bicyclic heteroaryl, which contains one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In some embodiments, W is 5,5-ring fused heteroaryl, 6,6-ring fused heteroaryl, or 5,6-ring fused heteroaryl.

。In some embodiments of the compound of formula (I), formula (II), formula (II-A) or formula (II-B), or its stereoisomer or pharmaceutically acceptable salt, W is pyridazine Group, pyrazolyl, pyrrolyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl, pyridyl , Pyrimidyl, benzothiazolyl, indazolyl, benzoxazolyl, benzimidazolyl, benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothiophene Group, isoquinolinyl, quinoxalinyl, quinolinyl, naphthyridinyl or pyrrolyl. In certain embodiments of the compound of formula (I), formula (II), formula (II-A), or formula (II-B) or its stereoisomer or pharmaceutically acceptable salt, W is:

.

。In other embodiments of the compound of formula (I), formula (II), formula (II-A) or formula (II-B) or its stereoisomer or pharmaceutically acceptable salt, W is aryl . For example, in some embodiments, W is (C ₆ -C ₁₀ )aryl, such as C ₆ -aryl, (C ₇ -C ₁₀ )bicyclic aryl, (C ₈ -C ₁₀ )bicyclic aryl Or (C ₉ -C ₁₀ ) bicyclic aryl. In certain embodiments of the compound of formula (I), formula (II), formula (II-A) or formula (II-B), or its stereoisomer or pharmaceutically acceptable salt, W is benzene Base or naphthyl. In some embodiments, W is an aryl group containing a benzene ring fused to a cycloalkyl or heterocycloalkyl ring, for example, (C _7- C ₁₀ ) Bicyclic aryl, (C ₈ -C ₁₀ ) bicyclic aryl or (C ₉ -C ₁₀ ) bicyclic aryl. In certain embodiments of the compound of formula (I), formula (II), formula (II-A), or formula (II-B) or its stereoisomer or pharmaceutically acceptable salt, W is:

.

，如上文所描述，且

為

，其中t為0至5之整數。It should be understood that for the embodiments described herein, W may be unsubstituted or substituted by one to six formulas (I), (II), (II-A) and (II- R ^b12 substitution as described in B). For example, in some embodiments, W is

, As described above, and

for

, Where t is an integer from 0 to 5.

In some embodiments of the compound of formula (I), formula (II), formula (II-A) or formula (II-B), or its stereoisomer or pharmaceutically acceptable salt, t is from 0 to An integer of 6. In some embodiments, t is an integer from 0 to 5. In other embodiments, t is an integer from 0 to 4. In other embodiments, t is an integer from 0 to 3. In some embodiments, t is 0, 1, or 2. In other embodiments, t is an integer of 1 to 6, or 2 to 6, or 3 to 6, or 3 to 5, or 2 to 4. In some embodiments, t is 0. In other embodiments, t is 1. In some embodiments, t is 2. In other embodiments, t is 3. In another embodiment, t is 4. In some embodiments, t is 5. In some embodiments, t is 6.

為

，其中u為0至5之整數。In some embodiments of the compound of formula (I), formula (II), formula (II-A) or formula (II-B) or its stereoisomer or pharmaceutically acceptable salt, W is phenyl , And t is an integer from 0 to 5. In some embodiments of the compound of formula (I), formula (II), formula (II-A) or formula (II-B), or its stereoisomer or pharmaceutically acceptable salt,

for

, Where u is an integer from 0 to 5.

， 或其立體異構體或醫藥學上可接受之鹽，其中： p為0至7之整數； u為0至5之整數；及 B、X、R^b4 、R^b5 、R^b10 、R^b11 、R^b12 及n係針對式(II)所定義。In some embodiments, the compound of formula (II) is a compound of formula (II-A-ii):

, Or its stereoisomers or pharmaceutically acceptable salts, wherein: p is an integer from 0 to 7; u is an integer from 0 to 5; and B, X, R ^b4 , R ^b5 , R ^b10 , R ^b11 , R ^b12 and n are defined for formula (II).

In some embodiments of the compound of formula (II-A-ii) or its stereoisomer or pharmaceutically acceptable salt, p is an integer from 0 to 6, or an integer from 0 to 5, or 0 to 4 Integer, or an integer from 0 to 3, or an integer from 0 to 2, or an integer from 3 to 5. In some embodiments, p is 0. In other embodiments, p is 1. In another embodiment, p is 2. In some embodiments, p is 3. In other embodiments, p is an integer from 4 to 7. In some embodiments, u is 0. In other embodiments, u is 1. In another embodiment, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5.

， 或其立體異構體或醫藥學上可接受之鹽，其中： p為0至7之整數； Y為-C(R^b52 )₂ -、-S(O)_r -、-O-或-N(R^b52 )-，其中各R^b52 獨立地為氫或R^b4 ； r為0、1或2； u為0至5之整數；及 B、X、R^b4 、R^b5 、R^b10 、R^b11 、R^b12 及n係針對式(II)所定義。In some embodiments, the compound of formula (II) is a compound of formula (II-B-ii):

, Or its stereoisomer or pharmaceutically acceptable salt, wherein: p is an integer from 0 to 7; Y is -C(R ^b52 ) ₂ -, -S(O) _r -, -O- or- N(R ^b52 )-, wherein each R ^{b52 is} independently hydrogen or R ^b4 ; r is 0, 1 or 2; u is an integer from 0 to 5; and B, X, R ^b4 , R ^b5 , R ^b10 , R ^b11 , R ^b12 and n are defined for formula (II).

In some embodiments of the compound of formula (II-B-ii) or its stereoisomer or pharmaceutically acceptable salt, p is an integer from 0 to 6, or an integer from 0 to 5, or 0 to 4 Integer, or an integer from 0 to 3, or an integer from 0 to 2, or an integer from 3 to 5. In some embodiments, p is 0. In other embodiments, p is 1. In another embodiment, p is 2. In some embodiments, p is 3. In other embodiments, p is an integer from 4 to 7. In some embodiments, u is 0. In other embodiments, u is 1. In another embodiment, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5.

In certain embodiments of the compound of formula (II-B) or formula (II-B-ii) or its stereoisomer or pharmaceutically acceptable salt, Y is -C(R ^b52 ) ₂ -, Each R ^{b52 is} independently hydrogen or R ^b4 . In certain embodiments, Y is -CH ₂ -. In other embodiments, Y is -CHR ^b4- . In some embodiments, Y is -C(R ^b4 ) ₂ -. In other embodiments, Y is -S(O) _r -, where r is 0, 1, or 2. For example, in some embodiments, Y is -S-. In other embodiments, Y is -S(O)-. In another embodiment, Y is -S(O) ₂ -. In some embodiments, Y is -O-. In other embodiments, Y is -N(R ^b52 )-, where R ^b52 is hydrogen or R ^b4 . For example, in certain embodiments, Y is -NH-. In some embodiments, Y is -NR ^b4 -.

Compounds of formula (I), formula (II), formula (II-A), formula (II-A-ii), formula (II-B) or formula (II-B-ii) or their stereoisomers Or in some embodiments of a pharmaceutically acceptable salt, B is heteroaryl, cycloalkyl, or heterocycloalkyl. In some embodiments, B is 5 to 10 membered heteroaryl, or 5 to 10 membered heterocycloalkyl, wherein the heteroaryl or heterocycloalkyl contains one to five independently selected from O, N And S heterocyclic atoms. In certain embodiments, B is 5 or 6 membered heteroaryl, or 5 or 6 membered heterocycloalkyl, wherein the heterocycloalkyl or heteroaryl contains one to three independently selected from O, Ring heteroatoms of the group consisting of N and S In other embodiments, B is a 9- or 10-membered bicyclic heteroaryl, which contains one to three ring heteroatoms independently selected from the group consisting of O, N, and S.

烷基。在式(I)、式(II)、式(II-A)、式(II-A-ii)、式(II-B)或式(II-B-ii)之化合物或其立體異構體或醫藥學上可接受之鹽之某些實施例中，B為：

。在一些實施例中，B為

。Compounds of formula (I), formula (II), formula (II-A), formula (II-A-ii), formula (II-B) or formula (II-B-ii) or their stereoisomers Or in some embodiments of a pharmaceutically acceptable salt, B is heterocycloalkyl. For example, in some embodiments, B is a 3- to 10-membered heterocycloalkyl, which contains one to five ring heteroatoms independently selected from the group consisting of O, N, and S. In certain embodiments, B is a 5- to 10-membered heterocycloalkyl, which contains one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In other embodiments, B is a 5- or 6-membered heterocycloalkyl, which contains one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In some embodiments, B is a 9-membered or 10-membered heterocycloalkyl, which contains one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In certain embodiments, B is 5,5-ring fused heterocycloalkyl, 6,6-ring fused heterocycloalkyl, or 5,6-ring fused heterocycloalkyl. Compounds of formula (I), formula (II), formula (II-A), formula (II-A-ii), formula (II-B) or formula (II-B-ii) or their stereoisomers Or in some embodiments of a pharmaceutically acceptable salt, B is propylene oxide, azetidinyl, tetrahydrofuranyl, tetrahydropiperanyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolidinyl , Tetrahydropiperanyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl or

alkyl. Compounds of formula (I), formula (II), formula (II-A), formula (II-A-ii), formula (II-B) or formula (II-B-ii) or their stereoisomers Or in some embodiments of a pharmaceutically acceptable salt, B is:

. In some embodiments, B is

.

。在一些實施例中，B為

。Compounds of formula (I), formula (II), formula (II-A), formula (II-A-ii), formula (II-B) or formula (II-B-ii) or their stereoisomers Or in other examples of pharmaceutically acceptable salts, B is heteroaryl. For example, in some embodiments, B is a 5- to 10-membered heteroaryl group, which contains one to five ring heteroatoms independently selected from the group consisting of O, N, and S. In other embodiments, B is a 5- or 6-membered heteroaryl, which contains one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In certain embodiments, B is a 9- or 10-membered heteroaryl group that contains one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In some embodiments, B is a 9-membered or 10-membered bicyclic heteroaryl, which contains one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In some embodiments, B is 5,5-ring fused heteroaryl, 6,6-ring fused heteroaryl, or 5,6-ring fused heteroaryl. Compounds of formula (I), formula (II), formula (II-A), formula (II-A-ii), formula (II-B) or formula (II-B-ii) or their stereoisomers Or in some embodiments of a pharmaceutically acceptable salt, B is pyridazinyl, pyrazolyl, pyrrolyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxa Oxazolyl, thiazolyl, isothiazolyl, furanyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, indazolyl, benzoxazolyl, benzimidazolyl, benzofuranyl, isobenzoyl Furanyl, indolyl, isoindolyl, benzothienyl, isoquinolinyl, quinoxalinyl, quinolinyl, naphthyridinyl or pyrrolyl. Compounds of formula (I), formula (II), formula (II-A), formula (II-A-ii), formula (II-B) or formula (II-B-ii) or their stereoisomers Or in some embodiments of a pharmaceutically acceptable salt, B is:

. In some embodiments, B is

.

。Compounds of formula (I), formula (II), formula (II-A), formula (II-A-ii), formula (II-B) or formula (II-B-ii) or their stereoisomers Or in other embodiments of pharmaceutically acceptable salts, B is aryl. For example, in some embodiments, B is (C ₆ -C ₁₀ )aryl, such as C ₆ -aryl, (C ₇ -C ₁₀ )bicyclic aryl, (C ₈ -C ₁₀ )bicyclic aryl Or (C ₉ -C ₁₀ ) bicyclic aryl. Compounds of formula (I), formula (II), formula (II-A), formula (II-A-ii), formula (II-B) or formula (II-B-ii) or their stereoisomers Or in some embodiments of a pharmaceutically acceptable salt, B is phenyl or naphthyl. In some embodiments, B is an aryl group containing a benzene ring fused to a cycloalkyl or heterocycloalkyl ring, for example, a (C _7- C ₁₀ ) Bicyclic aryl, (C ₈ -C ₁₀ )bicyclic aryl, or (C ₉ -C ₁₀ )bicyclic aryl. Compounds of formula (I), formula (II), formula (II-A), formula (II-A-ii), formula (II-B) or formula (II-B-ii) or their stereoisomers Or in some embodiments of a pharmaceutically acceptable salt, B is:

.

。Compounds of formula (I), formula (II), formula (II-A), formula (II-A-ii), formula (II-B) or formula (II-B-ii) or their stereoisomers Or in another embodiment of a pharmaceutically acceptable salt, B is cycloalkyl. For example, in some embodiments, B is (C ₃ -C ₁₀ )cycloalkyl. In certain embodiments, B is (C ₅ -C ₁₀ )cycloalkyl. In other embodiments, B is (C ₅ -C ₇ )cycloalkyl. In other embodiments, B is (C ₈ -C ₁₀ )cycloalkyl. In some embodiments, B is C ₃ -cycloalkyl, C ₄ -cycloalkyl, C ₅ -cycloalkyl, C ₆ -cycloalkyl, C ₇ -cycloalkyl, C ₈ -cycloalkyl, C ₉ -cycloalkyl, or C ₁₀ -cycloalkyl. In some embodiments, B is 5,5-ring fused cycloalkyl, 6,6-ring fused cycloalkyl, or 5,6-ring fused cycloalkyl. Compounds of formula (I), formula (II), formula (II-A), formula (II-A-ii), formula (II-B) or formula (II-B-ii) or their stereoisomers Or in some embodiments of a pharmaceutically acceptable salt, B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, dicyclopentyl, bicyclohexyl, bicycloheptyl, Bicyclic octyl or tricyclic octyl. In formula (I), formula (II), formula (II-A), formula (II-A-ii), formula (II-B) and formula (II-B-ii) or their stereoisomers Or in some embodiments of a pharmaceutically acceptable salt, B is:

.

It should be understood that, for the embodiments described herein, when the valence allows, B may be unsubstituted or substituted from one to eleven such as formula (I), formula (II), formula (II-A), formula (II- A-ii), formula (II-B) and formula (II-B-ii) described in the R ^b5 substitution.

，如上文所描述，且

為

，其中n為0至5之整數。For example, in some embodiments, B is

, As described above, and

for

, Where n is an integer from 0 to 5.

，如上文所描述，且

為

，其中n為0至11之整數。In other embodiments, B is

, As described above, and

for

, Where n is an integer from 0 to 11.

，如上文所描述，且

為

，其中n為0至10之整數。舉例而言，在一些實施例中，

為

。在取代基(例如R^b5 )之多個個例存在時，應理解，除非另有規定，否則其可視情況不同。In other embodiments, B is

, As described above, and

for

, Where n is an integer from 0 to 10. For example, in some embodiments,

for

. When multiple instances of a substituent (for example, R ^b5 ) exist, it should be understood that unless otherwise specified, they may differ according to circumstances.

Compounds of formula (I), formula (II), formula (II-A), formula (II-A-ii), formula (II-B) or formula (II-B-ii) or their stereoisomers Or in some embodiments of a pharmaceutically acceptable salt, n is an integer from 0 to 11. In some embodiments, n is an integer from 0 to 9. In other embodiments, n is an integer from 0 to 7. In other embodiments, n is an integer from 0 to 5. In some embodiments, n is an integer from 0 to 3. In other embodiments, n is an integer of 3 to 11, or 5 to 11, or 7 to 11, or 3 to 7, or 3 to 5. In some embodiments, n is 0. In other embodiments, n is 1. In some embodiments, n is 2. In other embodiments, n is 3. In another embodiment, n is 4.

。在取代基(例如R^b5 )之多個個例存在時，應理解，除非另有規定，否則其可視情況不同。Compounds of formula (I), formula (II), formula (II-A), formula (II-A-ii), formula (II-B) or formula (II-B-ii) or their stereoisomers Or in some embodiments of a pharmaceutically acceptable salt, B is phenyl and n is an integer from 0 to 5. Thus, for example, a compound of formula (II), formula (II-A), formula (II-A-ii), formula (II-B), or formula (II-B-ii) or its stereoisomer or In some embodiments of pharmaceutically acceptable salts,

. When multiple instances of a substituent (for example, R ^b5 ) exist, it should be understood that unless otherwise specified, they may differ according to circumstances.

為

。Compounds of formula (I), formula (II), formula (II-A), formula (II-A-ii), formula (II-B) or formula (II-B-ii) or their stereoisomers Or some examples of pharmaceutically acceptable salts,

for

.

， 或其立體異構體或醫藥學上可接受之鹽，其中： p為0至7之整數； u為0至5之整數；及 X、R^b4 、R^b5 、R^b10 、R^b11 及R^b12 係針對式(II)所定義。In some embodiments, the compound of formula (II) is a compound of formula (II-Ai):

, Or its stereoisomers or pharmaceutically acceptable salts, wherein: p is an integer from 0 to 7; u is an integer from 0 to 5; and X, R ^b4 , R ^b5 , R ^b10 , R ^b11 and R ^b12 is defined for formula (II).

In some embodiments of the compound of formula (I), formula (II-Ai), or its stereoisomer or pharmaceutically acceptable salt, p is an integer from 0 to 6, or an integer from 0 to 5, or An integer from 0 to 4, or an integer from 0 to 3, or an integer from 0 to 2, or an integer from 3 to 5. In some embodiments, p is 0. In other embodiments, p is 1. In another embodiment, p is 2. In some embodiments, p is 3. In other embodiments, p is an integer from 4 to 7. In some embodiments, u is 0. In other embodiments, u is 1. In another embodiment, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5.

為

，且p為0至6之整數。在其他實施例中，

為

，且p為0至6之整數。In some embodiments of the compound of formula (I), formula (II-A), formula (II-Ai) or formula (II-A-ii), or its stereoisomer or pharmaceutically acceptable salt,

for

, And p is an integer from 0 to 6. In other embodiments,

for

, And p is an integer from 0 to 6.

， 或其立體異構體或醫藥學上可接受之鹽，其中： p為0至7之整數； Y為-C(R^b52 )₂ -、-S(O)_r -、-O-或-N(R^b52 )-，其中各R^b52 獨立地為氫或R^b4 ； r為0、1或2； u為0至5之整數；及 X、R^b4 、R^b5 、R^b10 、R^b11 及R^b12 係針對式(II)所定義。In some embodiments, the compound of formula (II) is a compound of formula (II-Bi):

, Or its stereoisomer or pharmaceutically acceptable salt, wherein: p is an integer from 0 to 7; Y is -C(R ^b52 ) ₂ -, -S(O) _r -, -O- or- N(R ^b52 )-, wherein each R ^{b52 is} independently hydrogen or R ^b4 ; r is 0, 1 or 2; u is an integer from 0 to 5; and X, R ^b4 , R ^b5 , R ^b10 , R ^b11 and R ^b12 is defined for formula (II).

In certain embodiments of the compound of formula (I), formula (II-B-ii) or its stereoisomer or pharmaceutically acceptable salt, Y is -C(R ^b52 ) ₂ -, wherein each R ^{b52 is} independently hydrogen or R ^b4 . In certain embodiments, Y is -CH ₂ -. In other embodiments, Y is -CHR ^b4- . In some embodiments, Y is -C(R ^b4 ) ₂ -. In other embodiments, Y is -S(O) _r -, where r is 0, 1, or 2. For example, in some embodiments, Y is -S-. In other embodiments, Y is -S(O)-. In another embodiment, Y is -S(O) ₂ -. In some embodiments, Y is -O-. In other embodiments, Y is -N(R ^b52 )-, where R ^b52 is hydrogen or R ^b4 . For example, in certain embodiments, Y is -NH-. In other embodiments, Y is -NR ^b4 -. In some embodiments of the compound of formula (II-Bi) or its stereoisomer or pharmaceutically acceptable salt, p is an integer of 0 to 6, or an integer of 0 to 5, or an integer of 0 to 4. , Or an integer from 0 to 3, or an integer from 0 to 2, or an integer from 3 to 5. In some embodiments, p is 0. In other embodiments, p is 1. In another embodiment, p is 2. In some embodiments, p is 3. In other embodiments, p is an integer from 4 to 7. In some embodiments, u is 0. In other embodiments, u is 1. In another embodiment, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5.

為

，且p為0至6之整數。在其他實施例中，

為

，且p為0至6之整數。In some embodiments of the compound of formula (I), formula (II-B), formula (II-Bi) or formula (II-B-ii), or its stereoisomer or pharmaceutically acceptable salt,

for

, And p is an integer from 0 to 6. In other embodiments,

for

, And p is an integer from 0 to 6.

為

。在某些實施例中，

為

。在一些實施例中，

為

。在取代基(例如R^b12 )之多個個例存在時，應理解，除非另有規定，否則其可視情況不同。Compounds of formula (I), formula (II), formula (II-A), formula (II-A-ii), formula (II-B) or formula (II-B-ii) or their stereoisomers Or some examples of pharmaceutically acceptable salts,

for

. In some embodiments,

for

. In some embodiments,

for

. When multiple instances of a substituent (for example, R ^b12 ) exist, it should be understood that unless otherwise specified, they may differ according to circumstances.

In formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or (II -B-ii) In some embodiments of the compound or its stereoisomer or pharmaceutically acceptable salt, each R ^b12 is independently selected from the group consisting of halo, alkyl, haloalkyl and -OR ^b32 , wherein R ^b32 is hydrogen, alkyl or haloalkyl. In certain embodiments, each R ^b12 is independently selected from the group consisting of halo, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, -OH, -O- (C ₁ -C ₆ )alkyl and -O-(C ₁ -C ₆ )haloalkyl. In some embodiments, each R ^{b12 is} independently fluorine, chlorine, bromine, methyl, ethyl, propyl, butyl, pentyl, hexyl, -OCH ₃ , -OCH ₂ CH ₃ , -OCH(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ Cl, -CHCl ₂ , -CCl ₃ , -CH ₂ Br, -CHBr ₂ , -CBr ₃ , -CH ₂ I, -CHFI ₂ , -CI ₃ , -OCH ₂ Cl, -OCHCl ₂ , -OCCl ₃ , -OCH ₂ Br, -OCHBr ₂ , -OCBr ₃ , -OCH ₂ I, -OCHFI ₂ , -OCI ₃ , -OCH ₂ F,- OCHF ₂ or -OCF ₃ . In certain embodiments, each R ^{b12 is} independently fluorine, chlorine, -OCH ₃ or -CF ₃ . In some embodiments, each R ^{b12 is} independently fluorine, chlorine, bromine, methyl, ethyl, propyl, butyl, pentyl, hexyl, -OCH ₃ , -OCH ₂ CH ₃ , -OCH(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , -CF ₃ , -OCH ₂ F, -OCHF ₂ or -OCF ₃ . In certain embodiments, each R ^{b12 is} independently fluorine, chlorine, -OCH ₃ or -CF ₃ .

為

。在一些實施例中，

為

。In the compound of formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-B) or formula (II-Bi) or its stereoisomer or pharmaceutical In some examples of acceptable salts,

for

. In some embodiments,

for

.

為

。在一些實施例中，

為

。In some embodiments of the compound of formula (II-A-ii) or formula (II-B-ii) or its stereoisomer or pharmaceutically acceptable salt,

for

. In some embodiments,

for

.

In formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula ( In some embodiments of compounds of II-B-ii) or their stereoisomers or pharmaceutically acceptable salts, each R ^b4 is independently selected from the group consisting of halo, alkyl, cycloalkyl , Heterocycloalkyl, heteroaryl, aryl, -NO ₂ , -CN, -SO ₂ NH ₂ , -NR ^b13 R ^b14 , -OR ^b15 , =O, -SR ^b60 and -SO ₂ R ^b16 , where Each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo groups. In some embodiments, each R ^b4 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, -NO ₂ , -CN, -SO ₂ NH ₂ , -NR ^b13 R ^b14 , -OR ^b15 , =O, -SR ^b60 and -SO ₂ R ^b16 , wherein each alkyl group, cycloalkyl group and heterocycloalkyl group are independently unsubstituted or substituted with one or more halo groups. In some embodiments, each R ^b13 , R ^b14 , R ^b15 , R ^b16 and R ^{b60 is} independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl or halo heterocycle alkyl. In certain embodiments, each R ^b13 , R ^b14 , R ^b15 , R ^b16 and R ^{b60 is} independently hydrogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl. In certain embodiments, each R ^b13 , R ^b14 , R ^b15 , R ^b16 and R ^{b60 are} independently hydrogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₃ -C ₆ )cycloalkyl, (C ₃ -C ₆ )halocycloalkyl, 3 to 8 membered heterocycloalkyl, or 3 to 8 membered halogenated heterocycloalkyl. In some embodiments, each R ^b13 , R ^b14 , R ^b15 , R ^b16 and R ^{b60 is} independently hydrogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₃ -C ₆ )cycloalkyl and (C ₃ -C ₆ )halocycloalkyl.

In formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula ( In some embodiments of compounds of II-B-ii) or their stereoisomers or pharmaceutically acceptable salts, each R ^b4 is independently selected from the group consisting of fluorine, chlorine, bromine, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₃ -C ₆ )cycloalkyl, (C ₃ -C ₆ )halocycloalkyl, 3 to 6 membered heterocycloalkyl , -NO ₂ , -CN, -SO ₂ NH ₂ , -NH ₂ , -NH(C ₁ -C ₆ )alkyl, -N((C ₁ -C ₆ )alkyl)((C ₁ -C ₆ )Alkyl), -OH, -O-(C ₁ -C ₆ )alkyl, -O-(C ₁ -C ₆ )haloalkyl, -SO ₂ H, =O and -SO ₂ -(C ₁ -C ₆ )alkyl. In some embodiments, each R ^b4 is independently selected from the group consisting of fluorine, chlorine, bromine, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, -OH,- O-(C ₁ -C ₆ )alkyl and -O-(C ₁ -C ₆ )haloalkyl. In certain embodiments, at least one R ^b4 is fluorine, chlorine, bromine, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₃ -C ₆ )cycloalkyl, (C ₃ -C ₆ )halocycloalkyl, 3- to 6-membered heterocycloalkyl, -NO ₂ , -CN, -SO ₂ NH ₂ , -NH ₂ , -NH(C ₁ -C ₆ )alkyl , -N((C ₁ -C ₆ )alkyl)((C ₁ -C ₆ )alkyl), -OH, -O-(C ₁ -C ₆ )alkyl, -O-(C ₁ -C ₆ ) Haloalkyl, -SO ₂ H, =O or -SO ₂ -(C ₁ -C ₆ )alkyl. In some embodiments, at least one R ^b4 is fluorine, chlorine, bromine, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, -OH, -O-(C ₁ -C ₆ )Alkyl or -O-(C ₁ -C ₆ )haloalkyl. In certain embodiments, at least one R ^b4 is fluorine, chlorine, methyl, ethyl, propyl, -OH, methoxy, ethoxy, propoxy, -OCH ₂ F, -OCHF ₂ ,- OCF ₃ , -CH ₂ F, -CHF ₂ or -CF ₃ .

In formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula ( In some embodiments of compounds of II-B-ii) or their stereoisomers or pharmaceutically acceptable salts, two to four R ^b4 together with the atoms to which they are attached form aryl, heteroaryl, ring Alkyl or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo groups. In some embodiments, two to four R ^b4 together with the atoms to which they are attached form (C ₆ -C ₁₀ )aryl, 3 to 6 member heteroaryl, (C ₃ -C ₆ )cycloalkyl or 3 Member to 6 membered heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo groups. In some embodiments, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted. In some embodiments, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is fused to ring A. In other embodiments, cycloalkyl or heterocycloalkyl forms a spiro ring system with ring A. In some embodiments, two to four R ^b4 together with the atoms to which they are attached form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or Heterocycloalkyl is unsubstituted or substituted with one or more halo; one or more other R ^b4 independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl may be present , Heteroaryl, aryl, -NO ₂ , -CN, -SO ₂ NH ₂ , -NR ^b13 R ^b14 , -OR ^b15 , =O, -SR ^b60 and -SO ₂ R ^b16 , where each alkyl, ring The alkyl, heterocycloalkyl, aryl and heteroaryl groups are independently unsubstituted or substituted with one or more halo groups.

In formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula ( In some embodiments of compounds of II-B-ii) or their stereoisomers or pharmaceutically acceptable salts, each R ^b5 is independently selected from the group consisting of halo, alkyl, cycloalkyl , heterocycloalkyl, aryl, heteroaryl, _{alkynyl, -NO 2, -CN, -SO 2} NR b54 R b55, -NR b17 R b18, -OR b19, -SO 2 R b20, = O and -SR ^b21 . In some embodiments, one or more R ^b5 is independently selected from the group consisting of: halo; -O-(C ₁ -C ₆ ) alkyl, which is unsubstituted or substituted by one or more fluorine or Chlorine substitution; phenyl; heteroaryl; heterocycloalkyl; -SO ₂ NH ₂ ; -NO ₂ ; -CN; (C ₃ -C ₆ )cycloalkyl, which is unsubstituted or substituted by one or more fluorine Or chloro substituted; -O-(C ₂ -C ₄ ) alkynyl; and (C ₁ -C ₆ ) alkyl, which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of : (C ₃ -C ₆ )cycloalkyl, 3 to 6 membered heterocycloalkyl, aryl, heteroaryl, halo, -OH, -O-(C ₁ -C ₄ )alkyl, =O , -NR ^b26 R ^b27 and -CN. In certain embodiments, one or more R ^{b5 is} independently selected from the group consisting of halo, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, -O-( C ₁ -C ₆ )alkyl and -O-(C ₁ -C ₆ )haloalkyl. In certain embodiments, each R ^{b5 is} independently selected from the group consisting of halo, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, -O-(C _1- C ₆ )alkyl, -O-(C ₁ -C ₆ )haloalkyl and -CN. In certain embodiments, one or more R ^{b5 is} independently selected from the group consisting of halo, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, -O-( C ₁ -C ₆ )alkyl, -O-(C ₁ -C ₆ )haloalkyl, and -CN. In some embodiments, one or more R ^b5 is independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, butyl, pentyl, hexyl, -OCH ₃ ,- OCH ₂ CH ₃ , -OCH(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , -CF ₃ , -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -NO ₂ , phenyl, =O,- SO ₂ NH ₂ , —CN, cyclopropyl, cyclohexyl, and —OCH ₂ CCH. In some embodiments, at least one R ^b5 is independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, butyl, pentyl, hexyl, -OCH ₃ , -OCH ₂ CH ₃ , -OCH(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ Cl, -CHCl ₂ , -CCl ₃ , -CH ₂ Br, -CHBr ₂ , -CBr ₃ , -CH ₂ I, -CHFI ₂ , -CI ₃ , -OCH ₂ Cl, -OCHCl ₂ , -OCCl ₃ , -OCH ₂ Br, -OCHBr ₂ , -OCBr ₃ , -OCH ₂ I, -OCHFI ₂ , -OCI ₃ , -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -NO ₂ , phenyl, =O, -SO ₂ NH ₂ , -CN, cyclopropyl, cyclohexyl, and -OCH ₂ CCH.

In formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula ( In some embodiments of compounds of II-B-ii) or their stereoisomers or pharmaceutically acceptable salts, at least one R ^b5 is an alkyl group, wherein each alkyl group is independently unsubstituted or Multiple substituents independently selected from the group consisting of halo, -OR ^b25 , =O, -NR ^b26 R ^b27 , -CN, ^-SF ₅ , -SO ₂ NR ^b61 R ^b62 , -SR ^b63 , -SO ₂ R ^b64 and R ^b65 , wherein each R ^{b65 is} independently cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, each R ^{b65 is} independently (C ₃ -C ₆ )cycloalkyl, 3 to 8 membered heterocycloalkyl, (C ₆ -C ₁₀ )aryl or 3 to 8 membered heteroaryl base. In certain embodiments, at least one R ^b5 is an alkyl group, wherein the alkyl group is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halogen ring Alkyl, heterocycloalkyl, aryl, heteroaryl, halo, -OR ^b25 , =O, -NR ^b26 R ^b27 , -CN, and ^-SF ₅ . In some embodiments, the alkyl group is a (C ₁ -C ₁₂ ) alkyl group, wherein the alkyl group is unsubstituted or substituted as described above. In other embodiments, the alkyl group is a (C ₁ -C ₈ ) alkyl group, wherein the alkyl group is unsubstituted or substituted as described above. In other embodiments, the alkyl group is a (C ₁ -C ₆ ) alkyl group, wherein the alkyl group is unsubstituted or substituted as described above. In other embodiments, the alkyl group is a (C ₁ -C ₄ ) alkyl group, wherein the alkyl group is unsubstituted or substituted as described above. In some embodiments, at least one R ^b5 is methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluoromethyl, difluoromethyl, or fluoromethyl.

In formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula ( In some embodiments of the compound of II-B-ii) or its stereoisomer or pharmaceutically acceptable salt, at least one R ^b5 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein Each cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, -OR ^b22 , =O , -NR ^b23 R ^b24 , -CN, -SF ₅ , -SO ₂ NR ^b56 R ^b57 , -SR ^b58 , -SO ₂ R ^b59 and R ^b28 , where each R ^{b28 is} independently alkyl, cycloalkyl, hetero Cycloalkyl, aryl or heteroaryl. In certain embodiments, each R ^{b28 is} independently (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, 3 to 8 membered heterocycloalkyl, (C ₆ -C ₁₀ ) Aryl or 3 to 8 member heteroaryl. In some embodiments, R ^b28 is unsubstituted alkyl. In some embodiments, R ^b28 is unsubstituted (C ₁ -C ₆ )alkyl. In other embodiments, R ^b28 is an alkyl substituted with one or more substituents independently selected from the group consisting of halo, =O, -CN, aryl, heteroaryl, alkynyl, cyclic Alkyl, heterocycloalkyl, -NR ^b29 R ^b30 , -OR ^b31 and ^-SF ₅ . In certain embodiments, R ^b28 is (C ₁ -C ₆ )alkyl substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, aryl, Heteroaryl, alkynyl, cycloalkyl, heterocycloalkyl, -NR ^b29 R ^b30 , -OR ^b31 and ^-SF ₅ . In some embodiments, R ^b28 is (C ₁ -C ₆ )alkyl substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, aryl, hetero Aryl, cycloalkyl, heterocycloalkyl, -NR ^b29 R ^b30 , ^-SF ₅ , -OH, -O-(C ₁ -C ₆ ) alkyl and -O-(C ₁ -C ₆ ) haloalkanes base. In certain embodiments, R ^b28 is alkyl substituted with aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with haloalkyl or -SF ₅ .

In formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula ( In some embodiments of compounds of II-B-ii) or their stereoisomers or pharmaceutically acceptable salts, at least one R ^b5 is cycloalkyl, wherein each cycloalkyl is independently unsubstituted or Or more substituents independently selected from the group consisting of halo, -OR ^b22 , =O, -NR ^b23 R ^b24 , -CN, -SF ₅ , -SO ₂ NR ^b56 R ^b57 , -SR ^b58 , -SO ₂ R ^b59 and R ^b28 , wherein each R ^{b28 is} independently alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, each R ^{b28 is} independently (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, 3 to 8 membered heterocycloalkyl, (C ₆ -C ₁₀ ) Aryl or 3 to 8 member heteroaryl. In some embodiments, at least one R ^b5 is cycloalkyl, wherein each cycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: alkyl, haloalkane Group, cycloalkyl, aryl, heteroaryl, halo, -OR ^b22 , =O, -NR ^b23 R ^b24 , -CN, -SF ₅ , -SO ₂ NR ^b56 R ^b57 , -SR ^b58 and -SO ₂ R ^b59 . In some embodiments, at least one R ^b5 is cycloalkyl, wherein each cycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) haloalkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl, 3 to 6 member heteroaryl, halo,- OH, -OH-(C ₁ -C ₆ )alkyl, =O, -NR ^b23 R ^b24 , -CN and -SF ₅ . In some embodiments, at least one R ^b5 is unsubstituted cycloalkyl.

In formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula ( In certain embodiments of compounds of II-B-ii) or their stereoisomers or pharmaceutically acceptable salts, at least one R ^b5 is an aryl group, where each aryl group is independently unsubstituted or Or more substituents independently selected from the group consisting of halo, -OR ^b22 , =O, -NR ^b23 R ^b24 , -CN, -SF ₅ , -SO ₂ NR ^b56 R ^b57 , -SR ^b58 , -SO ₂ R ^b59 and R ^b28 , wherein each R ^{b28 is} independently alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, each R ^{b28 is} independently (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, 3 to 8 membered heterocycloalkyl, (C ₆ -C ₁₀ ) Aryl or 3 to 8 member heteroaryl. In some embodiments, at least one R ^b5 is aryl, wherein the aryl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, =O, -SF ₅ and R ^b28 . In some embodiments, R ^b28 is unsubstituted (C ₁ -C ₆ )alkyl. In other embodiments, R ^b28 is (C ₁ -C ₆ )alkyl substituted with one or more substituents independently selected from the group consisting of halo, =O, -CN, aryl, hetero Aryl, alkynyl, cycloalkyl, heterocycloalkyl, -NR ^b29 R ^b30 , ^-SF ₅ and -OR ^b31 . In some embodiments, R ^b28 is (C ₁ -C ₆ )alkyl substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, aryl, hetero Aryl, cycloalkyl, heterocycloalkyl, -NR ^b29 R ^b30 , ^-SF ₅ , -OH, -O-(C ₁ -C ₆ ) alkyl and -O-(C ₁ -C ₆ ) haloalkanes base. In some embodiments, at least one R ^b5 is unsubstituted aryl.

In formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula ( In certain embodiments of compounds of II-B-ii) or their stereoisomers or pharmaceutically acceptable salts, at least one R ^b5 is heteroaryl, wherein each heteroaryl is independently unsubstituted or Substituted by one or more substituents independently selected from the group consisting of: halo, -OR ^b22 , =O, -NR ^b23 R ^b24 , -CN, -SF ₅ , -SO ₂ NR ^b56 R ^b57 ,- SR ^b58 , -SO ₂ R ^b59 and R ^b28 , wherein each R ^{b28 is} independently an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group. In some embodiments, each R ^{b28 is} independently (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, 3 to 8 membered heterocycloalkyl, (C ₆ -C ₁₀ ) Aryl or 3 to 8 member heteroaryl. In some embodiments, at least one R ^b5 is heteroaryl, wherein the heteroaryl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, =O, -SF ₅ and R ^b28 . In some embodiments, R ^b28 is unsubstituted (C ₁ -C ₆ )alkyl. In other embodiments, R ^b28 is (C ₁ -C ₆ )alkyl substituted with one or more substituents independently selected from the group consisting of halo, =O, -CN, aryl, hetero Aryl, alkynyl, cycloalkyl, heterocycloalkyl, -NR ^b29 R ^b30 , ^-SF ₅ and -OR ^b31 . In some embodiments, R ^b28 is (C ₁ -C ₆ )alkyl substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, aryl, hetero Aryl, cycloalkyl, heterocycloalkyl, -NR ^b29 R ^b30 , ^-SF ₅ , -OH, -O-(C ₁ -C ₆ ) alkyl and -O-(C ₁ -C ₆ ) haloalkanes base. In some embodiments, at least one R ^b5 is unsubstituted heteroaryl.

In formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula ( In certain embodiments of compounds of II-B-ii) or their stereoisomers or pharmaceutically acceptable salts, at least one R ^b5 is heterocycloalkyl, wherein each heterocycloalkyl is independently Substitution or substitution by one or more substituents independently selected from the group consisting of: halo, -OR ^b22 , =O, -NR ^b23 R ^b24 , -CN, -SF ₅ , -SO ₂ NR ^b56 R ^b57 , -SR ^b58 , -SO ₂ R ^b59, and R ^b28 , wherein each R ^{b28 is} independently an alkyl group, a cycloalkyl group, a heterocyclic alkyl group, an aryl group, or a heteroaryl group. In some embodiments, each R ^{b28 is} independently (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, 3 to 8 membered heterocycloalkyl, (C ₆ -C ₁₀ ) Aryl or 3 to 8 member heteroaryl. In some embodiments, at least one R ^b5 is heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, =O, -SF ₅ and R ^b28 . In some embodiments, R ^b28 is unsubstituted (C ₁ -C ₆ )alkyl. In other embodiments, R ^b28 is (C ₁ -C ₆ )alkyl substituted with one or more substituents independently selected from the group consisting of halo, =O, -CN, aryl, hetero Aryl, alkynyl, cycloalkyl, heterocycloalkyl, -NR ^b29 R ^b30 , ^-SF ₅ and -OR ^b31 . In some embodiments, R ^b28 is (C ₁ -C ₆ )alkyl substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, aryl, hetero Aryl, cycloalkyl, heterocycloalkyl, -NR ^b29 R ^b30 , ^-SF ₅ , -OH, -O-(C ₁ -C ₆ ) alkyl and -O-(C ₁ -C ₆ ) haloalkanes base. In some embodiments, at least one R ^b5 is unsubstituted heterocycloalkyl.

In formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula ( II-B-ii) In certain embodiments of the compound or its stereoisomer or pharmaceutically acceptable salt, each R ^b17 , R ^b18 , R ^b19 , R ^b20 , R ^b21 , R ^b22 , R ^{b23 , R b24, R b25, R} b26, R b27, R b54, R b55, R b56, R b57, R b58, R b59, R b61, R b62, R b63 and R ^b64 are independently hydrogen, an alkyl group, Haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl or haloalkynyl. In certain embodiments, each ^{R b17, R b18, R b19} , R b20, R b21, R b22, R b23, R b24, R b25, R b26, R b27, R b54, R b55, R b56, R ^b57 , R ^b58 , R ^b59 , R ^b61 , R ^b62 , R ^b63 and R ^{b64 are} independently hydrogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C _3- C ₆ )cycloalkyl, (C ₃ -C ₆ )halocycloalkyl, 3 to 10 membered heterocycloalkyl, (C ₆ -C ₁₀ )aryl, 3 to 10 membered heteroaryl, (C ₂ -C ₆ )alkynyl or (C ₂ -C ₆ )haloalkynyl.

In formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula ( II-B-ii) In certain embodiments of the compound or its stereoisomer or pharmaceutically acceptable salt, each R ^b20 , R ^b21 , R ^b22 , R ^b23 , R ^b24 , R ^b54 , R ^{b55 , R b56, R b57, R} b58, R b59, R b61, R b62, R b63 and R ^b64 are independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl. In certain embodiments, each ^{R b20, R b21, R b22} , R b23, R b24, R b25, R b54, R b55, R b56, R b57, R b58, R b59, R b61, R b62, R ^b63 and R ^{b64 are} independently hydrogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₃ -C ₆ )cycloalkyl or (C ₃ -C ₆ )halo Cycloalkyl. In some embodiments, each ^{R b17, R b18, R b25} , R b26 and R ^b27 are independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In certain embodiments, each ^{R b17, R b18, R b25} , R b26 and R ^b27 independently hydrogen, (C ₁ -C ₆₎ alkyl, (C ₃ -C ₆₎ cycloalkyl, 3 To 10-membered heterocycloalkyl, 3 to 10 membered heteroaryl or (C ₆ -C ₁₀ ) aryl. In some embodiments, each R ^{b19 is} independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkynyl. In certain embodiments, each R ^{b19 is} independently hydrogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, 3 to 10 membered heterocycloalkyl, (C _6- C ₁₀ ) aryl, 3- to 10-membered heteroaryl or (C ₃ -C ₆ ) alkynyl.

In formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula ( In certain embodiments of compounds of II-B-ii) or their stereoisomers or pharmaceutically acceptable salts, one or more R ^b5 are independently selected from the group consisting of: halo; -O -(C ₁ -C ₆ ) alkyl, which is unsubstituted or substituted with one or more fluorine; -O-(C ₂ -C ₄ ) alkynyl; phenyl; heteroaryl; heterocycloalkyl;- SO ₂ NH ₂ ; —NO ₂ ; —CN; (C ₃ -C ₆ )cycloalkyl, which is unsubstituted or substituted with one or more fluorine; and (C ₁ -C ₆ )alkyl, which is not Substitution or substitution by one or more substituents independently selected from the group consisting of (C ₃ -C ₆ )cycloalkyl, aryl, halo, -OH, -O-(C ₁ -C ₄ ) Alkyl, =O, -NR ^b26 R ^b27 and -CN.

In some embodiments, one or more R ^{b5 is} independently selected from the group consisting of: chlorine; fluorine; bromine; -O-(C ₁ -C ₆ ) alkyl, which is unsubstituted or substituted by one or more Fluorine substitution; -O-(C ₂ -C ₄ ) alkynyl; and -CN. Compounds of formula (I), formula (II), formula (II-A), formula (II-A-ii), formula (II-B) or formula (II-B-ii) or their stereoisomers Or in some embodiments of a pharmaceutically acceptable salt, n is 1 or 2, and each R ^b5 is independently selected from the group consisting of: chlorine; fluorine; bromine; -O-(C ₁ -C ₆ ) Alkyl, which is unsubstituted or substituted with one or more fluorine; -O-(C ₂ -C ₄ ) alkynyl; and -CN.

In formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula ( II-B-ii) In certain embodiments of the compound or its stereoisomer or pharmaceutically acceptable salt, R ^b17 , R ^b18 , R ^b19 , R ^b22 , R ^b23 , R ^b24 , R ^b25 , Each alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group and heteroaryl group of R ^b26 , R ^b27 and R ^b28 and each cycloalkyl group, heterocycloalkyl group, aryl group and heteroaryl group of R ^b65 are independent Is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, =O, -CN, aryl, heteroaryl, alkyl, alkynyl, cycloalkyl, hetero Cycloalkyl, -NR ^b29 R ^b30 , ^-SF ₅ and -OR ^b31 , where each aryl, heteroaryl, alkyl, cycloalkyl, and heterocycloalkyl are independently unsubstituted or substituted by one or more Substituent substituents independently selected from the group consisting of: alkyl, haloalkyl, alkynyl, halo, -CN, -SF ₅ , =O, -NR ^b43 R ^b44 , -NR ^b45 C(O)R ^b46 , -OR ^b47, and R ^b66 , wherein each R ^{b66 is} independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each R ^b66 is independently unsubstituted or substituted by one or more The ground is selected from the group consisting of substituent substitution: =O, -NH ₂ , -SF ₅ , -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl.

In certain embodiments, each alkyl group ^{R b17, R b18, R b19} , R b22, R b23, R b24, R b25, R b26, R b27 and R ^b28, the cycloalkyl, heterocycloalkyl, Aryl and heteroaryl and each cycloalkyl, heterocycloalkyl, aryl and heteroaryl of R ^b65 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of : Halo, =O, -CN, (C ₆ -C ₁₀ ) aryl, 5 to 10 member heteroaryl, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkynyl, ( C ₃ -C ₆ )cycloalkyl, 5- to 10-membered heterocycloalkyl, -NR ^b29 R ^b30 , -OR ^b31 and ^-SF ₅ , where each alkyl, cycloalkyl, heterocycloalkyl, aryl And heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₂ -C ₆ ) alkynyl, halo, -CN, -SF ₅ , =O, -NR ^b43 R ^b44 , -NR ^b45 C(O)R ^b46 , -OR ^b47 and R ^b66 , where each R ^b66 Independently (C ₃ -C ₆ )cycloalkyl, 5-membered to 10-membered heterocycloalkyl, (C ₆ -C ₁₀ )aryl, or 5-membered to 10-membered heteroaryl, and wherein each R ^b66 is Independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: =O, -NH ₂ , -SF ₅ , -OH, -O-(C ₁ -C ₆ )alkyl , -O-(C ₁ -C ₆ )haloalkyl, halo, (C ₁ -C ₆ )alkyl and (C ₁ -C ₆ )haloalkyl.

In certain embodiments, each alkyl group ^{R b17, R b18, R b19} , R b25, R b26, R b27 and R ^b28, the cycloalkyl, heterocycloalkyl, aryl and heteroaryl and R ^b65 The cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, =O, -CN , Aryl, heteroaryl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, -NR ^b29 R ^b30 , ^-SF ₅ and -OR ^b31 ; where each alkyl, cycloalkyl, heterocycloalkyl , Aryl and heteroaryl are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SF ₅ , =O, -NR ^b43 R ^b44 , -NR ^b45 C(O)R ^b46 , -OR ^b47 and R ^b66 , where each R ^{b66 is} independently cycloalkyl, heterocycloalkyl, aryl or heteroaryl , And wherein each R ^b66 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: =O, -NH ₂ , -SF ₅ , -OH, -O-alkyl , -O-haloalkyl, halo, alkyl and haloalkyl.

In some embodiments, each alkyl group ^{R b17, R b18, R b19} , R b25, R b26, R b27 and R ^b28, the cycloalkyl, heterocycloalkyl, aryl and heteroaryl and R ^b65 of Each cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, =O, -CN, (C ₆ -C ₁₀ )aryl, 5- to 10-membered heteroaryl, (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkynyl, (C ₃ -C ₆ )cycloalkyl, 5- to 10-membered heterocycloalkyl, -NR ^b29 R ^b30 , ^-SF ₅ and -OR ^b31 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently unsubstituted Or substituted by one or more substituents independently selected from the group consisting of: (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₂ -C ₆ )alkynyl, Halogen, -CN, -SF ₅ , =O, -NR ^b43 R ^b44 , -NR ^b45 C(O)R ^b46 , -OR ^b47 and R ^b66 , where each R ^{b66 is} independently (C ₃ -C ₆ ) Cycloalkyl, 5-membered to 10-membered heterocycloalkyl, (C ₆ -C ₁₀ )aryl, or 5-membered to 10-membered heteroaryl, and wherein each R ^b66 is independently unsubstituted or substituted by one or more Substituents independently selected from the group consisting of: =O, -NH ₂ , -SF ₅ , -OH, -O-(C ₁ -C ₆ )alkyl, -O-(C ₁ -C ₆ ) Haloalkyl, halo, (C ₁ -C ₆ )alkyl and (C ₁ -C ₆ )haloalkyl.

In some embodiments, each R ^b29 , R ^b30 , R ^b31 , R ^b43 , R ^b44 , R ^b45 , R ^b46 and R ^{b47 are} independently hydrogen, alkyl or haloalkyl. In certain embodiments, each R ^b29 , R ^b30 , R ^b31 , R ^b43 , R ^b44 , R ^b45 , R ^b46 and R ^{b47 are} independently hydrogen, (C ₁ -C ₆ )alkyl, or (C _1- C ₆ ) Haloalkyl.

， 其中： R^b33 為氫、烷基、炔基、環烷基、雜環烷基、雜芳基或芳基； 其中該烷基、環烷基、雜環烷基、雜芳基或芳基未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、烷基、環烷基、芳基、雜芳基、雜環烷基、=O、-OR^b36 、-SF₅ 及-NR^b37 R^b38 ； 其中各烷基、環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：烷基、鹵烷基、炔基、鹵基、-SF₅ 、=O、-OR^b39 、-NR^b48 R^b49 、-NR^b50 C(O)R^b51 、環烷基及雜環烷基，其中各環烷基及雜環烷基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：=O、鹵基、-OH及-SF₅ ； 各R^b34 及R^b35 獨立地為氫、鹵基或烷基； 其中各烷基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、環烷基、雜環烷基、芳基、雜芳基、-OR^b40 及-NR^b41 R^b42 ， 其中各環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、鹵烷基、烷基、-OH、=O及-SF₅ ； 或連接至同一原子之一個R^b34 及一個R^b35 與其所連接之原子一起形成環烷基或雜環烷基，其中該環烷基或雜環烷基未經取代或經一或多個鹵基取代； 各R^b36 、R^b37 、R^b38 、R^b39 、R^b40 、R^b41 、R^b42 、R^b48 、R^b49 、R^b50 及R^b51 獨立地為氫、烷基或鹵烷基； 且q為1或2。In formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula ( In certain embodiments of compounds of II-B-ii) or their stereoisomers or pharmaceutically acceptable salts, at least one R ^b5 is:

, Where: R ^b33 is hydrogen, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl Unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, =O, -OR ^b36 , -SF ₅ and -NR ^b37 R ^b38 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently unsubstituted or independently selected by one or more of the following Group substituent substitution: alkyl, haloalkyl, alkynyl, halo, -SF ₅ , =O, -OR ^b39 , -NR ^b48 R ^b49 , -NR ^b50 C(O)R ^b51 , cycloalkyl and Heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: =O, halo, -OH, and- SF ₅ ; each R ^b34 and R ^{b35 are} independently hydrogen, halo or alkyl; wherein each alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen Group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, -OR ^b40 and -NR ^b41 R ^b42 , wherein each cycloalkyl group, heterocycloalkyl group, aryl group and heteroaryl group are independently Substitution or substitution by one or more substituents independently selected from the group consisting of halo, haloalkyl, alkyl, -OH, =O, and -SF ₅ ; or one R ^b34 connected to the same atom and One R ^b35 and the atom to which it is connected form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group is unsubstituted or substituted with one or more halo groups; each R ^b36 , R ^b37 , R ^b38 , R ^b39 , R ^b40 , R ^b41 , R ^b42 , R ^b48 , R ^b49 , R ^b50 and R ^{b51 are} independently hydrogen, alkyl or haloalkyl; and q is 1 or 2.

In some embodiments, each ^{R b36, R b37, R b38} , R b39, R b40, R b41, R b42, R b48, R b49, R b50 and R ^b51 independently hydrogen, (C ₁ -C ₆ ) Alkyl or (C ₁ -C ₆ ) haloalkyl. In certain embodiments, each ^{R b36, R b37, R b38} , R b39, R b40, R b41, R b42, R b48, R b49, R b50 and R ^b51 are independently hydrogen, methyl, ethyl, , Propyl, butyl, halomethyl, haloethyl, halopropyl or halobutyl.

In some embodiments, R ^b33 is hydrogen. In other embodiments, R ^b33 is an alkyl group, wherein the alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, haloalkyl, cycloalkane ^Group , ^{halocycloalkyl} , aryl, heteroaryl, heterocycloalkyl, =O, -OR ^b36 , ^-SF ₅ and -NR ^b37 R ^b38 . In other embodiments, R ^b33 is an aryl group, wherein the aryl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, haloalkyl, cycloalkane ^Group , ^{halocycloalkyl} , aryl, heteroaryl, heterocycloalkyl, =O, -OR ^b36 , ^-SF ₅ and -NR ^b37 R ^b38 .

In certain embodiments, R ^b33 is an alkyl group, wherein the alkyl group is unsubstituted or substituted with an aryl or heteroaryl group, wherein the aryl or heteroaryl group is independently unsubstituted or substituted with one or more Substituent substituents independently selected from the group consisting of: alkynyl, alkyl, haloalkyl, halo, -SF ₅ , =O, -OR ^b39 , -NR ^b48 R ^b49 , -NR ^b50 C(O) R ^b51 and heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with =O. In some embodiments, the aryl or heteroaryl group is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: (C ₂ -C ₆ )alkynyl, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, halo, -SF ₅ ,=O, -OH, -O(C ₁ -C ₆ )alkyl, -O-(C _1- C ₆ )haloalkyl, -NHC(O)H, -NHC(O)-(C ₁ -C ₆ )alkyl, -NH ₂ ,-NH(C ₁ -C ₆ )alkyl and 3 to 6 Member heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with =O.

In some embodiments, R ^b33 is an alkyl group, wherein the alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, —SF ₅ , (C ₃ -C ₆ ) Cycloalkyl, 3 to 6 membered heterocycloalkyl, (C ₆ -C ₁₀ )aryl and 3 to 6 membered heteroaryl; wherein the aryl, cycloalkyl, heterocycloalkyl and hetero Aryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )alkyl , -SF ₅ , -OH, -O(C ₁ -C ₆ )alkyl, =O, -NR ^b48 R ^b49 and -NR ^b50 C(O)R ^b51 . In some embodiments, R ^b33 is an alkyl group substituted with one or more (C ₆ -C ₁₀ ) aryl groups, wherein each aryl group is independently unsubstituted or independently selected from the group consisting of Substituted by a group of substituents: (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, -OH, -O(C ₁ -C ₆ )alkyl, -SF ₅ , -NHC( O)-(C ₁ -C ₆ )alkyl and 3- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with =O. In certain embodiments, R ^b33 is (C ₁ -C ₆ )alkyl, wherein the alkyl is unsubstituted or substituted with one or more (C ₆ -C ₁₀ )aryl or 3 to 6 member heteroaryl Radical substitution.

In certain embodiments, R ^b33 is unsubstituted (C ₁ -C ₆ )alkyl. In other embodiments, R ^b33 is (C ₁ -C ₆ )alkyl substituted with 3 to 6 membered heteroaryl. In other embodiments, R ^b33 is (C ₁ -C ₆ )alkyl via phenyl, wherein the phenyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: ( C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkynyl, (C ₁ -C ₆ )haloalkyl, -OH, -O(C ₁ -C ₆ )alkyl, -SF ₅ ,- NHC(O)H and -NHC(O)-(C ₁ -C ₆ )alkyl. In other embodiments, R ^b33 is (C ₁ -C ₆ )alkyl via phenyl, wherein the phenyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: ( C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, -OH, -O(C ₁ -C ₆ )alkyl, -SF ₅ , -NHC(O)H, -NHC(O )-(C ₁ -C ₆ )alkyl, =O, -NH ₂ and -NH(C ₁ -C ₆ )alkyl.

In some embodiments, R ^b33 is (C ₁ -C ₆ )alkyl substituted with (C ₃ -C ₆ )cycloalkyl, wherein the cycloalkyl is unsubstituted or independently selected by one or more Substituted by substituents of the following group: halo, alkyl, haloalkyl, -OH and -O(C ₁ -C ₆ ) alkyl. In other embodiments, R ^b33 is (C ₁ -C ₆ )alkyl substituted with 3 to 6 membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or independently selected by one or more Substituted by substituents of the following group: halo, alkyl, haloalkyl, -OH and -O(C ₁ -C ₆ ) alkyl.

In some embodiments, R ^b33 is (C ₃ -C ₆ )cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, Alkyl, haloalkyl, -OH and -O(C ₁ -C ₆ )alkyl. In other embodiments, R ^b33 is a 3- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, Alkyl, haloalkyl, -OH and -O(C ₁ -C ₆ )alkyl.

In some embodiments, R ^b33 is a 3- to 10-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, -OH, -O(C ₁ -C ₆ )alkyl, -SF ₅ , -NHC(O)-(C _1- C ₆ )alkyl and 3- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with =O. In other embodiments, R ^b33 is a 3- to 10-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, Alkyl, haloalkyl, -OH and -O(C ₁ -C ₆ )alkyl.

In another embodiment, R ^b33 is an aryl group, wherein the aryl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: (C ₁ -C ₆ )alkyl, ( C ₁ -C ₆ )haloalkyl, -OH, -O(C ₁ -C ₆ )alkyl, -SF ₅ , -NHC(O)-(C ₁ -C ₆ )alkyl and 3 to 6 members Heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with =O. In other embodiments, R ^b33 is phenyl, wherein the phenyl is unsubstituted or substituted with one or more (C ₁ -C ₆ ) alkyl groups, wherein each alkyl group is independently unsubstituted or substituted with one or Multiple substituents independently selected from the group consisting of: (C ₁ -C ₆ )haloalkyl, -OH, -O(C ₁ -C ₆ )alkyl, -SF ₅ , -NHC(O) H, -NHC(O)-(C ₁ -C ₆ )alkyl, =O, -NH ₂ and -NH(C ₁ -C ₆ )alkyl.

In another embodiment, R ^b33 is heteroaryl, wherein the heteroaryl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: (C ₁ -C ₆ )alkyl , (C ₁ -C ₆ )haloalkyl, -OH, -O(C ₁ -C ₆ )alkyl, -SF ₅ , -NHC(O)-(C ₁ -C ₆ )alkyl and 3 members to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with =O.

In some embodiments, R ^b33 is alkynyl. In certain embodiments, R ^b33 is (C ₂ -C ₆ )alkynyl.

。In certain embodiments, R ^b33 is:

.

。In certain embodiments, R ^b33 is:

.

In some embodiments, R ^b34 and R ^b35 attached to the same carbon form a cycloalkyl group, wherein the cycloalkyl group is unsubstituted or substituted with one or more halo groups. In some embodiments, the cycloalkyl is (C ₃ -C ₆ )cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more halo groups. In certain embodiments, R ^b34 and R ^b35 attached to the same carbon form unsubstituted cyclopropyl or cyclobutyl. In some embodiments, R ^b34 and R ^b35 attached to the same carbon form a cyclopropyl or cyclobutyl group, wherein the cyclopropyl or cyclobutyl group is substituted with one or more halo groups.

In some embodiments, each R ^b34 and R ^b35 are hydrogen. In some embodiments, at least one R ^b34 or R ^b35 is an alkyl group, wherein the alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cycloalkyl, Halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR ^b40 and -NR ^b41 R ^b42 ; wherein each cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently unsubstituted Or substituted by one or more substituents independently selected from the group consisting of halo, haloalkyl, alkyl, -OH, =O, and -SF ₅ . In some embodiments, at least one R ^b34 or R ^b35 is an alkyl group, wherein the alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: fluorine, chlorine, bromine, ( C ₃ -C ₆ )cycloalkyl, (C ₃ -C ₆ )halocycloalkyl, 3 to 10 membered heterocycloalkyl, aryl, 3 to 6 membered heteroaryl, -OH, -O- (C ₁ -C ₆ )alkyl, -O-(C ₁ -C ₆ )haloalkyl, -NH ₂ , -NH(C ₁ -C ₆ )alkyl, -N((C ₁ -C ₆ ) Alkyl) ((C ₁ -C ₆ )alkyl). In some embodiments, one R ^b34 or one R ^b35 is (C ₁ -C ₆ ) alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: Fluorine, chlorine, (C ₃ -C ₆ )cycloalkyl, (C ₃ -C ₆ )halocycloalkyl and -OH. In certain embodiments, one R ^b34 or one R ^b35 is (C ₁ -C ₆ )alkyl, wherein the alkyl is unsubstituted or substituted by fluorine, chlorine, (C ₃ -C ₆ )cycloalkyl, ( C ₃ ) Halocycloalkyl or -OH substitution. In some embodiments, one R ^b34 or one R ^b35 is ethyl substituted with difluorocyclopropyl.

In some embodiments, at least one R ^b34 or R ^b35 is an alkyl group substituted with a 3- to 10-membered heterocycloalkyl group, wherein the heterocycloalkyl group is unsubstituted or independently selected from the group consisting of Substituted by a group of substituents: halo, haloalkyl, alkyl and =O. In certain embodiments, at least one R ^b34 or R ^b35 is an alkyl substituted with 4 to 10 membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or independently selected by one or more selected from The substituents of the constituent groups are substituted: fluorine, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl and =O. In certain embodiments, the 4- to 10-membered heterocycloalkyl is a polycyclic heterocycloalkyl. In some embodiments, at least one R ^b34 or R ^b35 is an alkyl substituted with 5 to 6 membered heteroaryl.

In some embodiments, q is 1. In other embodiments, q is 2. In some embodiments, q is 1, and one of R ^b34 or R ^b35 is hydrogen. In other embodiments, q is 2, and one R ^b34 and two R ^b35 are hydrogen. In other embodiments, q is 2, and two R ^b34 and one R ^b35 are hydrogen. In some embodiments, q is 2, and two R ^b34 and three R ^b35 are hydrogen. In some embodiments, q is 2, and three R ^b34 and two R ^b35 are hydrogen.

為

。Compounds of formula (I), formula (II), formula (II-A), formula (II-A-ii), formula (II-B) or formula (II-B-ii) or their stereoisomers Or some examples of pharmaceutically acceptable salts,

for

.

為

。In some embodiments of the compound of formula (I), formula (II-Ai) or formula (II-Bi), or its stereoisomer or pharmaceutically acceptable salt,

for

.

In formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula ( In some embodiments of the compound of II-B-ii) or its stereoisomer or pharmaceutically acceptable salt, X is -S(O)-, -S(O) ₂ -, -S(O) NR ^b53 -, -C(S)-, -C(O)- or -C(R ^b13 ) ₂ -. In some embodiments, X is -S(O) ₂ -, -C(O)-, or -C(R ^b13 ) ₂ -. In certain embodiments, X is -S(O)-, -S(O) ₂ -, or -S(O)NR ^b53 -. In other embodiments, X is -C(S)-, -C(O)-, or -C(R ^b13 ) ₂ -.

In formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula ( In some embodiments of the compound of II-B-ii) or its stereoisomer or pharmaceutically acceptable salt, X is -S(O)-.

In formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula ( In some embodiments of the compound of II-B-ii) or its stereoisomer or pharmaceutically acceptable salt, X is -S(O) ₂ -.

In formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula ( II-B-ii) In some embodiments of the compound or its stereoisomer or pharmaceutically acceptable salt, X is -S(O)NR ^b53 -, wherein R ^b53 is hydrogen or alkyl, wherein the The alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and =O. In some embodiments, R ^b53 is hydrogen or (C ₁ -C ₆ )alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, Cycloalkyl, heterocycloalkyl, aryl, heteroaryl and =O. In certain embodiments, R ^b53 is hydrogen. In other embodiments, R ^b53 is unsubstituted (C ₁ -C ₆ )alkyl, such as methyl, ethyl, propyl, butyl, pentyl, or hexyl. In other embodiments, R ^b53 is (C ₁ -C ₆ )alkyl substituted with one or more substituents independently selected from the group consisting of: fluorine, chlorine, (C ₃ -C ₆ )cycloalkane Group, 3-membered to 6-membered heterocycloalkyl, (C ₆ -C ₁₀ )aryl, 5-membered to 7-membered heteroaryl and =O. In another embodiment, R ^b53 is (C ₁ -C ₆ )alkyl substituted with one or more substituents independently selected from the group consisting of fluorine, chlorine, (C ₃ -C ₆ ) ring Alkyl and =O.

In formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula ( In some embodiments of the compound of II-B-ii) or its stereoisomer or pharmaceutically acceptable salt, X is -C(S)-.

In formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula ( In some embodiments of the compound of II-B-ii) or its stereoisomer or pharmaceutically acceptable salt, X is -C(O)-.

In formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula ( In some embodiments of the compound of II-B-ii) or its stereoisomer or pharmaceutically acceptable salt, X is -C(R ^b13 ) ₂ -, wherein each R ^{b13 is} independently hydrogen or halo , Alkyl or haloalkyl. In certain embodiments, each R ^{b13 is} independently hydrogen, halo, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )haloalkyl. In some embodiments, each R ^{b13 is} independently hydrogen, chlorine, fluorine, methyl, ethyl, propyl, -CH ₂ F, -CHF ₂ or -CF ₃ . In some embodiments, each R ^b13 is H, and X is -CH ₂ -.

In formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula ( In some embodiments of the compound of II-B-ii) or its stereoisomer or pharmaceutically acceptable salt, X is -S(O) ₂ -, -C(O)- or -CH ₂ -.

，或前述任一者之立體異構體或醫藥學上可接受之鹽。In some embodiments, formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II- The compound of Bi) or formula (II-B-ii) is:

, Or the stereoisomers or pharmaceutically acceptable salts of any of the foregoing.

，或前述任一者之立體異構體或醫藥學上可接受之鹽。In some embodiments, the compound of formula (I) or formula (II) is:

, Or the stereoisomers or pharmaceutically acceptable salts of any of the foregoing.

， 或前述任一者之立體異構體或醫藥學上可接受之鹽。In some embodiments, formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II- The compound of Bi) or formula (II-B-ii) is:

, Or a stereoisomer or pharmaceutically acceptable salt of any of the foregoing.

，或前述任一者之立體異構體或醫藥學上可接受之鹽。In some embodiments, the compound of formula (I) or formula (II) is:

, Or the stereoisomers or pharmaceutically acceptable salts of any of the foregoing.

，但本文亦提供此等式之立體異構體及具有如

的呈順式定向之R^b10 及R^b11 的化合物。當本文所描述之化合物含有其他烯系雙鍵或其他幾何不對稱中心時且除非另外說明，否則意欲化合物包括E與Z型幾何異構體。同樣，亦意欲包括所有互變異構形式。Compounds described herein include formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II -Bi) or the compound of formula (II-B-ii), its stereoisomer or pharmaceutically acceptable salt, may contain one or more asymmetric centers and can thus produce enantiomers, diastereomers Isomers or other stereoisomeric forms in terms of absolute stereochemistry can be defined as ( R )- or ( S )-. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-) or ( R )- and ( S )-isomers can be prepared using palatal synthons or palatal reagents, or using conventional techniques (such as chromatography and analysis) Step crystallization) to decompose. Techniques for preparation/separation of individual enantiomers include palmitic synthesis from suitable optically pure precursors or the use of, for example, palmitic high pressure liquid chromatography (HPLC) racemates (or salts or derivatives) Racemate) to decompose. Although formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) and formula (II-B-ii ) And the compounds of this equation disclosed herein depict R ^b10 and R ^{b11 in} reverse orientation as

, But this article also provides stereoisomers of this equation and has

Of R ^b10 and R ^b11 in cis orientation. When the compounds described herein contain other olefinic double bonds or other centers of geometric asymmetry and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, it is intended to include all tautomeric forms.

"Pharmaceutically acceptable salts" include salts that are generally safe, harmless, and biologically or otherwise undesirable, and include salts that are acceptable for veterinary use and acceptable for use as human medicine. Such salts may include acid addition salts and base addition salts. Acid addition salts can be formed by: inorganic acids such as (but not limited to) hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as (but not limited to) acetic acid, 2,2- Dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, Caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexylamine sulfonic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid Acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxoglutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, Isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucinic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid Acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyruvic acid, pyruvic acid, salicylic acid, 4-amino Salicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid or undecylenic acid. Salts derived from inorganic bases may include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from organic bases may include (but are not limited to): salts of primary, secondary, or tertiary amines; substituted amines, including naturally occurring substituted amines; cyclic amines; ammonia, isopropylamine, trimethylamine , Diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, danol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, group Amino acids, caffeine, procaine, hydrabamine, choline, betaine, phenamine, benzathine, ethylenediamine, glucosamine, methylglucosamine, Cocoa base, triethanolamine, tromethamine, purine, piperazine, piperidine or N-ethylpiperidine.

Unless otherwise stated, the compounds provided herein (including formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II- B), compounds of formula (II-Bi) or formula (II-B-ii) or their stereoisomers or pharmaceutically acceptable salts) also include only one or more atoms that are isotopically enriched There are different compounds. For example, the compound has the structure of the present invention except that hydrogen is replaced with deuterium (D or ² H) or tritium ( ³ H) or carbon 12 is replaced with carbon 13 ( ¹³ C) or carbon 14 ( ¹⁴ C).

Compounds disclosed herein, such as formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II -Bi) or the compound of formula (II-B-ii) or its stereoisomer or pharmaceutically acceptable salt, for example, through general procedure II-1, general procedure II-2 and general procedure II-3 Preparation of the depicted reaction route. General process II-1:

General Scheme II-1 provides for the preparation of compounds disclosed herein (such as formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), Two routes of the compound of formula (II-Bi) or formula (II-B-ii) or its stereoisomer or pharmaceutically acceptable salt). In this procedure, the compound II-102 and the third butyl butyn-3-ylcarbamate (compound II-104 ), RhCl (PPh ₃ ) ₃ and a solvent (such as dichloroethane, DCE ) Combined, and the mixture was stirred at room temperature to produce compound II-106 . This compound is then combined with m-chloroperoxybenzoic acid ( m CPBA) and a solvent (such as dichloromethane, DCM), and the mixture is stirred from 0°C to room temperature to produce compound II-108 . This compound was combined with trifluoroacetic acid (TFA) and a solvent (such as DCM), and stirred from 0°C to room temperature to remove the BOC protecting group and produce compound II-110 . Combine compound II-110 with compound II-112 , hexafluorophosphate 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3 -The oxide, triethylamine (Et ₃ N) and solvent (such as DCM) are combined and stirred at room temperature to produce compound II-114 . This compound was combined with TFA and a solvent (such as DCM) and stirred from 0°C to room temperature to remove the BOC protecting group and produce compound II-116 . After BOC removal, in route (A), the product is combined with triethylamine, a solvent (such as DCM), and RB-carbonyl chloride reactant, where R ^B is substituted or unsubstituted aryl, hetero Aryl, cycloalkyl or heterocycloalkyl. This mixture is then stirred at room temperature to produce compound II-118 , ie formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), Examples of compounds of formula (II-Bi) or formula (II-B-ii) or their stereoisomers or pharmaceutically acceptable salts, wherein X is -C(O)-. Alternatively, in route (B) in the product with triethylamine, the solvent (such as DCM), HATU, and R ^B -COOH reactions were combined and stirred at room temperature to give Compound II-118, i.e., of formula (II) , Compound of formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula (II-B-ii) or Examples of stereoisomers or pharmaceutically acceptable salts, where X is -C(O)-. General process II-2 :

General Scheme II-2 provides for the preparation of compounds disclosed herein (such as Formula (II), Formula (II-A), Formula (II-Ai), Formula (II-A-ii), Formula (II-B), Another route of the compound of formula (II-Bi) or formula (II-B-ii) or its stereoisomer or pharmaceutically acceptable salt). In this scheme, compound II-202 is combined with 4-(trifluoromethyl)thiophenol (compound II-204 ), Pd(OAc) ₂ and a solvent (such as tetrahydrofuran, THF), and stirred at room temperature to produce Compound II-206 . This compound is then combined with m CPBA and a solvent (such as DCM) and stirred from 0°C to room temperature to produce compound II-208 , which is formula (II), formula (II-A), formula (II-Ai) , Compounds of formula (II-A-ii), formula (II-B), formula (II-Bi) or formula (II-B-ii) or stereoisomers or pharmaceutically acceptable salts thereof , Where X is -C(O)-. General process II-3 :

General Scheme II-3 provides for the preparation of compounds disclosed herein (such as Formula (II), Formula (II-A), Formula (II-Ai), Formula (II-A-ii), Formula (II-B), Two routes of the compound of formula (II-Bi) or formula (II-B-ii) or its stereoisomer or pharmaceutically acceptable salt). In this scheme, compound II-302 is combined with tert-butyl-3-butyn-1-ylcarbamate (compound II-304 ), Cp ₂ Zr(H)Cl, and a solvent (such as tetrahydrofuran, THF) , And the mixture was stirred from room temperature to 60°C to produce compound II-306 . This compound is then combined with TFA and a solvent (such as DCM) and stirred from 0°C to room temperature to produce compound II-308 . Compound II-308 was combined with compound II-310 , HATU, triethylamine, and a solvent (such as DCM), and stirred at room temperature to produce compound II-312 . This compound was combined with TFA and a solvent (such as DCM) and stirred from 0°C to room temperature to remove the BOC protecting group and produce compound II-314 . After BOC removal, in route (A), compound II-314 can be combined with triethylamine, a solvent (such as DCM), and R ^B -carbonyl chloride reactant, where R ^B is a substituted or unsubstituted aromatic Radical, heteroaryl, cycloalkyl or heterocycloalkyl. This mixture is then stirred at room temperature to produce compound II-316 , namely formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), Examples of compounds of formula (II-Bi) or formula (II-B-ii) or their stereoisomers or pharmaceutically acceptable salts, where X is -C(O)-. Alternatively, in route (B), the compound II-314 with triethylamine and a solvent (such as DCM), HATU, and R ^B -COOH reactions were combined and stirred at room temperature to give Compound II-316, i.e., of formula ( Compound II), Formula (II-A), Formula (II-Ai), Formula (II-A-ii), Formula (II-B), Formula (II-Bi) or Formula (II-B-ii) Or an example of a stereoisomer or a pharmaceutically acceptable salt thereof, wherein X is -C(O)-.

Although the general schemes II-1, II-2 and II-3 depict formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii) with certain substituents or moieties ), the compound of formula (II-B), formula (II-Bi) or formula (II-B-ii) or its stereoisomer or pharmaceutically acceptable salt, but in some embodiments, Other compounds according to this equation can also be prepared following similar reaction procedures. For example, compounds similar to general schemes II-1, II-2, and II-3 can also be used to synthesize compounds, where ring A is not a 5- or 6-membered heterocycloalkyl; where ring A is substituted; ring W is not phenyl, or contains a substituent other than Cl; wherein R ^b6 , R ^b7 , R ^b8 , R ^b9 , R ^b10 or R ^{b11 are} not hydrogen; or z is not 1. Furthermore, in some embodiments of any of these routes, one or more other solvents are used in one or more steps. In some embodiments, amines other than triethylamine are used in one or more steps. In some embodiments, the temperature is adjustable. To prepare formula (II), formula (II-A), formula (II-Ai), formula (II-A-) by the following general procedure II-1, II-2 or II-3 or by another route ii), compounds of formula (II-B), formula (II-Bi) or formula (II-B-ii) or their stereoisomers or pharmaceutically acceptable salts of reactants, solvents and other compounds may It is commercially available or may be prepared following organic chemistry techniques.

Further provided herein is a pharmaceutical composition comprising formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi ) Or the compound of formula (II-B-ii) or its stereoisomer or pharmaceutically acceptable salt, and pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients can include, for example, adjuvants, carriers, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents Agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers, which have been approved by the US Food and Drug Administration as acceptable for human use. Pharmaceutically acceptable excipients can include (but are not limited to): water, NaCl, standard physiological saline solution, lactated Ringer's solution (lactated Ringer's solution), standard sucrose, standard glucose, binder, filler, disintegration Solution, lubricant, coating, sweetener, flavoring agent, salt solution (such as Ringer's solution), alcohol, oil, gelatin, carbohydrate (such as lactose, amylose or starch), fatty acid ester, hydroxyl Methyl cellulose, polyvinylpyrrolidine and pigments. II. Treatment

Provided herein is a method of treating a disorder in an individual in need thereof, which comprises administering to the individual a therapeutically effective amount of formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II -A-ii), Formula (II-B), Formula (II-Bi) or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof. Also provided is a method of treating a disorder in an individual in need thereof, which comprises administering to the individual a therapeutically effective amount of a pharmaceutical composition, the pharmaceutical composition comprising formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula (II-B-ii) or its stereoisomer or pharmaceutical Accepted salts and pharmaceutically acceptable excipients. In some embodiments, the compound administered to an individual in need according to the methods described herein is the compound described in the examples, examples, schemes or tables herein, or the stereoisomers or pharmaceuticals thereof Acceptable salt.

Also provided herein are formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or The use of the compound of formula (II-B-ii) or its stereoisomer or pharmaceutically acceptable salt is for the manufacture of a medicament for the treatment of a disorder in an individual in need.

This document further provides formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or The compound of formula (II-B-ii) or its stereoisomer or pharmaceutically acceptable salt is used in a method for treating a condition in an individual in need.

In some embodiments of the methods and uses provided herein, the disorder is associated with K-Ras, such as a disorder associated with mutations in K-Ras or abnormal regulation of K-Ras. In some embodiments, provided herein are methods and uses of, the disorder associated with KRAS gene, e.g. disorder associated with mutations in the KRAS gene regulation or KRAS gene. The mutation or abnormal regulation of K-Ras or KRAS may include the mutation or abnormal regulation of human K-Ras4a and/or human K-Ras4b. In some embodiments, the disorder is associated with K-Ras (eg, human K-Ras4a and/or human K-Ras4b) signaling pathway activity, such as a disorder associated with abnormal K-Ras signaling pathway activity. In some embodiments, the disorder is associated with mutations or dysregulation of K-Ras4b in humans. In certain embodiments, the disorder is associated with abnormal K-Ras4b signaling pathway activity.

In some embodiments, the condition is neurofibromatosis type 1 (NF1), Noonan syndrome, heart-face-skin syndrome, or Regis syndrome. In certain embodiments, the condition is neurofibromatosis type 1 (NF1). NF1 is a condition that makes individuals susceptible to cancer. Individuals with NF1 are at greater risk compared to the general population who develops malignant diseases (which may include pediatric malignant diseases or adult malignant diseases). Pediatric malignancies may include glioma, rhabdomyosarcoma, neuroblastoma, and juvenile myelomonocytic leukemia in the optic nerve pathway. Adult malignancies may include malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, somatostatin tumors, pheochromocytoma, and breast cancer.

In some embodiments of the methods and uses provided herein, the disorder is cancer. In some embodiments, the cancer is associated with K-Ras, such as cancer associated with mutations in K-Ras or abnormal regulation of K-Ras. In some embodiments, provided herein are methods and uses of, the cancer is associated with the KRAS gene, such as cancer related to abnormal regulation of the mutant gene or KRAS KRAS gene. The mutation or abnormal regulation of K-Ras or KRAS may include the mutation or abnormal regulation of human K-Ras4a and/or human K-Ras4b. In some embodiments, the cancer is associated with K-Ras (eg, human K-Ras4a and/or human K-Ras4b) signaling pathway activity, such as cancer associated with abnormal K-Ras signaling pathway activity. In some embodiments, the cancer is associated with mutations or dysregulation of human K-Ras4b. In certain embodiments, the cancer is associated with abnormal K-Ras4b signaling pathway activity.

In some embodiments, the cancer is pancreatic cancer, lung cancer, colorectal cancer, optic nerve path glioma, rhabdomyosarcoma, neuroblastoma, juvenile myelomonocytic leukemia, malignant peripheral nerve sheath tumor, gastrointestinal stromal tumor, Somatostatin tumor, pheochromocytoma or breast cancer. Therefore, in one aspect, provided herein is a method of treating cancer in an individual in need thereof, which comprises administering formula (I), formula (II), formula (II-A), formula (II-Ai) to the individual ), the compound of formula (II-A-ii), formula (II-B), formula (II-Bi) or formula (II-B-ii) or its stereoisomer or pharmaceutically acceptable salt, The cancers are pancreatic cancer, lung cancer, colorectal cancer, optic nerve path glioma, rhabdomyosarcoma, neuroblastoma, juvenile bone marrow mononuclear leukemia, malignant peripheral schwannoma, gastrointestinal stromal tumor, somatostatin tumor, Pheochromocytoma or breast cancer. In some embodiments, the cancer is breast cancer. In other embodiments, the cancer is pancreatic cancer. In another embodiment, the cancer is colorectal cancer. In certain embodiments, the cancer is lung cancer. In some embodiments, formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II- Bi) or the compound of formula (II-B-ii) or its stereoisomer or pharmaceutically acceptable salt is administered to an individual in need together with one or more chemotherapeutic agents.

In another aspect, provided herein is a method for reducing the content of K-Ras protein in an individual in need thereof, which comprises administering to the individual a therapeutically effective amount of formula (I), formula (II), formula (II- A), compounds of formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula (II-B-ii) or their stereoisomers or Pharmaceutically acceptable salt. In yet another aspect, provided herein are formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or the compound of formula (II-B-ii) or its stereoisomer or pharmaceutically acceptable salt, which is used in a method for reducing the content of K-Ras protein in an individual in need . In another aspect, provided herein are formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula The use of the compound of (II-Bi) or formula (II-B-ii) or its stereoisomer or pharmaceutically acceptable salt, which is used to reduce the content of K-Ras protein in individuals in need Used in the manufacture of medicines. In some embodiments of these aspects, the K-Ras protein is human K-Ras4a and/or human K-Ras4b. In certain embodiments, K-Ras is human K-Ras4b. In certain embodiments, K-Ras is human K-Ras4a. In some embodiments, K-Ras is abnormal K-Ras. In some embodiments, K-Ras is a mutant K-Ras. The reduction in K-Ras content can be evaluated, for example, by immunoblotting of a biological sample using one or more specific anti-K-Ras antibodies or by a method based on mass spectrometry.

In some embodiments, formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), Compounds of formula (II-Bi) or formula (II-B-ii) or their stereoisomers or pharmaceutically acceptable salts can block K-Ras precursors (such as K-Ras4a precursors or K-Ras4b Precursor) One or more post-translational processing steps. This untreated precursor can then be degraded by the body, thereby reducing the content of K-Ras protein. In some embodiments, formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II- Bi) or the compound of formula (II-B-ii) or its stereoisomer or pharmaceutically acceptable salt is covalently bound to a K-Ras precursor (such as K-Ras4a precursor or K-Ras4b precursor) C185 amino acid residues to block one or more post-translational modifications. In some embodiments, the blocked post-translational modification is farnesylation.

In another aspect, provided herein is a method of reducing the activity of K-Ras protein in an individual in need thereof, which comprises administering to the individual a therapeutically effective amount of formula (I), formula (II), formula (II -A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or formula (II-B-ii) or their stereoisomers Or a pharmaceutically acceptable salt. In yet another aspect, provided herein are formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula (II-Bi) or the compound of formula (II-B-ii) or its stereoisomer or pharmaceutically acceptable salt, which is used in a method for reducing the activity of K-Ras protein in an individual in need . In another aspect, provided herein are formula (I), formula (II), formula (II-A), formula (II-Ai), formula (II-A-ii), formula (II-B), formula The use of a compound of (II-Bi) or formula (II-B-ii) or a stereoisomer or pharmaceutically acceptable salt thereof for reducing the activity of K-Ras protein in an individual in need The manufacture and use of the medicine. In some embodiments of these aspects, the K-Ras protein is human K-Ras4a and/or human K-Ras4b. In certain embodiments, K-Ras is human K-Ras4b.

In some embodiments, both the activity of K-Ras and the content of K-Ras are reduced in individuals in need.

"Effective amount" or "therapeutically effective amount" refers to an amount of a compound of the present invention that is sufficient to affect treatment when administered to a mammal (eg, a human). The amount of the compound of the present invention constituting the "therapeutically effective amount" may vary depending on the compound, the condition and its severity, the mode of administration, and the age of the mammal to be treated.

The term "treat/treating/treatment" refers to any sign of success in the improvement of an injury, disease, disorder, lesion, or condition, including any objective or subjective parameters, such as slowing, alleviating, or alleviating symptoms; or allowing the individual Be more tolerant to injuries, diseases, disorders, lesions, or conditions; delay or stop the rate of deterioration, decline, or progression; delay the progression of injuries, diseases, disorders, diseases, or conditions; make the end point of deterioration less debilitating; improve the individual's Physical or mental health; or alleviate or cause the regression of injury, disease, illness, pathology, or condition. Treatment of symptoms, including improvement of symptoms, can be based on objective or subjective parameters, which can include results of physical examination, neuropsychiatric examination, and/or mental assessment. Certain methods disclosed herein can treat cancer, for example, by: reducing the incidence of cancer; easing cancer; slowing the growth rate of cancer cells; slowing the rate of cancer cell proliferation; reducing cancer metastasis or reducing metastatic tumors Growth; reducing the size of one or more tumors; reducing the number of one or more tumors; or any combination thereof.

"Co-administration" includes administration of a compound as described herein, its stereoisomer, or a pharmaceutically acceptable salt thereof at the same time, before, or after administration of one or more other therapies (such as chemotherapeutic agents) A composition containing any of these. One or more compounds or salts thereof and one or more other therapies disclosed herein may be co-administered as a single combination, or may be co-administered simultaneously or sequentially as two or more separate forms. Enumerated examples

， 或其立體異構體或醫藥學上可接受之鹽，其中： A為4員至8員雜環烷基； B為芳基、雜芳基、環烷基或雜環烷基； W為芳基或雜芳基； X為-S(O)-、-S(O)₂ -、-S(O)NR^b53 -、-C(S)-、-C(O)-或-C(R^b13 )₂ -； 各R^b13 獨立地為氫、鹵基、烷基或鹵烷基； R^b53 為氫或烷基，其中該烷基未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、環烷基、雜環烷基、芳基、雜芳基及=O； R^b1 為氫、烷基、鹵烷基、環烷基或鹵環烷基； z為0、1或2； R^b2 、R^b3 、R^b6 、R^b7 、R^b8 、R^b9 、R^b10 及R^b11 係獨立地選自由以下組成之群：氫、鹵基、烷基、環烷基、雜環烷基、-CN、-NO₂ 、 -NR^b13 R^b14 、-OR^b15 、-SO₂ R^b16 及-SO₂ NH₂ ，其中各烷基、環烷基及雜環烷基係獨立地未經取代或經一或多個鹵基取代，且其中在R^b6 及R^b7 中之一者為烷基時，z為1； 各R^b4 獨立地選自由以下組成之群：鹵基、烷基、環烷基、雜環烷基、雜芳基、芳基、-NO₂ 、-CN、-SO₂ NH₂ 、-NR^b13 R^b14 、-OR^b15 、=O、-SR^b60 及-SO₂ R^b16 ，其中各烷基、環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個鹵基取代； 各R^b13 、R^b14 、R^b15 、R^b16 及R^b60 獨立地為氫、烷基、鹵烷基、環烷基、鹵環烷基、雜環烷基或鹵雜環烷基； 或R^b2 及R^b3 一起形成=O； 或R^b6 及R^b1 與其所連接之原子一起形成雜環烷基，其未經取代或經一或多個鹵基取代； 或R^b10 及R^b1 與其所連接之原子一起形成雜環烷基，其未經取代或經一或多個鹵基取代； 或R^b8 及R^b1 與其所連接之原子一起形成雜環烷基，其未經取代或經一或多個鹵基取代； 或兩個至四個R^b2 、R^b3 、R^b6 及R^b7 與其所連接之原子一起形成雜環烷基或雜芳基，其中該雜環烷基或雜芳基未經取代或經一或多個鹵基取代； 或R^b1 及一個R^b4 與其所連接之原子一起形成雜環烷基，其未經取代或經一或多個鹵基取代； 或兩個至四個R^b4 與其所連接之原子一起形成芳基、雜芳基、環烷基或雜環烷基，其中該芳基、雜芳基、環烷基或雜環烷基未經取代或經一或多個鹵基取代； 各R^b5 係獨立地選自由以下組成之群：鹵基、烷基、環烷基、雜環烷基、芳基、雜芳基、炔基、-NO₂ 、-CN、-SO₂ NR^b54 R^b55 、-NR^b17 R^b18 、 -OR^b19 、-SO₂ R^b20 、=O及-SR^b21 ； 其中各環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、-OR^b22 、=O、 -NR^b23 R^b24 、-CN、-SF₅ 、-SO₂ NR^b56 R^b57 、-SR^b58 、-SO₂ R^b59 及R^b28 ，其中各R^b28 獨立地為烷基、環烷基、雜環烷基、芳基或雜芳基； 各烷基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、-OR^b25 、=O、-NR^b26 R^b27 、-CN、-SF₅ 、 -SO₂ NR^b61 R^b62 、-SR^b63 、-SO₂ R^b64 及R^b65 ，其中各R^b65 獨立地為環烷基、雜環烷基、芳基或雜芳基； 各R^b17 、R^b18 、R^b19 、R^b20 、R^b21 、R^b22 、R^b23 、R^b24 、R^b25 、R^b26 、R^b27 、R^b54 、R^b55 、R^b56 、R^b57 、R^b58 、R^b59 、R^b61 、R^b62 、R^b63 及R^b64 獨立地為氫、烷基、鹵烷基、環烷基、鹵環烷基、雜環烷基、芳基、雜芳基、炔基或鹵炔基； 其中R^b17 、R^b18 、R^b19 、R^b22 、R^b23 、R^b24 、R^b25 、R^b26 、R^b27 及R^b28 之各烷基、環烷基、雜環烷基、芳基及雜芳基以及R^b65 之各環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、=O、-CN、芳基、雜芳基、烷基、炔基、環烷基、雜環烷基、-NR^b29 R^b30 、-SF₅ 及-OR^b31 ； 其中各芳基、雜芳基、烷基、環烷基及雜環烷基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：烷基、鹵烷基、炔基、鹵基、-CN、-SF₅ 、=O、-NR^b43 R^b44 、-NR^b45 C(O)R^b46 、-OR^b47 及R^b66 ，其中各R^b66 獨立地為環烷基、雜環烷基、芳基或雜芳基，且其中各R^b66 係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：=O、-NH₂ 、-SF₅ 、-OH、-O-烷基、-O-鹵烷基、鹵基、烷基及鹵烷基； 各R^b29 、R^b30 、R^b31 、R^b43 、R^b44 、R^b45 、R^b46 及R^b47 獨立地為氫、烷基或鹵烷基； 各R^b12 係獨立地選自由以下組成之群：鹵基、烷基、鹵烷基及 -OR^b32 ，其中R^b32 為氫、烷基或鹵烷基； m為0至13之整數； n為0至11之整數；及 t為0至6之整數。Example I-1. A compound of formula (I):

, Or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: A is a 4- to 8-membered heterocycloalkyl; B is an aryl, heteroaryl, cycloalkyl or heterocycloalkyl; W is Aryl or heteroaryl; X is -S(O)-, -S(O) ₂ -, -S(O)NR ^b53 -, -C(S)-, -C(O)- or -C( R ^b13 ) ₂ -; each R ^{b13 is} independently hydrogen, halo, alkyl or haloalkyl; R ^b53 is hydrogen or alkyl, wherein the alkyl is unsubstituted or independently selected by one or more of the following Substituted by the group of substituents: halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and =O; R ^b1 is hydrogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl ; Z is 0, 1 or 2; R ^b2 , R ^b3 , R ^b6 , R ^b7 , R ^b8 , R ^b9 , R ^b10 and R ^b11 are independently selected from the group consisting of hydrogen, halo, alkyl, Cycloalkyl, heterocycloalkyl, -CN, -NO ₂ , -NR ^b13 R ^b14 , -OR ^b15 , -SO ₂ R ^b16 and -SO ₂ NH ₂ , where each alkyl, cycloalkyl and heterocycloalkane The radicals are independently unsubstituted or substituted with one or more halo groups, and where one of R ^b6 and R ^b7 is alkyl, z is 1; each R ^{b4 is} independently selected from the group consisting of: Halo, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, -NO ₂ , -CN, -SO ₂ NH ₂ , -NR ^b13 R ^b14 , -OR ^b15 , =O, -SR ^b60 and -SO ₂ R ^b16 , wherein each alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group and heteroaryl group are independently unsubstituted or substituted with one or more halogen groups; each R ^b13 , R ^b14 , R ^b15 , R ^b16 and R ^{b60 are} independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl or haloheterocycloalkyl; or R ^b2 and R ^b3 together form = O; or R ^b6 and R ^b1 together with the atoms to which they are attached form a heterocycloalkyl, which is unsubstituted or substituted with one or more halo groups; or R ^b10 and R ^b1 together with the atoms to which they are attached form a heterocycloalkane Group, which is unsubstituted or substituted with one or more halo groups; or R ^b8 and R ^b1 together with the atoms to which they are attached form a heterocycloalkyl group, which is unsubstituted or substituted with one or more halo groups; or both From four to four R ^b2 , R ^b3 , R ^b6 and R ^b7 together with the atoms to which they are attached form a heterocycloalkyl or heteroaryl group, wherein the heterocycloalkyl or heteroaryl group is unsubstituted or substituted by one or more Halo substitution; or R ^b1 and one R ^b4 together with the atoms to which they are attached form a heterocycloalkyl group which is unsubstituted or substituted with one or more halo groups; or two to four R ^b4 and the atoms to which they are attached Together form an aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl is not Substituted or substituted with one or more halo groups; each R ^b5 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl,- _{NO 2, -CN, -SO 2 NR} b54 R b55, -NR b17 R b18, -OR b19, -SO 2 R b20, = O and -SR ^b21; wherein each cycloalkyl, heterocycloalkyl, aryl, And heteroaryl groups are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -OR ^b22 , =O, -NR ^b23 R ^b24 , -CN, -SF ₅ , -SO ₂ NR ^b56 R ^b57 , -SR ^b58 , -SO ₂ R ^b59 and R ^b28 , where each R ^{b28 is} independently alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; The alkyl group is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, -OR ^b25 , =O, -NR ^b26 R ^b27 , -CN, ^-SF ₅ , -SO ₂ NR ^b61 R ^b62 , -SR ^b63 , -SO ₂ R ^b64 and R ^b65 , where each R ^{b65 is} independently cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each R ^b17 , R ^{b18 , R b19, R b20, R} b21, R b22, R b23, R b24, R b25, R b26, R b27, R b54, R b55, R b56, R b57, R b58, R b59, R b61, R ^b62 , R ^b63 and R ^{b64 are} independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl or haloalkynyl; wherein R ^b17 , R ^b18 , R ^b19 , R ^b22 , R ^b23 , R ^b24 , R ^b25 , R ^b26 , R ^b27 and R ^b28 each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl and R ^b65 Each cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, =O, -CN , Aryl, heteroaryl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, -NR ^b29 R ^b30 , ^-SF ₅ and -OR ^b31 ; where each aryl, heteroaryl, alkyl, ring Alkyl and heterocycloalkyl are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SF ₅ , =O, -NR ^b43 R ^b44 , -NR ^b45 C(O)R ^b46 , -OR ^b47 and R ^b66 , where each R ^{b 66 is} independently cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and wherein each R ^b66 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: =O, -NH ₂ , -SF ₅ , -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl; each R ^b29 , R ^b30 , R ^b31 , R ^b43 , R ^b44 , R ^b45 , R ^b46 and R ^{b47 are} independently hydrogen, alkyl or haloalkyl; each R ^b12 is independently selected from the group consisting of halo, alkyl, haloalkyl and -OR ^b32 , Where R ^b32 is hydrogen, alkyl or haloalkyl; m is an integer from 0 to 13; n is an integer from 0 to 11; and t is an integer from 0 to 6.

Example I-2. The compound as in Example I-1 or its stereoisomer or pharmaceutically acceptable salt, wherein: A is a 4-membered to 8-membered heterocycloalkyl; B is an aryl, heteroaryl Group, cycloalkyl or heterocycloalkyl; W is aryl or heteroaryl; X is -S(O)-, -S(O) ₂ -, -S(O)NR ^b53 -, -C(S )-, -C(O)- or -C(R ^b13 ) ₂ -; each R ^{b13 is} independently hydrogen, halo, alkyl or haloalkyl; R ^b53 is hydrogen or alkyl, wherein the alkyl group is not Substituted or substituted with one or more substituents independently selected from the group consisting of halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and =O; R ^b1 is hydrogen, alkyl Or cycloalkyl; z is 0 or 1; R ^b2 , R ^b3 , R ^b6 , R ^b7 , R ^b8 , R ^b9 , R ^b10 and R ^b11 are independently selected from the group consisting of hydrogen, halo, alkyl Group, haloalkyl, -CN, -OH, -NO ₂ , -NH ₂ and -SO ₂ NH ₂ , where one of R ^b6 and R ^b7 is alkyl, z is 1; each R ^b4 is Independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO ₂ , -CN, -SO ₂ NH ₂ , -NR ^b13 R ^b14 , -OR ^b15 , =O, -SR ^b60 and -SO ₂ R ^b16 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently unsubstituted or substituted by one or more halogen ^Group substitution; and each R ^b13 , R ^b14 , R ^b15 , R ^b16 and R ^{b60 is} independently hydrogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; or R ^b2 and R ^b3 together form =O ; Or R ^b6 and R ^b1 together with the atoms to which they are attached form a heterocycloalkyl; or R ^b10 and R ^b1 together with the atoms to which they are attached form a heterocycloalkyl; or R ^b8 and R ^b1 together with the atoms to which they are attached Heterocycloalkyl; or two to four R ^b2 , R ^b3 , R ^b6 and R ^b7 together with the atoms to which they are attached form a heterocycloalkyl or heteroaryl; or R ^b1 and one R ^b4 to the atoms to which they are attached Together form a heterocycloalkyl; or two to four R ^b4 together with the atoms to which they are attached form an aryl, heteroaryl, cycloalkyl or heterocycloalkyl; each R ^b5 is independently selected from the group consisting of : halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, _{alkynyl, -NO 2, -CN, -SO 2} NR b54 R b55, -NR b17 R b18, -OR b19 , -SO ₂ R ^b20 , =O and -SR ^b21 ; wherein each cycloalkyl group is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, -OR ^b22 , = O, -NR ^b23 R ^b24 , -CN, -SF ₅ , -SO ₂ NR ^b56 R ^b57 , -SR ^b58 , -SO ₂ R ^b59 and R ^b28 , where each R ^{b28 is} independently alkyl, cycloalkyl, Heterocycloalkyl, aryl or heteroaryl; each aryl, heteroaryl and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen Group, =O, -SF ₅ and R ^b28 , wherein each R ^{b28 is} independently alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each alkyl group is independently unsubstituted or Or more substituents independently selected from the group consisting of halo, -OR ^b25 , =O, -NR ^b26 R ^b27 , -CN, ^-SF ₅ , -SO ₂ NR ^b61 R ^b62 , -SR ^b63 , -SO ₂ R ^b64 and R ^b65 , where each R ^{b65 is} independently cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each R ^b20 , R ^b21 , R ^b22 , R ^b23 , R ^b24 , R ^{b54, R b55, R b56,} R b57, R b58, R b59, R b61, R b62, R b63 and R ^b64 are independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl; each ^{R b17, R b18, R b25} , R b26 and R ^b27 are independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R ^b19 independently hydrogen, alkyl, cycloalkyl, alkyl, heterocycloalkyl, aryl, heteroaryl, or alkynyl; wherein each alkyl ^{R b17, R b18, R b19} , R b25, R b26, R b27 and R ^b28, the cycloalkyl, heterocyclyl Alkyl, aryl and heteroaryl and each cycloalkyl, heterocycloalkyl, aryl and heteroaryl of R ^b65 are independently unsubstituted or independently selected by one or more groups from the group consisting of Substituent substitution: halo, =O, -CN, aryl, heteroaryl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, -NR ^b29 R ^b30 , ^-SF ₅ and -OR ^b31 ; where Each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: alkyl, haloalkyl , Alkynyl, halo, -CN, -SF ₅ , =O, -NR ^b43 R ^b44 , -NR ^b45 C(O)R ^b46 , -OR ^b47 and R ^b66 , where each R ^{b66 is} independently cycloalkyl , Heterocycloalkyl, aryl or heteroaryl, and wherein each R ^b66 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: =O, -NH ₂ , -SF ₅ , -OH, -O-alkyl, -O-haloalkane ^Radical , halo, alkyl and haloalkyl; each R ^b29 , R ^b30 , R ^b31 , R ^b43 , R ^b44 , R ^b45 , R ^b46 and R ^{b47 are} independently hydrogen, alkyl or haloalkyl; each R ^b12 is independently selected from the group consisting of halo, alkyl, haloalkyl and -OR ^b32 , where R ^b32 is hydrogen, alkyl or haloalkyl; m is an integer from 0 to 13; n is from 0 to An integer of 11; and t is an integer of 0 to 6.

， 或其立體異構體或醫藥學上可接受之鹽，其中： p為0至7之整數；及 B、W、X、R^b4 、R^b5 、R^b10 、R^b11 、R^b12 、n及t係針對式(II)所定義。Embodiment I-3. The compound as in embodiment I-1 or I-2, wherein the compound is a compound of formula (II-A):

, Or its stereoisomer or pharmaceutically acceptable salt, wherein: p is an integer from 0 to 7; and B, W, X, R ^b4 , R ^b5 , R ^b10 , R ^b11 , R ^b12 , n and t is defined for formula (II).

， 或其立體異構體或醫藥學上可接受之鹽，其中： p為0至7之整數； u為0至5之整數；及 B、X、R^b4 、R^b5 、R^b10 、R^b11 、R^b12 及n係針對式(II)所定義。Embodiment I-4. The compound according to any one of embodiments I-1 to I-3, wherein the compound is a compound of formula (II-A-ii):

, Or its stereoisomers or pharmaceutically acceptable salts, wherein: p is an integer from 0 to 7; u is an integer from 0 to 5; and B, X, R ^b4 , R ^b5 , R ^b10 , R ^b11 , R ^b12 and n are defined for formula (II).

， 或其立體異構體或醫藥學上可接受之鹽，其中： p為0至7之整數； Y為-C(R^b52 )₂ -、-S(O)_r -、-O-或-N(R^b52 )-，其中各R^b52 獨立地為氫或R^b4 ； r為0、1或2；及 B、W、X、R^b4 、R^b5 、R^b10 、R^b11 、R^b12 、n及t係針對式(II)所定義。Embodiment I-5. The compound as in embodiment I-1 or I-2, wherein the compound is a compound of formula (II-B):

, Or its stereoisomer or pharmaceutically acceptable salt, wherein: p is an integer from 0 to 7; Y is -C(R ^b52 ) ₂ -, -S(O) _r -, -O- or- N(R ^b52 )-, wherein each R ^{b52 is} independently hydrogen or R ^b4 ; r is 0, 1 or 2; and B, W, X, R ^b4 , R ^b5 , R ^b10 , R ^b11 , R ^b12 , n And t are defined for formula (II).

， 或其立體異構體或醫藥學上可接受之鹽，其中： p為0至7之整數； Y為-C(R^b52 )₂ -、-S(O)_r -、-O-或-N(R^b52 )-，其中各R^b52 獨立地為氫或R^b4 ； r為0、1或2； u為0至5之整數；及 B、X、R^b4 、R^b5 、R^b10 、R^b11 、R^b12 及n係針對式(II)所定義。Embodiment I-6. The compound according to any one of embodiments I-1, I-2 or I-5, wherein the compound is a compound of formula (II-B-ii):

, Or its stereoisomer or pharmaceutically acceptable salt, wherein: p is an integer from 0 to 7; Y is -C(R ^b52 ) ₂ -, -S(O) _r -, -O- or- N(R ^b52 )-, wherein each R ^{b52 is} independently hydrogen or R ^b4 ; r is 0, 1 or 2; u is an integer from 0 to 5; and B, X, R ^b4 , R ^b5 , R ^b10 , R ^b11 , R ^b12 and n are defined for formula (II).

Example I-7. The compound as in Example I-5 or I-6, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Y is -CH ₂ -.

Embodiment I-8. The compound as in Embodiment I-1 or I-2, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein A is a 5-membered or 6-membered heterocycloalkyl group.

Embodiment I-9. The compound according to any one of Embodiments I-1 to I-8 or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is a 5-membered or 6-membered heterocycloalkyl or A 5- or 6-membered heteroaryl group, wherein the heterocycloalkyl or heteroaryl group contains one to three ring heteroatoms independently selected from the group consisting of O, N, and S.

Embodiment I-10. The compound according to any one of Embodiments I-1 to I-8, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein B is a 9-membered or 10-membered bicyclic heteroaryl group, It contains one to three ring heteroatoms independently selected from the group consisting of O, N and S.

Embodiment I-11. The compound according to any one of embodiments I-1 to I-8, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein B is (C ₉ -C ₁₀ ) bicyclic aryl .

Embodiment I-12. The compound according to any one of Embodiments I-1 to I-8, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein B is (C ₅ -C ₁₀ )cycloalkyl .

Embodiment I-13. The compound of any one of Embodiments I-1 to I-12, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein one or more R ^b5 are independently selected from Group consisting of: halo; -O-(C ₁ -C ₆ ) alkyl, which is unsubstituted or substituted with one or more fluorine; (C ₂ -C ₄ ) alkynyloxy; phenyl; heteroaryl ; Heterocycloalkyl; -SO ₂ NH ₂ ; -NO ₂ ; -CN; (C ₃ -C ₆ )cycloalkyl, which is unsubstituted or substituted with one or more fluorine; and (C ₁ -C ₆ ) Alkyl, which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: (C ₃ -C ₆ )cycloalkyl, aryl, halo, -OH, -O- (C ₁ -C ₄ )alkyl, =O, -NR ^b26 R ^b27 and -CN.

Embodiment I-14. The compound according to any one of Embodiments I-1 to I-8 or I-13 or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is phenyl and n is 0 Integer to 5.

， 或其立體異構體或醫藥學上可接受之鹽，其中： p為0至7之整數； u為0至5之整數；及 X、R^b4 、R^b5 、R^b10 、R^b11 及R^b12 係針對式(II)所定義。Embodiment I-15. The compound according to any one of embodiments I-1 to I-4, I-8 or I-13, wherein the compound is a compound of formula (II-Ai):

, Or its stereoisomers or pharmaceutically acceptable salts, wherein: p is an integer from 0 to 7; u is an integer from 0 to 5; and X, R ^b4 , R ^b5 , R ^b10 , R ^b11 and R ^b12 is defined for formula (II).

， 或其立體異構體或醫藥學上可接受之鹽，其中： p為0至7之整數； Y為-C(R^b52 )₂ -、-S(O)_r -、-O-或-N(R^b52 )-，其中各R^b52 獨立地為氫或R^b4 ； r為0、1或2； u為0至5之整數；及 X、R^b4 、R^b5 、R^b10 、R^b11 及R^b12 係針對式(II)所定義。Embodiment I-16. The compound according to any one of embodiments I-1, I-2, I-5 to I-8 or I-13, wherein the compound is a compound of formula (II-Bi):

, Or its stereoisomer or pharmaceutically acceptable salt, wherein: p is an integer from 0 to 7; Y is -C(R ^b52 ) ₂ -, -S(O) _r -, -O- or- N(R ^b52 )-, wherein each R ^{b52 is} independently hydrogen or R ^b4 ; r is 0, 1 or 2; u is an integer from 0 to 5; and X, R ^b4 , R ^b5 , R ^b10 , R ^b11 and R ^b12 is defined for formula (II).

, 其中： R^b33 為氫、烷基、炔基、環烷基、雜環烷基、雜芳基或芳基； 其中該烷基、環烷基、雜環烷基、雜芳基或芳基未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、烷基、環烷基、芳基、雜芳基、雜環烷基、=O、-OR^b36 、-SF₅ 及-NR^b37 R^b38 ； 其中各烷基、環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：烷基、鹵烷基、炔基、鹵基、-SF₅ 、=O、-OR^b39 、-NR^b48 R^b49 、-NR^b50 C(O)R^b51 、環烷基及雜環烷基，其中各環烷基及雜環烷基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：=O、鹵基、-OH及-SF₅ ； 各R^b34 及R^b35 獨立地為氫、鹵基或烷基； 其中各烷基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、環烷基、雜環烷基、芳基、雜芳基、-OR^b40 及-NR^b41 R^b42 ； 其中各環烷基、雜環烷基、芳基及雜芳基係獨立地未經取代或經一或多個獨立地選自由以下組成之群的取代基取代：鹵基、鹵烷基、烷基、-OH、=O及-SF₅ ； 或連接至同一原子之一個R^b34 及一個R^b35 與其所連接之原子一起形成環烷基或雜環烷基，其中該環烷基或雜環烷基未經取代或經一或多個鹵基取代； 各R^b36 、R^b37 、R^b38 、R^b39 、R^b40 、R^b41 、R^b42 、R^b48 、R^b49 、R^b50 及R^b51 獨立地為氫、烷基或鹵烷基； 且q為1或2。Embodiment I-17. The compound according to any one of embodiments I-1 to I-16, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein at least one R ^b5 is:

, Where: R ^b33 is hydrogen, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl Unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, =O, -OR ^b36 , -SF ₅ and -NR ^b37 R ^b38 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently unsubstituted or independently selected by one or more of the following Group substituent substitution: alkyl, haloalkyl, alkynyl, halo, -SF ₅ , =O, -OR ^b39 , -NR ^b48 R ^b49 , -NR ^b50 C(O)R ^b51 , cycloalkyl and Heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: =O, halo, -OH, and- SF ₅ ; each R ^b34 and R ^{b35 are} independently hydrogen, halo or alkyl; wherein each alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen Radical, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR ^b40 and -NR ^b41 R ^b42 ; wherein each cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently Substitution or substitution by one or more substituents independently selected from the group consisting of halo, haloalkyl, alkyl, -OH, =O, and -SF ₅ ; or one R ^b34 connected to the same atom and One R ^b35 and the atom to which it is connected form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group is unsubstituted or substituted with one or more halo groups; each R ^b36 , R ^b37 , R ^b38 , R ^b39 , R ^b40 , R ^b41 , R ^b42 , R ^b48 , R ^b49 , R ^b50 and R ^{b51 are} independently hydrogen, alkyl or haloalkyl; and q is 1 or 2.

Example I-18. The compound as in Example I-17, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein q is 1 and R ^b34 is hydrogen.

Embodiment I-19. The compound according to any one of Embodiments I-1 to I-18, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein at least one R ^b5 is heteroaryl or heterocycloalkane Group, wherein the heteroaryl or heterocycloalkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: =O, -SF ₅ and R ^b28 .

Embodiment I-20. The compound as in Embodiment I-19, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R ^b28 is an alkyl group substituted with an aryl or heteroaryl group, wherein the aryl or Heteroaryl is unsubstituted or substituted with haloalkyl or -SF ₅ .

Embodiment I-21. The compound of any one of Embodiments I-1, I-2, I-8 to I-14, or I-17 to I-20, or its stereoisomer or pharmaceutically acceptable Accepted salts in which R ^b1 and one R ^b4 together with the atoms to which they are attached form a 3- to 6-membered heterocycloalkyl.

Embodiment I-22. The compound according to any one of Embodiments I-1, I-2, I-8 to I-14, or I-17 to I-20, or a stereoisomer or pharmaceutically acceptable Accepted salts in which R ^b1 and R ^b8 together with the atoms to which they are attached form a 3 to 6 membered heterocycloalkyl.

Embodiment I-23. The compound of any one of Embodiments I-1, I-2, I-8 to I-14, or I-17 to I-20, or a stereoisomer or pharmaceutically acceptable Accepted salts in which R ^b1 and R ^b10 together with the atoms to which they are attached form a 3- to 6-membered heterocycloalkyl.

Embodiment I-24. The compound as in any one of Embodiments I-1 to I-23, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -S(O) ₂ -.

Embodiment I-25. The compound or stereoisomer or pharmaceutically acceptable salt thereof according to any one of Embodiments I-1 to I-23, wherein X is -C(O)-.

Embodiment I-26. The compound or stereoisomer or pharmaceutically acceptable salt thereof according to any one of Embodiments I-1 to I-23, wherein X is -CH ₂ -.

Embodiment I-27. The compound according to any one of Embodiments I-1 to I-14 or I-17 to I-26, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein n is 1 or 2.

Embodiment I-28. The compound of any one of Embodiments I-1, I-2, I-8 to I-14 or I-17 to I-27, or a stereoisomer or pharmaceutically acceptable thereof Salt, where m is 0.

Embodiment I-29. The compound according to any one of Embodiments I-3 to I-7, I-15 or I-16, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein p is 0.

Embodiment I-30. The compound or stereoisomer or pharmaceutically acceptable salt thereof according to any one of Embodiments I-1 to I-29, wherein R ^b10 and R ^b11 are independently selected from the group consisting of Groups: hydrogen, fluorine, -CN, unsubstituted methyl and methyl substituted with one to three fluorine.

Embodiment I-31. The compound or stereoisomer or pharmaceutically acceptable salt thereof according to any one of Embodiments I-1 to I-30, wherein at least one R ^b12 is chlorine.

為

。Embodiment I-32. The compound of any one of Embodiments I-1 to I-3, I-5, I-7 to I-14, or I-17 to I-30 or a stereoisomer thereof or Pharmaceutically acceptable salts, of which

for

.

為

。Embodiment I-33. The compound according to any one of Embodiments I-4, I-6, I-15 or I-16, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein

for

.

Embodiment I-34. The compound of any one of Embodiments I-1 to I-32, wherein z is 0 or 1.

，或前述任一者之立體異構體或醫藥學上可接受之鹽。Embodiment I-35. The compound as in embodiment I-1 or I-34, wherein the compound is:

, Or the stereoisomers or pharmaceutically acceptable salts of any of the foregoing.

，或前述任一者之立體異構體或醫藥學上可接受之鹽。Example I-36. The compound as in Example I-1, wherein the compound is:

, Or the stereoisomers or pharmaceutically acceptable salts of any of the foregoing.

Embodiment I-37. A pharmaceutical composition comprising the compound according to any one of Embodiments I-1 to I-36 or a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable Of excipients.

Example I-38. A method of reducing the content of K-Ras protein in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a pharmaceutical composition comprising the embodiment I-1 The compound of any one of I-36 or its stereoisomer or pharmaceutically acceptable salt and pharmaceutically acceptable excipient.

Example I-39. The method as in Example I-38, wherein the K-Ras protein is human K-Ras4b.

Embodiment I-40. A method of reducing a condition in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a pharmaceutical composition comprising any of Embodiments I-1 to I-36 A compound or its stereoisomer or pharmaceutically acceptable salt and pharmaceutically acceptable excipient.

Example I-41. The method as in Example I-40, wherein the disorder is cancer.

Embodiment I-42. The method as in Embodiment I-41, wherein the cancer is pancreatic cancer, lung cancer, colorectal cancer, optic nerve path glioma, rhabdomyosarcoma, neuroblastoma, juvenile myelomonocytic leukemia, Malignant peripheral nerve sheath tumor, gastrointestinal stromal tumor, somatostatin tumor, pheochromocytoma or breast cancer.

Embodiment I-43. The method as in embodiment I-40, wherein the condition is neurofibromatosis type 1, Noonan syndrome, heart-face-skin syndrome, or Regis syndrome.

Embodiment I-44. The method as in any one of embodiments I-40 to I-43, wherein the disorder is associated with a mutation in K-Ras.

Example I-45. The use of a compound as described in any one of Examples I-1 to I-36 or a stereoisomer or pharmaceutically acceptable salt thereof for use in reducing individuals in need Manufacture and use of pharmaceuticals with the content of K-Ras protein.

Example I-46. The use as in Example I-45, wherein the K-Ras protein is human K-Ras4b.

Embodiment I-47. The use of a compound as described in any one of Embodiments I-1 to I-36 or a stereoisomer or pharmaceutically acceptable salt thereof for the treatment of an individual in need Manufacture and use of medicament for illness.

Example I-48. The use as in Example I-47, wherein the condition is cancer.

Embodiment I-49. The use as in Embodiment I-48, wherein the cancer is pancreatic cancer, lung cancer, colorectal cancer, optic nerve path glioma, rhabdomyosarcoma, neuroblastoma, juvenile myelomonocytic leukemia, Malignant peripheral nerve sheath tumor, gastrointestinal stromal tumor, somatostatin tumor, pheochromocytoma or breast cancer.

Example I-50. The use as in Example I-47, wherein the condition is neurofibromatosis type 1, Noonan syndrome, heart-face-skin syndrome, or Regis syndrome.

Embodiment I-51. The use as in any one of embodiments I-47 to I-50, wherein the disorder is associated with a mutation in K-Ras.

Example I-52. The compound of any one of Examples I-1 to I-36, or a stereoisomer or pharmaceutically acceptable salt thereof, for use in reducing K-Ras in an individual in need The method of protein content.

Example I-53. The compound as used in Example I-52, wherein the K-Ras protein is human K-Ras4b.

Example I-54. The compound as in any one of Examples I-1 to I-36, or a stereoisomer or pharmaceutically acceptable salt thereof, which is a method for treating a disorder in an individual in need in.

Example I-55. The compound as used in Example I-54, wherein the disorder is cancer.

Example I-56. The compound as used in Example I-55, wherein the cancer is pancreatic cancer, lung cancer, colorectal cancer, optic nerve path glioma, rhabdomyosarcoma, neuroblastoma, juvenile bone marrow mononuclear cell Leukemia, malignant peripheral nerve sheath tumor, gastrointestinal stromal tumor, somatostatin tumor, pheochromocytoma or breast cancer.

Example I-57. A compound as used in Example I-54, wherein the condition is neurofibromatosis type 1, Noonan syndrome, heart-face-skin syndrome, or Regis syndrome.

Example I-58. The compound as used in any one of Examples I-54 to I-57, wherein the disorder is associated with a mutation in K-Ras. Examples

The following examples are merely illustrative and are not intended to limit any aspect of the invention in any way. Example II-1 : Synthesis of the third ester of (3-((4- chlorophenyl ) thio ) but- 3 -en- 1 -yl ) aminocarboxylic acid and (E)-(4-((4- chlorobenzene Yl ) thio ) but- 3 -en- 1 -yl ) aminocarbamic acid third butyl ester

Stir a mixture of 4-chlorobenzenethiol, tert-butyl-3-yn-1-ylcarbamate, dichloroethane (DCE) and RhCl(PPh ₃ ) ₃ (5 mol%) at room temperature 18 Hour to produce (3-((4-chlorophenyl)thio)but-3-en-1-yl)aminocarboxylic acid third ester and (E)-(4-((4-chlorophenyl) Thio)but-3-en-1-yl)aminocarboxylic acid third butyl ester. These two compounds are inseparable. Example II-2 : Synthesis of (3-((4- chlorophenyl ) sulfonyl ) but- 3 -en- 1 -yl ) aminocarboxylic acid third ester and (E)-(4-((4- chloro Phenyl ) sulfonyl ) but- 3 -en- 1 -yl ) aminocarbamic acid third butyl ester

(3-((4-chlorophenyl)thio)but-3-en-1-yl)aminocarboxylic acid third ester and (E)-(4-((4-chlorophenyl)thio) A mixture of but-3-en-1-yl)aminocarboxylic acid tert-butyl ester and methylene chloride (DCM) containing m-chloroperoxybenzoic acid ( m CPBA; 77%) and combined from 0°C to room temperature Stir for 18 hours to produce (3-((4-chlorophenyl)sulfonyl)but-3-en-1-yl)aminocarboxylic acid third ester and (E)-(4-((4-chloro A mixture of phenyl)sulfonyl)but-3-en-1-yl)carbamic acid third butyl ester. These compounds are isolated. Example II-3 : Synthesis of (E)-4-((4- chlorophenyl ) sulfonyl ) but- 3 -en- 1- amine

Compound (E)-(4-((4-chlorophenyl)sulfonyl)but-3-en-1-yl)aminocarboxylic acid third ester was combined with trifluoroacetic acid and dichloromethane and at room temperature Stir for 1 hour to produce (E)-4-((4-chlorophenyl)sulfonyl)but-3-en-1-amine. Example II-4 : Synthesis of (S,E)-3-((4-((4- chlorophenyl ) sulfonyl ) but- 3 -en- 1 -yl ) aminemethylacetoyl ) piperidine- 1- acid tert-butyl ester

Compound (E)-4-((4-chlorophenyl)sulfonyl)but-3-en-1-amine and ( S )-1-(third butoxycarbonyl)piperidine-3-carboxylic acid 1. Hexafluorophosphate 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide (HATU), triethylamine Combined with dichloromethane, and the mixture was stirred at room temperature for 18 h to produce (S,E)-3-((4-((4-chlorophenyl)sulfonyl)but-3-en-1-yl ) Aminomethyl acetyl) piperidine-1-carboxylic acid tert-butyl ester. Example II-5 : (S,E)-1-(5- chloro -2- methoxybenzyl )-N-(4-((4- chlorophenyl ) sulfonyl ) but- 3 -ene Two synthesis of -1 -yl ) piperidine- 3 -carboxamide

Two different methods were used to select from (S,E)-3-((4-((4-chlorophenyl)sulfonyl)but-3-en-1-yl)aminomethylacetoyl)piperidine-1- Synthesis of compound (S,E)-1-(5-chloro-2-methoxybenzyl)-N-(4-((4-chlorophenyl)sulfonyl)butan-3 -En-1-yl)piperidine-3-carboxamide.

Route 1 : In the first route, (S,E)-3-((4-((4-chlorophenyl)sulfonyl)but-3-en-1-yl)aminomethylamide)piper The third butyl pyridine-1-carboxylate was combined with trifluoroacetic acid and dichloromethane, and the mixture was stirred from 0°C to room temperature for 18 h to remove the third butoxycarbonyl (BOC) protecting group. The deprotected product was combined with 5-chloro-2-methoxybenzoic acid, AHTU, triethylamine, and dichloromethane, and the mixture was stirred at room temperature for 18 h to produce (S,E)-1-( 5-chloro-2-methoxybenzyl)-N-(4-((4-chlorophenyl)sulfonyl)but-3-en-1-yl)piperidine-3-carboxamide.

Route 2 : In the second route, (S,E)-3-((4-((4-chlorophenyl)sulfonyl)but-3-en-1-yl)aminomethylamide)piper Deprotection of the third butyl pyridine-1-carboxylate as described for Route 1, followed by removal of the deprotection product with 5-chloro-2-methoxybenzyl chloride, triethylamine and dichloromethane Combine and stir the mixture at room temperature for 4 h to produce (S,E)-1-(5-chloro-2-methoxybenzyl)-N-(4-((4-chlorophenyl)sulfonyl Yl)but-3-en-1-yl)piperidine-3-carboxamide. Example II-6 : Synthesis of (S)-1-(5- chloro -2- methoxybenzyl )-N-(4-((4-( trifluoromethyl ) phenyl ) sulfonyl ) butane -3 -en- 1 -yl ) piperidine- 3 -carboxamide

Compound (S)-N-(but-3-yn-1-yl)-1-(5-chloro-2-methoxybenzyl)piperidine-3-carboxamide and 4-(trifluoro Methyl)thiol, Pd(OAc) ₂ (5 mol%) and tetrahydrofuran are combined, and the mixture is stirred at room temperature for 18 h to produce (S)-1-(5-chloro-2-methoxybenzyl) -N-(4-((4-(trifluoromethyl)phenyl)thio)but-3-en-1-yl)piperidine-3-carboxamide. This product was then combined with m CPBA (77%) and dichloromethane, and the mixture was stirred from 0°C to room temperature for 18 h to produce (S)-1-(5-chloro-2-methoxybenzoyl cyanide) Yl)-N-(4-((4-(trifluoromethyl)phenyl)sulfonyl)but-3-en-1-yl)piperidine-3-carboxamide. Example II-7 : Synthesis of (E)-(4-((4- chlorophenyl ) sulfonyl ) but- 3 -en- 1 -yl ) aminocarboxylic acid third butyl ester

The compound 4-chlorobenzenesulfonyl chloride was combined with the third butyl but-3-yn-1-ylcarbamate, Cp ₂ Zr(H)Cl (1.2 equivalents) and tetrahydrofuran, and the mixture was stirred from room temperature to 60°C 18 h to produce (E)-(4-((4-chlorophenyl)sulfonyl)but-3-en-1-yl)aminocarboxylic acid third butyl ester. Example II-8 : Synthesis of (E)-4-((4- chlorophenyl ) sulfonyl ) but- 3 -en- 1- amine

Compound (S)-1-(5-chloro-2-methoxybenzyl)-N-(4-((4-(trifluoromethyl)phenyl)sulfonyl)but-3-ene -1-yl)piperidine-3-carboxamide is combined with trifluoroacetic acid and dichloromethane, and the mixture is stirred from 0°C to room temperature for one hour to produce (E)-4-((4-chlorophenyl )Sulfonyl)but-3-en-1-amine. Example II-9 : Synthesis of (S,E)-3-((4-((4- chlorophenyl ) sulfonyl ) but- 3 -en- 1 -yl ) amine, methylamino ) pyrrolidine- 1- acid tert-butyl ester

The compound (E)-4-((4-chlorophenyl)sulfonyl)but-3-en-1-amine and ( S )-1-(third butoxycarbonyl)pyrrolidine-3-carboxylic acid , HATU, triethylamine and dichloromethane were combined, and the mixture was stirred at room temperature for 18 h to produce (S,E)-3-((4-((4-chlorophenyl)sulfonyl)butan-3- Alkenyl-1-yl)aminecarboxamide)pyrrolidine-1-carboxylic acid tert-butyl ester. Example II-10 : (S,E)-1-(5- chloro -2- methoxybenzyl )-N-(4-((4- chlorophenyl ) sulfonyl ) but- 3 -ene -1 -yl ) pyrrolidine- 3 -carboxamide two kinds of synthesis

Two different methods were used to select from (S,E)-3-((4-((4-chlorophenyl)sulfonyl)but-3-en-1-yl)amine, methylacetyl)pyrrolidine-1- Synthesis of compound (S,E)-1-(5-chloro-2-methoxybenzyl)-N-(4-((4-chlorophenyl)sulfonyl)butan-3 -En-1-yl)pyrrolidin-3-carboxamide.

Route 1 : In the first route, (S,E)-3-((4-((4-chlorophenyl)sulfonyl)but-3-en-1-yl)aminomethanyl)pyrrole The third butyl pyridine-1-carboxylate was combined with trifluoroacetic acid and dichloromethane, and the mixture was stirred from 0°C to room temperature for 18 h to remove the third butoxycarbonyl (BOC) protecting group. The deprotected product was combined with 5-chloro-2-methoxybenzoic acid, HATU, triethylamine and dichloromethane, and the mixture was stirred at room temperature for 18 h to produce (S,E)-1- (5-chloro-2-methoxybenzyl)-N-(4-((4-chlorophenyl)sulfonyl)but-3-en-1-yl)pyrrolidine-3-carboxamide .

Route 2 : In the second route, (S,E)-3-((4-((4-chlorophenyl)sulfonyl)but-3-en-1-yl)aminomethanyl)pyrrole Deprotection of the third butyl pyridine-1-carboxylate is as described in Scheme 1. The deprotected product was then combined with 5-chloro-2-methoxybenzyl chloride, dichloromethane and triethylamine, and the mixture was stirred at room temperature for 4 h to produce (S,E)-1-( 5-chloro-2-methoxybenzyl)-N-(4-((4-chlorophenyl)sulfonyl)but-3-en-1-yl)pyrrolidine-3-carboxamide.

表 II-2 .所合成化合物之特徵化

Table II-1 provides compounds synthesized using methods similar to those described in the above examples. Table II-1. Compounds synthesized

Table II-2 . Characterization of synthesized compounds

NMR spectroscopy : ¹ H NMR spectrum at 300 MHz was recorded on a Varian Mercury NMR spectrometer at ambient temperature. Prepare samples in deuterated chloroform (CDCl ₃ ), or deuterated dimethyl sulfoxide (DMSO- d ₆ ) or other suitable deuterated solvents. Chemical shifts are reported in parts per million (ppm) relative to deuterated solvents or TMS internal standards. The multiplicity is reported as follows: s=single peak; d=doublet; t=triplet; q=quartet; m=multiplet; br=broad.

LCMS analysis : for certain compounds. LCMS analysis was performed using an Agilent 6120b single quadrupole mass spectrometer with an Agilent 1260 infinity II chromatography separation module controlled by Agilent Chemstation software and an Agilent 1260 infinity II photodiode array detector. The HPLC column used was an Agilent ZORBAX Eclipse XDB-C18 4.6×150, 3.5u Rapid Resol column, in which the mobile phase was water (0.1% formic acid)/MeCN (0.1% formic acid) and the gradient was 5-95% MeCN. Minute, flow rate 1 mL/min.

For other compounds, LCMS analysis was performed on Thermo Scientific-Finnigan, performed on a Phenomenex Gemini 5μM C18 110Å, 50 × 3.0 mm column with a flow rate of 1 mL/min. Perform UV and mass ion detection. Two different analysis methods were used for this study, the details of which are presented below.

6mins-0.5mL-min-Pos-only method (6 min): On a 50 × 3.0 mm column of Phenomenex Gemini 5μM C18 110Å at a flow rate of 1mL/min, use 0.1% v/v formic acid in water [dissolve A] 、MeCN [dissolving agent B] is executed with a flow rate of 1mL/min.

實例 II-11 ： 使用基質輔助雷射脫附 / 電離 - 飛行時間質譜 (MALDI-TOF MS) 之共價修飾分析 10mins-0.5mL-min-Pos-only method (10 min): 0.1% v/v formic acid aqueous solution [dissolving agent A]; 0.1% v/v formic acid/MeCN [dissolving agent B]; flow rate 0.8mL/min; injection The volume was 2 μL and the equilibration time between samples was 1.5 min.

Example II-11 : Covalent modification analysis using matrix-assisted laser desorption / ionization - time -of- flight mass spectrometry (MALDI-TOF MS)

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was used to evaluate the compounds of the synthetic library of KRAS4b 1-188 protein to confirm the covalent labeling at C185.

Reaction : A 20 mM HEPES buffer containing 20 µM KRAS4b (1-188) protein (Protein Expression Laboratory, FNLCR/Leidos Biomed.), containing 150 mM NaCl, 1 mM MgCl ₂ , pH 7.3, was newly prepared before analysis. Dispense a 20 µl aliquot of protein into a 384-well polypropylene plate, and then add the compound to be tested (0.8 µl, 10 mM in DMSO) to different wells. For each analysis, three blank samples and three control samples were prepared by mixing 20 µl protein solution with 0.8 µl DMSO or 10 mM standard compounds. The contents of the wells were mixed by suction, then the plate was sealed with a rubber cap, centrifuged at 2000 g for 1 minute, and incubated at room temperature in the dark for 24 h.

Target pretreatment : Before each analysis, pretreat the MALDI target (Bruker MTP 384 frosted steel BC) by pipetting 1 µl of succinic acid-containing acetonitrile (ACN) into each spot. It can improve the homogeneity of the sample crystals across the board, thereby enhancing sensitivity.

Sample preparation : After the above 24 h reaction, pipette 2 µl of the reaction mixture into 20 µl of MALDI matrix solution (erucic acid in 1:1 ACN containing 0.75% trifluoroacetic acid (TFA): saturated solution in aqueous solution) and Deposited on a 384-well polypropylene MALDI plate. The resulting solution was mixed by suction, centrifuged at 2000 g for 1 minute, and then a 2 µl aliquot was dispensed onto the above-mentioned pretreated target plate using a Beckman Coulter Biomek FX ^P 96/Span-8 laboratory automatic workstation. The MALDI target plate was dried under a light vacuum to produce spots with fine crystal structure.

Measurement : MALDI-TOF measurement is performed on the Bruker Daltonics ultraflex III TOF-TOF mass spectrometer using linear mode and a mass range of 5 to 45 kDa. The detector gain is set to ×9 (1734 V), the sampling rate is set to 1 GS/s, the smart beam parameter set: use 3_median, and the radio frequency rate is 66.7 Hz. Use the conventional AutoXecute method to automatically collect the spectrum. Use fuzzy control to automatically adjust the laser power. The peak selection range is set between 20500 and 23000 Da. Peak evaluation uses a half-width parameter set with less than 30 Da. Fuzzy control uses a protein/oligonucleotide scheme with a minimum half-width of 1/6× or more. Collect up to 1500 frames in 500 shooting steps. Implement dynamic termination to complete data collection when the peak intensity reaches a value of 1200 [arbitrary units].

Spectrum processing : With the SavitzkyGolay algorithm, the spectrum is smoothed using 12 m/z width and six cycles. The centroid peak detection algorithm is used under the signal-to-noise ratio threshold set to 11, relative intensity threshold 5%, minimum intensity threshold 50 [arbitrary units], peak width 20 m/z and TopHat baseline subtraction law. Evaluate the peak intensity and the area under the peak and record all peaks between 21,460 Da and 23,500 Da.

The analysis results of the selected compounds are listed in Table II-3 below. Compound II-0096 (pyrrolidine) has a greater reactivity than II-0017 (piperidine). Due to the lower water solubility, the reduced reactivity of other pyrrolidine compounds as assessed by MALDI may be caused by the precipitation of the compound in the aqueous MALDI matrix. Its hydrophobicity can lead to greater cell penetration and therefore better activity in cells. Table II-3. Covalent modification of KRAS4b 1-188 protein by pyrrolidine compounds

實例 II-12 ： GDP 相較於 KRAS4b 蛋白之 GppNHp 形式之化合物標記 The analysis results of the selected piperidine-containing compounds are listed in Table II-4 below. Table II-4. Covalent bonding of selected piperidine-containing compounds

Example II-12 : GppNHp compound labeling of GDP compared to KRAS4b protein

MALDI-TOF mass spectrometry was used to evaluate the labeling of KRAS4b cells in the active (GppNHp) form and inactive (GDP) form by the selected compounds. The nucleotide exchange of GDP KRAS4b was used to prepare GppNHp-loaded KRAS4b 1-188 (non-hydrolyzable analogue of GTP KRAS4b).

GppNHp nucleotide exchange : Prepare a solution of 150 to 300 µM GDP-loaded protein in KRAS buffer (20 mM HEPES, 150 mM NaCl, 1 mM MgCl ₂ , 0.05 mM TCEP, pH 7.3). Add the remaining 1500 mol of KRAS buffer containing 1 M ammonium sulfate and mix gently by inverting the tube. Prepare a 250 mM GppNHp solution (150 mol excess GppNHp for protein on ice). Ten percent of the prepared GppNHp solution was added to the protein, followed by the suspension of alkaline phosphatase from bovine small intestine on agarose (Sigma-Aldrich, P0726) until the final concentration was 2 units of enzyme per mg of protein. The reaction mixture was incubated at room temperature and tumbling for 1 h 30 min. The alkaline phosphatase on the agarose beads was removed by filtering the solution using a Millex-GP syringe filter to a new vial. Add remaining GppNHp solution and incubate for another 45 min. At the end of the exchange, the protein was filtered again, placed on ice, and purified on an NGC medium-pressure chromatography system (Bio-Rad). Five inwardly connected desalting columns (5×GE Healthcare HiTrap desalting column 5 mL, 17-1408-01) were used with 4 ml/min of isocratic KRAS buffer. The protein dissolution was monitored at 280 nm. The NanoDrop 2000 spectrophotometer (Thermo Fisher) was used to evaluate the final protein concentration using the Mohr attenuation coefficient ε = 19685 l∙mol ^{- 1} ∙cm ^{- 1} . The quality of the protein was confirmed by MALDI-TOF MS, and the exchange rate evaluated by HPLC-based analysis exceeded 98%.

A heat map comparing the covalent labeling of selected compounds to two different proteins is provided in Figure 1. The figure shows that nucleotide loading (active GppNHp, compared to KRAS4b for GDP loading) does not affect the level of KRAS4b 1-188 covalent labeling. It may indicate that the non-covalent docking of different protein bags different from the switch II bag can only be used in GDP-KRAS. Example II-13 : Cell uptake and stability in cells

The cell uptake and stability of Compound II-0017 in cells were evaluated in MiaPaCa-2 pancreatic cancer cells grown on 10 cm Petri dishes. Compound with a final concentration of 10 μM was added to the complete growth medium. After the time point indicated on the incubation curve (Figure 2), the cells were rinsed with ice cold PBS three times, then placed on ice, and the remaining PBS was removed by suction. Scrape the cells into 300 μl of ice-cold methanol, spin at a speed of 20,000 g × 15 min, and filter the resulting supernatant to an HPCL vial, then use a Phenomenex Kinetex C18 by using a Finnigan LTQ mass spectrometer connected to an Agilent micro HPLC system The pipe column analyzes it. A graph of the detected compound concentration as a function of time is provided in Figure 2. After 72h incubation, compound II-0017 could still be detected in the cells. The half-life of compound II-0017 with 10 mM GSH was also measured and was equal to 250 min.

MiaPaCa-2 cells were applied to a 10 cm petri dish at 2×10 ⁵ per petri dish, and allowed to attach overnight. Cells were treated with DMSO or Compound II-0017 from 10 µM to 50 µM for 72 h (compound addition once). Compound II-0017 appears to be active at a concentration of 20 µM, resulting in growth arrest but not characterized by acute poisoning. Figure 3 shows the image of the cell. Example II-14 : Cell proliferation analysis

Cell-based screening has also been used in RASless mouse embryonic fibroblasts (MEF) to evaluate synthetic library compounds. CellTiter-Glo® (Promega) was used to measure cell viability in the presence of synthetic compounds. Proliferation analysis was performed using mouse embryonic fibroblasts (MEF) expressing a single isoform of RAS (KRAS4b Q61R, KRAS4b G12V as a model system, and Myr-KRAS4b G12D/C185S, and HRAS WT as controls).

Using a Multidrop Combi reagent dispenser (Thermo), cells were implanted into black-walled 384-well plates (Greiner, 781091) at a density according to their doubling time (usually 1,000 cells/well in 20 μl for MEF). They were then incubated overnight at 37°C in a humidified atmosphere of 5% CO ₂ before adding the compound. The Access ^TM laboratory workstation (Labcyte®) and Echo 555 (Labcyte®) liquid processors were used to perform the compound and DMSO addition to the microtiter plate. Prepare a source plate with compound and DMSO, and use Echo 555 to transfer 50 nL compound, DMSO, or combination to the appropriate wells. After compound addition, add 5 µL of complete medium to all wells of the microtiter plate. The highest final compound concentration in each analysis was 100 µM or 50 µM between seven and 12 dilutions. The final DMSO concentration in all wells was 0.2%.

The cells were incubated with the compound for 72h. Complete all conditions in triplicate and perform the experiment at least three times. Using CellTiter-Glo (CTG, Promega G7573) luminescence analysis, the EnVision plate reader (PerkinElmer) was used to determine the cell ATP level (indicator of cell count).

The board was collected at two points in time. At the time of drug addition, one plate for each cell line without compound addition received 5 µL of medium and was collected to represent the measured value of the cell population at the time of compound addition (T0). After incubation at 72 h, the compound-treated plates were collected using CTG reagent, and the luminescence was read using EnVision to obtain control growth (C) and compound-treated well (T72) measurements. Calculate growth inhibition by:

Prism 7 software (GraphPad) was used to generate dose response curves.

Figure 4 is a heat map of IC ₅₀ values of selected compounds in KRAS G12 mutants and control MEF cell lines. Compared with cells driven by HRAS WT or Myr-KRAS4b G12D/C185S (negative control), cells expressing the oncogenic mutants KRAS4b G12V and KRAS4b Q61R showed higher sensitivity to these compounds. Example II-15: Western blotting assessment of the compound II-0017

Compound II-0017 was evaluated in Western blot analysis of total protein content of KRAS. Two cancer cell lines were used: HupT4 (KRAS G12V mutant loaded with pancreatic cancer strain) and H1792 (G12C mutant loaded with lung adenocarcinoma). After 72 hours of treatment with the compound, three different anti-RAS antibodies were used to assess the KRAS protein content by Western blotting (as indicated in Figure 5A). The MEK total protein content was used as an internal reference. II-0017 caused a dose-dependent decrease in KRAS protein content in both cell lines. Inhibition of cell proliferation was also observed, as shown in the example of H1792 lung adenocarcinoma cell line treated with increasing concentrations of compound II-0017 for 72 h (Figure 5B). Example II-16 : Evaluation of compound II-0144 via cycloaddition

The alkyne analogs of compound II-0096 and compound II-0144 were evaluated in a cycloaddition reaction with Alexa Fluor 647-azido compound to study target engagement in cells. HEK293 cells expressing 3xFLAG KRAS4b G12V in a doxycycline-inducible lentiviral vector were used. The KRAS expression in these cells was induced by 200 ng/ml doxycycline for 24h, followed by addition of compound for 24h. The cell fraction was separated into cytosolic and membrane solutes, and the cytosolic ions were used to purify KRAS4b G12V using Flag M1 agarose (Sigma-Aldrich) following the manufacturer's protocol. The protein was dissolved from Flag M1 agarose using 0.1 M glycine buffer pH 2.7 and immediately neutralized with 1:10 1M Tris pH 8.0. Whole cell lysates (WCL) of DMSO-treated cells and II-0144-treated cells were also collected.

Use Alexa Fluor 647-azido compounds to detect covalently attached cells from Flag M1 agarose via ligation or "click" conjugation between the alkyne moiety and the azide-containing fluorescent dye according to the following reaction scheme Purified compound II-0144 of KRAS4b G12D.

Fig. 6 depicts the Alexa Fluor 647 signal after the click reaction has been performed (negative from whole cell lysate not subjected to the click conjugation reaction) and the pull-down of Flag-KRAS4b for HEK293 that exhibits KRAS4b G12V treated with II-0144 (Pd) is a positive gel image. LMW = low molecular weight standard. Example II-17 : Immune dot analysis

To evaluate the effect of certain compounds of the synthetic library on the localization of KRAS in the cell membrane.

The cells were washed three times with ice-cold PBS, and then the cells were lysed on ice using ice-cold TNE buffer supplemented with stop protease and phosphatase inhibitors (Thermo Scientific). It was then centrifuged at 15,000 g for 15 minutes to collect whole cell lysate. The protein concentration was measured by BCA protein analysis (Pierce). Thirty micrograms of total protein per sample was loaded onto 4%-12% NuPAGE Bis-Tris gradient gel (Life Technologies) and separated by SDS-PAGE. Transfer protein to polyvinylidene fluoride (PVDF) membrane. The following antibodies were used in immunoblotting: mouse monoclonal anti-KRAS (Sigma WH0003845M1, pure line 3B10-2F2), mouse anti-RAS (Thermo 1862335), rabbit anti-pERK1/2 (T202/Y204; Cell Signaling Technology 4370) , Mouse anti-ERK1/2 (Cell Signaling Technology 4696), rabbit anti-p-MEK1/2 (S217/221; Cell Signaling Technology 9154), mouse anti-MEK1/2 (Cell Signaling Technology 4694), rabbit anti-p-AKT (S473; Cell Signaling Technology 4060), mouse anti-AKT (Cell Signaling Technology 2920). Focal adhesion protein (rabbit anti-focal adhesion protein, Cell Signaling Technology 4650) was used as an internal reference. The primary antibody and the fluorescently bound (LI-COR) secondary antibody were detected together.

For the cell fractionation experiment, 2×10 ⁵ cells were seeded onto 10-cm petri dishes and allowed to grow for 24 h. Compounds were added to the medium until the final concentration was 10-30 μM for 72h. Wash cells three times with ice-cold PBS, then add digitonin [300 μl 190 μg/ml in lysis buffer (PBS containing 75 mM KCl, 250 mM sucrose, and stop protease and phosphatase inhibitors (Thermo) ] 10 min. Then gently scrape the cells and centrifuge at 12,000g for 10 min at 4°C. Remove the supernatant (cytosol fraction) and resuspend the remaining pellets (membrane fraction) in 100 μl TNE to dissolve Buffer (25 mM HEPES buffer containing 150 mM NaCl, 5 mM MgCl ₂ , 1% SDS, 10% glycerol, 2.5 mM EDTA, supplemented with stop proteases and phosphatase inhibitors), and using standard immunoblotting Incubate for 30 min before protocol treatment. Use the following antibodies: mouse monoclonal anti-KRAS (Sigma WH0003845M1, pure line 3B10-2F2), mouse anti-RAS (Thermo 1862335), as a reference for cytosol dissociation Mouse anti-MEK1/2 (Cell Signaling Technology 4694) and rabbit anti-Na, K-ATPase (Cell Signaling Technology 3010) as a reference within the membrane fraction. Example II-18 : Tumor xenotransplantation

Human pancreas or lung adenocarcinoma cell lines were obtained from the American Type Culture Collection and cultured for a maximum of 4 generations before use according to the cell supplier's protocol. The cells were collected at 70-80% confluence, washed with phosphate buffered saline, suspended in phosphate buffered saline, and implanted subcutaneously at 5×10 ⁶ cells/0.2 mL into NCr nu/nu obtained from Charles River In athymic mice. Frederick National Cancer Research Laboratory is recognized by the International AAALAC and follows the public health service strategy for the care and use of laboratory animals. Animal care is provided according to the procedures outlined in "Guide for Care and Use of Laboratory Animals" (National Research Council, 1996; National Academy Press, Washington, DC). When the tumor reached approximately 3 mm×3 mm, the mice were randomly distributed into 12 groups for treatment.

The compound was injected into the tail vein of mice at 100 μmol/kg body weight 3 times a week for 4 weeks. The control group was treated with physiological saline. The mice were weighed and the tumor was measured twice a week. The tumor volume (in mm ³ ) is estimated by the formula (π/2 × length × width ² ). Almost immediately after the last treatment, the mice were euthanized. Blood was collected under isoflurane anesthesia. The tumor was removed and immediately frozen for biochemical analysis. Example II-19: Synthesis of (E) -4- (2 - ( (4- chlorophenyl) sulfonyl acyl) vinyl) piperidine-1-carboxylic acid tertiary butyl ester

The compound 3-butyl 3-ethynylpiperidine-1-carboxylate was combined with bis(cyclopentadienyl) zirconium hydroxide under argon at room temperature. A solution of 4-chlorobenzene-1-sulfonyl chloride in THF was added and the solution was stirred at 60°C. The reaction mixture was cooled to room temperature and about 50 ml of water was added. The mixture was extracted with EtOAc, washed, filtered, and the solvent was evaporated to give (E)-4-(2-((4-chlorophenyl)sulfonyl)vinyl)piperidine-1-carboxylic acid tert-butyl ester . Example II-20 : Synthesis of (E)-4-(2-((4- chlorophenyl ) sulfonyl ) vinyl ) piperidine

Treatment of compound (E)-4-(2-((4-chlorophenyl)sulfonyl)vinyl)piperidine-1-carboxylic acid tert-butyl ester with TFA at room temperature for 30 minutes to give (E)-4 -(2-((4-chlorophenyl)sulfonyl)vinyl)piperidine. Example II-21 : Synthesis of (S,E)-(4-(2-((4- chlorophenyl ) sulfonyl ) vinyl ) piperidin- 1 -yl )( pyrrolidin- 3 -yl ) methanone

Compound (E)-4-(2-((4-chlorophenyl)sulfonyl)vinyl)piperidine and HATU, (S)-1-(third butoxycarbonyl))pyrrolidine-3 -Formic acid, DCM and triethylamine are combined and the resulting solution is stirred at room temperature for 18 hours. The resulting compound was treated with TFA and stirred at room temperature for 30 minutes to produce (S,E)-(4-(2-((4-chlorophenyl)sulfonyl)vinyl)piperidin-1-yl) (Pyrrolidin-3-yl)methanone. Example II-22 : Synthesis of (S,E)-(1-(5- chloro -2- methoxybenzyl ) pyrrolidin- 3 -yl )(4-(2-((4- chlorophenyl ) Sulfonyl ) vinyl ) piperidin- 1 -yl ) methanone (I-0000756)

The compound (S,E)-(4-(2-((4-chlorophenyl)sulfonyl)vinyl)piperidin-1-yl)(pyrrolidin-3-yl)methanone was added to 5- Chloro-2-methoxybenzoyl chloride and triethylamine solution, and the reaction mixture was stirred at room temperature overnight to produce (S,E)-(1-(5-chloro-2-methoxybenzoyl amide Yl)pyrrolidin-3-yl)(4-(2-((4-chlorophenyl)sulfonyl)vinyl)piperidin-1-yl)methanone. Example II-23 : Synthesis of (E)-3-(2-((4- chlorophenyl ) sulfonyl ) vinyl ) azetidine

The compound 3-ethynylazetidine-1-carboxylic acid tert-butyl ester was combined with bis(cyclopentadienyl)zirconium hydroxide under argon at room temperature. A solution of 4-chlorobenzene-1-sulfonyl chloride in THF was added and the solution was stirred at 60°C. The reaction mixture was cooled to room temperature and about 50 ml of water was added. The mixture was extracted with EtOAc, washed, filtered, and the solvent was evaporated. The resulting compound was treated with trifluoroacetic acid to produce (E)-3-(2-((4-chlorophenyl)sulfonyl)vinyl)azetidine. Example II-24 : Synthesis of (S,E)-(3-(2-((4- chlorophenyl ) sulfonyl ) vinyl ) azetidin- 1 -yl )( pyrrolidin- 3 -yl ) Ketone

(V)，且攪拌該溶液30分鐘。添加(E)-3-(2-((4-氯苯基)磺醯基)乙烯基)氮雜環丁烷與三乙胺之溶液，且於室溫攪拌該溶液3小時，以產生(S,E)-3-(3-(2-((4-氯苯基)磺醯基)乙烯基)氮雜環丁烷-1-羰基)吡咯啶-1-甲酸第三丁酯，其經TFA處理以產生(S,E)-(3-(2-((4-氯苯基)磺醯基)乙烯基)氮雜環丁-1-基)(吡咯啶-3-基)甲酮。實例 II-25 ： 合成 (S,E)-(1-(5- 氯 -2- 甲氧苯甲醯基 ) 吡咯啶 -3- 基 )(3-(2-((4- 氯苯基 ) 磺醯基 ) 乙烯基 ) 氮雜環丁 -1- 基 ) 甲酮 (I-0000757)

Add compound (S)-1-(third butoxycarbonyl))pyrrolidin-3-carboxylic acid to hexafluorophosphate 2-(3H-[1,2,3]triazolo[4,5-b] Pyridin-3-yl)-1,1,3,3-tetramethyliso

(V), and the solution was stirred for 30 minutes. A solution of (E)-3-(2-((4-chlorophenyl)sulfonyl)vinyl)azetidine and triethylamine was added, and the solution was stirred at room temperature for 3 hours to produce ( S,E)-3-(3-(3-(2-((4-chlorophenyl)sulfonyl)vinyl)azetidine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester, which Treated with TFA to produce (S,E)-(3-(2-((4-chlorophenyl)sulfonyl)vinyl)azetidin-1-yl)(pyrrolidin-3-yl)methyl ketone. Example II-25 : Synthesis of (S,E)-(1-(5- chloro -2- methoxybenzyl ) pyrrolidin- 3 -yl )(3-(2-((4- chlorophenyl ) Sulfonyl ) vinyl ) azetidin- 1 -yl ) methanone (I-0000757)

Treatment of compound (S,E)-(3-(2-((4-chlorophenyl)sulfonyl)vinyl)nitrogen with triethylamine and 5-chloro-2-methoxybenzyl chloride at room temperature Heterocyclic-1-yl)(pyrrolidin-3-yl)methanone, and the resulting solution was stirred at room temperature overnight to produce (S,E)-(1-(5-chloro-2-methoxybenzoyl Acetyl)pyrrolidin-3-yl)(3-(2-((4-chlorophenyl)sulfonyl)vinyl)azetidin-1-yl)methanone.

The application can be understood with reference to the following description in conjunction with the accompanying drawings.

Figure 1 is a heat map comparing the covalent labeling of different proteins GppNHp-K-Ras4b and GDP-K-Ras4b with the selected compounds described herein.

Figure 2 is a graph of the absorption of compound II-0017 by MiaPaCa-2 pancreatic cancer cells over time.

Figure 3 depicts images of pancreatic cancer cells of MiaPaCa-2 cells incubated with dimethyl sulfoxide (DMSO) or different concentrations of compound II-0017 for 72 h. Cell viability is indicated by growth arrest.

FIG 4 lines as IC ₅₀ values of selected compounds of the amount measured in different embryonic fibroblasts (MEF) in mice thermal FIG.

Figure 5A depicts Western blot analysis of compound II-0017 absorbed by two cancer cell lines HupT4 (K-Ras G12V mutant loaded with pancreatic cancer cell line) and H1792 (G12C mutant loaded with lung adenocarcinoma).

FIG. 5B depicts an image of cell proliferation in the presence of dimethylsulfonylate (DMSO, control) and different amounts of compound II-0017 in the H1792 lung adenocarcinoma cell line.

Figure 6 depicts the Alexa Fluor 647 signal (negative from whole-cell lysate without click conjugation) and the pull-down of Flag-K-Ras4b (Pd ) Is a positive gel image. LMW = low molecular weight standard.

Claims (58)

A compound of formula (I):

, Or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: A is a 4- to 8-membered heterocycloalkyl; B is an aryl, heteroaryl, cycloalkyl or heterocycloalkyl; W is Aryl or heteroaryl; X is -S(O)-, -S(O) ₂ -, -S(O)NR ^b53 -, -C(S)-, -C(O)- or -C( R ^b13 ) ₂ -; each R ^{b13 is} independently hydrogen, halo, alkyl or haloalkyl; R ^b53 is hydrogen or alkyl, wherein the alkyl is unsubstituted or independently selected by one or more of the following Substituted by the group of substituents: halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and =O; R ^b1 is hydrogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl ; Z is 0, 1 or 2; R ^b2 , R ^b3 , R ^b6 , R ^b7 , R ^b8 , R ^b9 , R ^b10 and R ^b11 are independently selected from the group consisting of hydrogen, halo, alkyl, Cycloalkyl, heterocycloalkyl, -CN, -NO ₂ , -NR ^b13 R ^b14 , -OR ^b15 , -SO ₂ R ^b16 and -SO ₂ NH ₂ , where each alkyl, cycloalkyl and heterocycloalkane The radicals are independently unsubstituted or substituted with one or more halo groups, and where one of R ^b6 and R ^b7 is alkyl, z is 1; each R ^{b4 is} independently selected from the group consisting of: Halo, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, -NO ₂ , -CN, -SO ₂ NH ₂ , -NR ^b13 R ^b14 , -OR ^b15 , =O, -SR ^b60 and -SO ₂ R ^b16 , wherein each alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group and heteroaryl group are independently unsubstituted or substituted with one or more halogen groups; each R ^b13 , R ^b14 , R ^b15 , R ^b16 and R ^{b60 are} independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl or haloheterocycloalkyl; or R ^b2 and R ^b3 together form = O; or R ^b6 and R ^b1 together with the atoms to which they are attached form a heterocycloalkyl, which is unsubstituted or substituted with one or more halo groups; or R ^b10 and R ^b1 together with the atoms to which they are attached form a heterocycloalkane Group, which is unsubstituted or substituted with one or more halo groups; or R ^b8 and R ^b1 together with the atoms to which they are attached form a heterocycloalkyl group, which is unsubstituted or substituted with one or more halo groups; or both From four to four R ^b2 , R ^b3 , R ^b6 and R ^b7 together with the atoms to which they are attached form a heterocycloalkyl or heteroaryl group, wherein the heterocycloalkyl or heteroaryl group is unsubstituted or substituted by one or more Halo substitution; or R ^b1 and one R ^b4 together with the atoms to which they are attached form a heterocycloalkyl group which is unsubstituted or substituted with one or more halo groups; or two to four R ^b4 and the atoms to which they are attached Together form an aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl is not taken Substituted or substituted with one or more halo groups; each R ^b5 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl,- _{NO 2, -CN, -SO 2 NR} b54 R b55, -NR b17 R b18, -OR b19, -SO 2 R b20, = O and -SR ^b21; wherein each cycloalkyl, heterocycloalkyl, aryl, And heteroaryl groups are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, -OR ^b22 , =O, -NR ^b23 R ^b24 , -CN, -SF ₅ , -SO ₂ NR ^b56 R ^b57 , -SR ^b58 , -SO ₂ R ^b59 and R ^b28 , where each R ^{b28 is} independently alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; The alkyl group is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, -OR ^b25 , =O, -NR ^b26 R ^b27 , -CN, ^-SF ₅ , -SO ₂ NR ^b61 R ^b62 , -SR ^b63 , -SO ₂ R ^b64 and R ^b65 , where each R ^{b65 is} independently cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each R ^b17 , R ^{b18 , R b19, R b20, R} b21, R b22, R b23, R b24, R b25, R b26, R b27, R b54, R b55, R b56, R b57, R b58, R b59, R b61, R ^b62 , R ^b63 and R ^{b64 are} independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl or haloalkynyl; wherein R ^b17 , R ^b18 , R ^b19 , R ^b22 , R ^b23 , R ^b24 , R ^b25 , R ^b26 , R ^b27 and R ^b28 each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl and R ^b65 Each cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, =O, -CN , Aryl, heteroaryl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, -NR ^b29 R ^b30 , ^-SF ₅ and -OR ^b31 ; where each aryl, heteroaryl, alkyl, ring Alkyl and heterocycloalkyl are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SF ₅ , =O, -NR ^b43 R ^b44 , -NR ^b45 C(O)R ^b46 , -OR ^b47 and R ^b66 , where each R ^{b 66 is} independently cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and wherein each R ^b66 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: =O, -NH ₂ , -SF ₅ , -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl; each R ^b29 , R ^b30 , R ^b31 , R ^b43 , R ^b44 , R ^b45 , R ^b46 and R ^{b47 are} independently hydrogen, alkyl or haloalkyl; each R ^b12 is independently selected from the group consisting of halo, alkyl, haloalkyl and -OR ^b32 , Where R ^b32 is hydrogen, alkyl or haloalkyl; m is an integer from 0 to 13; n is an integer from 0 to 11; and t is an integer from 0 to 6. The compound of claim 1, or its stereoisomer or pharmaceutically acceptable salt, wherein: A is a 4- to 8-membered heterocycloalkyl; B is an aryl, heteroaryl, cycloalkyl or heterocyclic Alkyl; W is aryl or heteroaryl; X is -S(O)-, -S(O) ₂ -, -S(O)NR ^b53 -, -C(S)-, -C(O) ^-Or- C(R ^b13 ) ₂ -; each R ^{b13 is} independently hydrogen, halo, alkyl or haloalkyl; R ^b53 is hydrogen or alkyl, wherein the alkyl is unsubstituted or substituted by one or more Substituent substituents independently selected from the group consisting of halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and =O; R ^b1 is hydrogen, alkyl or cycloalkyl; z is 0 Or 1; R ^b2 , R ^b3 , R ^b6 , R ^b7 , R ^b8 , R ^b9 , R ^b10 and R ^b11 are independently selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, -CN , -OH, -NO ₂ , -NH ₂ and -SO ₂ NH ₂ , wherein when one of R ^b6 and R ^b7 is alkyl, z is 1; each R ^b4 is independently selected from the group consisting of : Halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO ₂ , -CN, -SO ₂ NH ₂ , -NR ^b13 R ^b14 , -OR ^b15 , =O,- SR ^b60 and -SO ₂ R ^b16 ; wherein each alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group and heteroaryl group are independently unsubstituted or substituted with one or more halo groups; and each R ^b13 , R ^b14 , R ^b15 , R ^b16 and R ^{b60 are} independently hydrogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; or R ^b2 and R ^b3 together form =O; or R ^b6 and R ^b1 and The connected atoms together form a heterocycloalkyl; or R ^b10 and R ^b1 together with the atoms to which they are connected form a heterocycloalkyl; or R ^b8 and R ^b1 together with the atoms to which they are connected form a heterocycloalkyl; or two ^Up to four R ^b2 , R ^b3 , R ^b6 and R ^b7 together with the atoms to which they are attached form a heterocycloalkyl or heteroaryl; or R ^b1 and one R ^b4 together with the atoms to which they are attached form a heterocycloalkyl; or Two to four R ^b4 together with the atoms to which they are attached form aryl, heteroaryl, cycloalkyl or heterocycloalkyl; each R ^b5 is independently selected from the group consisting of halo, alkyl, ring alkyl, heterocycloalkyl, aryl, heteroaryl, _{alkynyl, -NO 2, -CN, -SO 2} NR b54 R b55, -NR b17 R b18, -OR b19, -SO 2 R b20, = O and -SR ^b21 ; wherein each cycloalkyl group is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -OR ^b22 , =O, -NR ^b23 R ^b24 , -CN, -SF ₅ , -SO ₂ NR ^b56 R ^b57 , -SR ^b58 , -SO ₂ R ^b59 and R ^b28 , where each R ^{b28 is} independently alkyl, cycloalkyl, heterocycloalkyl, Aryl or heteroaryl; each aryl, heteroaryl, and heterocycloalkyl are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, =O, -SF ₅ and R ^b28 , wherein each R ^{b28 is} independently an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each alkyl group is independently unsubstituted or independently substituted by one or more Substituent substitution selected from the group consisting of: halo, -OR ^b25 , =O, -NR ^b26 R ^b27 , -CN, ^-SF ₅ , -SO ₂ NR ^b61 R ^b62 , -SR ^b63 , -SO ₂ R ^b64 and R ^b65 , wherein each R ^{b65 is} independently cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each R ^b20 , R ^b21 , R ^b22 , R ^b23 , R ^b24 , R ^b54 , R ^b55 , ^{R b56, R b57, R b58} , R b59, R b61, R b62, R b63 and R ^b64 are independently hydrogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl group; each R ^b17, R ^b18 , R ^b25 , R ^b26 and R ^{b27 are} independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each R ^{b19 is} independently hydrogen, alkyl, cycloalkyl, heterocycle alkyl, aryl, heteroaryl, or alkynyl; wherein each alkyl ^{R b17, R b18, R b19} , R b25, R b26, R b27 and R ^b28, the cycloalkyl, heterocycloalkyl, aryl, And heteroaryl and each cycloalkyl, heterocycloalkyl, aryl and heteroaryl of R ^b65 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen ^Group , =O, -CN, aryl, heteroaryl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, -NR ^b29 R ^b30 , ^-SF ₅ and -OR ^b31 ; wherein each alkyl, ring Alkyl, heterocycloalkyl, aryl and heteroaryl are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo ^Group , -CN, -SF ₅ , =O, -NR ^b43 R ^b44 , -NR ^b45 C(O)R ^b46 , -OR ^b47 and R ^b66 , where each R ^{b66 is} independently cycloalkyl, heterocycloalkyl , Aryl or heteroaryl, and wherein each R ^b66 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: =O, -NH ₂ , -SF ₅ ,- OH, -O-alkyl, -O-haloalkyl, halo, alkyl and Haloalkyl; each R ^b29 , R ^b30 , R ^b31 , R ^b43 , R ^b44 , R ^b45 , R ^b46 and R ^{b47 are} independently hydrogen, alkyl or haloalkyl; each R ^b12 is independently selected from the group consisting of Group: halo, alkyl, haloalkyl and -OR ^b32 , wherein R ^b32 is hydrogen, alkyl or haloalkyl; m is an integer from 0 to 13; n is an integer from 0 to 11; and t is 0 Integer to 6. A compound according to claim 1 or 2, wherein the compound is a compound of formula (II-A):

, Or its stereoisomer or pharmaceutically acceptable salt, wherein: p is an integer from 0 to 7; and B, W, X, R ^b4 , R ^b5 , R ^b10 , R ^b11 , R ^b12 , n and t is defined for formula (II). The compound according to any one of claims 1 to 3, wherein the compound is a compound of formula (II-A-ii):

, Or its stereoisomers or pharmaceutically acceptable salts, wherein: p is an integer from 0 to 7; u is an integer from 0 to 5; and B, X, R ^b4 , R ^b5 , R ^b10 , R ^b11 , R ^b12 and n are defined for formula (II). A compound according to claim 1 or 2, wherein the compound is a compound of formula (II-B):

, Or its stereoisomer or pharmaceutically acceptable salt, wherein: p is an integer from 0 to 7; Y is -C(R ^b52 ) ₂ -, -S(O) _r -, -O- or- N(R ^b52 )-, wherein each R ^{b52 is} independently hydrogen or R ^b4 ; r is 0, 1 or 2; and B, W, X, R ^b4 , R ^b5 , R ^b10 , R ^b11 , R ^b12 , n And t are defined for formula (II). The compound according to any one of 2 or 5, wherein the compound is a compound of formula (II-B-ii):

, Or its stereoisomer or pharmaceutically acceptable salt, wherein: p is an integer from 0 to 7; Y is -C(R ^b52 ) ₂ -, -S(O) _r -, -O- or- N(R ^b52 )-, wherein each R ^{b52 is} independently hydrogen or R ^b4 ; r is 0, 1 or 2; u is an integer from 0 to 5; and B, X, R ^b4 , R ^b5 , R ^b10 , R ^b11 , R ^b12 and n are defined for formula (II). A compound as claimed in claim 5 or 6, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Y is -CH ₂ -. The compound or stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein A is a 5-membered or 6-membered heterocycloalkyl. A compound as claimed in any one of claims 1 to 8, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is a 5-membered or 6-membered heterocycloalkyl group or a 5-membered or 6-membered heteroaryl group, wherein The heterocycloalkyl or heteroaryl group contains one to three ring heteroatoms independently selected from the group consisting of O, N, and S. The compound according to any one of claims 1 to 8 or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is a 9-membered or 10-membered bicyclic heteroaryl group, which contains one to three independently selected from Ring heteroatoms of the group consisting of O, N and S. The compound according to any one of claims 1 to 8, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is (C ₉ -C ₁₀ ) bicyclic aryl group. The compound according to any one of claims 1 to 8, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein B is (C ₅ -C ₁₀ )cycloalkyl. A compound as claimed in any one of claims 1 to 12, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein one or more R ^b5 is independently selected from the group consisting of: halo; -O- (C ₁ -C ₆ )alkyl, which is unsubstituted or substituted with one or more fluorine; (C ₂ -C ₄ ) alkynyloxy; phenyl; heteroaryl; heterocycloalkyl; -SO ₂ NH ₂ ; -NO ₂ ; -CN; (C ₃ -C ₆ ) cycloalkyl, which is unsubstituted or substituted with one or more fluorine; and (C ₁ -C ₆ ) alkyl, which is unsubstituted or substituted One or more substituents independently selected from the group consisting of (C ₃ -C ₆ )cycloalkyl, aryl, halo, -OH, -O-(C ₁ -C ₄ )alkyl, =O, -NR ^b26 R ^b27 and -CN. A compound as claimed in any one of claims 1 to 8 or 13 or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is phenyl and n is an integer from 0 to 5. The compound according to any one of claims 1 to 4, 8, or 13, wherein the compound is a compound of formula (II-Ai):

, Or its stereoisomers or pharmaceutically acceptable salts, wherein: p is an integer from 0 to 7; u is an integer from 0 to 5; and X, R ^b4 , R ^b5 , R ^b10 , R ^b11 and R ^b12 is defined for formula (II). 2. A compound according to any one of 5 to 8 or 13, wherein the compound is a compound of formula (II-Bi):

, Or its stereoisomer or pharmaceutically acceptable salt, wherein: p is an integer from 0 to 7; Y is -C(R ^b52 ) ₂ -, -S(O) _r -, -O- or- N(R ^b52 )-, wherein each R ^{b52 is} independently hydrogen or R ^b4 ; r is 0, 1 or 2; u is an integer from 0 to 5; and X, R ^b4 , R ^b5 , R ^b10 , R ^b11 and R ^b12 is defined for formula (II). The compound of any one of claims 1 to 16, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein at least one R ^b5 is:

, Where: R ^b33 is hydrogen, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl Unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, =O, -OR ^b36 , -SF ₅ and -NR ^b37 R ^b38 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently unsubstituted or independently selected by one or more of the following Group substituent substitution: alkyl, haloalkyl, alkynyl, halo, -SF ₅ , =O, -OR ^b39 , -NR ^b48 R ^b49 , -NR ^b50 C(O)R ^b51 , cycloalkyl and Heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: =O, halo, -OH, and- SF ₅ ; each R ^b34 and R ^{b35 are} independently hydrogen, halo or alkyl; wherein each alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen Radical, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR ^b40 and -NR ^b41 R ^b42 ; wherein each cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently Substitution or substitution by one or more substituents independently selected from the group consisting of halo, haloalkyl, alkyl, -OH, =O, and -SF ₅ ; or one R ^b34 connected to the same atom and One R ^b35 and the atom to which it is connected form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group is unsubstituted or substituted with one or more halo groups; each R ^b36 , R ^b37 , R ^b38 , R ^b39 , R ^b40 , R ^b41 , R ^b42 , R ^b48 , R ^b49 , R ^b50 and R ^{b51 are} independently hydrogen, alkyl or haloalkyl; and q is 1 or 2. The compound of claim 17, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein q is 1 and R ^b34 is hydrogen. The compound according to any one of claims 1 to 18, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein at least one R ^b5 is heteroaryl or heterocycloalkyl, wherein the heteroaryl or heterocycle The alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: =O, -SF ₅ and R ^b28 . The compound of claim 19 or its stereoisomer or pharmaceutically acceptable salt, wherein R ^b28 is an alkyl group substituted with an aryl or heteroaryl group, wherein the aryl or heteroaryl group is unsubstituted or substituted Haloalkyl or -SF ₅ substitution. 2. The compound of any one of 8 to 14, or 17 to 20, or its stereoisomer or pharmaceutically acceptable salt, wherein R ^b1 and one R ^b4 together with the atoms to which they are connected form 3 to 6 members Heterocycloalkyl. 2. A compound of any one of 8 to 14, or 17 to 20, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R ^b1 and R ^b8 together with the atoms to which they are connected form a 3 to 6 membered hetero Cycloalkyl. 2. The compound of any one of 8 to 14, or 17 to 20, or its stereoisomer or pharmaceutically acceptable salt, wherein R ^b1 and R ^b10 together with the atoms to which they are connected form a 3 to 6 membered hetero Cycloalkyl. The compound according to any one of claims 1 to 23 or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -S(O) ₂ -. The compound according to any one of claims 1 to 23, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -C(O)-. The compound according to any one of claims 1 to 23 or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -CH ₂ -. A compound as claimed in any one of claims 1 to 14, or 17 to 26, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein n is 1 or 2. 2. The compound of any one of 8 to 14, or 17 to 27, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein m is 0. A compound as claimed in any one of claims 3 to 7, 15 or 16, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein p is 0. A compound as claimed in any one of claims 1 to 29 or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R ^b10 and R ^b11 are independently selected from the group consisting of hydrogen, fluorine, -CN, Unsubstituted methyl and methyl substituted with one to three fluorines. The compound according to any one of claims 1 to 30, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein at least one R ^b12 is chlorine. A compound as claimed in any one of claims 1 to 3, 5, 7 to 14, or 17 to 30, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein

for

. 6. The compound of any one of 15, 15 or 16 or a stereoisomer or pharmaceutically acceptable salt thereof, wherein

for

. The compound according to any one of claims 1 to 33, wherein z is 0 or 1. The compound of claim 1 or 34, wherein the compound is:

, Or the stereoisomers or pharmaceutically acceptable salts of any of the foregoing. The compound of claim 1, wherein the compound is:

, Or the stereoisomers or pharmaceutically acceptable salts of any of the foregoing. A pharmaceutical composition comprising the compound according to any one of claims 1 to 36 or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. A method of reducing the content of K-Ras protein in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a pharmaceutical composition comprising the compound of any one of claims 1 to 36 Or its stereoisomers or pharmaceutically acceptable salts, and pharmaceutically acceptable excipients. The method of claim 38, wherein the K-Ras protein is human K-Ras4b. A method of treating a disorder in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a pharmaceutical composition comprising the compound or stereoisomer of any one of claims 1 to 36 Or pharmaceutically acceptable salts, and pharmaceutically acceptable excipients. The method of claim 40, wherein the condition is cancer. The method of claim 41, wherein the cancer is pancreatic cancer, lung cancer, colorectal cancer, optic nerve path glioma, rhabdomyosarcoma, neuroblastoma, juvenile bone marrow mononuclear leukemia, malignant peripheral schwannoma, gastrointestinal tract Stromal tumor, somatostatin tumor, pheochromocytoma or breast cancer. The method of claim 40, wherein the condition is neurofibromatosis type 1, Noonan syndrome, heart-face-skin syndrome, or Legius syndrome. The method according to any one of claims 40 to 43, wherein the disorder is associated with a mutation in K-Ras. A use of a compound as claimed in any one of claims 1 to 36, or a stereoisomer or pharmaceutically acceptable salt thereof, for an agent for reducing the content of K-Ras protein in an individual in need Manufacturing use. The use according to claim 45, wherein the K-Ras protein is human K-Ras4b. A use of a compound as claimed in any one of claims 1 to 36, or a stereoisomer or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disorder in an individual in need. The use according to claim 47, wherein the condition is cancer. The use according to claim 48, wherein the cancer is pancreatic cancer, lung cancer, colorectal cancer, optic nerve path glioma, rhabdomyosarcoma, neuroblastoma, juvenile bone marrow mononuclear leukemia, malignant peripheral schwannoma, gastrointestinal tract Stromal tumor, somatostatin tumor, pheochromocytoma or breast cancer. The use according to claim 47, wherein the condition is neurofibromatosis type 1, Noonan syndrome, heart-face-skin syndrome or Regis syndrome. Use according to any one of claims 47 to 50, wherein the disorder is associated with mutations in K-Ras. A compound as claimed in any one of claims 1 to 36, or a stereoisomer or pharmaceutically acceptable salt thereof, which is used in a method for reducing the content of K-Ras protein in an individual in need. The compound as used in claim 52, wherein the K-Ras protein is human K-Ras4b. A compound as claimed in any one of claims 1 to 36, or a stereoisomer or a pharmaceutically acceptable salt thereof, which is used in a method of treating a disorder in an individual in need. The compound as used in claim 54 wherein the condition is cancer. The compound as used in claim 55, wherein the cancer is pancreatic cancer, lung cancer, colorectal cancer, optic nerve path glioma, rhabdomyosarcoma, neuroblastoma, juvenile myelomonocytic leukemia, malignant peripheral schwannoma, Gastrointestinal stromal tumor, somatostatin tumor, pheochromocytoma or breast cancer. The compound as used in claim 54 wherein the condition is neurofibromatosis type 1, Noonan syndrome, heart-face-skin syndrome, or Regis syndrome. The compound as claimed in any one of claims 54 to 57, wherein the disorder is associated with a mutation in K-Ras.

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