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CN-122029167-A - Condensed heteroaryl compound, preparation method and medical application thereof

CN122029167ACN 122029167 ACN122029167 ACN 122029167ACN-122029167-A

Abstract

The present disclosure relates to fused heteroaryl compounds, methods of making and their use in medicine. In particular, the present disclosure relates to a fused heteroaryl compound represented by general formula (I'), a preparation method thereof, a pharmaceutical composition containing the compound, and use thereof as a therapeutic agent, particularly use thereof in preparation of a medicament for inhibiting KRAS amplification and/or mutant activity. Wherein each group in the general formula (I') is defined in the specification.

Inventors

  • LI XIN
  • SHEN FENG
  • GUI BIN
  • CHEN YANG
  • HE FENG

Assignees

  • 江苏恒瑞医药股份有限公司
  • 上海恒瑞医药有限公司

Dates

Publication Date
20260512
Application Date
20241030
Priority Date
20231030

Claims (20)

  1. A compound of the general formula (I') or a pharmaceutically acceptable salt thereof: Wherein: R A is selected from A hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, NR 11 R 12 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more R 3 ; Ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; ring a is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; g 1 is CR G1 or N, G is selected from C, CR G and N; G 8 is CR 7 or N, G 9 is CR 2 or N; R B is selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, NR 11 R 12 , hydroxy, hydroxyalkyl, alkenyl, alkynyl, OR 14 、C(O)OR 14 、S(O) v R 14 , cycloalkyl, heterocyclyl, aryl, and heteroaryl, each independently optionally substituted with one OR more R 6 ; R 2 、R G1 、R G and R 7 are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkenyl, alkynyl, NR 11 R 12 、C(O)NR 11 R 12 , alkylene NR 11 R 12 , alkylene C(O)NR 11 R 12 、NR 13 C(O)R 14 、NR 13 C(O)NR 11 R 12 、C(O)R 14 、C(O)OR 14 、OC(O)R 14 、OC(O)OR 14 、S(O) v R 14 、S(O) v OR 14 、OS(O) v R 14 、S(O) v NR 11 R 12 、NR 13 S(O) v R 14 、C(＝NR 13 )R 14 、C(＝NR 13 )NR 11 R 12 、S(＝NR 13 )(O)R 14 、P(O)R 11 R 12 、OR 14 、 cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more R 01 ; Or G, R 7 together with the carbon atom to which it is attached form a ring B, which is optionally substituted with one or more R 8 ; ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; R 4 and R 5 are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, NR 11 R 12 、C(O)R 14 , cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is independently optionally substituted with one or more R 01 ; Or, R 4 、R 5 together with the carbon atom to which it is attached form cycloalkyl or heterocyclyl, each of which is independently optionally substituted with one or more R 3 ; W is selected from CR 3a R 3b , O, S, and NR w ; R 3a and R 3b are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxy, and hydroxyalkyl, or R 3a 、R 3b together with the carbon atoms to which they are attached form cycloalkyl or heterocyclyl, said cycloalkyl or heterocyclyl being optionally substituted with one or more R 0 ; R w is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each independently optionally substituted with one or more R 0 ; Each R 1 、R 3 、R 6 、R 01 、R 8 and R 0 is the same or different and is each independently selected from oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, nitro, NR 11 R 12 、C(O)NR 11 R 12 , alkylene NR 11 R 12 , alkylene C(O)NR 11 R 12 、NR 13 C(O)R 14 、NR 13 C(O)NR 11 R 12 、C(O)R 14 、C(O)OR 14 、OC(O)R 14 、OC(O)OR 14 、S(O) v R 14 、S(O) v OR 14 、OS(O) v R 14 、S(O) v NR 11 R 12 、NR 13 S(O) v R 14 、C(＝NR 13 )R 14 、C(＝NR 13 )NR 11 R 12 、S(＝NR 13 )(O)R 14 、P(O)R 11 R 12 、OR 14 、＝CR 15 R 16 、＝NR 13 、 cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is independently optionally substituted with one or more R * ; Each R 11 、R 12 、R 13 and R 14 is the same or different and is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a hydroxyl group, an alkenyl group, an alkynyl group, NR 20 R 21 、C(O)NR 20 R 21 group, an alkylene NR 20 R 21 group, an alkylene C(O)NR 20 R 21 、NR 22 C(O)R 23 、NR 22 C(O)NR 20 R 21 、C(O)R 23 、C(O)OR 23 、OC(O)R 23 、OC(O)OR 23 、OR 23 、S(O) v R 23 、S(O) v NR 20 R 21 、 cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, each of which is independently optionally substituted with one or more R * groups, or R 11 、R 12 and the nitrogen atom to which it is attached form a heterocyclic group, which is optionally substituted with one or more R * groups; R 15 and R 16 are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is independently optionally substituted with one or more R * ; Each R 20 、R 21 、R 22 and R 23 is the same or different and is independently selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, NR a R b 、C(O)NR a R b 、C(O)R c , cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl, and heteroaryl, each of which is independently optionally substituted with one or more R * , or R 20 、R 21 and the nitrogen atom to which it is attached form a heterocyclyl substituted with one or more R * ; Each R * is the same or different and is each independently selected from oxo, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, NR a R b 、C(O)NR a R b 、C(O)R c , alkylene NR a R b , alkylene C (O) NR a R b , nitro, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryloxy, and heteroaryloxy; the alkyl, alkoxy, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryloxy, and heteroaryloxy are each independently optionally substituted with one or more groups selected from oxo, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl 、NR a R b 、NR a OR c 、NR a C(O)NR a R b 、NR a C(O)OR c 、C(O)NR a R b 、C(O)R c 、C(O)OR c 、 alkylene NR a R b , alkylene C(O)NR a R b 、S(O) v R c 、S(O) v OR c 、S(O) v NR a R b 、 cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryloxy, and heteroaryloxy; R a 、R b and R c are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, and a heterocyclic group; r is 0,1, 2, 3, 4 or 5, v is 0,1 or 2; m is 0, 1,2, 3, 4, 5 or 6; p is 0, 1, 2, 3, 4, 5 or 6, and j is 0, 1, 2, 3, 4, 5 or 6.
  2. The compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (I): Wherein R A is selected from Hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, NR 11 R 12 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more R 3 , each R * is the same or different and is each independently selected from oxo, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, NR a R b 、C(O)NR a R b 、C(O)R c , alkylene NR a R b , alkylene C (O) NR a R b , nitro, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl and heteroaryl, ring A, R 1 、m、G、G 1 、R 2 、R 7 、R B 、W、R 3a 、R 3b , R, ring C, Y, R 3 、R 4 、R 5 、p、R 11 、R 12 、R a 、R b and R c are as defined in claim 1; Preferably, R A is W, R 3a 、R 3b , r, Y, ring C, R 3 、R 4 、R 5 and p are as defined in claim 1.
  3. The compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a compound represented by the general formula (II): Wherein R 6a is a hydrogen atom or R 6 ; R 6b is R 6 , or two R 6b together with the carbon atom to which they are attached form CH (CR 6c R 6d ) u CH; R 6c and R 6d are the same or different and are each independently a hydrogen atom or R 6 ; n is 0,1, 2, 3, 4, 5 or 6, u is 0,1 or 2; Ring a, ring C、R 1 、m、G、G 1 、R 2 、R 7 、R 6 、W、R 3a 、R 3b 、r、Y、R 3 、R 4 、R 5 and p are as defined in claim 1.
  4. The compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a compound represented by the general formula (IN): Wherein G is C or N, q is 0,1, 2, 3 or 4; Ring a, ring B, ring C, R 1 、m、R 8 、R 2 、G 1 、R B 、W、R 3a 、R 3b 、r、R 3 , and j are as defined in claim 1.
  5. The compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof according to claim 1, 2 or 4, wherein R B is selected from the group consisting of a hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and 3 to 6 membered cycloalkyl, each of which is independently optionally substituted with one or more R 6 groups, R 6a is a hydrogen atom or R 6 ,R 6b is R 6 , u is 0, 1 or 2, n1 is 0, 1, 2 or 3;R 6 as defined in claim 1, preferably R B is selected from a hydrogen atom, R 6a is a hydrogen atom or R 6 ,R 6b is R 6 , u is 0,1 or 2, n1 is 0,1,2 or 3;R 6 as defined in claim 1, more preferably R B is selected from a hydrogen atom,
  6. A compound of the general formula (I') or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, which is a compound of the general formula (V): Wherein, the Q is selected from CR 8a R 8b 、O、S、C(O)、C(O)NR 8c and NR 8c ; R 8a and R 8b are the same or different and are each independently a hydrogen atom or R 8 ; R 8c is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group; s is 0, 1, 2 or 3;t is 0, 1, 2 or 3, q is 0, 1, 2, 3 or 4; Ring a, ring C、R 1 、m、R 2 、G 1 、R 8 、R 6a 、R 6b 、n、W、R 3a 、R 3b 、r、Y、R 3 、R 4 、R 5 and p are as defined in claim 3.
  7. The compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof according to claim 1 or2, which is a compound represented by the general formula (VII-1) or (VII-2) or a pharmaceutically acceptable salt thereof: Wherein, the U is selected from NR 1a , O, S and Se, V is N or CR 1b ; R 1a is a hydrogen atom or R 1 ;R 1b is a hydrogen atom or R 1 ;R 3c is a hydrogen atom or R 3 ; m2 is 0,1, 2, 3 or 4;q is 0,1, 2, 3 or 4; R 1 、R 8 、R 2 、G 1 、R B 、R 3 、R 4 and R 5 are as defined in claim 1.
  8. The compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof according to claim 3, 5 or 6, wherein Selected from the group consisting of Preferably is N1 is 0,1,2 or 3, R 6b is R 6 ,R 6 and u is as defined in claim 3, more preferably * The terminal is connected with R 6a .
  9. The compound represented by the general formula (I') according to claim 3, 5, 6, 7 OR 8, wherein R 6a is selected from the group consisting of a hydrogen atom, a C 1-6 alkyl group and OR 14 , the C 1-6 alkyl group is optionally substituted with one OR more selected from the group consisting of a halogen, a hydroxyl group, a C 1-6 alkoxy group and a 3 to 6 membered heterocyclic group, R 14 is selected from the group consisting of a hydrogen atom, a C 1-6 alkyl group and a 3 to 6 membered cycloalkyl group, preferably R 6a is a hydrogen atom OR a C 1-6 alkyl group, the C 1-6 alkyl group is optionally substituted with one OR more selected from the group consisting of a hydroxyl group, a C 1-6 alkoxy group and a 3 to 6 membered heterocyclic group, more preferably R 6a is a C 1-6 alkyl group, the C 1-6 alkyl group is optionally substituted with one OR more selected from the group consisting of a hydroxyl group, a C 1-6 alkoxy group and a 3 to 6 membered heterocyclic group, and further preferably R 6a is a C 1-6 hydroxyalkyl group.
  10. The compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3,5 to 9, wherein R 4 and R 5 are the same or different and are each independently selected from a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl, preferably R 4 and R 5 are the same or different and are each independently a hydrogen atom or halogen.
  11. The compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 or 8 to 10, wherein ring C is a 3-to 8-membered heterocyclic group, and/or each R 3 is the same or different and each is independently halogen or = CR 15 R 16 ,R 15 and R 16 is the same or different and each is independently hydrogen atom or halogen.
  12. A compound of formula (I') according to any one of claims 1 to 6 or 8 to 11, or a pharmaceutically acceptable salt thereof, wherein W is O and/or R 3a and R 3b are hydrogen atoms, or R 3a 、R 3b together with the attached carbon atom form a cyclopropyl group, and/or R is 1 or 3.
  13. The compound of formula (I') or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 or 8to 12, wherein ring a is a 6 to 10 membered aryl or a 5 to 14 membered heteroaryl, preferably ring a is selected from naphthyl, phenyl, pyridyl, benzothienyl, benzothiazolyl, benzopyrazolyl, pyridothienyl, pyridothiazolyl, pyridopyrazolyl, benzoselenophenyl and pyridoselenophenyl, more preferably ring a is selected from phenyl, benzothienyl and pyridothienyl.
  14. A compound of the general formula (I') or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 or 8 to 13, wherein Selected from the group consisting of R 1 and m are as defined in claim 1, preferably, Selected from the group consisting of
  15. A compound of formula (I') according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein each R 1 is the same or different and is each independently selected from halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, hydroxy, C 1-6 hydroxyalkyl, cyano, -NR 11 R 12 and 3 to 8 membered cycloalkyl, preferably each R 1 is the same or different and is each independently selected from halogen, C 1-6 haloalkyl, cyano and-NR 11 R 12 ,R 11 and R 12 are as defined in claim 1, and/or m is 1, 2 or 3.
  16. A compound of formula (I') according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein G 1 is N and/or R 2 is halogen.
  17. A compound of formula (I') according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, selected from the following compounds:
  18. A compound represented by the general formula (VA): Wherein, the Ring a, ring C、R 1 、m、Q、s、t、R 8 、q、R 2 、G 1 、R 6b 、n、W、R 3a 、R 3b 、r、Y、R 3 、R 4 、R 5 and p are as defined in claim 6.
  19. A compound of formula (I') according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the following compounds:
  20. A process for preparing a compound of formula (V) or a pharmaceutically acceptable salt thereof, which comprises: The compound shown in the general formula (VA) or salt thereof and the compound shown in the general formula (IIB) or salt thereof undergo a ring-opening reaction to obtain a compound shown in the general formula (V) or pharmaceutically acceptable salt thereof; Wherein R 6a is R is a hydrogen atom or an alkyl group; Ring a, ring C、R 1 、m、Q、s、t、R 8 、q、R 2 、G 1 、R 6b 、n、W、R 3a 、R 3b 、r、Y、R 3 、R 4 、R 5 and p are as defined in claim 6.

Description

Condensed heteroaryl compound, preparation method and medical application thereof Technical Field The present disclosure belongs to the field of medicine, and relates to a fused heteroaryl compound, a preparation method thereof and application thereof in medicine. In particular, the disclosure relates to fused heteroaryl compounds represented by general formula (I'), methods for preparing the same, pharmaceutical compositions containing the same, and use thereof in preparing medicaments for inhibiting KRAS amplification and/or mutant activity. Background The KRAS protein encoded by the KARS gene is a small gtpase (SMALL GTPASE) belonging to the RAS superfamily of proteins. In cells, KRAS proteins transition between an inactive and an active state, when KRAS binds Guanosine Diphosphate (GDP), in an inactive state, and when Guanosine Triphosphate (GTP) binds, in an active state, causing activation of downstream signaling pathways. KRAS can be activated by tyrosine kinases such as upstream growth factors (e.g., EGFR), and the downstream pathways activated by KRAS are commonly known as RAS-RAF-MEK-ERK and PI3K-AKT-mTOR signaling pathways that regulate cell proliferation and growth. KRAS is one of the most common oncogenes in solid tumors, and about 19% of tumors have KRAS mutations, including 90% pancreatic cancer, 50% colon cancer, 30% lung adenocarcinoma, and the like. There is also a proportion of other cancer types such as cholangiocarcinoma, cervical cancer, bladder cancer, liver cancer, breast cancer, etc. The sites where the most frequent gene mutation occurs are codons 12, 13 and 61, with mutations at codon 12 being the most common. KRAS mutations will place the RAS more in an activated state in conjunction with GTP, activating downstream pathways. In addition, KRAS amplification/overexpression or upstream activation also occurs in tumors, which can cause continued activation of RAS downstream pathways, resulting in tumorigenesis. The KRAS protein surface lacks a small molecule binding site in the traditional sense, has extremely high affinity to guanylic acid and is difficult to be competitively inhibited by small molecules, and is long considered as a non-patent drug target. But based on the importance and prevalence of abnormal activation of KRAS in cancer progression, KRAS has been and remains a very interesting target for drug development. Currently, only inhibitors against KRAS G12C and G12D are available in bulk or in clinical stages, and therefore there remains a need to develop pan KRAS inhibitors for the treatment of various KRAS mutant tumors or KRAS dependent tumors. Related patent applications which have been published so far are WO2021041671A1、WO2020146613A1、WO2017172979A1、WO2020238791A1、WO2022132200A1、WO2022188729A1、WO2022194245A1、WO2022199587A1、WO2022216762A1、WO2021000885A1 and WO2023183585A1, etc. Disclosure of Invention The object of the present disclosure is to provide a compound represented by the general formula (I'): Wherein: R A is selected from A hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, NR 11R12, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more R 3; Ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; ring a is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; g 1 is CR G1 or N, G is selected from C, CR G and N; G 8 is CR 7 or N, G 9 is CR 2 or N; R B is selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, NR 11R12, hydroxy, hydroxyalkyl, alkenyl, alkynyl, OR 14、C(O)OR14、S(O)vR14, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each independently optionally substituted with one OR more R 6; R 2、RG1、RG and R 7 are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkenyl, alkynyl, NR 11R12、C(O)NR11R12, alkylene NR 11R12, alkylene C(O)NR11R12、NR13C(O)R14、NR13C(O)NR11R12、C(O)R14、C(O)OR14、OC(O)R14、OC(O)OR14、S(O)vR14、S(O)vOR14、OS(O)vR14、S(O)vNR11R12、NR13S(O)vR14、C(＝NR13)R14、C(＝NR13)NR11R12、S(＝NR13)(O)R14、P(O)R11R12、OR14、 cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more R 01; Or G, R 7 together with the carbon atom to which it is attached form a ring B, which is optionally substituted with one or more R 8; ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; R 4 and R 5 are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, NR 11R12、C(O)R14, cycloalkyl, heterocyclyl, aryl