IONIZABLE LIPID COMPOUNDS
20230348361 · 2023-11-02
Inventors
- Lin ZHANG (Beijing, CN)
- Liu Yang (Beijing, CN)
- Andong LIU (Beijing, CN)
- Caida LAI (Hangzhou, CN)
- Wenshou WANG (Hangzhou, CN)
Cpc classification
C07C229/12
CHEMISTRY; METALLURGY
C07C231/12
CHEMISTRY; METALLURGY
C07C227/18
CHEMISTRY; METALLURGY
C07D211/34
CHEMISTRY; METALLURGY
C07C275/16
CHEMISTRY; METALLURGY
C07C329/06
CHEMISTRY; METALLURGY
A61K9/0019
HUMAN NECESSITIES
C07C271/22
CHEMISTRY; METALLURGY
A61K47/543
HUMAN NECESSITIES
C07D211/14
CHEMISTRY; METALLURGY
C07C327/22
CHEMISTRY; METALLURGY
International classification
C07C229/12
CHEMISTRY; METALLURGY
C07C235/06
CHEMISTRY; METALLURGY
C07C231/12
CHEMISTRY; METALLURGY
C07C227/18
CHEMISTRY; METALLURGY
Abstract
Provided herein is a class of ionizable lipid compounds represented by formula (IV), or pharmaceutically acceptable salts, isotopic variants, tautomers or stereoisomers thereof. Also provided is a nanoparticle pharmaceutical composition comprising said compound, and the application of said compound and its composition in the delivery of nucleic acids.
##STR00001##
Claims
1. A compound of formula (IV), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof: ##STR00265## wherein, M.sub.1 and M.sub.2 are independently selected from —C(O)O—, —O—, —SC(O)O—, —OC(O)NR.sub.a—, —NR.sub.aC(O)NR.sub.a—, —OC(O)S—, —OC(O)O—, —NR.sub.aC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR.sub.a—, —C(O)NR.sub.a—, —NR.sub.aC(O)—, —NR.sub.aC(O)S—, —SC(O)NR.sub.a—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR.sub.a—, —NR.sub.aC(S)O—, —S—S— and —S(O).sub.0-2—; Q is selected from a chemical bond, —C(O)O—, —O—, —SC(O)O—, —OC(O)NR.sub.b—, —NR.sub.bC(O)NR.sub.b—, —OC(O)S—, —OC(O)O—, —NR.sub.bC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR.sub.b—, —C(O)NR.sub.b—, —NR.sub.bC(O)—, —NR.sub.bC(O)S—, —SC(O)NR.sub.b—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR.sub.b—, —NR.sub.bC(S)O—, —S—S—, —S(O).sub.0-2—, phenylene and pyridylidene, wherein, the phenylene or pyridylidene is optionally substituted with one or more R*; G.sub.5 is a chemical bond or C.sub.1-8 alkylene, which is optionally substituted with one or more R**; G.sub.6a and G.sub.6b are independently a chemical bond or C.sub.1-7 alkylene, which is optionally substituted with one or more R**; G.sub.6a and G.sub.6b have a total length of 0, 1, 2, 3, 4, 5, 6 or 7 carbon atoms; R.sub.9, R.sub.10 and R** are independently H, C.sub.1-8 alkyl, -L.sub.c-OR.sub.c, -L.sub.c-SR.sub.c or -L.sub.c-NR.sub.cR′.sub.c; G.sub.1, G.sub.2, G.sub.3 and G.sub.4 are independently a chemical bond, C.sub.1-13 alkylene, C.sub.2-13 alkenylene or C.sub.2-13 alkynylene, which is optionally substituted with one or more R.sup.s; G.sub.1 and G.sub.2 have a total length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms; G.sub.3 and G.sub.4 have a total length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms; R.sub.3 and R.sub.4 are independently H, C.sub.1-10 alkyl, C.sub.1-10 haloalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl, C.sub.6-10 aryl or 5- to 14-membered heteroaryl, which is optionally substituted with one or more R*: or, R.sub.3 and R.sub.4 are taken together with the N atom to which they are attached to form 3- to 14-membered heterocyclyl, which is optionally substituted with one or more R*; or, R.sub.4 and R.sub.9 are taken together with the atoms to which they are attached to form 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl, which is optionally substituted with one or more R*; R* is independently H, halogen, cyano, C.sub.1-10 alkyl, C.sub.1-10 haloalkyl, -L.sub.b-OR.sub.b, -L.sub.b-SR.sub.b or -L.sub.b-NR.sub.bR′.sub.b; R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-8 alkyl, which is optionally substituted with one or more R*; R.sub.1 and R.sub.2 are independently C.sub.4-20 alkyl, C.sub.4-20 alkenyl or C.sub.4-20 alkynyl, which is optionally substituted with one or more R, and wherein one or more methylene units are optionally and independently replaced with —NR″—; R.sup.s is independently H, C.sub.1-14 alkyl, -L.sub.d-OR.sub.d, -L.sub.d-SR.sub.d or -L.sub.d-NR.sub.dR′.sub.d; R is independently H, C.sub.1-20 alkyl, -L.sub.a-OR.sub.a, -L.sub.a-SR.sub.a or -L.sub.a-NR.sub.aR′.sub.a; R″ is independently H or C.sub.1-20 alkyl; L.sub.a and L.sub.e are independently a chemical bond or C.sub.1-20 alkylene; L.sub.b and L.sub.f are independently a chemical bond or C.sub.1-10 alkylene; L.sub.e is independently a chemical bond or C.sub.1-8 alkylene; L.sub.a is independently a chemical bond or C.sub.1-14 alkylene; R.sub.a and R′.sub.a are independently H, C.sub.1-20 alkyl, 3- to 14-membered cycloalkyl, and 3- to 14-membered heterocyclyl, which are optionally substituted with one or more of the following substituents: H, C.sub.1-20 alkyl, -L.sub.e-OR.sub.c, -L.sub.e-SR.sub.e and -L.sub.e-NR.sub.eR′.sub.e; R.sub.b and R′.sub.b are independently selected from H, C.sub.1-10 alkyl, 3- to 14-membered cycloalkyl, and 3- to 14-membered heterocyclyl, which are optionally substituted with one or more of the following substituents: H, C.sub.1-10 alkyl, -L.sub.f-OR.sub.f, -L.sub.f-SR.sub.f and -L.sub.f-NR.sub.fR′.sub.f; R.sub.c and R′.sub.c are independently H or C.sub.1-8 alkyl; R.sub.d and R′.sub.a are independently H or C.sub.1-14 alkyl; R.sub.e and R′.sub.e are independently H or C.sub.1-20 alkyl; R.sub.f and R′.sub.f are independently H or C.sub.1-10 alkyl.
2. The compound of formula (IV) of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, which has the structure of formula (V): ##STR00266## wherein, Q is selected from —C(O)O—, —O—, —SC(O)O—, —OC(O)NR.sub.b—, —NR.sub.bC(O)NR.sub.b—, —OC(O)S—, —OC(O)O—, —NR.sub.bC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR.sub.b—, —C(O)NR.sub.b—, —NR.sub.bC(O)—, —NR.sub.bC(O)S—, —SC(O)NR.sub.b—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR.sub.b—, —NR.sub.bC(S)O—, —S—S—, and —S(O).sub.0-2—; G.sub.6a and G.sub.6b are independently a chemical bond or C.sub.1-5 alkylene, which is optionally substituted with 1, 2, 3 or 4 R**; G.sub.6a and G.sub.6b have a total length of 0, 1, 2, 3, 4 or 5 carbon atoms; R.sub.9 and R** are independently H, C.sub.1-6 alkyl, -L.sub.c-OR.sub.c or -L.sub.c-NR.sub.cR′.sub.c; one of L.sub.3 and L.sub.5, or one of L.sub.4 and L.sub.6 is —(CR.sup.sR.sup.s′).sub.2—, —CH═CH—, or —C≡C—, and the other is a chemical bond; G.sub.1a, G.sub.1b, G.sub.2a, G.sub.2b, G.sub.3a, G.sub.3b, G.sub.4a and G.sub.4b are independently a chemical bond or C.sub.1-7 alkylene, which is optionally substituted with 1, 2, 3, 4 or 5 R.sup.s; G.sub.1a, G.sub.1b, G.sub.2a and G.sub.2b have a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms; G.sub.3a, G.sub.3b, G.sub.4a and G.sub.4b have a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms; R.sub.3 and R.sub.4 are independently selected from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, 3- to 10-membered cycloalkyl and 3- to 10-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; or, R.sub.3 and R.sub.4 are taken together with the N atom to which they are attached to form 3- to 10-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; or, R.sub.4 and R.sub.9 are taken together with the atoms to which they are attached to form 3- to 10-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; R* is independently H, halogen, cyano, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, -L.sub.b-OR.sub.b or -L.sub.b-NR.sub.bR′.sub.b; R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-6 alkyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; Y.sub.1 and Y.sub.2 are independently O, S or NR.sub.a; L.sub.1 and L.sub.2 are independently —(CRR′).sub.2—, —CH═CH—, —C≡C— or —NR″—; G.sub.7, G.sub.8, G.sub.9 and G.sub.10 are independently a chemical bond or C.sub.1-12 alkylene, which is optionally substituted with 1, 2, 3, 4, 5 or 6 R; G.sub.7 and G.sub.8 have a total length of 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms; G.sub.9 and G.sub.10 have a total length of 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms; 1, 2 or 3 methylenes in G.sub.7, G.sub.8, G.sub.9 or G.sub.10 are optionally and independently substituted with 1 R; R.sup.s and R.sup.s′ are independently H, C.sub.1-10 alkyl, -L.sub.d-OR.sub.d or -L.sub.d-NR.sub.dR′.sub.d; R and R′ are independently H, C.sub.1-14 alkyl, -L.sub.a-OR.sub.a or -L.sub.a-NR.sub.aR′.sub.a; R″ is independently H or C.sub.1-14 alkyl; L.sub.a is independently a chemical bond or C.sub.1-14 alkylene; L.sub.b is independently a chemical bond or C.sub.1-6 alkylene; L, is independently a chemical bond or C.sub.1-6 alkylene; L.sub.a is independently a chemical bond or C.sub.1-10 alkylene; R.sub.a and R′.sub.a are independently H, C.sub.1-14 alkyl, 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl; R.sub.b and R′.sub.b are independently H, C.sub.1-6 alkyl, 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl; R.sub.e and R′.sub.c are independently H or C.sub.1-6 alkyl; R.sub.d and R′.sub.a are independently H or C.sub.1-10 alkyl.
3. The compound of formula (V) of claim 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, Q is selected from —C(O)O—, —O—, —SC(O)O—, —OC(O)NH—, —NHC(O)NH—, —OC(O)S—, —OC(O)O—, —NHC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NH—, —C(O)NH—, —NHC(O)—, —NHC(O)S—, —SC(O)NH—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NH— and —NHC(S)O—; G.sub.6a is a chemical bond or C.sub.1-4 alkylene, which is optionally substituted with 1, 2, 3 or 4 R**; G.sub.6b is a chemical bond or C.sub.1-2 alkylene, which is optionally substituted with 1 or 2 R**; G.sub.6a and G.sub.6b have a total length of 0, 1, 2, 3 or 4 carbon atoms; R.sub.9 and R** are independently H or C.sub.1-6 alkyl; one of L.sub.3 and L.sub.5, or one of L.sub.4 and L.sub.6 is —(CHR.sup.s).sub.2—, —CH═CH— or —C≡C—, and the other is a chemical bond; G.sub.1a and G.sub.3a are independently a chemical bond or C.sub.1-7 alkylene; G.sub.1b and G.sub.3b are independently a chemical bond or C.sub.1-3 alkylene; G.sub.2a and G.sub.4a are independently a chemical bond or C.sub.1-3 alkylene; G.sub.2b and G.sub.4b are independently a chemical bond or C.sub.1-4 alkylene; G.sub.1a, G.sub.1b, G.sub.2a and G.sub.2b have a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms; G.sub.3a, G.sub.3b, G.sub.4a and G.sub.4b have a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms; R.sub.3 and R.sub.4 are independently H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, 3- to 7-membered cycloalkyl or 3- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; or, R.sub.3 and R.sub.4 are taken together with the N atom to which they are attached to form 3- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; or, R.sub.4 and R.sub.9 are taken together with the atoms to which they are attached to form 3- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; R* is independently H, halogen, cyano, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, -L.sub.b-OR.sub.b or -L.sub.b-NR.sub.bR′.sub.b; R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-6 alkyl; Y.sub.1 and Y.sub.2 are independently O, S or NR.sub.a; L.sub.1 and L.sub.2 are independently —(CHR).sub.2—, —CH═CH—, —C≡C— or —NR″—; G.sub.7 and G.sub.9 are independently a chemical bond or C.sub.1-6 alkylene; G.sub.8 and G.sub.10 are independently C.sub.1-10 alkylene; G.sub.7 and G.sub.8 have a total length of 4, 5, 6, 7, 8, 9 or 10 carbon atoms; G.sub.9 and G.sub.10 have a total length of 4, 5, 6, 7, 8, 9 or 10 carbon atoms; 1, 2 or 3 methylenes in G.sub.7, G.sub.8, G.sub.9 or G.sub.10 are optionally and independently substituted with 1 R; R.sup.s is independently H or C.sub.1-6 alkyl; R is independently H or C.sub.1-10 alkyl; R″ is independently H or C.sub.1-10 alkyl; L.sub.b is independently a chemical bond or C.sub.1-6 alkylene; R.sub.a is independently H or C.sub.1-10 alkyl; R.sub.b and R′.sub.b are independently H or C.sub.1-6 alkyl; alternatively, ##STR00267## is independently selected from the following groups: —(CH.sub.2).sub.3—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.4—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.5—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.6—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.7—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.8—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.3—CH═CH—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.3—C—C—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.4—C(CH.sub.3).sub.2—CH.sub.2—, —(CH.sub.2).sub.3—C(CH.sub.3).sub.2—(CH.sub.2).sub.2—, —(CH.sub.2).sub.2—C(CH.sub.3).sub.2—(CH.sub.2).sub.3—, —(CH.sub.2).sub.2—CH═CH—C(CH.sub.3).sub.2—CH.sub.2—, —(CH.sub.2).sub.2—C(CH.sub.3).sub.2—C—C—CH.sub.2—, —(CH.sub.2).sub.2—C(CH.sub.3).sub.2—CH═CH—CH.sub.2—, —(CH.sub.2).sub.2—C—C—C(CH.sub.3).sub.2—CH.sub.2— and —(CH.sub.2).sub.3—C(CH.sub.3).sub.2—C≡C—; -G.sub.7-L.sub.1-G.sub.8-H or -G.sub.9-L.sub.2-G.sub.10-H is independently selected from the following groups: —(CH.sub.2).sub.5CH.sub.3, —(CH.sub.2).sub.6CH.sub.3, —(CH.sub.2).sub.7CH.sub.3, —(CH.sub.2).sub.8CH.sub.3, —(CH.sub.2).sub.9CH.sub.3, —(CH.sub.2).sub.10CH.sub.3, —(CH.sub.2).sub.11CH.sub.3, —CH.sub.2—C≡C—(CH.sub.2).sub.5CH.sub.3, —CH.sub.2—C≡C—(CH.sub.2).sub.6CH.sub.3, —(CH.sub.2).sub.2—C≡C—(CH.sub.2).sub.5CH.sub.3, —(CH.sub.2).sub.4—C≡C—(CH.sub.2).sub.3CH.sub.3, —CH.sub.2—CH═CH—(CH.sub.2).sub.5CH.sub.3, —CH.sub.2—CH═CH—(CH.sub.2).sub.6CH.sub.3, —(CH.sub.2).sub.2—CH═CH—(CH.sub.2).sub.5CH.sub.3, —(CH.sub.2).sub.4—CH═CH—(CH.sub.2).sub.3CH.sub.3, —(CH.sub.2).sub.5—CH═CH—CH.sub.2CH.sub.3, ##STR00268##
4. The compound of formula (IV) of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, which has the structure of formula (VI) or formula (VII): ##STR00269## wherein, a, a′, b and g are independently 0, 1, 2, 3, 4 or 5, a′ and b are not 0 at the same time; a′+g=0, 1, 2, 3, 4 or 5; c and e are independently 3, 4, 5, 6, 7, 8 or 9; d and f are independently 0, 1, 2, 3 or 4; c+d=3, 4, 5, 6, 7, 8 or 9, e+f=3, 4, 5, 6, 7, 8 or 9; methylenes in ##STR00270## or are optionally and independently substituted with 1, 2, 3, 4 or 5 C.sub.1-6 alkyl; R.sub.3 and R.sub.4 are independently H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; or, R.sub.3 and R.sub.4 are taken together with the N atom to which they are attached to form 3- to 10-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; R* is independently H, halogen, cyano, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, -L.sub.b-OR.sub.b or -L.sub.b-NR.sub.bR′.sub.b; R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-6 alkyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; Y.sub.1 and Y.sub.2 are independently O, S or NR.sub.a; L.sub.1 and L.sub.2 are independently —(CRR′).sub.2—, —CH═CH—, —C≡C— or —NR″—; G.sub.7, G.sub.8, G.sub.9 and G.sub.10 are independently a chemical bond or C.sub.1-12 alkylene, which is optionally substituted with 1, 2, 3, 4, 5 or 6 R; G.sub.7 and G.sub.8 have a total length of 6, 7, 8, 9, 10, 11 or 12 carbon atoms; G.sub.9 and G.sub.10 have a total length of 6, 7, 8, 9, 10, 11 or 12 carbon atoms; 1, 2 or 3 methylenes in G.sub.7, G.sub.8, G.sub.9 or G.sub.10 are optionally and independently substituted with 1 R; R and R′ are independently H, C.sub.1-14 alkyl, -L.sub.a-OR.sub.a or -L.sub.a-NR.sub.aR′.sub.a; L.sub.a is independently a chemical bond or C.sub.1-14 alkylene; L.sub.b is independently a chemical bond or C.sub.1-6 alkylene; R.sub.a and R′.sub.a are independently H, C.sub.1-14 alkyl, 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl; R.sub.b and R′.sub.b are independently H, C.sub.1-6 alkyl, 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl; R″ is independently H or C.sub.1-14 alkyl.
5. The compound of formula (VI) or formula (VII) of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, a is 0, 1, 2, 3 or 4, alternatively 1, 2, 3 or 4, alternatively 2, 3 or 4; a′ and b are independently 0, 1, 2, 3 or 4, alternatively 2; g is 0, 1 or 2, alternatively 0 or 1; a′+g=0, 1, 2, 3, 4 or 5, alternatively a′+g=2 or 3; c and e are independently 3, 4, 5 or 6; d and f are independently 0, 1 or 2; c+d=4, 5 or 6, e+f=4, 5 or 6; methylenes in ##STR00271## are optionally and independently substituted with 1, 2, 3, 4 or 5 C.sub.1-6 alkyl; methylenes in ##STR00272## are optionally and independently substituted with 1 or 2 C.sub.1-6 alkyl; R.sub.3 and R.sub.4 are independently C.sub.1-6 alkyl, which is optionally substituted with 1, 2 or 3 R*; R* is independently H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or —OR.sub.b; or, R.sub.3 and R.sub.4 are taken together with the N atom to which they are attached to form 3- to 7-membered heterocyclyl, alternatively 5-membered heterocyclyl, which is optionally substituted with 1, 2 or 3 R*; R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-6 alkyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; Y.sub.1 and Y.sub.2 are independently O, S or NR.sub.a, alternatively O or S; L.sub.1 and L.sub.2 are independently —(CHR).sub.2—, —CH═CH—, —C≡C— or —NR″—, alternatively —(CHR).sub.2—, —CH═CH— or —C≡C—; G.sub.7 and G.sub.9 are independently a chemical bond or C.sub.1-6 alkylene; G.sub.8 and G.sub.10 are independently C.sub.1-10 alkylene; G.sub.7 and G.sub.8 have a total length of 6, 7, 8, 9 or 10 carbon atoms; G.sub.9 and G.sub.10 have a total length of 6, 7, 8, 9 or 10 carbon atoms; 1, 2 or 3 methylenes in G.sub.7, G.sub.8, G.sub.9 or G.sub.10 are optionally and independently substituted with 1 R; R is independently H or C.sub.1-8 alkyl; R″ is independently H or C.sub.1-10 alkyl; R.sub.a is independently H or C.sub.1-10 alkyl; R.sub.b is independently H or C.sub.1-6 alkyl, alternatively H.
6. The compound of formula (VI) of claim 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, a is 0, 1, 2, 3 or 4, alternatively 1, 2, 3 or 4, alternatively 2, 3 or 4; c and e are independently 3, 4, 5 or 6; d and f are independently 0, 1 or 2; c+d=4, 5 or 6, e+f=4, 5 or 6; R.sub.3 and R.sub.4 are independently C.sub.1-6 alkyl; or, R.sub.3 and R.sub.4 are taken together with the N atom to which they are attached to form 4- to 6-membered heterocyclyl, alternatively 5-membered heterocyclyl, which is optionally substituted with 1, 2 or 3 R*; R* is independently H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-6 alkyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; Y.sub.1 and Y.sub.2 are independently O, S or NR.sub.a, alternatively O or S; L.sub.1 and L.sub.2 are independently —(CHR).sub.2—, —CH═CH—, —C≡C— or —NR″—, alternatively —(CHR).sub.2—, —CH═CH— or —C≡C—; G.sub.7 and G.sub.9 are independently a chemical bond or C.sub.1-5 alkylene; G.sub.8 and G.sub.10 are independently C.sub.1-8 alkylene; G.sub.7 and G.sub.8 have a total length of 6, 7, 8, 9 or 10 carbon atoms; G.sub.9 and G.sub.10 have a total length of 6, 7, 8, 9 or 10 carbon atoms; 1, 2 or 3 methylenes in G.sub.7, G.sub.8, G.sub.9 or G.sub.10 are optionally and independently substituted with 1 R; R is independently H or C.sub.1-8 alkyl, alternatively H or C.sub.1-7 alkyl, alternatively H or C.sub.1-6 alkyl; R″ is independently H or C.sub.7-9 alkyl; R.sub.a is independently H or C.sub.8-10 alkyl.
7. The compound of formula (VI) of claim 6, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, a is 2, 3 or 4; c and e are independently 3, 4, 5 or 6; d and f are independently 0, 1 or 2; c+d=4, 5 or 6, e+f=4, 5 or 6; R.sub.3 and R.sub.4 are independently C.sub.1-6 alkyl; R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-6 alkyl; Y.sub.1 and Y.sub.2 are independently O or S; L.sub.1 and L.sub.2 are independently —(CHR).sub.2—, —CH═CH— or —C≡C—; G.sub.7 and G.sub.9 are independently C.sub.1-4 alkylene; G.sub.8 and G.sub.10 are independently C.sub.2-7 alkylene; G.sub.7 and G.sub.8 have a total length of 6, 7 or 8 carbon atoms; G.sub.9 and G.sub.10 have a total length of 6, 7 or 8 carbon atoms; 1, 2 or 3 methylenes in G.sub.7, G.sub.8, G.sub.9 or G.sub.10 are optionally and independently substituted with 1 R; R is independently H or C.sub.1-7 alkyl; provided that, when L.sub.1 is —C≡C—, then G.sub.7 is C.sub.1-2 alkylene, or when L.sub.2 is —C≡C—, then G.sub.9 is C.sub.1-2 alkylene.
8. The compound of formula (VI) of claim 6, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, a is 2, 3 or 4, alternatively 2 or 3; c and e are independently 4, 5 or 6; d and fare 0; R.sub.3 and R.sub.4 are independently C.sub.1-6 alkyl; R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-6 alkyl; Y.sub.1 and Y.sub.2 are O; L.sub.1 and L.sub.2 are independently —(CHR).sub.2— or —CH═CH—; G.sub.7 and G.sub.9 are independently —CH.sub.2— or —CH.sub.2CHR—; G.sub.8 and G.sub.10 are independently —(CH.sub.2).sub.6— or —(CH.sub.2).sub.7—; G.sub.7 and G.sub.8 have a total length of 7 or 8 carbon atoms; G.sub.9 and G.sub.10 have a total length of 7 or 8 carbon atoms; 1, 2 or 3 methylenes in G.sub.8 or G.sub.10 are optionally and independently substituted with 1 R; R is independently H or C.sub.4-6 alkyl, alternatively H or C.sub.5 alkyl; alternatively -G.sub.7-L.sub.1-G.sub.8-H and -G.sub.9-L.sub.2-G.sub.10-H are not —(CH.sub.2).sub.9CH.sub.3 at the same time.
9. The compound of formula (VI) of claim 6, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, a is 2; c and e are independently 4, 5 or 6, alternatively 5; d and fare 0; R.sub.3 and R.sub.4 are independently C.sub.1-6 alkyl; R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-6 alkyl; Y.sub.1 and Y.sub.2 are independently O or S; one of L.sub.1 and L.sub.2 is —C≡C—, the other is —(CHR).sub.2—, or both of L.sub.1 and L.sub.2 are —C≡C—; alternatively one of L.sub.1 and L.sub.2 is —C≡C—, the other is —(CHR).sub.2—; G.sub.7 and G.sub.9 are —CH.sub.2—; G.sub.8 and G.sub.10 are independently —(CH.sub.2).sub.6— or —(CH.sub.2).sub.7—; 1 methylene in G.sub.8 or G.sub.10 is optionally and independently substituted with 1 R, alternatively G.sub.8 and G.sub.10 are independently —CHR—(CH.sub.2).sub.5—, —CHR—(CH.sub.2).sub.6—, —CH.sub.2—CHR—(CH.sub.2).sub.4— or —(CH.sub.2).sub.2—CHR—(CH.sub.2).sub.4—; R is independently H or C.sub.4-6 alkyl, alternatively H or C.sub.5 alkyl; provided that, only one of the -G.sub.7-L.sub.1-G.sub.8-H and -G.sub.9-L.sub.2-G.sub.10-H is substituted with one non-hydrogen R substituent and the other is unsubstituted.
10. The compound of formula (VI) of claim 6, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, a is 2; c and e are independently 4, 5 or 6, alternatively 5; d and fare 0; R.sub.3 and R.sub.4 are independently C.sub.1-3 alkyl, alternatively Me; R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-3 alkyl, alternatively Me; Y.sub.1 and Y.sub.2 are independently O or S, alternatively 0; both of L.sub.1 and L.sub.2 are —C≡C—; G.sub.7 and G.sub.9 are —CH.sub.2—; G.sub.8 and G.sub.10 are independently —(CH.sub.2).sub.6— or —(CH.sub.2).sub.7—, alternatively —(CH.sub.2).sub.7—.
11. The compound of formula (VI) of claim 6, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, a is 2; c and e are 3; d and fare 2; R.sub.3 and R.sub.4 are independently C.sub.1-3 alkyl, alternatively Me; R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-3 alkyl; Y.sub.1 and Y.sub.2 are independently O or S, alternatively 0; L.sub.1 and L.sub.2 are —(CHR).sub.2—; G.sub.7 and G.sub.9 are independently —CH.sub.2— or —CH.sub.2CHR—; G.sub.8 and G.sub.10 are independently —(CH.sub.2).sub.5—, —(CH.sub.2).sub.6— or —(CH.sub.2).sub.7—; G.sub.7 and G.sub.8 have a total length of 6, 7 or 8 carbon atoms, alternatively 7 carbon atoms; G.sub.9 and G.sub.10 have a total length of 6, 7 or 8 carbon atoms, alternatively 7 carbon atoms; 1, 2 or 3 methylenes in G.sub.8 or G.sub.10 are optionally and independently substituted with 1 R; R is independently H or C.sub.1-7 alkyl, alternatively H or C.sub.1-6 alkyl, alternatively Me.
12. The compound of formula (VI) of claim 6, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, a is 2; c and e are 4, 5, or 6, alternatively 5; d and fare 0; R.sub.3 and R.sub.4 are independently C.sub.1-6 alkyl; R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-6 alkyl; Y.sub.1 and Y.sub.2 are S; L.sub.1 and L.sub.2 are —(CHR).sub.2—; G.sub.7 and G.sub.9 are independently —CH.sub.2— or —CH.sub.2CHR—; G.sub.8 and G.sub.10 are independently —(CH.sub.2).sub.5—, —(CH.sub.2).sub.6— or —(CH.sub.2).sub.7—; G.sub.7 and G.sub.8 have a total length of 7 or 8 carbon atoms, alternatively 8 carbon atoms; G.sub.9 and G.sub.10 have a total length of 7 or 8 carbon atoms, alternatively 8 carbon atoms; 1, 2 or 3 methylenes in G.sub.8 or G.sub.10 are optionally and independently substituted with 1 R; R is independently H or C.sub.4-6 alkyl, alternatively H or C.sub.5 alkyl.
13. The compound of formula (VII) of claim 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, a′ and b are 2; g is 0 or 1; c and e are 5; d and fare 0; R.sub.3 is C.sub.1-6 alkyl, which is optionally substituted with 1, 2 or 3 R*; R* is independently H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or —OR.sub.b, alternatively H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-3 alkyl; Y.sub.1 and Y.sub.2 are independently O or S; L.sub.1 and L.sub.2 are —(CHR).sub.2—; G.sub.7 and G.sub.9 are independently —CH.sub.2— or —CH.sub.2CHR—; G.sub.8 and G.sub.10 are independently —(CH.sub.2).sub.5—, —(CH.sub.2).sub.6— or —(CH.sub.2).sub.7—; G.sub.7 and G.sub.8 have a total length of 6, 7 or 8 carbon atoms; G.sub.9 and G.sub.10 have a total length of 6, 7 or 8 carbon atoms; 1, 2 or 3 methylenes in G.sub.8 or G.sub.10 are optionally and independently substituted with 1 R; R is independently H or C.sub.4-6 alkyl; R.sub.b is independently H or C.sub.1-6 alkyl, alternatively H.
14. The compound of formula (VII) of claim 13, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, R.sub.3 is Me or —CH.sub.2CH.sub.3, alternatively Me; both of Y.sub.1 and Y.sub.2 are O; G.sub.7 and G.sub.8 have a total length of 6 or 7 carbon atoms, alternatively 7 carbon atoms; G.sub.9 and G.sub.10 have a total length of 6 or 7 carbon atoms, alternatively 7 carbon atoms.
15. The compound of formula (VII) of claim 13, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, R.sub.3 is Me or —CH.sub.2CH.sub.3; Y.sub.1 and Y.sub.2 are independently O or S, where Y.sub.1 and Y.sub.2 are not O at the same time; G.sub.7 and G.sub.8 have a total length of 6, 7 or 8 carbon atoms; G.sub.9 and G.sub.10 have a total length of 6, 7 or 8 carbon atoms.
16. The compound of formula (VII) of claim 15, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, g is 0 or 1, alternatively 1; R.sub.3 is Me or —CH.sub.2CH.sub.3, alternatively Me; one of Y.sub.1 and Y.sub.2 is O, and the other is S; G.sub.7 and G.sub.8 have a total length of 7 carbon atoms; G.sub.9 and G.sub.10 have a total length of 7 carbon atoms.
17. The compound of formula (VII) of claim 15, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, g is 0 or 1, alternatively 0; R.sub.3 is Me or —CH.sub.2CH.sub.3; both of Y.sub.1 and Y.sub.2 are S; G.sub.7 and G.sub.8 have a total length of 7 or 8 carbon atoms; G.sub.9 and G.sub.10 have a total length of 7 or 8 carbon atoms.
18. The compound of formula (IV) of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, the compound is selected from the following: ##STR00273## ##STR00274## ##STR00275## ##STR00276## ##STR00277## ##STR00278## ##STR00279## ##STR00280## ##STR00281## ##STR00282## ##STR00283## ##STR00284## ##STR00285## ##STR00286## ##STR00287## ##STR00288## ##STR00289## ##STR00290## ##STR00291## ##STR00292## ##STR00293## ##STR00294## ##STR00295## ##STR00296## ##STR00297## ##STR00298## ##STR00299## ##STR00300## ##STR00301## ##STR00302## ##STR00303## or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.
19. A pharmaceutical composition, comprising the compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and pharmaceutically acceptable excipient(s).
20. A method of treating, diagnosing, or preventing a disease in a subject, comprising administering to the subject the pharmaceutical composition of claim 19.
21. A method of delivering a load in a subject, comprising administering to the subject the pharmaceutical composition of claim 19; wherein, the load is one or more of therapeutic, prophylactic or diagnostic agents.
22. The method of claim 21, wherein, the therapeutic, prophylactic or diagnostic agent is a nucleic acid; alternatively, the nucleic acid is one or more of ASO, RNA or DNA; alternatively, the RNA is one or more of interfering RNA (RNAi), small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), modified messenger RNA (mmRNA), long non-coding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), multimeric coding nucleic acid (MCNA), polymeric coding nucleic acid (PCNA), guide RNA (gRNA), CRISPRRNA (crRNA) or nucleases, alternatively mRNA, more alternatively, modified mRNA.
23. A method for preparing the compound of general formula (II), comprising: ##STR00304## reacting the compound of general formula (IIb) with the compound of general formula (IIc), to give the compound of general formula (II); wherein, G.sub.1, G.sub.2, G.sub.3 or G.sub.4 is independently a bond, C.sub.1-20 alkyl, C.sub.2-20 alkenyl and C.sub.2-20 alkynyl; G.sub.6 is independently a bond or C.sub.1-8 alkyl; M.sub.1 or M.sub.2 is independently biodegradable groups; R.sub.1 or R.sub.2 is independently C.sub.4-28 alkyl, C.sub.4-28 alkenyl or C.sub.4-28 alkynyl; R.sub.3 or R.sub.4 is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; or, R.sub.3 and R.sub.4 are taken together with the N atom to which they are attached to form 3- to 14-membered heterocyclyl; R.sub.5, R.sub.6, R.sub.7 or R.sub.8 is each independently C.sub.1-8 alkyl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is each independently and optionally further substituted.
24. A method of preparing the compound of general formula (II′), comprising: ##STR00305## reacting the compound of general formula (II′a) with the compound of general formula (II′b), to give the compound of general formula (II′); wherein, G.sub.1, G.sub.2, G.sub.3 or G.sub.4 is each independently a bond, C.sub.1-20 alkyl, C.sub.2-20 alkenyl and C.sub.2-20 alkynyl; G.sub.5 or G.sub.6 is each independently a bond or C.sub.1-8 alkyl; M.sub.1 or M.sub.2 is each independently biodegradable groups; R.sub.1 or R.sub.2 is each independently C.sub.4-28 alkyl, C.sub.4-28 alkenyl or C.sub.4-28 alkynyl; R′.sub.3, R′.sub.4, R′.sub.5 or R′.sub.6 is each independently C.sub.1-8 alkyl; R′.sub.7 is selected from H, halogen, cyano, OH, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, —NH.sub.2, —NHC.sub.1-6 alkyl and —N(C.sub.1-6 alkyl).sub.2; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is each independently and optionally further substituted.
Description
DETAILED DESCRIPTION OF THE INVENTION
[0112] As used herein, “compounds of the present disclosure” refers to the following compounds of formula (IV), formula (V), formula (VI), formula (VII), and the like, pharmaceutically acceptable salts, isotopic variants, tautomers or stereoisomers thereof.
[0113] In the present disclosure, compounds are named using standard nomenclature. For compounds having an asymmetric center, it should be understood, unless otherwise stated, that all optical isomers and mixtures thereof are included. Furthermore, unless otherwise specified, all isomer compounds and carbon-carbon double bonds included in the present disclosure may occur in the form of Z and E. Compounds which exist in different tautomeric forms, one of which is not limited to any particular tautomer, but is intended to cover all tautomeric forms.
[0114] In one embodiment, the present disclosure relates to a compound of formula (IV), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:
##STR00003## [0115] wherein, [0116] M.sub.1 and M.sub.2 are independently selected from —C(O)O—, —O—, —SC(O)O—, —OC(O)NR.sub.a—, —NR.sub.aC(O)NR.sub.a—, —OC(O)S—, —OC(O)O—, —NR.sub.aC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR.sub.a—, —C(O)NR.sub.a—, —NR.sub.aC(O)—, —NR.sub.aC(O)S—, —SC(O)NR.sub.a—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR.sub.a—, —NR.sub.aC(S)O—, —S—S— and —S(O).sub.0-2—; [0117] Q is selected from a chemical bond, —C(O)O—, —O—, —SC(O)O—, —OC(O)NR.sub.b—, —NR.sub.bC(O)NR.sub.b—, —OC(O)S—, —OC(O)O—, —NR.sub.bC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR.sub.b—, —C(O)NR.sub.b—, —NR.sub.bC(O)—, —NR.sub.bC(O)S—, —SC(O)NR.sub.b—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR.sub.b—, —NR.sub.bC(S)O—, —S—S—, —S(O).sub.0-2—, phenylene and pyridylidene, wherein, the phenylene or pyridylidene is optionally substituted with one or more R*; [0118] G.sub.5 is a chemical bond or C.sub.1-8 alkylene, which is optionally substituted with one or more R**; [0119] G.sub.6a and G.sub.6b are independently a chemical bond or C.sub.1-7 alkylene, which is optionally substituted with one or more R**; [0120] G.sub.6a and G.sub.6b have a total length of 0, 1, 2, 3, 4, 5, 6 or 7 carbon atoms; [0121] R.sub.9, R.sub.10 and R** are independently H, C.sub.1-8 alkyl, -L.sub.c-OR.sub.c, -L.sub.c-SR.sub.c or -L.sub.c-NR.sub.cR′.sub.c; [0122] G.sub.1, G.sub.2, G.sub.3 and G.sub.4 are independently a chemical bond, C.sub.1-13 alkylene, C.sub.2-13 alkenylene or C.sub.2-13 alkynylene, which is optionally substituted with one or more R.sup.s; [0123] G.sub.1 and G.sub.2 have a total length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms; [0124] G.sub.3 and G.sub.4 have a total length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms; [0125] R.sub.3 and R.sub.4 are independently H, C.sub.1-10 alkyl, C.sub.1-10 haloalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl, C.sub.6-10 aryl or 5- to 14-membered heteroaryl, which is optionally substituted with one or more R*: [0126] or, R.sub.3 and R.sub.4 are taken together with the N atom to which they are attached to form 3- to 14-membered heterocyclyl, which is optionally substituted with one or more R*; [0127] or, R.sub.4 and R.sub.9 are taken together with the atoms to which they are attached to form 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl, which is optionally substituted with one or more R*; [0128] R* is independently H, halogen, cyano, C.sub.1-10 alkyl, C.sub.1-10 haloalkyl, -L.sub.b-OR.sub.b, -L.sub.b-SR.sub.b or -L.sub.b-NR.sub.bR′.sub.b; [0129] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-8 alkyl, which is optionally substituted with one or more R*; [0130] R.sub.1 and R.sub.2 are independently C.sub.4-20 alkyl, C.sub.4-20 alkenyl or C.sub.4-20 alkynyl, which is optionally substituted with one or more R, and wherein one or more methylene units are optionally and independently replaced with —NR″—; [0131] R.sup.s is independently H, C.sub.1-14 alkyl, -L.sub.d-OR.sub.d, -L.sub.d-SR.sub.d or -L.sub.d-NR.sub.dR′.sub.d; [0132] R is independently H, C.sub.1-20 alkyl, -L.sub.a-OR.sub.a, -L.sub.a-SR.sub.a or -L.sub.a-NR.sub.aR′.sub.a; [0133] R″ is independently H or C.sub.1-20 alkyl; [0134] L.sub.a and L.sub.e are independently a chemical bond or C.sub.1-20 alkylene; [0135] L.sub.b and L.sub.f are independently a chemical bond or C.sub.1-10 alkylene; [0136] L.sub.c is independently a chemical bond or C.sub.1-8 alkylene; [0137] L.sub.d is independently a chemical bond or C.sub.1-14 alkylene; [0138] R.sub.a and R′.sub.a are independently selected from H, C.sub.1-20 alkyl, 3- to 14-membered cycloalkyl, and 3- to 14-membered heterocyclyl, which are optionally substituted with one or more of the following substituents: H, C.sub.1-20 alkyl, -L.sub.e-OR.sub.e, -L.sub.e-SR.sub.e and -L.sub.e-NR.sub.eR′.sub.e; [0139] R.sub.b and R′.sub.b are independently selected from H, C.sub.1-10 alkyl, 3- to 14-membered cycloalkyl, and 3- to 14-membered heterocyclyl, which are optionally substituted with one or more of the following substituents: H, C.sub.1-10 alkyl, -L.sub.f-OR.sub.f, -L.sub.f-SR.sub.f and -L.sub.f-NR.sub.fR′.sub.f; [0140] R.sub.c and R′.sub.c are independently H or C.sub.1-8 alkyl; [0141] R.sub.d and R′.sub.d are independently H or C.sub.1-14 alkyl; [0142] R.sub.e and R′.sub.e are independently H or C.sub.1-20 alkyl; [0143] R.sub.f and R′.sub.f are independently H or C.sub.1-10 alkyl.
[0144] M.sub.1 and M.sub.2
[0145] In one embodiment, M.sub.1 is —C(O)O—; in another embodiment, M.sub.1 is —O—; in another embodiment, M.sub.1 is —SC(O)O—; in another embodiment, M.sub.1 is —OC(O)NR.sub.a—; in another embodiment, M.sub.1 is —NR.sub.aC(O)NR.sub.a—; in another embodiment, M.sub.1 is —OC(O)S—; in another embodiment, M.sub.1 is —OC(O)O—; in another embodiment, M.sub.1 is —NR.sub.aC(O)O—; in another embodiment, M.sub.1 is —OC(O)—; in another embodiment, M.sub.1 is —SC(O)—; in another embodiment, M.sub.1 is —C(O)S—; in another embodiment, M.sub.1 is —NR.sub.a—; in another embodiment, M.sub.1 is —C(O)NR.sub.a—; in another embodiment, M.sub.1 is —NR.sub.aC(O)—; in another embodiment, M.sub.1 is —NR.sub.aC(O)S—; in another embodiment, M.sub.1 is —SC(O)NR.sub.a—; in another embodiment, M.sub.1 is —C(O)—; in another embodiment, M.sub.1 is —OC(S)—; in another embodiment, M.sub.1 is —C(S)O—; in another embodiment, M.sub.1 is —OC(S)NR.sub.a—; in another embodiment, M.sub.1 is —NR.sub.aC(S)O—; in another embodiment, M.sub.1 is —S—S—; in another embodiment, M.sub.1 is —S(O).sub.0-2—.
[0146] In one embodiment, M.sub.2 is —C(O)O—; in another embodiment, M.sub.2 is —O—; in another embodiment, M.sub.2 is —SC(O)O—; in another embodiment, M.sub.2 is —OC(O)NR.sub.a—; in another embodiment, M.sub.2 is —NR.sub.aC(O)NR.sub.a—; in another embodiment, M.sub.2 is —OC(O)S—; in another embodiment, M.sub.2 is —OC(O)O—; in another embodiment, M.sub.2 is —NR.sub.aC(O)O—; in another embodiment, M.sub.2 is —OC(O)—; in another embodiment, M.sub.2 is —SC(O)—; in another embodiment, M.sub.2 is —C(O)S—; in another embodiment, M.sub.2 is —NR.sub.a—; in another embodiment, M.sub.2 is —C(O)NR.sub.a—; in another embodiment, M.sub.2 is —NR.sub.aC(O)—; in another embodiment, M.sub.2 is —NR.sub.aC(O)S—; in another embodiment, M.sub.2 is —SC(O)NR.sub.a—; in another embodiment, M.sub.2 is —C(O)—; in another embodiment, M.sub.2 is —OC(S)—; in another embodiment, M.sub.2 is —C(S)O—; in another embodiment, M.sub.2 is —OC(S)NR.sub.a—; in another embodiment, M.sub.2 is —NR.sub.aC(S)O—; in another embodiment, M.sub.2 is —S—S—; in another embodiment, M.sub.2 is —S(O).sub.0-2—.
[0147] In a more specific embodiment, M.sub.1 and M.sub.2 are independently selected from —C(O)O—, —SC(O)O—, —OC(O)NR.sub.a—, —NR.sub.aC(O)NR.sub.a—, —OC(O)S—, —OC(O)O—, —NR.sub.aC(O)O—, —C(O)S—, —C(O)NR.sub.a—, —NR.sub.aC(O)S—, —SC(O)NR.sub.a—, —C(S)O—, —OC(S)NR.sub.a— and —NR.sub.aC(S)O—; in another more specific embodiment, M.sub.1 and M.sub.2 are independently —C(O)O—, —C(O)S—, —C(O)NR.sub.a—, or —C(S)O—; in another more specific embodiment, M.sub.1 and M.sub.2 are independently —C(O)O—, —C(O)S— or —C(O)NR.sub.a—.
[0148] Q
[0149] In one embodiment, Q is a chemical bond; in another embodiment, Q is —C(O)O—; in another embodiment, Q is —O—; in another embodiment, Q is —SC(O)O—; in another embodiment, Q is —OC(O)NR.sub.b—; in another embodiment, Q is —NR.sub.bC(O)NR.sub.b—; in another embodiment, Q is —OC(O)S—; in another embodiment, Q is —OC(O)O—; in another embodiment, Q is —NR.sub.bC(O)O—; in another embodiment, Q is —OC(O)—; in another embodiment, Q is —SC(O)—; in another embodiment, Q is —C(O)S—; in another embodiment, Q is —NR.sub.b—; in another embodiment, Q is —C(O)NR.sub.b—; in another embodiment, Q is —NR.sub.bC(O)—; in another embodiment, Q is —NR.sub.bC(O)S—; in another embodiment, Q is —SC(O)NR.sub.b—; in another embodiment, Q is —C(O)—; in another embodiment, Q is —OC(S)—; in another embodiment, Q is —C(S)O—; in another embodiment, Q is —OC(S)NR.sub.b—; in another embodiment, Q is —NR.sub.bC(S)O—; in another embodiment, Q is —S—S—; in another embodiment, Q is —S(O).sub.0-2—; in another embodiment, Q is phenylene; in another embodiment, Q is pyridylidene; in another embodiment, the phenylene or pyridylidene is optionally substituted with one or more R*.
[0150] In a more specific embodiment, Q is selected from a chemical bond, —C(O)O—, —O—, —SC(O)O—, —OC(O)NR.sub.b—, —NR.sub.bC(O)NR.sub.b—, —OC(O)S—, —OC(O)O—, —NR.sub.bC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR.sub.b—, —C(O)NR.sub.b—, —NR.sub.bC(O)—, —NR.sub.bC(O)S—, —SC(O)NR.sub.b—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR.sub.b—, —NR.sub.bC(S)O—, —S—S—, and —S(O).sub.0-2—; in another more specific embodiment, Q is selected from —C(O)O—, —O—, —SC(O)O—, —OC(O)NH—, —NHC(O)NH—, —OC(O)S—, —OC(O)O—, —NHC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NH—, —C(O)NH—, —NHC(O)—, —NHC(O)S—, —SC(O)NH—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NH— and —NHC(S)O—; in another more specific embodiment, Q is selected from —C(O)O—, —O—, —SC(O)O—, —OC(O)NH—, —NHC(O)NH—, —OC(O)S—, —OC(O)O— and —NHC(O)O—; in another more specific embodiment, Q is —C(O)O—.
[0151] G.sub.5
[0152] In one embodiment, G.sub.5 is a chemical bond; in another embodiment, G.sub.5 is C.sub.1-8 alkylene; in another embodiment, G.sub.5 is optionally substituted with one or more R**.
[0153] G.sub.6a and G.sub.6b
[0154] In one embodiment, G.sub.6a is a chemical bond; in another embodiment, G.sub.6a is C.sub.1-7 alkylene; in another embodiment, G.sub.6a is C.sub.1-5 alkylene; in another embodiment, G.sub.6a is C.sub.1-4 alkylene; in another embodiment, G.sub.6a is C.sub.1-4 linear alkylene; in another embodiment, G.sub.6a is (CH.sub.2).sub.2—; in another embodiment, G.sub.6a is optionally substituted with one or more R**; in another embodiment, G.sub.6a is optionally substituted with 1, 2, 3 or 4 R**.
[0155] In one embodiment, G.sub.6b is a chemical bond; in another embodiment, G.sub.6b is C.sub.1-7 alkylene; in another embodiment, G.sub.6b is C.sub.1-5 alkylene; in another embodiment, G.sub.6b is C.sub.1-2 alkylene; in another embodiment, G.sub.6b is methylene; in another embodiment, G.sub.6b is optionally substituted with one or more R**; in another embodiment, G.sub.6b is optionally substituted with 1, 2, 3 or 4 R**; in another embodiment, G.sub.6b is optionally substituted with 1 or 2 R**.
[0156] In one embodiment, G.sub.6a and G.sub.6b have a total length of 0 carbon atoms; in another embodiment, G.sub.6a and G.sub.6b have a total length of 1 carbon atom; in another embodiment, G.sub.6a and G.sub.6b have a total length of 2 carbon atoms; in another embodiment, G.sub.6a and G.sub.6b have a total length of 3 carbon atoms; in another embodiment, G.sub.6a and G.sub.6b have a total length of 4 carbon atoms; in another embodiment, G.sub.6a and G.sub.6b have a total length of 5 carbon atoms; in another embodiment, G.sub.6a and G.sub.6b have a total length of 6 carbon atoms; in another embodiment, G.sub.6a and G.sub.6b have a total length of 7 carbon atoms.
[0157] In a more specific embodiment, G.sub.6a and G.sub.6b are independently a chemical bond or C.sub.1-5 alkylene, which is optionally substituted with 1, 2, 3 or 4 R**; G.sub.6a and G.sub.6b have a total length of 0, 1, 2, 3, 4 or 5 carbon atoms.
[0158] In another more specific embodiment, G.sub.6a is a chemical bond or C.sub.1-4 alkylene, which is optionally substituted with 1, 2, 3 or 4 R**; G.sub.6b is a chemical bond or C.sub.1-2 alkylene, which is optionally substituted with 1 or 2 R**; G.sub.6a and G.sub.6b have a total length of 0, 1, 2, 3 or 4 carbon atoms.
[0159] In another more specific embodiment, G.sub.6a is a chemical bond or C.sub.1-4 alkylene, alternatively C.sub.2-4 alkylene, alternatively C.sub.2-3 alkylene, more alternatively —(CH.sub.2).sub.2—; G.sub.6b is a chemical bond or methylene; G.sub.6a and G.sub.6b have a total length of 0, 1, 2, 3 or 4 carbon atoms, alternatively 1, 2, 3 or 4 carbon atoms, alternatively 2 or 3 carbon atoms.
[0160] In another more specific embodiment, G.sub.6a is a chemical bond or C.sub.1-4 linear alkylene, alternatively C.sub.2-4 linear alkylene, alternatively C.sub.2-3 linear alkylene, more alternatively —(CH.sub.2).sub.2—; G.sub.6b is a chemical bond or methylene; G.sub.6a and G.sub.6b have a total length of 0, 1, 2, 3 or 4 carbon atoms, alternatively 1, 2, 3 or 4 carbon atoms, alternatively 2 or 3 carbon atoms.
[0161] R.sub.9
[0162] In one embodiment, R.sub.9 is H; in another embodiment, R.sub.9 is C.sub.1-8 alkyl; in another embodiment, R.sub.9 is -L.sub.c-OR.sub.c; in another embodiment, R.sub.9 is -L.sub.c-SR.sub.c; in another embodiment, R.sub.9 is -L.sub.c-NR.sub.cR′.sub.c; in another embodiment, R.sub.9 is C.sub.1-6 alkyl.
[0163] In a more specific embodiment, R.sub.9 is H, C.sub.1-6 alkyl, -L.sub.c-OR.sub.c or -L.sub.c-NR.sub.0R′.sub.c; in another more specific embodiment, R.sub.9 is H or C.sub.1-6 alkyl; in another more specific embodiment, R.sub.9 is H.
[0164] R.sub.10
[0165] In one embodiment, R.sub.10 is H; in another embodiment, R.sub.10 is C.sub.1-8 alkyl; in another embodiment, R.sub.10 is -L.sub.c-OR.sub.c; in another embodiment, R.sub.10 is -L.sub.c-SR.sub.c; in another embodiment, R.sub.10 is -L.sub.c-NR.sub.cR′.sub.c.
[0166] In a more specific embodiment, R.sub.10 is H, C.sub.1-6 alkyl, -L.sub.c-OR.sub.c or -L.sub.c-NR.sub.cR′.sub.c; in another more specific embodiment, R.sub.10 is H.
[0167] R**
[0168] In one embodiment, R** is H; in another embodiment, R** is C.sub.1-8 alkyl; in another embodiment, R** is -L.sub.c-OR.sub.c; in another embodiment, R** is -L.sub.c-SR.sub.c; in another embodiment, R** is -L.sub.c-NR.sub.cR′.sub.c; in another embodiment, R** is C.sub.1-6 alkyl.
[0169] In a more specific embodiment, R** is H, C.sub.1-6 alkyl, -L.sub.c-OR.sub.c or -L.sub.c-NR.sub.cR′.sub.c; in another more specific embodiment, R** is H or C.sub.1-6 alkyl; in another more specific embodiment, R** is H.
[0170] G.sub.1, G.sub.2, G.sub.3 and G.sub.4
[0171] In one embodiment, G.sub.1 is a chemical bond; in another embodiment, G.sub.1 is C.sub.1-13 alkylene; in another embodiment, G.sub.1 is C.sub.2-13 alkenylene; in another embodiment, G.sub.1 is C.sub.2-13 alkynylene; in another embodiment, G.sub.1 is optionally substituted with one or more R.sup.s.
[0172] In one embodiment, G.sub.2 is a chemical bond; in another embodiment, G.sub.2 is C.sub.2-13 alkylene; in another embodiment, G.sub.2 is C.sub.2-13 alkenylene; in another embodiment, G.sub.2 is C.sub.2-13 alkynylene; in another embodiment, G.sub.2 is optionally substituted with one or more R.sup.s.
[0173] In one embodiment, G.sub.1 and G.sub.2 have a total length of 3 carbon atoms; in another embodiment, G.sub.1 and G.sub.2 have a total length of 4 carbon atoms; in another embodiment, G.sub.1 and G.sub.2 have a total length of 5 carbon atoms; in another embodiment, G.sub.1 and G.sub.2 have a total length of 6 carbon atoms; in another embodiment, G.sub.1 and G.sub.2 have a total length of 7 carbon atoms; in another embodiment, G.sub.1 and G.sub.2 have a total length of 8 carbon atoms; in another embodiment, G.sub.1 and G.sub.2 have a total length of 9 carbon atoms; in another embodiment, G.sub.1 and G.sub.2 have a total length of 10 carbon atoms; in another embodiment, G.sub.1 and G.sub.2 have a total length of 11 carbon atoms; in another embodiment, G.sub.1 and G.sub.2 have a total length of 12 carbon atoms; in another embodiment, G.sub.1 and G.sub.2 have a total length of 13 carbon atoms.
[0174] In a more specific embodiment, -G.sub.1-C(R.sub.5R.sub.6)-G.sub.2- is
##STR00004##
[0175] In one embodiment, G.sub.1a is a chemical bond; in another embodiment, G.sub.1a is C.sub.1-7 alkylene; in another embodiment, G.sub.1a is —CH.sub.2—; in another embodiment, G.sub.1a is —(CH.sub.2).sub.2—; in another embodiment, G.sub.1a is —(CH.sub.2).sub.3—; in another embodiment, G.sub.1a is —(CH.sub.2).sub.4—; in another embodiment, G.sub.1a is —(CH.sub.2).sub.5—; in another embodiment, G.sub.1a is —(CH.sub.2).sub.6—; in another embodiment, G.sub.1a is optionally substituted with 1, 2, 3, 4 or 5 R.sup.s.
[0176] In one embodiment, G.sub.1b is a chemical bond; in another embodiment, G.sub.1b is C.sub.1-7 alkylene; in another embodiment, G.sub.1b is C.sub.1-3 alkylene; in another embodiment, G.sub.1b is —CH.sub.2—; in another embodiment, G.sub.1b is —(CH.sub.2).sub.2—; in another embodiment, G.sub.1b is —(CH.sub.2).sub.3—; in another embodiment, G.sub.1b is optionally substituted with 1, 2, 3, 4 or 5 R.sup.s.
[0177] In one embodiment, G.sub.2a is a chemical bond; in another embodiment, G.sub.2a is C.sub.1-7 alkylene; in another embodiment, G.sub.2a is C.sub.1-3 alkylene; in another embodiment, G.sub.2a is optionally substituted with 1, 2, 3, 4 or 5 R.sup.s.
[0178] In one embodiment, G.sub.2b is a chemical bond; in another embodiment, G.sub.2b is C.sub.1-7 alkylene; in another embodiment, G.sub.2b is C.sub.1-4 alkylene; in another embodiment, G.sub.2b is —CH.sub.2—; in another embodiment, G.sub.2b is —(CH.sub.2).sub.2—; in another embodiment, G.sub.2b is —(CH.sub.2).sub.3—; in another embodiment, G.sub.2b is optionally substituted with 1, 2, 3, 4 or 5 R.sup.s.
[0179] In a more specific embodiment, G.sub.1a, G.sub.1b, G.sub.2a and G.sub.2b have a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms; in another more specific embodiment, G.sub.1a, G.sub.1b, G.sub.2a and G.sub.2b have a total length of 1, 2, 3, 4, 5 or 6 carbon atoms.
[0180] In one embodiment, one of L.sub.3 and L.sub.5 is —(CR.sup.sR.sup.s′).sub.2—, and the other is a chemical bond; in another embodiment, one of L.sub.3 and L.sub.5 is —(CHR.sup.s).sub.2—, and the other is a chemical bond; in another embodiment, one of L.sub.3 and L.sub.5 is —CH═CH—, and the other is a chemical bond; in another embodiment, one of L.sub.3 and L.sub.5 is —C≡C—, and the other is a chemical bond.
[0181] In one embodiment, G.sub.3 is a chemical bond; in another embodiment, G.sub.3 is C.sub.1-13 alkylene; in another embodiment, G.sub.3 is C.sub.2-13 alkenylene; in another embodiment, G.sub.3 is C.sub.2-13 alkynylene; in another embodiment, G.sub.3 is optionally substituted with one or more R.sup.s.
[0182] In one embodiment, G.sub.4 is a chemical bond; in another embodiment, G.sub.4 is C.sub.2-13 alkylene; in another embodiment, G.sub.4 is C.sub.2-13 alkenylene; in another embodiment, G.sub.4 is C.sub.2-13 alkynylene; in another embodiment, G.sub.4 is optionally substituted with one or more R.sup.s.
[0183] In one embodiment, G.sub.3 and G.sub.4 have a total length of 3 carbon atoms; in another embodiment, G.sub.3 and G.sub.4 have a total length of 4 carbon atoms; in another embodiment, G.sub.3 and G.sub.4 have a total length of 5 carbon atoms; in another embodiment, G.sub.3 and G.sub.4 have a total length of 6 carbon atoms; in another embodiment, G.sub.3 and G.sub.4 have a total length of 7 carbon atoms; in another embodiment, G.sub.3 and G.sub.4 have a total length of 8 carbon atoms; in another embodiment, G.sub.3 and G.sub.4 have a total length of 9 carbon atoms; in another embodiment, G.sub.3 and G.sub.4 have a total length of 10 carbon atoms; in another embodiment, G.sub.3 and G.sub.4 have a total length of 11 carbon atoms; in another embodiment, G.sub.3 and G.sub.4 have a total length of 12 carbon atoms; in another embodiment, G.sub.3 and G.sub.4 have a total length of 13 carbon atoms.
[0184] In a more specific embodiment, -G.sub.3-C(R.sub.7R.sub.8)-G.sub.4- is
##STR00005##
[0185] In one embodiment, G.sub.3a is a chemical bond; in another embodiment, G.sub.3a is C.sub.1-7 alkylene; in another embodiment, G.sub.3a is —CH.sub.2—; in another embodiment, G.sub.3a is —(CH.sub.2).sub.2—; in another embodiment, G.sub.3a is —(CH.sub.2).sub.3—; in another embodiment, G.sub.3a is —(CH.sub.2).sub.4—; in another embodiment, G.sub.3a is —(CH.sub.2).sub.5—; in another embodiment, G.sub.3a is —(CH.sub.2).sub.6—; in another embodiment, G.sub.3a is optionally substituted with 1, 2, 3, 4 or 5 R.sup.s.
[0186] In one embodiment, G.sub.3b is a chemical bond; in another embodiment, G.sub.3b is C.sub.1-7 alkylene; in another embodiment, G.sub.3b is C.sub.1-3 alkylene; in another embodiment, G.sub.3b is —CH.sub.2—; in another embodiment, G.sub.3b is —(CH.sub.2).sub.2—; in another embodiment, G.sub.3b is —(CH.sub.2).sub.3—; in another embodiment, G.sub.3b is optionally substituted with 1, 2, 3, 4 or 5 R.sup.s.
[0187] In one embodiment, G.sub.4a is a chemical bond; in another embodiment, G.sub.4a is C.sub.1-7 alkylene; in another embodiment, G.sub.4a is C.sub.1-3 alkylene; in another embodiment, G.sub.4a is optionally substituted with 1, 2, 3, 4 or 5 R.sup.s.
[0188] In one embodiment, G.sub.4b is a chemical bond; in another embodiment, G.sub.4b is C.sub.1-7 alkylene; in another embodiment, G.sub.4b is C.sub.1-4 alkylene; in another embodiment, G.sub.4b is —CH.sub.2—; in another embodiment, G.sub.4b is —(CH.sub.2).sub.2—; in another embodiment, G.sub.4b is —(CH.sub.2).sub.3—; in another embodiment, G.sub.4b is optionally substituted with 1, 2, 3, 4 or 5 R.sup.s;
[0189] In a more specific embodiment, G.sub.3a, G.sub.3b, G.sub.4a and G.sub.4b have a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms; in another more specific embodiment, G.sub.3a, G.sub.3b, G.sub.4a and G.sub.4b have a total length of 1, 2, 3, 4, 5 or 6 carbon atoms.
[0190] In one embodiment, one of L.sub.4 and L.sub.6 is —(CR.sup.sR.sup.s′).sub.2—, and the other is a chemical bond; in another embodiment, one of L.sub.4 and L.sub.6 is —(CHR.sup.s).sub.2—, and the other is a chemical bond; in another embodiment, one of L.sub.4 and L.sub.6 is —CH═CH—, and the other is a chemical bond; in another embodiment, one of L.sub.4 and L.sub.6 is —C≡C—, and the other is a chemical bond.
[0191] In a more specific embodiment, one of L.sub.3 and L.sub.5, or one of L.sub.4 and L.sub.6 is —(CHR.sup.s).sub.2—, —CH═CH— or —C≡C—, and the other is a chemical bond; [0192] G.sub.1a and G.sub.3a are independently a chemical bond or C.sub.1-7 alkylene; [0193] G.sub.1b and G.sub.3b are independently a chemical bond or C.sub.1-3 alkylene; [0194] G.sub.2a and G.sub.4a are independently a chemical bond or C.sub.1-3 alkylene; [0195] G.sub.2b and G.sub.4b are independently a chemical bond or C.sub.1-4 alkylene; [0196] G.sub.1a, G.sub.1b, G.sub.2a and G.sub.2b have a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms; [0197] G.sub.3a, G.sub.3b, G.sub.4a and G.sub.4b have a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms.
[0198] In another more specific embodiment, one of L.sub.3 and L.sub.5, or one of L.sub.4 and L.sub.6 is —(CH.sub.2).sub.2—, —CH═CH— or —C≡C—, and the other is a chemical bond; [0199] G.sub.1a and G.sub.3a are independently a chemical bond, —CH.sub.2—, —(CH.sub.2).sub.2—, —(CH.sub.2).sub.3—, —(CH.sub.2).sub.4—, —(CH.sub.2).sub.5— or —(CH.sub.2).sub.6—; [0200] G.sub.1b and G.sub.3b is a chemical bond; [0201] G.sub.2a and G.sub.4a is a chemical bond; [0202] G.sub.2b and G.sub.4b are independently a chemical bond, —CH.sub.2—, —(CH.sub.2).sub.2— or —(CH.sub.2).sub.3—; [0203] G.sub.1a, G.sub.1b, G.sub.2a and G.sub.2b have a total length of 1, 2, 3, 4, 5 or 6 carbon atoms; [0204] G.sub.3a, G.sub.3b, G.sub.4a and G.sub.4b have a total length of 1, 2, 3, 4, 5 or 6 carbon atoms.
[0205] Alternatively, R.sup.s and R.sup.s′ are independently H, C.sub.1-10 alkyl, -L.sub.d-OR.sub.d or -L.sub.d-NR.sub.dR′.sub.d; alternatively H or C.sub.1-6 alkyl; more alternatively H.
[0206] In a more specific embodiment, -G.sub.1a-L.sub.3-G.sub.1b- or -G.sub.3a-L.sub.4-G.sub.3b- is independently selected from: —(CH.sub.2).sub.2—, —(CH.sub.2).sub.3—, —(CH.sub.2).sub.4—, —(CH.sub.2).sub.5—, —(CH.sub.2).sub.6—, —(CH.sub.2).sub.7—, —(CH.sub.2).sub.8—, —(CH.sub.2).sub.3—CH═CH—, —(CH.sub.2).sub.3—C≡C—, —(CH.sub.2).sub.2—CH═CH— and —(CH.sub.2).sub.2—C≡C—.
[0207] In a more specific embodiment, -G.sub.2a-L.sub.5-G.sub.2b- or -G.sub.4a-L.sub.6-G.sub.4b- is independently selected from: a chemical bond, —CH.sub.2—, —(CH.sub.2).sub.2—, —(CH.sub.2).sub.3—, —CH═CH—CH.sub.2—, —C≡C— and —C═C—CH.sub.2—.
[0208] In a more specific embodiment,
##STR00006##
have a total length of 4, 5, 6, 7, 8 or 9 carbon atoms.
[0209] In a more specific embodiment,
##STR00007##
is independently selected from: —(CH.sub.2).sub.3—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.4—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.5—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.6—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.7—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.8—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.3—CH═CH—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.3—C—C—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.4—C(CH.sub.3).sub.2—CH.sub.2—, —(CH.sub.2).sub.3—C(CH.sub.3).sub.2—(CH.sub.2).sub.2—, —(CH.sub.2).sub.2—C(CH.sub.3).sub.2—(CH.sub.2).sub.3—, —(CH.sub.2).sub.2—CH═CH—C(CH.sub.3).sub.2—CH.sub.2—, —(CH.sub.2).sub.2—C(CH.sub.3).sub.2—C—C—CH.sub.2—, —(CH.sub.2).sub.2—C(CH.sub.3).sub.2—CH═CH—CH.sub.2—, —(CH.sub.2).sub.2—C—C—C(CH.sub.3).sub.2—CH.sub.2— and —(CH.sub.2).sub.3—C(CH.sub.3).sub.2—C═C—; in another more specific embodiment,
##STR00008##
is independently —(CH.sub.2).sub.4—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.5—C(CH.sub.3).sub.2— or —(CH.sub.2).sub.6—C(CH.sub.3).sub.2—; in another more specific embodiment,
##STR00009##
is —(CH.sub.2).sub.5—C(CH.sub.3).sub.2—.
[0210] R.sub.3 and R.sub.4
[0211] In one embodiment, R.sub.3 is H; in another embodiment, R.sub.3 is C.sub.1-10 alkyl; in another embodiment, R.sub.3 is C.sub.1-10 haloalkyl; in another embodiment, R.sub.3 is C.sub.2-10 alkenyl; in another embodiment, R.sub.3 is C.sub.2-10 alkynyl; in another embodiment, R.sub.3 is 3- to 14-membered cycloalkyl; in another embodiment, R.sub.3 is 3- to 14-membered heterocyclyl; in another embodiment, R.sub.3 is C.sub.6-10 aryl; in another embodiment, R.sub.3 is 5- to 14-membered heteroaryl; in another embodiment, R.sub.3 is C.sub.1-6 alkyl; in another embodiment, R.sub.3 is C.sub.1-6 haloalkyl; in another embodiment, R.sub.3 is 3- to 10-membered cycloalkyl; in another embodiment, R.sub.3 is 3- to 10-membered heterocyclyl; in another embodiment, R.sub.3 is 3- to 7-membered cycloalkyl; in another embodiment, R.sub.3 is 3- to 7-membered heterocyclyl; in another embodiment, R.sub.3 is Me; in another embodiment, R.sub.3 is —CH.sub.2CH.sub.3; in another embodiment, R.sub.3 is —CH.sub.2CH.sub.2OH; in another embodiment, R.sub.3 is —CH(CH.sub.3).sub.2; in another embodiment, R.sub.3 is substituted with one or more R*; in another embodiment, R.sub.3 is optionally substituted with 1, 2, 3, 4 or 5 R*.
[0212] In one embodiment, R.sub.4 is H; in another embodiment, R.sub.4 is C.sub.1-10 alkyl; in another embodiment, R.sub.4 is C.sub.1-10 haloalkyl; in another embodiment, R.sub.4 is C.sub.2-10 alkenyl; in another embodiment, R.sub.4 is C.sub.2-10 alkynyl; in another embodiment, R.sub.4 is 3- to 14-membered cycloalkyl; in another embodiment, R.sub.4 is 3- to 14-membered heterocyclyl; in another embodiment, R.sub.4 is C.sub.6-10 aryl; in another embodiment, R.sub.4 is 5- to 14-membered heteroaryl; in another embodiment, R.sub.4 is C.sub.1-6 alkyl; in another embodiment, R.sub.4 is C.sub.1-6 haloalkyl; in another embodiment, R.sub.4 is 3- to 10-membered cycloalkyl; in another embodiment, R.sub.4 is 3- to 10-membered heterocyclyl; in another embodiment, R.sub.4 is 3- to 7-membered cycloalkyl; in another embodiment, R.sub.4 is 3- to 7-membered heterocyclyl; in another embodiment, R.sub.4 is Me; in another embodiment, R.sub.4 is substituted with one or more R*; in another embodiment, R.sub.4 is optionally substituted with 1, 2, 3, 4 or 5 R*.
[0213] In one embodiment, R.sub.3, R.sub.4 are taken together with the N atom to which they are attached to form 3- to 14-membered heterocyclyl; in another embodiment, R.sub.3, R.sub.4 are taken together with the N atom to which they are attached to form 3- to 10-membered heterocyclyl; in another embodiment, R.sub.3, R.sub.4 are taken together with the N atom to which they are attached to form 3- to 7-membered heterocyclyl; in another embodiment, R.sub.3, R.sub.4 are taken together with the N atom to which they are attached to form 5- to 7-membered heterocyclyl; in another embodiment, R.sub.3, R.sub.4 are taken together with the N atom to which they are attached to form 4- to 6-membered heterocyclyl; in another embodiment, R.sub.3, R.sub.4 are taken together with the N atom to which they are attached to form 5-membered heterocyclyl; in another embodiment, R.sub.3, R.sub.4 are taken together with the N atom to which they are attached to form
##STR00010##
in another embodiment, R.sub.3, R.sub.4 are taken together with the N atom to which they are attached to form
##STR00011##
in another embodiment, R.sub.3, R.sub.4 are taken together with the N atom to which they are attached to form
##STR00012##
in another embodiment, R.sub.3, R.sub.4 are taken together with the N atom to which they are attached to form
##STR00013##
in another embodiment, the heterocyclyl formed by R.sub.3 and R.sub.4 taken together with the N atom to which they are attached is optionally substituted with one or more R*; in another embodiment, the heterocyclyl formed by R.sub.3 and R.sub.4 taken together with the N atom to which they are attached is optionally substituted with 1, 2, 3, 4 or 5 R*.
[0214] In one embodiment, R.sub.4, R.sub.9 are taken together with the atom to which they are attached to form 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl; in another embodiment, R.sub.4, R.sub.9 are taken together with the atom to which they are attached to form 3- to 10-membered heterocyclyl; in another embodiment, R.sub.4, R.sub.9 are taken together with the atom to which they are attached to form 3- to 7-membered heterocyclyl; in another embodiment, R.sub.4, R.sub.9 are taken together with the atom to which they are attached to form 6-membered heterocyclyl; in another embodiment, R.sub.4, R.sub.9 are taken together with the atom to which they are attached to form
##STR00014##
in another embodiment, the heterocyclyl formed by R.sub.4 and R.sub.9 taken together with the atom to which they are attached is optionally substituted with one or more R*; in another embodiment, the heterocyclyl formed by R.sub.4 and R.sub.9 taken together with the atom to which they are attached is optionally substituted with 1, 2, 3, 4 or 5 R*.
[0215] In a more specific embodiment, R.sub.3 and R.sub.4 are independently H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; [0216] or, R.sub.3 and R.sub.4 are taken together with the N atom to which they are attached to form 3- to 10-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; [0217] or, R.sub.4 and R.sub.9 are taken together with the atoms to which they are attached to form 3- to 10-membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 R*.
[0218] In another more specific embodiment, R.sub.3 and R.sub.4 are independently H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, 3- to 7-membered cycloalkyl or 3- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; [0219] or, R.sub.3 and R.sub.4 are taken together with the N atom to which they are attached to form 3- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; [0220] or, R.sub.4 and R.sub.9 are taken together with the atoms to which they are attached to form 3- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*.
[0221] In a more specific embodiment, R.sub.3 and R.sub.4 are independently C.sub.1-6 alkyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; [0222] or, R.sub.3 and R.sub.4 are taken together with the N atom to which they are attached to form 5- to 7-membered heterocyclyl, alternatively 4- to 6-membered heterocyclyl, more alternatively 5-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; [0223] or, R.sub.4 and R.sub.9 are taken together with the atoms to which they are attached to form 6-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*.
[0224] In a more specific embodiment, R.sub.3 is Me, —CH.sub.2CH.sub.3, —CH.sub.2CH.sub.2OH or —CH(CH.sub.3).sub.2, alternatively Me, —CH.sub.2CH.sub.3 or —CH(CH.sub.3).sub.2, more alternatively Me or —CH.sub.2CH.sub.3; R.sub.4 is Me; [0225] or, R.sub.3 and R.sub.4 are taken together with the N atom to which they are attached to form
##STR00015## alternatively
##STR00016## more alternatively
##STR00017## [0226] or, R.sub.4 and R.sub.9 are taken together with the atoms to which they are attached to form
##STR00018##
[0227] R*
[0228] In one embodiment, R* is H; in another embodiment, R* is halogen; in another embodiment, R* is cyano; in another embodiment, R* is C.sub.1-10 alkyl; in another embodiment, R* is C.sub.1-10 haloalkyl; in another embodiment, R* is -L.sub.b-OR.sub.b; in another embodiment, R* is -L.sub.b-SR.sub.b; in another embodiment, R* is -L.sub.b-NR.sub.bR′.sub.b; in another embodiment, R* is C.sub.1-6 alkyl; in another embodiment, R* is C.sub.1-6 haloalkyl; in another embodiment, R* is —OR.sub.b.
[0229] In a more specific embodiment, R* is independently H, halogen, cyano, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, -L.sub.b-OR.sub.b or -L.sub.b-NR.sub.bR′.sub.b; in another more specific embodiment, R* is independently H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or —OR.sub.b; in another more specific embodiment, R* is independently H, halogen, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; in another more specific embodiment, R* is independently H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; in another more specific embodiment, R* is H, Me or OH; in another more specific embodiment, R* is H or Me.
[0230] R.sub.5, R.sub.6, R.sub.7 and R.sub.8
[0231] In one embodiment, R.sub.5 is C.sub.1-8 alkyl; in another embodiment, R.sub.5 is C.sub.1-6 alkyl; in another embodiment, R.sub.5 is C.sub.1-3 alkyl; in another embodiment, R.sub.5 is Me; in another embodiment, R.sub.5 is optionally substituted with one or more R*; in another embodiment, R.sub.5 is optionally substituted with 1, 2, 3, 4 or 5 R*.
[0232] In one embodiment, R.sub.6 is C.sub.1-8 alkyl; in another embodiment, R.sub.6 is C.sub.1-6 alkyl; in another embodiment, R.sub.6 is C.sub.1-3 alkyl; in another embodiment, R.sub.6 is Me; in another embodiment, R.sub.6 is optionally substituted with one or more R*; in another embodiment, R.sub.6 is optionally substituted with 1, 2, 3, 4 or 5 R*.
[0233] In one embodiment, R.sub.7 is C.sub.1-8 alkyl; in another embodiment, R.sub.7 is C.sub.1-6 alkyl; in another embodiment, R.sub.7 is C.sub.1-3 alkyl; in another embodiment, R.sub.7 is Me; in another embodiment, R.sub.7 is optionally substituted with one or more R*; in another embodiment, R.sub.7 is optionally substituted with 1, 2, 3, 4 or 5 R*.
[0234] In one embodiment, R.sub.8 is C.sub.1-8 alkyl; in another embodiment, R.sub.8 is C.sub.1-6 alkyl; in another embodiment, R.sub.8 is C.sub.1-3 alkyl; in another embodiment, R.sub.8 is Me; in another embodiment, R.sub.8 is optionally substituted with one or more R*; in another embodiment, R.sub.8 is optionally substituted with 1, 2, 3, 4 or 5 R*.
[0235] R.sub.1 and R.sub.2
[0236] In one embodiment, R.sub.1 is C.sub.4-20 alkyl; in another embodiment, R.sub.1 is C.sub.4-20 alkenyl; in another embodiment, R.sub.1 is C.sub.4-20 alkynyl; in another embodiment, R.sub.1 is optionally substituted with one or more R; in another embodiment, one or more methylene units in R.sub.1 are optionally and independently replaced by —NR″—.
[0237] In a more specific embodiment, R.sub.1 is -G.sub.7-L.sub.1-G.sub.8-H.
[0238] In one embodiment, G.sub.7 is a chemical bond; in another embodiment, G.sub.7 is C.sub.1-12 alkylene; in another embodiment, G.sub.7 is C.sub.1-6 alkylene; in another embodiment, G.sub.7 is C.sub.1-8 alkylene; in another embodiment, G.sub.7 is C.sub.1-5 linear alkylene; in another embodiment, G.sub.7 is —CH.sub.2—; in another embodiment, G.sub.7 is —(CH.sub.2).sub.2—; in another embodiment, G.sub.7 is —(CH.sub.2).sub.4—; in another embodiment, G.sub.7 is —(CH.sub.2).sub.5—; in another embodiment, G.sub.7 is optionally substituted with 1, 2, 3, 4, 5 or 6 R; in another embodiment, 1, 2 or 3 methylenes in G.sub.7 are optionally and independently substituted with 1 R; in another embodiment, 1 or 2 methylenes in G.sub.7 are optionally and independently substituted with 1 R; in another embodiment, the methylene of G.sub.7 that is collected to M.sub.1 is not substituted with R.
[0239] In one embodiment, G.sub.8 is a chemical bond; in another embodiment, G.sub.8 is C.sub.1-12 alkylene; in another embodiment, G.sub.8 is C.sub.1-10 alkylene; in another embodiment, G.sub.8 is C.sub.1-8 alkylene; in another embodiment, G.sub.8 is C.sub.1-8 linear alkylene; in another embodiment, G.sub.8 is —(CH.sub.2).sub.2—; in another embodiment, G.sub.8 is —(CH.sub.2).sub.4—; in another embodiment, G.sub.8 is —(CH.sub.2).sub.6—; in another embodiment, G.sub.8 is —(CH.sub.2).sub.7—; in another embodiment, G.sub.8 is —(CH.sub.2).sub.8—; in another embodiment, G.sub.8 is optionally substituted with 1, 2, 3, 4, 5 or 6 R; in another embodiment, 1, 2 or 3 methylenes in G.sub.8 are optionally and independently substituted with 1 R; in another embodiment, 1 or 2 alkylene in G.sub.8 are optionally and independently substituted with 1 R.
[0240] In one embodiment, G.sub.7 and G.sub.8 have a total length of 4 carbon atoms; in another embodiment, G.sub.7 and G.sub.8 have a total length of 5 carbon atoms; in another embodiment, G.sub.7 and G.sub.8 have a total length of 6 carbon atoms; in another embodiment, G.sub.7 and G.sub.8 have a total length of 7 carbon atoms; in another embodiment, G.sub.7 and G.sub.8 have a total length of 8 carbon atoms; in another embodiment, G.sub.7 and G.sub.8 have a total length of 9 carbon atoms; in another embodiment, G.sub.7 and G.sub.8 have a total length of 10 carbon atoms; in another embodiment, G.sub.7 and G.sub.8 have a total length of 11 carbon atoms; in another embodiment, G.sub.7 and G.sub.8 have a total length of 12 carbon atoms.
[0241] In a more specific embodiment, G.sub.7 and G.sub.8 have a total length of 6, 7, 8, 9 or 10 carbon atoms.
[0242] In a more specific embodiment, G.sub.7 and G.sub.8 have a total length of 6, 7 or 8 carbon atoms.
[0243] In one embodiment, L.sub.1 is —(CRR′).sub.2—; in another embodiment, L.sub.1 is —CH═CH—; in another embodiment, L.sub.1 is —C≡C—; in another embodiment, L.sub.1 is —NR″—; in another embodiment, L.sub.1 is —(CHR).sub.2—.
[0244] In one embodiment, R.sub.2 is C.sub.4-20 alkyl; in another embodiment, R.sub.2 is C.sub.4-20 alkenyl; in another embodiment, R.sub.2 is C.sub.4-20 alkynyl; in another embodiment, R.sub.2 is optionally substituted with one or more R; in another embodiment, one or more methylene units in R.sub.2 are optionally and independently replaced by —NR″—.
[0245] In a more specific embodiment, R.sub.2 is -G.sub.9-L.sub.2-G.sub.10-H.
[0246] In one embodiment, G.sub.9 is a chemical bond; in another embodiment, G.sub.9 is C.sub.1-12 alkylene; in another embodiment, G.sub.9 is C.sub.1-6 alkylene; in another embodiment, G.sub.9 is C.sub.1-5 alkylene; in another embodiment, G.sub.9 is C.sub.1-5 linear alkylene; in another embodiment, G.sub.9 is —CH.sub.2—; in another embodiment, G.sub.9 is —(CH.sub.2).sub.2—; in another embodiment, G.sub.9 is —(CH.sub.2).sub.4—; in another embodiment, G.sub.9 is —(CH.sub.2).sub.5—; in another embodiment, G.sub.9 is optionally substituted with 1, 2, 3, 4, 5 or 6 R; in another embodiment, 1, 2 or 3 methylenes in G.sub.9 are optionally and independently substituted with 1 R; in another embodiment, 1 or 2 methylenes in G.sub.9 are optionally and independently substituted with 1 R; in another embodiment, the methylene of G.sub.9 that is collected to M.sub.2 is not substituted with R.
[0247] In one embodiment, G.sub.10 is a chemical bond; in another embodiment, G.sub.10 is C.sub.1-12 alkylene; in another embodiment, G.sub.10 is C.sub.1-10 alkylene; in another embodiment, G.sub.10 is C.sub.1-8 alkylene; in another embodiment, G.sub.10 is C.sub.1-8 linear alkylene; in another embodiment, G.sub.10 is —(CH.sub.2).sub.2—; in another embodiment, G.sub.10 is —(CH.sub.2).sub.4—; in another embodiment, G.sub.10 is —(CH.sub.2).sub.6—; in another embodiment, G.sub.10 is —(CH.sub.2).sub.7—; in another embodiment, G.sub.10 is —(CH.sub.2).sub.8—; in another embodiment, G.sub.10 is optionally substituted with 1, 2, 3, 4, 5 or 6 R; in another embodiment, 1, 2 or 3 methylenes in G.sub.10 are optionally and independently substituted with 1 R; in another embodiment, 1 or 2 methylenes in G.sub.10 are optionally and independently substituted with 1 R.
[0248] In one embodiment, G.sub.9 and G.sub.10 have a total length of 4 carbon atoms; in another embodiment, G.sub.9 and G.sub.10 have a total length of 5 carbon atoms; in another embodiment, G.sub.9 and G.sub.10 have a total length of 6 carbon atoms; in another embodiment, G.sub.9 and G.sub.10 have a total length of 7 carbon atoms; in another embodiment, G.sub.9 and G.sub.10 have a total length of 8 carbon atoms; in another embodiment, G.sub.9 and G.sub.10 have a total length of 9 carbon atoms; in another embodiment, G.sub.9 and G.sub.10 have a total length of 10 carbon atoms; in another embodiment, G.sub.9 and G.sub.10 have a total length of 11 carbon atoms; in another embodiment, G.sub.9 and G.sub.10 have a total length of 12 carbon atoms.
[0249] In a more specific embodiment, G.sub.9 and G.sub.10 have a total length of 6, 7, 8, 9 or 10 carbon atoms.
[0250] In a more specific embodiment, G.sub.9 and G.sub.10 have a total length of 6, 7 or 8 carbon atoms.
[0251] In one embodiment, L.sub.2 is —(CRR′).sub.2—; in another embodiment, L.sub.2 is —CH═CH—; in another embodiment, L.sub.2 is —C≡C—; in another embodiment, L.sub.2 is —NR″—; in another embodiment, L.sub.1 is —(CHR).sub.2—.
[0252] In a more specific embodiment, L.sub.1 and L.sub.2 are independently —(CRR′).sub.2—, —CH═CH—, —C≡C— or —NR″—; [0253] G.sub.7, G.sub.8, G.sub.9 and G.sub.10 are independently a chemical bond or C.sub.1-12 alkylene, which is optionally substituted with 1, 2, 3, 4, 5 or 6 R; [0254] G.sub.7 and G.sub.8 have a total length of 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms; [0255] G.sub.9 and G.sub.10 have a total length of 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms; [0256] 1, 2 or 3 methylenes in G.sub.7, G.sub.8, G.sub.9 or G.sub.10 are optionally and independently substituted with 1 R; [0257] R′ is independently H, C.sub.1-20 alkyl, -L.sub.a-OR.sub.a or -L.sub.a-NR.sub.aR′.sub.a.
[0258] In another more specific embodiment, L.sub.1 and L.sub.2 are independently —(CHR).sub.2—, —CH═CH—, —C≡C— or —NR″—; [0259] G.sub.7 and G.sub.9 are independently a chemical bond or C.sub.1-6 alkylene; [0260] G.sub.8 and G.sub.10 are independently C.sub.1-10 alkylene; [0261] G.sub.7 and G.sub.8 have a total length of 4, 5, 6, 7, 8, 9 or 10 carbon atoms; [0262] G.sub.9 and G.sub.10 have a total length of 4, 5, 6, 7, 8, 9 or 10 carbon atoms; [0263] 1, 2 or 3 methylenes in G.sub.7, G.sub.8, G.sub.9 or G.sub.10 are optionally and independently substituted with 1 R.
[0264] In another more specific embodiment, L.sub.1 and L.sub.2 are independently —(CHR).sub.2—, —CH═CH—, —C≡C— or —NR″—; [0265] G.sub.7 and G.sub.9 are independently a chemical bond or C.sub.1-5 alkylene, alternatively a chemical bond or C.sub.1-5 linear alkylene; [0266] G.sub.8 and G.sub.10 are independently C.sub.1-8 alkylene, alternatively C.sub.1-8 linear alkylene; [0267] G.sub.7 and G.sub.8 have a total length of 4, 5, 6, 7, 8, 9, 10 carbon atoms, alternatively 6, 7, 8, 9, 10 carbon atoms; [0268] G.sub.9 and G.sub.10 have a total length of 4, 5, 6, 7, 8, 9, 10 carbon atoms, alternatively 6, 7, 8, 9, 10 carbon atoms; [0269] 1 or 2 methylenes in G.sub.7, G.sub.8, G.sub.9 or G.sub.10 are optionally and independently substituted with 1 R.
[0270] Alternatively, the methylene collected to M.sub.1 and M.sub.2 is not substituted with R.
[0271] In another more specific embodiment, L.sub.1 and L.sub.2 are independently —(CHR).sub.2—, —CH═CH—, —C≡C— or —NR″—; [0272] G.sub.7 and G.sub.9 are independently a chemical bond, —CH.sub.2—, —(CH.sub.2).sub.2—, —(CH.sub.2).sub.4— or —(CH.sub.2).sub.5—; [0273] G.sub.8 and G.sub.10 are independently —(CH.sub.2).sub.2—, —(CH.sub.2).sub.4—, —(CH.sub.2).sub.6—, —(CH.sub.2).sub.7— or —(CH.sub.2).sub.8—; [0274] G.sub.7 and G.sub.8 have a total length of 4, 5, 6, 7, 8, 9, 10 carbon atoms, alternatively 6, 7, 8, 9, 10 carbon atoms; [0275] G.sub.9 and G.sub.10 have a total length of 4, 5, 6, 7, 8, 9, 10 carbon atoms, alternatively 6, 7, 8, 9, 10 carbon atoms; [0276] 1 or 2 methylenes in G.sub.7, G.sub.8, G.sub.9 or G.sub.10 are optionally and independently substituted with 1 R.
[0277] Alternatively, the methylene collected to M.sub.1 and M.sub.2 is not substituted with R.
[0278] In another more specific embodiment, -G.sub.7-L.sub.1-G.sub.8-H or -G.sub.9-L.sub.2-G.sub.10-H is independently selected from: —(CH.sub.2).sub.5CH.sub.3, —(CH.sub.2).sub.6CH.sub.3, —(CH.sub.2).sub.7CH.sub.3, —(CH.sub.2).sub.8CH.sub.3, —(CH.sub.2).sub.9CH.sub.3, —(CH.sub.2).sub.10CH.sub.3, —(CH.sub.2).sub.11CH.sub.3, —CH.sub.2—C≡C—(CH.sub.2).sub.5CH.sub.3, —CH.sub.2—C≡C—(CH.sub.2).sub.6CH.sub.3, —(CH.sub.2).sub.2—C≡C—(CH.sub.2).sub.5CH.sub.3, —(CH.sub.2).sub.4—C≡C—(CH.sub.2).sub.3CH.sub.3, —CH.sub.2—CH═CH—(CH.sub.2).sub.5CH.sub.3, —CH.sub.2—CH═CH—(CH.sub.2).sub.6CH.sub.3, —(CH.sub.2).sub.2—CH═CH—(CH.sub.2).sub.5CH.sub.3, —(CH.sub.2).sub.4—CH═CH—(CH.sub.2).sub.3CH.sub.3, —(CH.sub.2).sub.5—CH═CH—CH.sub.2CH.sub.3,
##STR00019## ##STR00020##
[0279] R.sup.s
[0280] In one embodiment, R.sup.s is H; in another embodiment, R.sup.s is C.sub.1-14 alkyl; in another embodiment, R.sup.s is -L.sub.d-OR.sub.d; in another embodiment, R.sup.s is -L.sub.d-SR.sub.d; in another embodiment, R.sup.s is -L.sub.d-NR.sub.dR′.sub.d; in another embodiment, R.sup.s is C.sub.1-10 alkyl; in another embodiment, R.sup.s is C.sub.1-6 alkyl.
[0281] In a more specific embodiment, R.sup.s is H, C.sub.1-10 alkyl, -L.sub.d-OR.sub.d or -L.sub.d-NR.sub.dR′.sub.d; in another more specific embodiment, R.sup.s is H or C.sub.1-6 alkyl.
[0282] R
[0283] In one embodiment, R is H; in another embodiment, R is C.sub.1-20 alkyl; in another embodiment, R is -L.sub.a-OR.sub.a; in another embodiment, R is -L.sub.a-SR.sub.a; in another embodiment, R is -L.sub.a-NR.sub.aR′.sub.a; in another embodiment, R is C.sub.1-10 alkyl; in another embodiment, R is C.sub.1-8 alkyl; in another embodiment, R is C.sub.1-8 linear alkyl.
[0284] In a more specific embodiment, R is H, Me, —(CH.sub.2).sub.3CH.sub.3, —(CH.sub.2).sub.4CH.sub.3, —(CH.sub.2).sub.5CH.sub.3, —(CH.sub.2).sub.6CH.sub.3 or —(CH.sub.2).sub.7CH.sub.3.
[0285] R″
[0286] In one embodiment, R″ is H; in another embodiment, R″ is C.sub.1-20 alkyl; in another embodiment, R″ is C.sub.1-14 alkyl; in another embodiment, R″ is C.sub.1-10 alkyl; in another embodiment, R″ is C.sub.7-9 alkyl; in another embodiment, R″ is —(CH.sub.2).sub.7CH.sub.3.
[0287] L.sub.a and L.sub.e
[0288] In one embodiment, L.sub.a and L.sub.e are independently a chemical bond; in another embodiment, L.sub.a and L.sub.e are independently C.sub.1-20 alkylene; in another embodiment, L.sub.a and L.sub.e are independently C.sub.1-14 alkylene; in another embodiment, L.sub.a and L.sub.e are independently C.sub.1-10 alkylene.
[0289] L.sub.b and L.sub.f
[0290] In one embodiment, L.sub.b and L.sub.f are independently a chemical bond; in another embodiment, L.sub.b and L.sub.f are independently C.sub.1-10 alkylene; in another embodiment, L.sub.b and L.sub.f are independently C.sub.1-6 alkylene.
[0291] L.sub.c
[0292] In one embodiment, L.sub.e is a chemical bond; in another embodiment, L.sub.c is C.sub.1-8 alkylene; in another embodiment, L.sub.c is C.sub.1-6 alkylene.
[0293] L.sub.d
[0294] In one embodiment, L.sub.d is a chemical bond; in another embodiment, L.sub.d is C.sub.1-14 alkylene; in another embodiment, L.sub.d is C.sub.1-10 alkylene.
[0295] R.sub.a and R′.sub.a
[0296] In one embodiment, R.sub.a is H; in another embodiment, R.sub.a is C.sub.1-20 alkyl; in another embodiment, R.sub.a is 3- to 14-membered cycloalkyl; in another embodiment, R.sub.a is 3- to 14-membered heterocyclyl; in another embodiment, R.sub.a is C.sub.1-14 alkyl; in another embodiment, R.sub.a is C.sub.1-10 alkyl; in another embodiment, R.sub.a is C.sub.8-10 alkyl; in another embodiment, R.sub.a is C.sub.8-10 linear alkyl; in another embodiment, R.sub.a is —(CH.sub.2).sub.8CH.sub.3; in another embodiment, R.sub.a is optionally substituted with one or more of the following substituents: H, C.sub.1-20 alkyl, -L.sub.e-OR.sub.e, -L.sub.e-SR.sub.e and -L.sub.e-NR.sub.eR′.sub.e.
[0297] In one embodiment, R′.sub.a is H; in another embodiment, R′.sub.a is C.sub.1-20 alkyl; in another embodiment, R′.sub.a is 3- to 14-membered cycloalkyl; in another embodiment, R′.sub.a is 3- to 14-membered heterocyclyl; in another embodiment, R′.sub.a is C.sub.1-14 alkyl; in another embodiment, R′.sub.a is C.sub.1-10 alkyl; in another embodiment, R′.sub.a is C.sub.8-10 alkyl; in another embodiment, R′.sub.a is C.sub.8-10 linear alkyl; in another embodiment, R′.sub.a is —(CH.sub.2).sub.8CH.sub.3; in another embodiment, R′.sub.a is optionally substituted with one or more of the following substituents: H, C.sub.1-20 alkyl, -L.sub.e-OR.sub.e, -L.sub.e-SR.sub.e and -L.sub.e-NR.sub.eR′.sub.e.
[0298] R.sub.b and R′.sub.b
[0299] In one embodiment, R.sub.b is H; in another embodiment, R.sub.b is C.sub.1-10 alkyl; in another embodiment, R.sub.b is 3- to 14-membered cycloalkyl; in another embodiment, R.sub.b is 3- to 14-membered heterocyclyl; in another embodiment, R.sub.b is C.sub.1-6 alkyl; in another embodiment, R.sub.b is 3- to 10-membered cycloalkyl; in another embodiment, R.sub.b is 3- to 10-membered heterocyclyl; in another embodiment, R.sub.b is optionally substituted with one or more of the following substituents: H, C.sub.1-10 alkyl, -L.sub.f-OR.sub.f, -L.sub.f-SR.sub.f and -L.sub.f-NR.sub.fR′.sub.f.
[0300] In one embodiment, R′.sub.b is H; in another embodiment, R′.sub.b is C.sub.1-10 alkyl; in another embodiment, R′.sub.b is 3- to 14-membered cycloalkyl; in another embodiment, R′.sub.b is 3- to 14-membered heterocyclyl; in another embodiment, R′.sub.b is C.sub.1-6 alkyl; in another embodiment, R′.sub.b is 3- to 10-membered cycloalkyl; in another embodiment, R′.sub.b is 3- to 10-membered heterocyclyl; in another embodiment, R.sub.b is optionally substituted with one or more of the following substituents: H, C.sub.1-10 alkyl, -L.sub.f-OR.sub.f, -L.sub.f-SR.sub.f and -L.sub.f-NR.sub.fR′.sub.f.
[0301] R.sub.c and R′.sub.c
[0302] In one embodiment, R.sub.c is H; in another embodiment, R.sub.c is C.sub.1-8 alkyl; in another embodiment, R.sub.c is C.sub.1-6 alkyl.
[0303] In one embodiment, R′.sub.c is H; in another embodiment, R′.sub.c is C.sub.1-8 alkyl; in another embodiment, R′.sub.c is C.sub.1-6 alkyl.
[0304] R.sub.d and R′.sub.a
[0305] In one embodiment, R.sub.d is H; in another embodiment, R.sub.d is C.sub.1-14 alkyl; in another embodiment, R.sub.d is C.sub.1-10 alkyl. In one embodiment, R′d is H; in another embodiment, R′d is C.sub.1-14 alkyl; in another embodiment, R′d is C.sub.1-10 alkyl.
[0306] R.sub.e and R′.sub.e
[0307] In one embodiment, R.sub.e is H; in another embodiment, R.sub.e is C.sub.1-20 alkyl.
[0308] In one embodiment, R′.sub.e is H; in another embodiment, R′.sub.e is C.sub.1-20 alkyl.
[0309] R.sub.f and R′.sub.f
[0310] In one embodiment, R.sub.f is H; in another embodiment, R.sub.f is C.sub.1-10 alkyl.
[0311] In one embodiment, R′.sub.f is H; in another embodiment, R′.sub.f is C.sub.1-10 alkyl.
[0312] Any of the above technical solutions in any specific embodiment or any combination thereof may be combined with any technical solution or any combination thereof in other specific embodiments. For example, any technical solution of Q, or any combination thereof, may be combined with any technical solution of M.sub.1, M.sub.2, G.sub.5, G.sub.6a, G.sub.6b, R.sub.9, R.sub.10, R**, G.sub.1, G.sub.2, G.sub.3, G.sub.4, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R, R″, R.sup.s, Ar.sub.2, L.sub.a, L.sub.e, L.sub.b, L.sub.f, L.sub.c, L.sub.d, R.sub.a, R′.sub.a, R.sub.b, R′.sub.b, R.sub.e, R′.sub.e, R.sub.d, R′d, R.sub.e, R′.sub.e, R.sub.f and R′.sub.f, or any combination thereof. The present disclosure is intended to include all of these combinations of technical solutions and, for reasons of space, will not be listed.
[0313] In a more specific embodiment, the present disclosure provides a compound of formula (IV), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:
##STR00021## [0314] wherein, [0315] M.sub.1 and M.sub.2 are independently selected from —C(O)O—, —O—, —SC(O)O—, —OC(O)NR.sub.a—, —NR.sub.aC(O)NR.sub.a—, —OC(O)S—, —OC(O)O—, —NR.sub.aC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR.sub.a—, —C(O)NR.sub.a—, —NR.sub.aC(O)—, —NR.sub.aC(O)S—, —SC(O)NR.sub.a—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR.sub.a—, —NR.sub.aC(S)O—, —S—S— and —S(O).sub.0-2—; [0316] Q is selected from a chemical bond, —C(O)O—, —O—, —SC(O)O—, —OC(O)NR.sub.b—, —NR.sub.bC(O)NR.sub.b—, —OC(O)S—, —OC(O)O—, —NR.sub.bC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR.sub.b—, —C(O)NR.sub.b—, —NR.sub.bC(O)—, —NR.sub.bC(O)S—, —SC(O)NR.sub.b—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR.sub.b—, —NR.sub.bC(S)O—, —S—S—, —S(O).sub.0-2—, phenylene and pyridylidene, wherein, the phenylene or pyridylidene is optionally substituted with one or more R*; [0317] G.sub.5 is a chemical bond or C.sub.1-8 alkylene, which is optionally substituted with one or more R**; [0318] G.sub.6a and G.sub.6b are independently a chemical bond or C.sub.1-7 alkylene, which is optionally substituted with one or more R**; [0319] G.sub.6a and G.sub.6b have a total length of 0, 1, 2, 3, 4, 5, 6 or 7 carbon atoms; [0320] R.sub.9, R.sub.10 and R** are independently H, C.sub.1-8 alkyl, -L.sub.c-OR.sub.c, -L.sub.c-SR.sub.c or -L.sub.c-NR.sub.cR′.sub.c; [0321] G.sub.1, G.sub.2, G.sub.3 and G.sub.4 are independently a chemical bond, C.sub.1-13 alkylene, C.sub.2-13 alkenylene or C.sub.2-13 alkynylene, which is optionally substituted with one or more R.sup.s; [0322] G.sub.1 and G.sub.2 have a total length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms; [0323] G.sub.3 and G.sub.4 have a total length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms; [0324] R.sub.3 and R.sub.4 are independently H, C.sub.1-10 alkyl, C.sub.1-10 haloalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl, C.sub.6-10 aryl or 5- to 14-membered heteroaryl, which is optionally substituted with one or more R*; [0325] or, R.sub.3 and R.sub.4 are taken together with the N atom to which they are attached to form 3- to 14-membered heterocyclyl, which is optionally substituted with one or more R*; [0326] or, R.sub.4 and R.sub.9 are taken together with the atoms to which they are attached to form 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl, which is optionally substituted with one or more R*; [0327] R* is independently H, halogen, cyano, C.sub.1-10 alkyl, C.sub.1-10 haloalkyl, -L.sub.b-OR.sub.b, -L.sub.b-SR.sub.b or -L.sub.b-NR.sub.bR′.sub.b; [0328] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-8 alkyl, which is optionally substituted with one or more R*; [0329] R.sub.1 and R.sub.2 are independently C.sub.4-20 alkyl, C.sub.4-20 alkenyl or C.sub.4-20 alkynyl, which is optionally substituted with one or more R, and wherein one or more methylene units are optionally and independently replaced with —NR″—; [0330] R.sup.s is independently H, C.sub.1-14 alkyl, -L.sub.d-OR.sub.d, -L.sub.d-SR.sub.d or -L.sub.d-NR.sub.dR′.sub.d; [0331] R is independently H, C.sub.1-20 alkyl, -L.sub.a-OR.sub.a, -L.sub.a-SR.sub.a or -L.sub.a-NR.sub.aR′.sub.a; [0332] R″ is independently H or C.sub.1-20 alkyl; [0333] L.sub.a and L.sub.e are independently a chemical bond or C.sub.1-20 alkylene; [0334] L.sub.b and L.sub.f are independently a chemical bond or C.sub.1-10 alkylene; [0335] L.sub.c is independently a chemical bond or C.sub.1-8 alkylene; [0336] L.sub.d is independently a chemical bond or C.sub.1-14 alkylene; [0337] R.sub.a and R′.sub.a are independently selected from H, C.sub.1-20 alkyl, 3- to 14-membered cycloalkyl, and 3- to 14-membered heterocyclyl, which are optionally substituted with one or more of the following substituents: H, C.sub.1-20 alkyl, -L.sub.c-OR.sub.c, -L.sub.c-SR.sub.c and -L.sub.c-NR.sub.cR′.sub.e; [0338] R.sub.b and R′.sub.b are independently selected from H, C.sub.1-10 alkyl, 3- to 14-membered cycloalkyl, and 3- to 14-membered heterocyclyl, which are optionally substituted with one or more of the following substituents: H, C.sub.1-10 alkyl, -L.sub.f-OR.sub.f, -L.sub.f-SR.sub.f and -L.sub.f-NR.sub.fR′.sub.f; [0339] R.sub.c and R′.sub.e are independently H or C.sub.1-8 alkyl; [0340] R.sub.d and R′.sub.a are independently H or C.sub.1-14 alkyl; [0341] R.sub.e and R′.sub.e are independently H or C.sub.1-20 alkyl; [0342] R.sub.f and R′.sub.f are independently H or C.sub.1-10 alkyl.
[0343] In a more specific embodiment, the present disclosure provides a compound of formula (IV) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, M.sub.1 and M.sub.2 are independently selected from —C(O)O—, —SC(O)O—, —OC(O)NR.sub.a—, —NR.sub.aC(O)NR.sub.a—, —OC(O)S—, —OC(O)O—, —NR.sub.aC(O)O—, —C(O)S—, —C(O)NR.sub.a—, —NR.sub.aC(O)S—, —SC(O)NR.sub.a—, —C(S)O—, —OC(S)NR.sub.a— and —NR.sub.aC(S)O—; alternatively —C(O)O—, —C(O)S—, —C(O)NR.sub.a—, and —C(S)O—; alternatively —C(O)O—, —C(O)S— and —C(O)NR.sub.a—.
[0344] In a more specific embodiment, the present disclosure provides a compound of formula (IV) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, Q is selected from a chemical bond, —C(O)O—, —O—, —SC(O)O—, —OC(O)NR.sub.b—, —NR.sub.bC(O)NR.sub.b—, —OC(O)S—, —OC(O)O—, —NR.sub.bC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR.sub.b—, —C(O)NR.sub.b—, —NR.sub.bC(O)—, —NR.sub.bC(O)S—, —SC(O)NR.sub.b—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR.sub.b—, —NR.sub.bC(S)O—, —S—S—, and —S(O).sub.0-2—; alternatively —C(O)O—, —O—, —SC(O)O—, —OC(O)NH—, —NHC(O)NH—, —OC(O)S—, —OC(O)O—, —NHC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NH—, —C(O)NH—, —NHC(O)—, —NHC(O)S—, —SC(O)NH—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NH— and —NHC(S)O—; alternatively —C(O)O—, —O—, —SC(O)O—, —OC(O)NH—, —NHC(O)NH—, —OC(O)S—, —OC(O)O— and —NHC(O)O—; more alternatively —C(O)O—.
[0345] In a more specific embodiment, the present disclosure provides a compound of formula (IV) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, G.sub.5 is a chemical bond.
[0346] In a more specific embodiment, the present disclosure provides a compound of formula (IV) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0347] G.sub.6a and G.sub.6b are independently a chemical bond or C.sub.1-5 alkylene, which is optionally substituted with 1, 2, 3 or 4 R**; [0348] G.sub.6a and G.sub.6b have a total length of 0, 1, 2, 3, 4 or 5 carbon atoms.
[0349] Alternatively, G.sub.6a is a chemical bond or C.sub.1-4 alkylene, which is optionally substituted with 1, 2, 3 or 4 R**; [0350] G.sub.6b is a chemical bond or C.sub.1-2 alkylene, which is optionally substituted with 1 or 2 R**; [0351] G.sub.6a and G.sub.6b have a total length of 0, 1, 2, 3 or 4 carbon atoms.
[0352] Alternatively, G.sub.6a is a chemical bond or C.sub.1-4 alkylene, alternatively C.sub.2-4 alkylene, alternatively C.sub.2-3 alkylene, more alternatively —(CH.sub.2).sub.2—; [0353] G.sub.6b is a chemical bond or methylene; [0354] G.sub.6a and G.sub.6b have a total length of 0, 1, 2, 3 or 4 carbon atoms, alternatively 1, 2, 3 or 4 carbon atoms, alternatively 2 or 3 carbon atoms.
[0355] Alternatively, G.sub.6a is a chemical bond or C.sub.1-4 linear alkylene, alternatively C.sub.2-4 linear alkylene, alternatively C.sub.2-3 linear alkylene, more alternatively —(CH.sub.2).sub.2—; [0356] G.sub.6b is a chemical bond or methylene; [0357] G.sub.6a and G.sub.6b have a total length of 0, 1, 2, 3 or 4 carbon atoms, alternatively 1, 2, 3 or 4 carbon atoms, alternatively 2 or 3 carbon atoms.
[0358] In a more specific embodiment, the present disclosure provides a compound of formula (IV) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, R.sub.9 and R** are independently H, C.sub.1-6 alkyl, -L.sub.c-OR.sub.c or -L.sub.c-NR.sub.cR′.sub.e, R.sub.10 is H.
[0359] Alternatively, R.sub.9 and R** are independently H or C.sub.1-6 alkyl, R.sub.10 is H.
[0360] Alternatively, R.sub.9, R** and R.sub.10 are H.
[0361] In a more specific embodiment, the present disclosure provides a compound of formula (IV) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein [0362] G.sub.1-C(R.sub.5R.sub.6)-G.sub.2- is
##STR00022## G.sub.3-C(R.sub.7R.sub.8)-G.sub.4- is
##STR00023## [0363] wherein, one of L.sub.3 and L.sub.5, or one of L.sub.4 and L.sub.6 is —(CR.sup.sR.sup.s′).sub.2—, —CH═CH— or —C≡C—, and the other is a chemical bond; [0364] G.sub.1a, G.sub.1b, G.sub.2a, G.sub.2b, G.sub.3a, G.sub.3b, G.sub.4a and G.sub.4b are independently a chemical bond or C.sub.1-7 alkylene, which is optionally substituted with 1, 2, 3, 4 or 5 R.sup.s; [0365] G.sub.1a, G.sub.1b, G.sub.2a and G.sub.2b have a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms; [0366] G.sub.3a, G.sub.3b, G.sub.4a and G.sub.4b have a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms; [0367] R.sup.s′ is independently H, C.sub.1-14 alkyl, -L.sub.d-OR.sub.d or -L.sub.d-NR.sub.dR′.sub.d; [0368] alternatively, one of L.sub.3 and L.sub.5, or one of L.sub.4 and L.sub.6 is —(CHR.sup.s).sub.2—, —CH═CH— or —C≡C—, and the other is a chemical bond; [0369] G.sub.1a and G.sub.3a are independently a chemical bond or C.sub.1-7 alkylene; [0370] G.sub.1b and G.sub.3b are independently a chemical bond or C.sub.1-3 alkylene; [0371] G.sub.2a and G.sub.4a are independently a chemical bond or C.sub.1-3 alkylene; [0372] G.sub.2b and G.sub.4b are independently a chemical bond or C.sub.1-4 alkylene; [0373] G.sub.1a, G.sub.1b, G.sub.2a and G.sub.2b have a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms; [0374] G.sub.3a, G.sub.3b, G.sub.4a and G.sub.4O have a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms.
[0375] Alternatively, one of L.sub.3 and L.sub.5, or one of L.sub.4 and L.sub.6 is —(CH.sub.2).sub.2—, —CH═CH— or —C≡C—, and the other is a chemical bond; [0376] G.sub.1a and G.sub.3a are independently a chemical bond, —CH.sub.2—, —(CH.sub.2).sub.2—, —(CH.sub.2).sub.3—, —(CH.sub.2).sub.4—, —(CH.sub.2).sub.5— or —(CH.sub.2).sub.6—; [0377] G.sub.1b and G.sub.3b is a chemical bond; [0378] G.sub.2a and G.sub.4a is a chemical bond; [0379] G.sub.2b and G.sub.4b are independently a chemical bond, —CH.sub.2—, —(CH.sub.2).sub.2— or —(CH.sub.2).sub.3—; [0380] G.sub.1a, G.sub.1b, G.sub.2a and G.sub.2b have a total length of 1, 2, 3, 4, 5 or 6 carbon atoms; [0381] G.sub.3a, G.sub.3b, G.sub.4a and G.sub.4b have a total length of 1, 2, 3, 4, 5 or 6 carbon atoms.
[0382] Alternatively, R.sup.s and R.sup.s′ are independently H, C.sub.1-10 alkyl, -L.sub.d-OR.sub.d or -L.sub.d-NR.sub.dR′.sub.d; [0383] alternatively H or C.sub.1-6 alkyl; more alternatively H; [0384] alternatively, -G.sub.1a-L.sub.3-G.sub.1b- or -G.sub.3a-L.sub.4-G.sub.3b- is independently selected from the following groups: [0385] —(CH.sub.2).sub.2—, —(CH.sub.2).sub.3—, —(CH.sub.2).sub.4—, —(CH.sub.2).sub.5—, —(CH.sub.2).sub.6—, —(CH.sub.2).sub.7—, —(CH.sub.2).sub.8—, —(CH.sub.2).sub.3—CH═CH—, —(CH.sub.2).sub.3—C≡C—, —(CH.sub.2).sub.2—CH═CH— and —(CH.sub.2).sub.2—C≡C—; [0386] G.sub.2a-L.sub.5-G.sub.2b- or -G.sub.4a-L.sub.6-G.sub.4b- is independently selected from the following groups: [0387] a chemical bond, —CH.sub.2—, —(CH.sub.2).sub.2—, —(CH.sub.2).sub.3—, —CH═CH—CH.sub.2—, —C≡C— and —C—C—CH.sub.2—;
##STR00024## have a total length of 4, 5, 6, 7, 8 or 9 carbon atoms.
[0388] Alternatively,
##STR00025##
is independently selected from the following groups: [0389] —(CH.sub.2).sub.3—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.4—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.5—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.6—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.7—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.8—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.3—CH═CH—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.3—C—C—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.4—C(CH.sub.3).sub.2—CH.sub.2—, —(CH.sub.2).sub.3—C(CH.sub.3).sub.2—(CH.sub.2).sub.2—, —(CH.sub.2).sub.2—C(CH.sub.3).sub.2—(CH.sub.2).sub.3—, —(CH.sub.2).sub.2—CH═CH—C(CH.sub.3).sub.2—CH.sub.2—, —(CH.sub.2).sub.2—C(CH.sub.3).sub.2—C—C—CH.sub.2—, —(CH.sub.2).sub.2—C(CH.sub.3).sub.2—CH═CH—CH.sub.2—, —(CH.sub.2).sub.2—C—C—C(CH.sub.3).sub.2—CH.sub.2— and —(CH.sub.2).sub.3—C(CH.sub.3).sub.2—C≡C—, alternatively —(CH.sub.2).sub.4—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.5—C(CH.sub.3).sub.2— and —(CH.sub.2).sub.6—C(CH.sub.3).sub.2—, more alternatively —(CH.sub.2).sub.5—C(CH.sub.3).sub.2—.
[0390] In a more specific embodiment, the present disclosure provides a compound of formula (IV) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0391] R.sub.3 and R.sub.4 are independently H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; [0392] or, R.sub.3 and R.sub.4 are taken together with the N atom to which they are attached to form 3- to 10-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; [0393] or, R.sub.4 and R.sub.9 are taken together with the atoms to which they are attached to form 3- to 10-membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 R*.
[0394] Alternatively, R.sub.3 and R.sub.4 are independently H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, 3- to 7-membered cycloalkyl or 3- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; [0395] or, R.sub.3 and R.sub.4 are taken together with the N atom to which they are attached to form 3- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; [0396] or, R.sub.4 and R.sub.9 are taken together with the atoms to which they are attached to form 3- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*.
[0397] Alternatively, R.sub.3 and R.sub.4 are independently C.sub.1-6 alkyl, alternatively C.sub.1-3 alkyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; [0398] or, R.sub.3 and R.sub.4 are taken together with the N atom to which they are attached to form 5- to 7-membered heterocyclyl, alternatively 4- to 6-membered heterocyclyl, more alternatively 5-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; [0399] or, R.sub.4 and R.sub.9 are taken together with the atoms to which they are attached to form 6-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*.
[0400] Alternatively, R* is independently H, halogen, cyano, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, -L.sub.b-OR.sub.b or -L.sub.b-NR.sub.bR′.sub.b; alternatively H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or —OR.sub.b; alternatively H, halogen, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; alternatively H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; alternatively independently H, Me or OH; more alternatively H or Me.
[0401] Alternatively, R.sub.3 is Me, —CH.sub.2CH.sub.3, —CH.sub.2CH.sub.2OH or —CH(CH.sub.3).sub.2, alternatively Me, —CH.sub.2CH.sub.3 or —CH(CH.sub.3).sub.2, more alternatively Me or —CH.sub.2CH.sub.3; [0402] R.sub.4 is Me; [0403] or, R.sub.3 and R.sub.4 are taken together with the N atom to which they are attached to form
##STR00026## alternatively
##STR00027## more alternatively
##STR00028## [0404] or, R.sub.4 and R.sub.9 are taken together with the atoms to which they are attached to form
##STR00029##
[0405] In a more specific embodiment, the present disclosure provides a compound of formula (IV) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-6 alkyl; alternatively C.sub.1-3 alkyl; more alternatively Me.
[0406] Alternatively, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 is optionally substituted with 1, 2, 3, 4 or 5 R*.
[0407] In a more specific embodiment, the present disclosure provides a compound of formula (IV) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0408] R.sub.1 is -G.sub.7-L.sub.1-G.sub.8-H, R.sub.2 is -G.sub.9-L.sub.2-G.sub.10-H, wherein, [0409] L.sub.1 and L.sub.2 are independently —(CRR′).sub.2—, —CH═CH—, —C≡C— or —NR″—; [0410] G.sub.7, G.sub.8, G.sub.9 and G.sub.10 are independently a chemical bond or C.sub.1-12 alkylene, which is optionally substituted with 1, 2, 3, 4, 5 or 6 R; [0411] G.sub.7 and G.sub.8 have a total length of 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms; [0412] G.sub.9 and G.sub.10 have a total length of 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms; [0413] 1, 2 or 3 methylenes in G.sub.7, G.sub.8, G.sub.9 or G.sub.10 are optionally and independently substituted with 1 R; [0414] R′ is independently H, C.sub.1-20 alkyl, -L.sub.a-OR.sub.a or -L.sub.a-NR.sub.aR′.sub.a.
[0415] Alternatively, L.sub.1 and L.sub.2 are independently —(CHR).sub.2—, —CH═CH—, —C≡C— or —NR″—; [0416] G.sub.7 and G.sub.9 are independently a chemical bond or C.sub.1-6 alkylene; [0417] G.sub.8 and G.sub.10 are independently C.sub.1-10 alkylene; [0418] G.sub.7 and G.sub.8 have a total length of 4, 5, 6, 7, 8, 9 or 10 carbon atoms; [0419] G.sub.9 and G.sub.10 have a total length of 4, 5, 6, 7, 8, 9 or 10 carbon atoms; [0420] 1, 2 or 3 methylenes in G.sub.7, G.sub.8, G.sub.9 or G.sub.10 are optionally and independently substituted with 1 R.
[0421] Alternatively, L.sub.1 and L.sub.2 are independently —(CHR).sub.2—, —CH═CH—, —C≡C— or —NR″—; [0422] G.sub.7 and G.sub.9 are independently a chemical bond or C.sub.1-5 alkylene, alternatively a chemical bond or C.sub.1-5 linear alkylene; [0423] G.sub.8 and G.sub.10 are independently C.sub.1-8 alkylene, alternatively C.sub.1-8 linear alkylene; [0424] G.sub.7 and G.sub.8 have a total length of 4, 5, 6, 7, 8, 9, 10 carbon atoms, alternatively 6, 7, 8, 9, 10 carbon atoms; [0425] G.sub.9 and G.sub.10 have a total length of 4, 5, 6, 7, 8, 9, 10 carbon atoms, alternatively 6, 7, 8, 9, 10 carbon atoms; [0426] 1 or 2 methylenes in G.sub.7, G.sub.8, G.sub.9 or G.sub.10 are optionally and independently substituted with 1 R.
[0427] Alternatively, L.sub.1 and L.sub.2 are independently —(CHR).sub.2—, —CH═CH—, —C≡C— or —NR″—; [0428] G.sub.7 and G.sub.9 are independently a chemical bond, —CH.sub.2—, —(CH.sub.2).sub.2—, —(CH.sub.2).sub.4— or —(CH.sub.2).sub.5—; [0429] G.sub.8 and G.sub.10 are independently —(CH.sub.2).sub.2—, —(CH.sub.2).sub.4—, —(CH.sub.2).sub.6—, —(CH.sub.2).sub.7— or —(CH.sub.2).sub.8—; [0430] G.sub.7 and G.sub.8 have a total length of 4, 5, 6, 7, 8, 9, 10 carbon atoms, alternatively 6, 7, 8, 9, 10 carbon atoms; [0431] G.sub.9 and G.sub.10 have a total length of 4, 5, 6, 7, 8, 9, 10 carbon atoms, alternatively 6, 7, 8, 9, 10 carbon atoms; [0432] 1 or 2 methylenes in G.sub.7, G.sub.8, G.sub.9 or G.sub.10 are optionally and independently substituted with 1 R.
[0433] Alternatively, R and R′ are independently H, C.sub.1-14 alkyl, -L.sub.a-OR.sub.a or -L.sub.a-NR.sub.aR′.sub.a; alternatively H or C.sub.1-10 alkyl; alternatively H or C.sub.1-8 alkyl; alternatively H or C.sub.1-7 alkyl; alternatively H or C.sub.1-6 alkyl; alternatively H or C.sub.1-8 linear alkyl; alternatively H or C.sub.1-7 linear alkyl; alternatively H or C.sub.1-6 linear alkyl; alternatively H, Me, —(CH.sub.2).sub.3CH.sub.3, —(CH.sub.2).sub.4CH.sub.3, —(CH.sub.2).sub.5CH.sub.3, —(CH.sub.2).sub.6CH.sub.3 or —(CH.sub.2).sub.7CH.sub.3; alternatively H, Me, —(CH.sub.2).sub.3CH.sub.3, —(CH.sub.2).sub.4CH.sub.3, —(CH.sub.2).sub.5CH.sub.3 or —(CH.sub.2).sub.6CH.sub.3; more alternatively H, Me, —(CH.sub.2).sub.3CH.sub.3, —(CH.sub.2).sub.4CH.sub.3 or —(CH.sub.2).sub.5CH.sub.3.
[0434] Alternatively, R″ is H or C.sub.1-14 alkyl; alternatively H or C.sub.1-10 alkyl; alternatively H or C.sub.7-9 alkyl; alternatively H or C.sub.7-9 linear alkyl; more alternatively —(CH.sub.2).sub.7CH.sub.3.
[0435] Alternatively, -G.sub.7-L.sub.1-G.sub.8-H or -G.sub.9-L.sub.2-G.sub.10-H is independently selected from the following groups: [0436] —(CH.sub.2).sub.5CH.sub.3, —(CH.sub.2).sub.6CH.sub.3, —(CH.sub.2).sub.7CH.sub.3, —(CH.sub.2).sub.8CH.sub.3, —(CH.sub.2).sub.9CH.sub.3, —(CH.sub.2).sub.10CH.sub.3, —(CH.sub.2).sub.11CH.sub.3, —CH.sub.2—C≡C—(CH.sub.2).sub.5CH.sub.3, —CH.sub.2—C≡C—(CH.sub.2).sub.6CH.sub.3, —(CH.sub.2).sub.2—C≡C—(CH.sub.2).sub.5CH.sub.3, —(CH.sub.2).sub.4—C≡C—(CH.sub.2).sub.3CH.sub.3, —CH.sub.2—CH═CH—(CH.sub.2).sub.5CH.sub.3, —CH.sub.2—CH═CH—(CH.sub.2).sub.6CH.sub.3, —(CH.sub.2).sub.2—CH═CH—(CH.sub.2).sub.5CH.sub.3, —(CH.sub.2).sub.4—CH═CH—(CH.sub.2).sub.3CH.sub.3, —(CH.sub.2).sub.5—CH═CH—CH.sub.2CH.sub.3,
##STR00030## ##STR00031##
[0437] In a more specific embodiment, the present disclosure provides a compound of formula (IV) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, which has the following structural formula:
##STR00032## [0438] wherein, [0439] a, a′, b and g are independently 0, 1, 2, 3, 4 or 5, a′ and b are not 0 at the same time; [0440] a′+g=0, 1, 2, 3, 4 or 5; [0441] c and e are independently 3, 4, 5, 6, 7, 8 or 9; [0442] d and fare independently 0, 1, 2, 3 or 4; [0443] c+d=3, 4, 5, 6, 7, 8 or 9, e+f=3, 4, 5, 6, 7, 8 or 9; [0444] methylenes in
##STR00033## or are optionally and independently substituted with 1, 2, 3, 4 or 5 C.sub.1-6 alkyl.
[0445] The remaining groups are defined in any one of the above.
[0446] In a more specific embodiment, the present disclosure provides a compound of formula (V) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0447] Q is selected from —C(O)O—, —O—, —SC(O)O—, —OC(O)NR.sub.b—, —NR.sub.bC(O)NR.sub.b—, —OC(O)S—, —OC(O)O—, —NR.sub.bC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR.sub.b—, —C(O)NR.sub.b—, —NR.sub.bC(O)—, —NR.sub.bC(O)S—, —SC(O)NR.sub.b—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR.sub.b—, —NR.sub.bC(S)O—, —S—S—, and —S(O).sub.0-2—; [0448] G.sub.6a and G.sub.6b are independently a chemical bond or C.sub.1-5 alkylene, which is optionally substituted with 1, 2, 3 or 4 R**; [0449] G.sub.6a and G.sub.6b have a total length of 0, 1, 2, 3, 4 or 5 carbon atoms; [0450] R.sub.9 and R** are independently H, C.sub.1-6 alkyl, -L.sub.c-OR.sub.c or -L.sub.c-NR.sub.cR′.sub.c; [0451] one of L.sub.3 and L.sub.5, or one of L.sub.4 and L.sub.6 is —(CR.sup.sR.sup.s′).sub.2—, —CH═CH—, —C≡C—, and the other is a chemical bond; [0452] G.sub.1a, G.sub.1b, G.sub.2a, G.sub.2b, G.sub.3a, G.sub.3b, G.sub.4a and G.sub.4b are independently a chemical bond or C.sub.1-7 alkylene, which is optionally substituted with 1, 2, 3, 4 or 5 R.sup.s; [0453] G.sub.1a, G.sub.1b, G.sub.2a and G.sub.2b have a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms; [0454] G.sub.3a, G.sub.3b, G.sub.4a and G.sub.4b have a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms; [0455] R.sub.3 and R.sub.4 are independently H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; [0456] or, R.sub.3 and R.sub.4 are taken together with the N atom to which they are attached to form 3- to 10-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; [0457] or, R.sub.4 and R.sub.9 are taken together with the atoms to which they are attached to form 3- to 10-membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 R*; [0458] R* is independently H, halogen, cyano, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, -L.sub.b-OR.sub.b or -L.sub.b-NR.sub.bR′.sub.b; [0459] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-6 alkyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; [0460] Y.sub.1 and Y.sub.2 are independently O, S or NR.sub.a; [0461] L.sub.1 and L.sub.2 are independently —(CRR′).sub.2—, —CH═CH—, —C≡C— or —NR″—; [0462] G.sub.7, G.sub.8, G.sub.9 and G.sub.10 are independently a chemical bond or C.sub.1-12 alkylene, which is optionally substituted with 1, 2, 3, 4, 5 or 6 R; [0463] G.sub.7 and G.sub.8 have a total length of 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms; [0464] G.sub.9 and G.sub.10 have a total length of 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms; [0465] 1, 2 or 3 methylenes in G.sub.7, G.sub.8, G.sub.9 or G.sub.10 are optionally and independently substituted with 1 R; [0466] R.sup.s and R.sup.s′ are independently H, C.sub.1-10 alkyl, -L.sub.d-OR.sub.d or -L.sub.d-NR.sub.dR′.sub.d; [0467] R and R′ are independently H, C.sub.1-14 alkyl, -L.sub.a-OR.sub.a or -L.sub.a-NR.sub.aR′.sub.a; [0468] R″ is independently H or C.sub.1-14 alkyl; [0469] L.sub.a is independently a chemical bond or C.sub.1-14 alkylene; [0470] L.sub.b is independently a chemical bond or C.sub.1-6 alkylene; [0471] L.sub.c is independently a chemical bond or C.sub.1-6 alkylene; [0472] L.sub.d is independently a chemical bond or C.sub.1-10 alkylene; [0473] R.sub.a and R′.sub.a are independently H, C.sub.1-14 alkyl, 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl; [0474] R.sub.b and R′.sub.b are independently H, C.sub.1-6 alkyl, 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl; [0475] R.sub.e and R′.sub.e are independently H or C.sub.1-6 alkyl; [0476] R.sub.d and R′.sub.a are independently H or C.sub.1-10 alkyl.
[0477] In a more specific embodiment, the present disclosure provides a compound of formula (V) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0478] Q is selected from —C(O)O—, —O—, —SC(O)O—, —OC(O)NH—, —NHC(O)NH—, —OC(O)S—, —OC(O)O—, —NHC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NH—, —C(O)NH—, —NHC(O)—, —NHC(O)S—, —SC(O)NH—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NH— and —NHC(S)O—; [0479] G.sub.6a is a chemical bond or C.sub.1-4 alkylene, which is optionally substituted with 1, 2, 3 or 4 R**; [0480] G.sub.6b is a chemical bond or C.sub.1-2 alkylene, which is optionally substituted with 1 or 2 R**; [0481] G.sub.6a and G.sub.6b have a total length of 0, 1, 2, 3 or 4 carbon atoms; [0482] R.sub.9 and R** are independently H or C.sub.1-6 alkyl; [0483] one of L.sub.3 and L.sub.5, or one of L.sub.4 and L.sub.6 is —(CHR.sup.s).sub.2—, —CH═CH— or —C≡C—, and the other is a chemical bond; [0484] G.sub.1a and G.sub.3a are independently a chemical bond or C.sub.1-7 alkylene; [0485] G.sub.1b and G.sub.3b are independently a chemical bond or C.sub.1-3 alkylene; [0486] G.sub.2a and G.sub.4a are independently a chemical bond or C.sub.1-3 alkylene; [0487] G.sub.2b and G.sub.4O are independently a chemical bond or C.sub.1-4 alkylene; [0488] G.sub.1a, G.sub.1b, G.sub.2a and G.sub.2b have a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms; [0489] G.sub.3a, G.sub.3b, G.sub.4a and G.sub.4O have a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms; [0490] R.sub.3 and R.sub.4 are independently H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, 3- to 7-membered cycloalkyl or 3- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; [0491] or, R.sub.3 and R.sub.4 are taken together with the N atom to which they are attached to form 3- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; [0492] or, R.sub.4 and R.sub.9 are taken together with the atoms to which they are attached to form 3- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; [0493] R* is independently H, halogen, cyano, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, -L.sub.b-OR.sub.b or -L.sub.b-NR.sub.bR′.sub.b; [0494] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-6 alkyl; [0495] Y.sub.1 and Y.sub.2 are independently O, S or NR.sub.a; [0496] L.sub.1 and L.sub.2 are independently —(CHR).sub.2—, —CH═CH—, —C≡C— or —NR″—; [0497] G.sub.7 and G.sub.9 are independently a chemical bond or C.sub.1-6 alkylene; [0498] G.sub.8 and G.sub.10 are independently C.sub.1-10 alkylene; [0499] G.sub.7 and G.sub.8 have a total length of 4, 5, 6, 7, 8, 9 or 10 carbon atoms; [0500] G.sub.9 and G.sub.10 have a total length of 4, 5, 6, 7, 8, 9 or 10 carbon atoms; [0501] 1, 2 or 3 methylenes in G.sub.7, G.sub.8, G.sub.9 or G.sub.10 are optionally and independently substituted with 1 R; [0502] R.sup.s is independently H or C.sub.1-6 alkyl; [0503] R is independently H or C.sub.1-10 alkyl; [0504] R″ is independently H or C.sub.1-10 alkyl; [0505] L.sub.b is independently a chemical bond or C.sub.1-6 alkylene; [0506] R.sub.a is independently H or C.sub.1-10 alkyl; [0507] R.sub.b and R′.sub.b are independently H or C.sub.1-6 alkyl.
[0508] In a more specific embodiment, the present disclosure provides a compound of formula (V) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0509] Q is —C(O)O—, —O—, —SC(O)O—, —OC(O)NH—, —NHC(O)NH—, —OC(O)S—, —OC(O)O— or —NHC(O)O—; [0510] G.sub.6a is a chemical bond or C.sub.1-4 alkylene, alternatively a chemical bond or C.sub.1-4 linear alkylene; [0511] G.sub.6b is a chemical bond or methylene; [0512] G.sub.6a and G.sub.6b have a total length of 0, 1, 2, 3 or 4 carbon atoms; [0513] R.sub.9 is H; [0514] one of L.sub.3 and L.sub.5, or one of L.sub.4 and L.sub.6 is —(CH.sub.2).sub.2—, —CH═CH—, or —C≡C—, and the other is a chemical bond; [0515] G.sub.1a and G.sub.3a are independently a chemical bond, —CH.sub.2—, —(CH.sub.2).sub.2—, —(CH.sub.2).sub.3—, —(CH.sub.2).sub.4—, —(CH.sub.2).sub.5— or —(CH.sub.2).sub.6—; [0516] G.sub.1b and G.sub.3b are a chemical bond; [0517] G.sub.2a and G.sub.4a are a chemical bond; [0518] G.sub.2b and G.sub.4b are independently a chemical bond, —CH.sub.2—, —(CH.sub.2).sub.2— or —(CH.sub.2).sub.3—; [0519] G.sub.1a, G.sub.1b, G.sub.2a and G.sub.2b have a total length of 1, 2, 3, 4, 5 or 6 carbon atoms; [0520] G.sub.3a, G.sub.3b, G.sub.4a and G.sub.4b have a total length of 1, 2, 3, 4, 5 or 6 carbon atoms; [0521] R.sub.3 and R.sub.4 are independently C.sub.1-6 alkyl, which is optionally substituted with 1, 2 or 3 R*; [0522] or, R.sub.3 and R.sub.4 are taken together with the N atom to which they are attached to form 5- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; [0523] or, R.sub.4 and R.sub.9 are taken together with the atoms to which they are attached to form 6-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; [0524] R* is independently H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or —OR.sub.b; [0525] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-3 alkyl; [0526] Y.sub.1 and Y.sub.2 are independently O, S or NR.sub.a, alternatively O or S; [0527] L.sub.1 and L.sub.2 are independently —(CHR).sub.2—, —CH═CH—, —C≡C— or —NR″—; [0528] G.sub.7 and G.sub.9 are independently a chemical bond or C.sub.1-5 alkylene, alternatively a chemical bond or C.sub.1-5 linear alkylene; [0529] G.sub.8 and G.sub.10 are independently C.sub.1-8 alkylene, alternatively C.sub.1-8 linear alkylene; [0530] G.sub.7 and G.sub.8 have a total length of 4, 5, 6, 7, 8, 9, 10 carbon atoms; [0531] G.sub.9 and G.sub.10 have a total length of 4, 5, 6, 7, 8, 9, 10 carbon atoms; [0532] 1 or 2 methylenes in G.sub.7, G.sub.8, G.sub.9 or G.sub.10 are optionally and independently substituted with 1 R; [0533] R is independently H or C.sub.1-8 alkyl, alternatively H or C.sub.1-8 linear alkyl; [0534] R″ is independently H or C.sub.7-9 alkyl, alternatively H or C.sub.7-9 linear alkyl; [0535] R.sub.a is independently H or C.sub.8-10 alkyl, alternatively H or C.sub.8-10 linear alkyl; [0536] R.sub.b is independently H or C.sub.1-6 alkyl, alternatively H.
[0537] In a more specific embodiment, the present disclosure provides a compound of formula (V) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0538] Q is —C(O)O—, —O—, —SC(O)O—, —OC(O)NH—, —NHC(O)NH—, —OC(O)S—, —OC(O)O— or —NHC(O)O—; [0539] G.sub.6a is a chemical bond, —CH.sub.2—, —(CH.sub.2).sub.2—, —(CH.sub.2).sub.3— or —(CH.sub.2).sub.4—; [0540] G.sub.6b is a chemical bond or methylene; [0541] G.sub.6a and G.sub.6b have a total length of 0, 1, 2, 3 or 4 carbon atoms; [0542] R.sub.9 is H; [0543] -G.sub.1a-L.sub.3-G.sub.1b- or -G.sub.3a-L.sub.4-G.sub.3b- is independently selected from the following groups: [0544] —(CH.sub.2).sub.2—, —(CH.sub.2).sub.3—, —(CH.sub.2).sub.4—, —(CH.sub.2).sub.5—, —(CH.sub.2).sub.6—, —(CH.sub.2).sub.7—, —(CH.sub.2).sub.8—, —(CH.sub.2).sub.3—CH═CH—, —(CH.sub.2).sub.3—C≡C—, —(CH.sub.2).sub.2—CH═CH— and —(CH.sub.2).sub.2—C≡C—; [0545] G.sub.2a-L.sub.5-G.sub.2b- or -G.sub.4a-L.sub.6-G.sub.4b- is independently selected from the following groups: [0546] a chemical bond, —CH.sub.2—, —(CH.sub.2).sub.2—, —(CH.sub.2).sub.3—, —CH═CH—CH.sub.2—, —C≡C— and —C—C—CH.sub.2—;
##STR00034## have a total length of 4, 5, 6, 7, 8 or 9 carbon atoms; [0547] R.sub.3 is Me, —CH.sub.2CH.sub.3, —CH.sub.2CH.sub.2OH or —CH(CH.sub.3).sub.2; [0548] R.sub.4 is Me; [0549] or, R.sub.3 and R.sub.4 are taken together with the N atom to which they are attached to form
##STR00035## [0550] or, R.sub.4 and R.sub.9 are taken together with the atoms to which they are attached to form
##STR00036## [0551] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are Me; [0552] Y.sub.1 and Y.sub.2 are independently O, S or NR.sub.a; [0553] L.sub.1 and L.sub.2 are independently —(CHR).sub.2—, —CH═CH—, —C≡C— or —NR″—; [0554] G.sub.7 and G.sub.9 are independently a chemical bond, —CH.sub.2—, —(CH.sub.2).sub.2—, —(CH.sub.2).sub.4— or —(CH.sub.2).sub.5—; [0555] G.sub.8 and G.sub.10 are independently —(CH.sub.2).sub.2—, —(CH.sub.2).sub.4—, —(CH.sub.2).sub.6—, —(CH.sub.2).sub.7— or —(CH.sub.2).sub.8—; [0556] G.sub.7 and G.sub.8 have a total length of 4, 5, 6, 7, 8, 9, 10 carbon atoms; [0557] G.sub.9 and G.sub.10 have a total length of 4, 5, 6, 7, 8, 9, 10 carbon atoms; [0558] 1 or 2 methylenes in G.sub.7, G.sub.8, G.sub.9 or G.sub.10 are optionally and independently substituted with 1 R; [0559] R is independently H, Me, —(CH.sub.2).sub.3CH.sub.3, —(CH.sub.2).sub.4CH.sub.3, —(CH.sub.2).sub.5CH.sub.3, —(CH.sub.2).sub.6CH.sub.3 or —(CH.sub.2).sub.7CH.sub.3; [0560] R″ is —(CH.sub.2).sub.7CH.sub.3; [0561] R.sub.a is independently H or —(CH.sub.2).sub.8CH.sub.3.
[0562] Alternatively,
##STR00037##
is independently selected from the following groups: [0563] —(CH.sub.2).sub.3—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.4—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.5—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.6—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.7—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.8—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.3—CH═CH—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.3—C—C—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.4—C(CH.sub.3).sub.2—CH.sub.2—, —(CH.sub.2).sub.3—C(CH.sub.3).sub.2—(CH.sub.2).sub.2—, —(CH.sub.2).sub.2—C(CH.sub.3).sub.2—(CH.sub.2).sub.3—, —(CH.sub.2).sub.2—CH═CH—C(CH.sub.3).sub.2—CH.sub.2—, —(CH.sub.2).sub.2—C(CH.sub.3).sub.2—C—C—CH.sub.2—, —(CH.sub.2).sub.2—C(CH.sub.3).sub.2—CH═CH—CH.sub.2—, —(CH.sub.2).sub.2—C—C—C(CH.sub.3).sub.2—CH.sub.2— and —(CH.sub.2).sub.3—C(CH.sub.3).sub.2—C≡C—; [0564] -G.sub.7-L.sub.1-G.sub.8-H or -G.sub.9-L.sub.2-G.sub.10-H is independently selected from the following groups: [0565] —(CH.sub.2).sub.5CH.sub.3, —(CH.sub.2).sub.6CH.sub.3, —(CH.sub.2).sub.7CH.sub.3, —(CH.sub.2).sub.8CH.sub.3, —(CH.sub.2).sub.9CH.sub.3, —(CH.sub.2).sub.10CH.sub.3, —(CH.sub.2).sub.11CH.sub.3, —CH.sub.2—C≡C—(CH.sub.2).sub.5CH.sub.3, —CH.sub.2—C≡C—(CH.sub.2).sub.6CH.sub.3, —(CH.sub.2).sub.2—C≡C—(CH.sub.2).sub.5CH.sub.3, —(CH.sub.2).sub.4—C≡C—(CH.sub.2).sub.3CH.sub.3, —CH.sub.2—CH═CH—(CH.sub.2).sub.5CH.sub.3, —CH.sub.2—CH═CH—(CH.sub.2).sub.6CH.sub.3, —(CH.sub.2).sub.2—CH═CH—(CH.sub.2).sub.5CH.sub.3, —(CH.sub.2).sub.4—CH═CH—(CH.sub.2).sub.3CH.sub.3, —(CH.sub.2).sub.5—CH═CH—CH.sub.2CH.sub.3,
##STR00038## ##STR00039##
[0566] In a more specific embodiment, the present disclosure provides a compound of formula (VI) or formula (VII) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0567] a, a′, b and g are independently 0, 1, 2, 3, 4 or 5, a′ and b are not 0 at the same time; [0568] a′+g=0, 1, 2, 3, 4 or 5; [0569] c and e are independently 3, 4, 5, 6, 7, 8 or 9; [0570] d and f are independently 0, 1, 2, 3 or 4; [0571] c+d=3, 4, 5, 6, 7, 8 or 9, e+f=3, 4, 5, 6, 7, 8 or 9; [0572] methylenes in
##STR00040## are optionally and independently substituted with 1, 2, 3, 4 or 5 C.sub.1-6 alkyl; [0573] R.sub.3 and R.sub.4 are independently H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; [0574] or, R.sub.3 and R.sub.4 are taken together with the N atom to which they are attached to form 3- to 10-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; [0575] R* is independently H, halogen, cyano, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, -L.sub.b-OR.sub.b or -L.sub.b-NR.sub.bR′.sub.b; [0576] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-6 alkyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; [0577] Y.sub.1 and Y.sub.2 are independently O, S or NR.sub.a; [0578] L.sub.1 and L.sub.2 are independently —(CRR′).sub.2—, —CH═CH—, —C≡C— or —NR″—; [0579] G.sub.7, G.sub.8, G.sub.9 and G.sub.10 are independently a chemical bond or C.sub.1-12 alkylene, which is optionally substituted with 1, 2, 3, 4, 5 or 6 R; [0580] G.sub.7 and G.sub.8 have a total length of 6, 7, 8, 9, 10, 11 or 12 carbon atoms; [0581] G.sub.9 and G.sub.10 have a total length of 6, 7, 8, 9, 10, 11 or 12 carbon atoms; [0582] 1, 2 or 3 methylenes in G.sub.7, G.sub.8, G.sub.9 or G.sub.10 are optionally and independently substituted with 1 R; [0583] R and R′ are independently H, C.sub.1-14 alkyl, -L.sub.a-OR.sub.a or -L.sub.a-NR.sub.aR′.sub.a; [0584] L.sub.a is independently a chemical bond or C.sub.1-14 alkylene; [0585] L.sub.b is independently a chemical bond or C.sub.1-6 alkylene; [0586] R.sub.a and R′.sub.a are independently H, C.sub.1-14 alkyl, 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl; [0587] R.sub.b and R′.sub.b are independently H, C.sub.1-6 alkyl, 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl; [0588] R″ is independently H or C.sub.1-14 alkyl.
[0589] In a more specific embodiment, the present disclosure provides a compound of formula (VI) or formula (VII) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0590] a is 0, 1, 2, 3 or 4, alternatively 1, 2, 3 or 4, alternatively 2, 3 or 4; [0591] a′ and b are independently 0, 1, 2, 3 or 4, alternatively 2; [0592] g is 0, 1 or 2, alternatively 0 or 1; [0593] a′+g=0, 1, 2, 3, 4 or 5, alternatively a′+g=2 or 3; [0594] c and e are independently 3, 4, 5 or 6; [0595] d and f are independently 0, 1 or 2; [0596] c+d=4, 5 or 6, e+f=4, 5 or 6; [0597] methylenes in
##STR00041## are optionally and independently substituted with 1, 2, 3, 4 or 5 C.sub.1-6 alkyl; [0598] methylenes in
##STR00042## are optionally and independently substituted with 1 or 2 C.sub.1-6 alkyl; [0599] R.sub.3 and R.sub.4 are independently C.sub.1-6 alkyl, which is optionally substituted with 1, 2 or 3 R*; [0600] R* is independently H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or —OR.sub.b; [0601] or, R.sub.3 and R.sub.4 are taken together with the N atom to which they are attached to form 3- to 7-membered heterocyclyl, alternatively 5-membered heterocyclyl, which is optionally substituted with 1, 2 or 3 R*; [0602] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-6 alkyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; [0603] Y.sub.1 and Y.sub.2 are independently O, S or NR.sub.a, alternatively O or S; [0604] L.sub.1 and L.sub.2 are independently —(CHR).sub.2—, —CH═CH—, —C≡C— or —NR″—, alternatively —(CHR).sub.2—, —CH═CH— or —C≡C—; [0605] G.sub.7 and G.sub.9 are independently a chemical bond or C.sub.1-6 alkylene; [0606] G.sub.8 and G.sub.10 are independently C.sub.1-10 alkylene; [0607] G.sub.7 and G.sub.8 have a total length of 6, 7, 8, 9 or 10 carbon atoms; [0608] G.sub.9 and G.sub.10 have a total length of 6, 7, 8, 9 or 10 carbon atoms; [0609] 1, 2 or 3 methylenes in G.sub.7, G.sub.8, G.sub.9 or G.sub.10 are optionally and independently substituted with 1 R, alternatively the methylene collected to Y.sub.1 and Y.sub.2 is not substituted with R; [0610] R is independently H or C.sub.1-8 alkyl; [0611] R″ is independently H or C.sub.1-10 alkyl; [0612] R.sub.a is independently H or C.sub.1-10 alkyl; [0613] R.sub.b is independently H or C.sub.1-6 alkyl, alternatively H.
[0614] In a more specific embodiment, the present disclosure provides a compound of formula (VI) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0615] a is 0, 1, 2, 3 or 4, alternatively 1, 2, 3 or 4, alternatively 2, 3 or 4; [0616] c and e are independently 3, 4, 5 or 6; [0617] d and f are independently 0, 1 or 2; [0618] c+d=4, 5 or 6, e+f=4, 5 or 6; [0619] R.sub.3 and R.sub.4 are independently C.sub.1-6 alkyl; [0620] or, R.sub.3 and R.sub.4 are taken together with the N atom to which they are attached to form 4- to 6-membered heterocyclyl, alternatively 5-membered heterocyclyl, which is optionally substituted with 1, 2 or 3 R*; [0621] R* is independently H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; [0622] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-6 alkyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*, alternatively C.sub.1-3 alkyl; [0623] Y.sub.1 and Y.sub.2 are independently O, S or NR.sub.a, alternatively O or S; [0624] L.sub.1 and L.sub.2 are independently —(CHR).sub.2—, —CH═CH—, —C≡C— or —NR″—, alternatively —(CHR).sub.2—, —CH═CH— or —C≡C—; [0625] G.sub.7 and G.sub.9 are independently a chemical bond or C.sub.1-5 alkylene, alternatively a chemical bond or C.sub.1-5 linear alkylene; [0626] G.sub.8 and G.sub.10 are independently C.sub.1-8 alkylene, alternatively C.sub.1-8 linear alkylene; [0627] G.sub.7 and G.sub.8 have a total length of 6, 7, 8, 9 or 10 carbon atoms; [0628] G.sub.9 and G.sub.10 have a total length of 6, 7, 8, 9 or 10 carbon atoms; [0629] 1, 2 or 3 methylenes in G.sub.7, G.sub.8, G.sub.9 or G.sub.10 are optionally and independently substituted with 1 R, alternatively the methylene collected to Y.sub.1 and Y.sub.2 is not substituted with R; [0630] R is independently H or C.sub.1-8 alkyl, alternatively H or C.sub.1-7 alkyl, alternatively H or C.sub.1-6 alkyl; [0631] R″ is independently H or C.sub.7-9 alkyl; [0632] R.sub.a is independently H or C.sub.8-10 alkyl.
[0633] Alternatively, R is independently H or C.sub.1-8 linear alkyl, alternatively H or C.sub.1-7 linear alkyl, alternatively H or C.sub.1-6 linear alkyl.
[0634] Alternatively, R″ is independently H or C.sub.7-9 linear alkyl.
[0635] Alternatively, R.sub.a is independently H or C.sub.8-10 linear alkyl.
[0636] In a more specific embodiment, the present disclosure provides a compound of formula (VI) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0637] a is selected from 0, 1, 2, 3 or 4, alternatively 1, 2, 3 or 4, alternatively 2, 3 or 4; [0638] c and e are independently 3, 4, 5 or 6; [0639] d and f are independently 0, 1 or 2; [0640] c+d=4, 5 or 6, e+f=4, 5 or 6; alternatively,
##STR00043## are independently —(CH.sub.2).sub.4—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.5—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.6—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.4—C(CH.sub.3).sub.2—CH.sub.2— or —(CH.sub.2).sub.3—C(CH.sub.3).sub.2—(CH.sub.2).sub.2—; [0641] R.sub.3 and R.sub.4 are independently C.sub.1-6 alkyl, alternatively Me; [0642] or, R.sub.3 and R.sub.4 are taken together with the N atom to which they are attached to form
##STR00044## alternatively
##STR00045## [0643] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are Me; [0644] Y.sub.1 and Y.sub.2 are independently O, S or NR.sub.a, alternatively O or S; [0645] L.sub.1 and L.sub.2 are independently —(CHR).sub.2—, —CH═CH—, —C≡C— or —NR″—, alternatively —(CHR).sub.2—, —CH═CH— or —C≡C—; [0646] G.sub.7 and G.sub.9 are independently a chemical bond, —CH.sub.2—, —(CH.sub.2).sub.2—, —(CH.sub.2).sub.4— or —(CH.sub.2).sub.5—; [0647] G.sub.8 and G.sub.10 are independently —(CH.sub.2).sub.2—, —(CH.sub.2).sub.4—, —(CH.sub.2).sub.6—, —(CH.sub.2).sub.7— or —(CH.sub.2).sub.8—; [0648] G.sub.7 and G.sub.8 have a total length of 6, 7, 8, 9, 10 carbon atoms; [0649] G.sub.9 and G.sub.10 have a total length of 6, 7, 8, 9, 10 carbon atoms; [0650] 1, 2 or 3 methylenes in G.sub.7, G.sub.8, G.sub.9 or G.sub.10 are optionally and independently substituted with 1 R, alternatively the methylene collected to Y.sub.1 and Y.sub.2 is not substituted with R; [0651] R is independently H, Me, —(CH.sub.2).sub.3CH.sub.3, —(CH.sub.2).sub.4CH.sub.3, —(CH.sub.2).sub.5CH.sub.3, —(CH.sub.2).sub.6CH.sub.3 or —(CH.sub.2).sub.7CH.sub.3, alternatively H, Me, —(CH.sub.2).sub.3CH.sub.3, —(CH.sub.2).sub.4CH.sub.3, —(CH.sub.2).sub.5CH.sub.3 or —(CH.sub.2).sub.6CH.sub.3, alternatively H, Me, —(CH.sub.2).sub.3CH.sub.3, —(CH.sub.2).sub.4CH.sub.3 or —(CH.sub.2).sub.5CH.sub.3; [0652] R.sub.a is independently H or —(CH.sub.2).sub.8CH.sub.3; [0653] R″ is —(CH.sub.2).sub.7CH.sub.3.
[0654] Alternatively, -G.sub.7-L.sub.1-G.sub.8-H or -G.sub.9-L.sub.2-G.sub.10-H is independently selected from the following groups: [0655] —(CH.sub.2).sub.7CH.sub.3, —(CH.sub.2).sub.8CH.sub.3, —(CH.sub.2).sub.9CH.sub.3, —(CH.sub.2).sub.11CH.sub.3, —CH.sub.2—C≡C—(CH.sub.2).sub.5CH.sub.3, —CH.sub.2—C≡C—(CH.sub.2).sub.6CH.sub.3, —(CH.sub.2).sub.2—C≡C—(CH.sub.2).sub.5CH.sub.3, —(CH.sub.2).sub.4—C≡C—(CH.sub.2).sub.3CH.sub.3, —CH.sub.2—CH═CH—(CH.sub.2).sub.6CH.sub.3, —(CH.sub.2).sub.2—CH═CH—(CH.sub.2).sub.5CH.sub.3, —(CH.sub.2).sub.4—CH═CH—(CH.sub.2).sub.3CH.sub.3, —(CH.sub.2).sub.5—CH═CH—CH.sub.2CH.sub.3
##STR00046## and alternatively is not
##STR00047## ##STR00048##
[0656] In a more specific embodiment, the present disclosure provides a compound of formula (VI) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0657] a is 2, 3 or 4; [0658] c and e are independently 3, 4, 5 or 6; [0659] d and f are independently 0, 1 or 2; [0660] c+d=4, 5 or 6, e+f=4, 5 or 6; [0661] R.sub.3 and R.sub.4 are independently C.sub.1-6 alkyl, alternatively C.sub.1-3 alkyl; [0662] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-6 alkyl, alternatively C.sub.1-3 alkyl; [0663] Y.sub.1 and Y.sub.2 are independently O or S; [0664] L.sub.1 and L.sub.2 are independently —(CHR).sub.2—, —CH═CH— or —C≡C—; [0665] G.sub.7 and G.sub.9 are independently C.sub.1-4 alkylene, alternatively C.sub.1-4 linear alkylene; [0666] G.sub.8 and G.sub.10 are independently C.sub.2-7 alkylene, alternatively C.sub.2-7 linear alkylene; [0667] G.sub.7 and G.sub.8 have a total length of 6, 7 or 8 carbon atoms; [0668] G.sub.9 and G.sub.10 have a total length of 6, 7 or 8 carbon atoms; [0669] 1, 2 or 3 methylenes in G.sub.7, G.sub.8, G.sub.9 or G.sub.10 are optionally and independently substituted with 1 R; [0670] R is independently H or C.sub.1-7 alkyl, alternatively H or C.sub.1-7 linear alkyl; [0671] provided that, when L.sub.1 is —C≡C—, then G.sub.7 is C.sub.1-2 alkylene, alternatively C.sub.1-2 linear alkylene; and when L.sub.2 is —C≡C—, then G.sub.9 is C.sub.1-2 alkylene, alternatively C.sub.1-2 linear alkylene.
[0672] Alternatively, the methylene collected to Y.sub.1 and Y.sub.2 is not substituted with R.
[0673] In a more specific embodiment, the present disclosure provides a compound of formula (VI) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0674] a is 2, 3 or 4; [0675] c and e are independently 3, 4, 5 or 6; [0676] d and f are independently 0, 1 or 2; [0677] c+d=4, 5 or 6, e+f=4, 5 or 6; alternatively,
##STR00049## are independently —(CH.sub.2).sub.4—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.5—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.6—C(CH.sub.3).sub.2—, —(CH.sub.2).sub.4—C(CH.sub.3).sub.2—CH.sub.2— or —(CH.sub.2).sub.3—C(CH.sub.3).sub.2—(CH.sub.2).sub.2—; [0678] R.sub.3 and R.sub.4 are independently C.sub.1-6 alkyl, alternatively Me; [0679] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-6 alkyl, alternatively Me; [0680] Y.sub.1 and Y.sub.2 are independently O or S; [0681] L.sub.1 and L.sub.2 are independently —(CHR).sub.2—, —CH═CH— or —C≡C—; [0682] G.sub.7 and G.sub.9 are independently —CH.sub.2—, —(CH.sub.2).sub.2— or —(CH.sub.2).sub.4—; [0683] G.sub.8 and G.sub.10 are independently —(CH.sub.2).sub.4—, —(CH.sub.2).sub.6— or —(CH.sub.2).sub.7—; [0684] G.sub.7 and G.sub.8 have a total length of 6, 7 or 8 carbon atoms; [0685] G.sub.9 and G.sub.10 have a total length of 6, 7 or 8 carbon atoms; [0686] 1, 2 or 3 methylenes in G.sub.7, G.sub.8, G.sub.9 or G.sub.10 are optionally and independently substituted with 1 R; [0687] R is independently H, Me, —(CH.sub.2).sub.3CH.sub.3, —(CH.sub.2).sub.4CH.sub.3, —(CH.sub.2).sub.5CH.sub.3 or —(CH.sub.2).sub.6CH.sub.3; [0688] provided that, when L.sub.1 is —C≡C—, then G.sub.7 is —CH.sub.2— or —(CH.sub.2).sub.2—, and when L.sub.2 is —C≡C—, then G.sub.9 is —CH.sub.2— or —(CH.sub.2).sub.2—; [0689] alternatively, -G.sub.7-L.sub.1-G.sub.8-H or -G.sub.9-L.sub.2-G.sub.10-H is independently selected from the following groups: [0690] —(CH.sub.2).sub.7CH.sub.3, —(CH.sub.2).sub.8CH.sub.3, —(CH.sub.2).sub.9CH.sub.3, —CH.sub.2—C≡C—(CH.sub.2).sub.5CH.sub.3, —CH.sub.2—C≡C—(CH.sub.2).sub.6CH.sub.3, —(CH.sub.2).sub.2—C≡C—(CH.sub.2).sub.5CH.sub.3, —CH.sub.2—CH═CH—(CH.sub.2).sub.6CH.sub.3, —(CH.sub.2).sub.2—CH═CH—(CH.sub.2).sub.5CH.sub.3, —(CH.sub.2).sub.4—CH═CH—(CH.sub.2).sub.3CH.sub.3,
##STR00050##
[0691] In a more specific embodiment, the present disclosure provides a compound of formula (VI) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0692] a is 2, 3 or 4, alternatively 2 or 3; [0693] c and e are independently 4, 5 or 6; [0694] d and f are 0; [0695] R.sub.3 and R.sub.4 are independently C.sub.1-6 alkyl, alternatively C.sub.1-3 alkyl; [0696] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-6 alkyl, alternatively C.sub.1-3 alkyl; [0697] Y.sub.1 and Y.sub.2 are O; [0698] L.sub.1 and L.sub.2 are independently —(CHR).sub.2— or —CH═CH—; [0699] G.sub.7 and G.sub.9 are independently —CH.sub.2— or —CH.sub.2CHR—; [0700] G.sub.8 and G.sub.10 are independently —(CH.sub.2).sub.6— or —(CH.sub.2).sub.7—; [0701] G.sub.7 and G.sub.8 have a total length of 7 or 8 carbon atoms; [0702] G.sub.9 and G.sub.10 have a total length of 7 or 8 carbon atoms; [0703] 1, 2 or 3 methylenes in G.sub.8 or G.sub.10 are optionally and independently substituted with 1 R; [0704] R is independently H or C.sub.4-6 alkyl, alternatively H or C.sub.5 alkyl; [0705] alternatively -G.sub.7-L.sub.1-G.sub.8-H and -G.sub.9-L.sub.2-G.sub.10-H are not —(CH.sub.2).sub.9CH.sub.3 at the same time.
[0706] Alternatively, R is independently H or C.sub.4-6 linear alkyl, alternatively H or C.sub.5 linear alkyl.
[0707] In a more specific embodiment, the present disclosure provides a compound of formula (VI) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0708] a is 2, 3 or 4, alternatively 2 or 3; [0709] c and e are independently 4, 5 or 6; [0710] d and f are 0; [0711] R.sub.3 and R.sub.4 are Me; [0712] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are Me; [0713] Y.sub.1 and Y.sub.2 are O; [0714] -G.sub.7-L.sub.1-G.sub.8-H and -G.sub.9-L.sub.2-G.sub.10-H are independently selected from the following groups: [0715] —(CH.sub.2).sub.8CH.sub.3, —(CH.sub.2)CH.sub.3, —CH.sub.2—CH═CH—(CH.sub.2).sub.6CH.sub.3, —(CH.sub.2).sub.2—CH═CH—(CH.sub.2).sub.5CH.sub.3,
##STR00051## alternatively —(CH.sub.2).sub.8CH.sub.3—(CH.sub.2).sub.9CH.sub.3, —CH.sub.2—CH═CH—(CH.sub.2).sub.6CH.sub.3, —(CH.sub.2).sub.2—CH═CH—(CH.sub.2).sub.5CH.sub.3 and
##STR00052## alternatively [0716] -G.sub.7-L.sub.1-G.sub.8-H and -G.sub.9-L.sub.2-G.sub.10-H are not —(CH.sub.2).sub.9CH.sub.3 at the same time.
[0717] In a more specific embodiment, the present disclosure provides a compound of formula (VI) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0718] a is 3; [0719] c and e are independently 5 or 6, alternatively 6; [0720] d and f are 0; [0721] R.sub.3 and R.sub.4 are independently C.sub.1-3 alkyl; [0722] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-3 alkyl; [0723] Y.sub.1 and Y.sub.2 are O; [0724] L.sub.1 and L.sub.2 are independently —(CHR).sub.2— or —CH═CH, alternatively —(CHR).sub.2—; [0725] G.sub.7 and G.sub.9 are independently —CH.sub.2— or —CH.sub.2CHR—; [0726] G.sub.8 and G.sub.10 are independently —(CH.sub.2).sub.6— or —(CH.sub.2).sub.7—; [0727] G.sub.7 and G.sub.8 have a total length of 7 or 8 carbon atoms, alternatively 7 carbon atoms; [0728] G.sub.9 and G.sub.10 have a total length of 7 or 8 carbon atoms, alternatively 7 carbon atoms; [0729] 1, 2 or 3 methylenes in G.sub.8 or G.sub.10 are optionally and independently substituted with 1 R; [0730] R is independently H or C.sub.4-6 alkyl, alternatively H or C.sub.5 alkyl.
[0731] Alternatively, R is independently H or C.sub.4-6 linear alkyl, alternatively H or C.sub.5 linear alkyl.
[0732] In a more specific embodiment, the present disclosure provides a compound of formula (VI) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0733] a is 3; [0734] c and e are 6; [0735] d and f are 0; [0736] R.sub.3 and R.sub.4 are Me; [0737] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are Me; [0738] Y.sub.1 and Y.sub.2 are O; [0739] -G.sub.7-L.sub.1-G.sub.8-H and -G.sub.9-L.sub.2-G.sub.10-H are independently selected from the following groups: [0740] —(CH.sub.2).sub.8CH.sub.3,
##STR00053## alternatively —(CH.sub.2).sub.8CH.sub.3 and
##STR00054##
[0741] In a more specific embodiment, the present disclosure provides a compound of formula (VI) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0742] a is 2 or 3, alternatively 2; [0743] c and e are independently 4, 5 or 6, alternatively 5; [0744] d and f are 0; [0745] R.sub.3 and R.sub.4 are independently C.sub.1-3 alkyl; [0746] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-3 alkyl; [0747] one of Y.sub.1 and Y.sub.2 is O, and the other is S; [0748] L.sub.1 and L.sub.2 are independently —(CHR).sub.2— or —CH═CH, alternatively —(CHR).sub.2—; [0749] G.sub.7 and G.sub.9 are independently —CH.sub.2— or —CH.sub.2CHR—; [0750] G.sub.8 and G.sub.10 are independently —(CH.sub.2).sub.5— or —(CH.sub.2).sub.6—; [0751] G.sub.7 and G.sub.8 have a total length of 7 carbon atoms; [0752] G.sub.9 and G.sub.10 have a total length of 7 carbon atoms; [0753] 1, 2 or 3 methylenes in G.sub.8 or G.sub.10 are optionally and independently substituted with 1 R; [0754] R is independently H or C.sub.4-6 alkyl, alternatively H or C.sub.5 alkyl.
[0755] Alternatively, R is independently H or C.sub.4-6 linear alkyl, alternatively H or C.sub.5 linear alkyl.
[0756] In a more specific embodiment, the present disclosure provides a compound of formula (VI) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0757] a is 2; [0758] c and e are 5; [0759] d and f are 0; [0760] R.sub.3 and R.sub.4 are Me; [0761] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are Me; [0762] one of Y.sub.1 and Y.sub.2 is O, and the other is S; [0763] -G.sub.7-L.sub.1-G.sub.8-H and -G.sub.9-L.sub.2-G.sub.10-H are independently selected from the following groups. [0764] —(CH.sub.2).sub.8CH.sub.3,
##STR00055## alternatively —(CH.sub.2).sub.8CH.sub.3.
[0765] In a more specific embodiment, the present disclosure provides a compound of formula (VI) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0766] a are 2; [0767] c and e are independently 4, 5 or 6, alternatively 5; [0768] d and f are 0; [0769] R.sub.3 and R.sub.4 are independently C.sub.1-6 alkyl, alternatively C.sub.1-3 alkyl; [0770] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-6 alkyl, alternatively C.sub.1-3 alkyl; [0771] Y.sub.1 and Y.sub.2 are independently O or S; [0772] one of L.sub.1 and L.sub.2 is —C≡C—, the other is —(CHR).sub.2—, or both of L.sub.1 and L.sub.2 are —C≡C—; alternatively one of L.sub.1 and L.sub.2 is —C≡C—, the other is —(CHR).sub.2—; [0773] G.sub.7 and G.sub.9 are —CH.sub.2—; [0774] G.sub.8 and G.sub.10 are independently —(CH.sub.2).sub.6— or —(CH.sub.2).sub.7—; [0775] 1 methylene in G.sub.8 or G.sub.10 optionally and independently substituted with 1 R, alternatively G.sub.8 and G.sub.10 are independently —CHR—(CH.sub.2).sub.5—, —CHR—(CH.sub.2).sub.6—, —CH.sub.2—CHR—(CH.sub.2).sub.4— or —(CH.sub.2).sub.2—CHR—(CH.sub.2).sub.4—; [0776] R is independently H or C.sub.4-6 alkyl, alternatively H or C.sub.5 alkyl; [0777] provided that, only one of the -G.sub.7-L.sub.1-G.sub.8-H and -G.sub.9-L.sub.2-G.sub.10-H is substituted with one non-hydrogen R substituent and the other is unsubstituted.
[0778] Alternatively, R is independently H or C.sub.4-6 linear alkyl, alternatively H or C.sub.5 linear alkyl.
[0779] In a more specific embodiment, the present disclosure provides a compound of formula (VI) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0780] a is 2; [0781] c and e are 5; [0782] d and f are 0; [0783] R.sub.3 and R.sub.4 are Me; [0784] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are Me; [0785] Y.sub.1 and Y.sub.2 are independently O or S; [0786] -G.sub.7-L.sub.1-G.sub.8-H and -G.sub.9-L.sub.2-G.sub.10-H are independently selected from the following groups:
[0787] —(CH.sub.2).sub.8CH.sub.3, —(CH.sub.2).sub.9CH.sub.3, —CH.sub.2—C≡C—(CH.sub.2).sub.6CH.sub.3,
##STR00056## [0788] provided that, at least one of -G.sub.7-L.sub.1-G.sub.8-H and -G.sub.9-L.sub.2-G.sub.10-H comprises alkynyl, and one of the two has a substituent while the other one has no substituent.
[0789] In a more specific embodiment, the present disclosure provides a compound of formula (VI) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0790] a is 2; [0791] c and e are independently 4, 5 or 6, alternatively 5; [0792] d and f are 0; [0793] R.sub.3 and R.sub.4 are independently C.sub.1-3 alkyl, alternatively Me; [0794] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-3 alkyl, alternatively Me; [0795] Y.sub.1 and Y.sub.2 are independently O or S, alternatively 0; [0796] both of L.sub.1 and L.sub.2 are —C≡C—; [0797] G.sub.7 and G.sub.9 are —CH.sub.2—; [0798] G.sub.8 and G.sub.10 are independently —(CH.sub.2).sub.6— or —(CH.sub.2).sub.7—, alternatively —(CH.sub.2).sub.7—.
[0799] In a more specific embodiment, the present disclosure provides a compound of formula (VI) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0800] a is 2; [0801] c and e are 3; [0802] d and f are 2; [0803] R.sub.3 and R.sub.4 are independently C.sub.1-3 alkyl, alternatively Me; [0804] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-3 alkyl; [0805] Y.sub.1 and Y.sub.2 are independently O or S, alternatively 0; [0806] L.sub.1 and L.sub.2 are —(CHR).sub.2—; [0807] G.sub.7 and G.sub.9 are independently —CH.sub.2— or —CH.sub.2CHR—; [0808] G.sub.8 and G.sub.10 are independently —(CH.sub.2).sub.5—, —(CH.sub.2).sub.6— or —(CH.sub.2).sub.7—; [0809] G.sub.7 and G.sub.8 have a total length of 6, 7 or 8 carbon atoms, alternatively 7 carbon atoms; [0810] G.sub.9 and G.sub.10 have a total length of 6, 7 or 8 carbon atoms, alternatively 7 carbon atoms; [0811] 1, 2 or 3 methylenes in G.sub.8 or G.sub.10 are optionally and independently substituted with 1 R; [0812] R is independently H or C.sub.1-7 alkyl, alternatively H or C.sub.1-6 alkyl, alternatively Me.
[0813] Alternatively, R is independently H or C.sub.1-7 linear alkyl, alternatively H or C.sub.1-6 linear alkyl, alternatively Me.
[0814] In a more specific embodiment, the present disclosure provides a compound of formula (VI) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0815] a is 2; [0816] c and e are 3; [0817] d and f are 2; [0818] R.sub.3 and R.sub.4 are Me; [0819] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are Me; [0820] Y.sub.1 and Y.sub.2 are independently O or S, alternatively 0; [0821] -G.sub.7-L.sub.1-G.sub.8-H and -G.sub.9-L.sub.2-G.sub.10-H are independently selected from the following groups:
##STR00057## [0822] alternatively
##STR00058## [0823] alternatively
##STR00059##
[0824] In a more specific embodiment, the present disclosure provides a compound of formula (VI) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0825] a is 2; [0826] c and e are 4, 5, or 6, alternatively 5; [0827] d and f are 0; [0828] R.sub.3 and R.sub.4 are independently C.sub.1-6 alkyl, alternatively C.sub.1-3 alkyl; [0829] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-6 alkyl, alternatively C.sub.1-3 alkyl; [0830] Y.sub.1 and Y.sub.2 are S; [0831] L.sub.1 and L.sub.2 are —(CHR).sub.2—; [0832] G.sub.7 and G.sub.9 are independently —CH.sub.2— or —CH.sub.2CHR—; [0833] G.sub.8 and G.sub.10 are independently —(CH.sub.2).sub.5—, —(CH.sub.2).sub.6— or —(CH.sub.2).sub.7—; [0834] G.sub.7 and G.sub.8 have a total length of 7 or 8 carbon atoms, alternatively 8 carbon atoms; [0835] G.sub.9 and G.sub.10 have a total length of 7 or 8 carbon atoms, alternatively 8 carbon atoms; [0836] 1, 2 or 3 methylenes in G.sub.8 or G.sub.10 are optionally and independently substituted with 1 R; [0837] R is independently H or C.sub.4-6 alkyl, alternatively H or C.sub.5 alkyl.
[0838] Alternatively, R is independently H or C.sub.4-6 linear alkyl, alternatively H or C.sub.5 linear alkyl.
[0839] In a more specific embodiment, the present disclosure provides a compound of formula (VI) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0840] a is 2; [0841] c and e are 5; [0842] d and f are 0; [0843] R.sub.3 and R.sub.4 are independently Me; [0844] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently Me; [0845] Y.sub.1 and Y.sub.2 are S; [0846] -G.sub.7-L.sub.1-G.sub.8-H and -G.sub.9-L.sub.2-G.sub.10-H are independently selected from the following. [0847] —(CH.sub.2).sub.8CH.sub.3, —(CH.sub.2).sub.9CH.sub.3,
##STR00060## alternatively —(CH.sub.2).sub.8CH.sub.3 or —(CH.sub.2).sub.9CH.sub.3, alternatively —(CH.sub.2).sub.9CH.sub.3.
[0848] In a more specific embodiment, the present disclosure provides a compound of formula (VII) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0849] a′ and b are 2; [0850] g is 0 or 1; [0851] c and e are 5; [0852] d and f are 0; [0853] R.sub.3 is C.sub.1-6 alkyl, which is optionally substituted with 1, 2 or 3 R*; [0854] R* is independently H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or —OR.sub.b, alternatively H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; [0855] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-3 alkyl; [0856] Y.sub.1 and Y.sub.2 are independently O or S; [0857] L.sub.1 and L.sub.2 are —(CHR).sub.2—; [0858] G.sub.7 and G.sub.9 are independently —CH.sub.2— or —CH.sub.2CHR—; [0859] G.sub.8 and G.sub.10 are independently —(CH.sub.2).sub.5—, —(CH.sub.2).sub.6— or —(CH.sub.2).sub.7—; [0860] G.sub.7 and G.sub.8 have a total length of 6, 7 or 8 carbon atoms; [0861] G.sub.9 and G.sub.10 have a total length of 6, 7 or 8 carbon atoms; [0862] 1, 2 or 3 methylenes in G.sub.8 or G.sub.10 are optionally and independently substituted with 1 R; [0863] R is independently H or C.sub.4-6 alkyl; [0864] R.sub.b is independently H or C.sub.1-6 alkyl, alternatively H.
[0865] Alternatively, R is independently H or C.sub.4-6 linear alkyl.
[0866] In a more specific embodiment, the present disclosure provides a compound of formula (VII) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0867] a′ and b are 2; [0868] g is 0 or 1; [0869] c and e are 5; [0870] d and f are 0; [0871] R.sub.3 is Me, —CH.sub.2CH.sub.3, —CH.sub.2CH.sub.2OH or —CH(CH.sub.3).sub.2, alternatively Me, —CH.sub.2CH.sub.3 or —CH(CH.sub.3).sub.2; [0872] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently Me; [0873] Y.sub.1 and Y.sub.2 are independently O or S; [0874] -G.sub.7-L.sub.1-G.sub.8-H or -G.sub.9-L.sub.2-G.sub.10-H is independently selected from the following groups: [0875] —(CH.sub.2).sub.7CH.sub.3, —(CH.sub.2).sub.8CH.sub.3, —(CH.sub.2).sub.9CH.sub.3,
##STR00061## alternatively —(CH.sub.2).sub.7CH.sub.3, —(CH.sub.2).sub.8CH.sub.3, —(CH.sub.2).sub.9CH.sub.3 and
##STR00062##
[0876] In a more specific embodiment, the present disclosure provides a compound of formula (VII) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0877] R.sub.3 is Me or —CH.sub.2CH.sub.3, alternatively Me; [0878] Both of Y.sub.1 and Y.sub.2 are O; [0879] G.sub.7 and G.sub.8 have a total length of 6 or 7 carbon atoms, alternatively 7 carbon atoms; [0880] G.sub.9 and G.sub.10 have a total length of 6 or 7 carbon atoms, alternatively 7 carbon atoms.
[0881] In a more specific embodiment, the present disclosure provides a compound of formula (VII) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0882] a′ and b are 2; [0883] g is 0 or 1; [0884] c and e are 5; [0885] d and f are 0; [0886] R.sub.3 is Me or —CH.sub.2CH.sub.3, alternatively Me; [0887] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently Me; [0888] both of Y.sub.1 and Y.sub.2 are O; [0889] -G.sub.7-L.sub.1-G.sub.8-H or -G.sub.9-L.sub.2-G.sub.10-H is independently selected from the following groups: [0890] —(CH.sub.2).sub.7CH.sub.3, —(CH.sub.2).sub.8CH.sub.3,
##STR00063## alternatively —(CH.sub.2).sub.7CH.sub.3, —(CH.sub.2).sub.8CH.sub.3 and
##STR00064## alternatively is not —(CH.sub.2).sub.7CH.sub.3.
[0891] In a more specific embodiment, the present disclosure provides a compound of formula (VII) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0892] R.sub.3 is Me or —CH.sub.2CH.sub.3; [0893] Y.sub.1 and Y.sub.2 are independently O or S, where Y.sub.1 and Y.sub.2 are not O at the same time; [0894] G.sub.7 and G.sub.8 have a total length of 6, 7 or 8 carbon atoms; [0895] G.sub.9 and G.sub.10 have a total length of 6, 7 or 8 carbon atoms.
[0896] In a more specific embodiment, the present disclosure provides a compound of formula (VII) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0897] g is 0 or 1, alternatively 1; [0898] R.sub.3 is Me or —CH.sub.2CH.sub.3, alternatively Me; [0899] one of Y.sub.1 and Y.sub.2 is O, and the other is S; [0900] G.sub.7 and G.sub.8 have a total length of 7 carbon atoms; [0901] G.sub.9 and G.sub.10 have a total length of 7 carbon atoms.
[0902] In a more specific embodiment, the present disclosure provides a compound of formula (VII) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0903] a′ and b are 2; [0904] g is 0 or 1, alternatively 1; [0905] c and e are 5; [0906] d and f are 0; [0907] R.sub.3 is Me or —CH.sub.2CH.sub.3, alternatively Me; [0908] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently Me; [0909] one of Y.sub.1 and Y.sub.2 is O, and the other is S; [0910] -G.sub.7-L.sub.1-G.sub.8-H or -G.sub.9-L.sub.2-G.sub.10-H is independently selected from the following groups: [0911] —(CH.sub.2).sub.8CH.sub.3
##STR00065## alternatively —(CH.sub.2).sub.8CH.sub.3 and
##STR00066##
[0912] In a more specific embodiment, the present disclosure provides a compound of formula (VII) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0913] g is 0 or 1, alternatively 0; [0914] R.sub.3 is Me or —CH.sub.2CH.sub.3; [0915] both of Y.sub.1 and Y.sub.2 are S; [0916] G.sub.7 and G.sub.8 have a total length of 7 or 8 carbon atoms; [0917] G.sub.9 and G.sub.10 have a total length of 7 or 8 carbon atoms.
[0918] In a more specific embodiment, the present disclosure provides a compound of formula (VII) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, [0919] a′ and b are 2; [0920] g is 0 or 1, alternatively 0; [0921] c and e are 5; [0922] d and f are 0; [0923] R.sub.3 is Me or —CH.sub.2CH.sub.3; [0924] R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently Me; [0925] both of Y.sub.1 and Y.sub.2 are S; [0926] -G.sub.7-L.sub.1-G.sub.8-H or -G.sub.9-L.sub.2-G.sub.10-H is independently selected from the following groups: [0927] —(CH.sub.2).sub.8CH.sub.3, —(CH.sub.2).sub.9CH.sub.3,
##STR00067## alternatively —(CH.sub.2).sub.8CH.sub.3, —(CH.sub.2).sub.9CH.sub.3 and
##STR00068##
[0928] In a more specific embodiment, the present disclosure provides a compound of formula (IV) described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, the compound is selected from the following:
##STR00069## ##STR00070## ##STR00071## ##STR00072## ##STR00073## ##STR00074## ##STR00075## ##STR00076## ##STR00077## ##STR00078## ##STR00079## ##STR00080## ##STR00081## ##STR00082## ##STR00083## ##STR00084## ##STR00085## ##STR00086## ##STR00087## ##STR00088## ##STR00089## ##STR00090## ##STR00091## ##STR00092## ##STR00093## ##STR00094## ##STR00095## ##STR00096## ##STR00097## ##STR00098## ##STR00099##
[0929] In a more specific embodiment, the present disclosure provides a nanoparticle composition, comprising a lipid component, and optionally comprising a load; wherein, the lipid component contains a compound of the present disclosure.
[0930] Alternatively, the lipid component comprises components in the following molar percentages: [0931] any of the above compounds of the present disclosure: 50 mol %; [0932] neutral lipids: 10 mol %; [0933] structure lipids: 38.5 mol %; [0934] polymer lipids: 1.5 mol %.
[0935] In a more specific embodiment, the present disclosure provides the nanoparticle composition described above, wherein, the neutral lipids are selected from one or more of DSPC, DMPC, DOPC, DPPC, POPC, DOPE, DMPE, POPE and DPPE, alternatively DSPC and/or DOPE.
[0936] In a more specific embodiment, the present disclosure provides the nanoparticle composition described above, wherein, the structure lipids are selected from one or more of cholesterol, sitosterol, coprosterol, fucosterol, brassicasterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, avenasterol, ergocalciferol and campestero, alternatively cholesterol and/or β-sitosterol, more alternatively cholesterol.
[0937] In a more specific embodiment, the present disclosure provides the nanoparticle composition described above, wherein, the polymer lipids are polyethylene glycolated lipids.
[0938] Optionally, the polyethylene glycolated lipids are selected from one or more of: PEG modified phosphatidylethanolamine, PEG modified phosphatidic acid, PEG modified ceramide, PEG modified dialkyl amine, PEG modified diacylglycerol, and PEG modified dialkylglycerol.
[0939] Alternatively, the polyethylene glycolated lipids contain a PEG moiety of about 1000 Da to about 20 kDa, alternatively a PEG moiety of about 1000 Da to about 5000 Da.
[0940] Alternatively, the polyethylene glycolated lipids are selected from one or more of DMPE-PEG1000, DPPE-PEG1000, DSPE-PEG1000, DOPE-PEG1000, DMG-PEG2000, Ceramide-PEG2000, DMPE-PEG2000, DPPE-PEG2000, DSPE-PEG2000, Azido-PEG2000, DSPE-PEG2000-Mannose, Ceramide-PEG5000, and DSPE-PEG5000, alternatively DMG-PEG2000.
[0941] In a more specific embodiment, the present disclosure provides the nanoparticle composition described above, wherein, the load is one or more of therapeutic, prophylactic or diagnostic agents; [0942] alternatively, the therapeutic, prophylactic or diagnostic agent is a nucleic acid; [0943] alternatively, the nucleic acid is one or more of ASO, RNA or DNA; [0944] alternatively, the RNA is selected from one or more of interfering RNA (RNAi), small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), modified messenger RNA (mmRNA), long non-coding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), multimeric coding nucleic acid (MCNA), polymeric coding nucleic acid (PCNA), guide RNA (gRNA), CRISPRRNA (crRNA) and nucleases, alternatively mRNA, more alternatively, modified mRNA.
[0945] In a more specific embodiment, the present disclosure also provides a lipid compound, a pharmaceutically acceptable salt or stereoisomer thereof, the lipid compound having the structure of general formula (I):
##STR00100## [0946] wherein, [0947] G.sub.1, G.sub.2, G.sub.3 or G.sub.4 is each independently a bond, C.sub.1-20 alkylene, C.sub.2-20 alkenylene or C.sub.2-20 alkynylene; [0948] G.sub.5 or G.sub.6 is each independently a bond or C.sub.1-8 alkylene; [0949] M.sub.1 or M.sub.2 is each independently biodegradable groups; [0950] Q is a bond or biodegradable groups; [0951] R.sub.1 or R.sub.2 is each independently C.sub.4-28 alkyl, C.sub.4-28 alkenyl or C.sub.4-28 alkynyl; [0952] R.sub.3 or R.sub.4 is each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; [0953] or, R.sub.3 and R.sub.4 are taken together with the N atom to which they are attached to form 3- to 14-membered heterocyclyl; [0954] R.sub.5, R.sub.6, R.sub.7 or R.sub.8 is each independently C.sub.1-8 alkyl; [0955] each of the alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, aryl or heteroaryl is each independently and optionally further substituted.
[0956] Further, disclosed herein is the lipid compound, which has the structure of general formula (I).
##STR00101## [0957] wherein, [0958] G.sub.1, G.sub.2, G.sub.3 or G.sub.4 is each independently a bond, C.sub.1-20 alkylene, C.sub.2-20 alkenylene or C.sub.2-20 alkynylene; the C.sub.1-20 alkylene, C.sub.2-20 alkenylene or C.sub.2-20 alkynylene is optionally substituted with one or more substituents selected from H, OH, alkyl, hydroxyalkyl, alkoxy, amino, alkylamino, and dialkylamino; [0959] G.sub.5 or G.sub.6 is each independently a bond or C.sub.1-6 alkylene; the C.sub.1-6 alkylene is optionally substituted with one or more substituents selected from H, OH, alkyl, hydroxyalkyl, alkoxy, amino, alkylamino, and dialkylamino; [0960] M.sub.1 or M.sub.2 is each independently selected from —OC(O)—, —C(O)O—, —SC(O)—, —C(O)S—, —O—, —OC(O)O—, —SC(O)O—, —OC(O)S—, —NR.sub.a—, —C(O)NR.sub.a—, —NR.sub.aC(O)—, —NR.sub.aC(O)O—, —OC(O)NR.sub.a—, —NR.sub.aC(O)S—, —SC(O)NR.sub.a—, —NR.sub.aC(O)NR.sub.a—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR.sub.a—, —NR.sub.aC(S)O—, —S—S— and —S(O).sub.m—; [0961] Q is selected from a bond, —OC(O)—, —C(O)O—, —SC(O)—, —C(O)S—, —O—, —OC(O)O—, —SC(O)O—, —OC(O)S—, —NR.sub.b—, —C(O)NR.sub.b—, —NR.sub.bC(O)—, —NR.sub.bC(O)O—, —OC(O)NR.sub.b—, —NR.sub.bC(O)S—, —SC(O)NR.sub.b—, —NR.sub.bC(O)NR.sub.b—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR.sub.b—, —NR.sub.aC(S)O—, —S—S—, —S(O).sub.n—, phenylene and pyridylidene; the phenylene or pyridylidene group is optionally substituted with one or more substituents selected from H, hydroxy, halogen, cyano, alkyl, hydroxyalkyl, haloalkyl and alkoxy; [0962] R.sub.1 or R.sub.2 is each independently C.sub.4-28 alkyl, C.sub.4-28 alkenyl or C.sub.4-28 alkynyl; the C.sub.4-28 alkyl, C.sub.4-28 alkenyl or C.sub.4-28 alkynyl is optionally substituted with one or more substituents selected from H, OH, alkyl, hydroxyalkyl, alkoxy, amino, alkylamino, and dialkylamino; [0963] R.sub.3 or R.sub.4 is each independently H or C.sub.1-20 alkyl; the C.sub.1-20 alkyl is optionally substituted with one or more substituents selected from H, OH, alkyl, hydroxyalkyl, alkoxy, amino, alkylamino, and dialkylamino; [0964] or, R.sub.3 and R.sub.4 are taken together with the N atom to which they are attached to form 3- to 14-membered heterocyclyl; the 3- to 14-membered heterocyclyl is optionally further substituted with a substituent selected from halogen, cyano, OH, alkyl, hydroxyalkyl, haloalkyl, alkoxy, amino, alkylamino, and dialkylamino; [0965] R.sub.5, R.sub.6, R.sub.7 or R.sub.8 is each independently C.sub.1-8 alkyl; [0966] each of R.sub.a or R.sub.b is each independently H, C.sub.1-28 alkyl or C.sub.3-14 cycloalkyl; the C.sub.1-28 alkyl or C.sub.3-14 cycloalkyl is optionally substituted with one or more substituents selected from H, OH, alkyl, hydroxyalkyl, alkoxy, amino, alkylamino, and dialkylamino; [0967] m or n is each independently 0, 1 or 2.
[0968] Further, the G.sub.1 and G.sub.3 are both C.sub.2-8 alkylene, and G.sub.2 and G.sub.4 are both a bond; alternatively G.sub.1 and G.sub.3 are both C.sub.5 alkylene, and G.sub.2 and G.sub.4 are both a bond.
[0969] Further, the G.sub.5 is a bond.
[0970] Further, the G.sub.6 is a bond or C.sub.1-6 alkylene.
[0971] Further, the M.sub.1 or M.sub.2 is each independently —C(O)O—, —OC(O)—, —C(O)S—, —SC(O)—, —NR.sub.aC(O)— or —C(O)NR.sub.a—, the R.sub.a is H or C.sub.4-24 alkyl; alternatively M.sub.1 or M.sub.2 is each independently —C(O)O— or —C(O)S—.
[0972] Further, the Q is a bond, —O—, —OC(O)—, —C(O)O—, —OC(O)O— or —OC(O)NH—, —NHC(O)O—, —NHC(O)NH—, —OC(O)S—, or —SC(O)O—; alternatively Q is —C(O)O—.
[0973] Further, the R.sub.1 or R.sub.2 is each independently C.sub.4-28 alkyl, C.sub.4-28 alkenyl or C.sub.4-28 alkynyl, the C.sub.4-28 alkyl, C.sub.4-28 alkenyl or C.sub.4-28 alkynyl is optionally substituted with one or more substituents H, hydroxyl or C.sub.2-14 alkyl; alternatively R.sub.1 or R.sub.2 is each independently C.sub.4-28 alkyl, C.sub.4-28 alkenyl or C.sub.4-28 alkynyl.
[0974] Further, the R.sub.3 or R.sub.4 is each independently C.sub.1-6 alkyl or hydroxyethyl; alternatively R.sub.3 or R.sub.4 are both methyl.
[0975] Further, the R.sub.5, R.sub.6, R.sub.7 or R.sub.8 is each independently C.sub.1-3 alkyl; alternatively R.sub.5, R.sub.6, R.sub.7 or R.sub.8 are both methyl.
[0976] Further, the lipid compound is the compounds of general formula (II) or general formula (III):
##STR00102## [0977] wherein the substituents are defined as described in general formula (I).
[0978] The present disclosure provides a lipid compound, a pharmaceutically acceptable salt or stereoisomer thereof, wherein the lipid compound is selected from the following compounds:
##STR00103## ##STR00104## ##STR00105## ##STR00106## ##STR00107## ##STR00108## ##STR00109## ##STR00110## ##STR00111## ##STR00112## ##STR00113## ##STR00114## ##STR00115## ##STR00116## ##STR00117## ##STR00118## ##STR00119## ##STR00120## ##STR00121## ##STR00122## ##STR00123## ##STR00124## ##STR00125##
[0979] The present disclosure provides a composition, the composition comprises a biologically active substance and lipid compounds of the present disclosure.
[0980] Further, the biologically active substance is DNA or RNA.
[0981] Further, the composition further comprises neutral lipids, structure lipids and polymeric lipids.
[0982] Further, the neutral lipids are DSPC, DMPC, DOPC, DPPC, POPC, DOPE, DMPE, POPE or DPPE.
[0983] Further, the structure lipids are selected from one of, or a combination of cholesterol, sitosterol, coprosterol, fucosterol, brassicasterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, avenasterol, ergocalciferol and campesterol.
[0984] Further, the polymeric lipids are selected from one of, or a combination of DMPE-PEG1000, DPPE-PEG1000, DSPE-PEG1000, DOPE-PEG1000, DMG-PEG2000, Ceramide-PEG2000, DMPE-PEG2000, DPPE-PEG2000, DSPE-PEG2000, Azido-PEG2000, DSPE-PEG2000-Mannose, Ceramide-PEG5000, and DSPE-PEG5000.
[0985] The present disclosure provides a lipid nanoparticle comprising the lipid compound of the present disclosure or the composition of the present disclosure.
[0986] The present disclosure provides a pharmaceutical composition comprising the lipid compound of the present disclosure, the composition of the present disclosure or the lipid nanoparticle of the present disclosure, and pharmaceutically acceptable excipient(s).
[0987] The present disclosure provides the use of the lipid compound of the present disclosure, the composition of the present disclosure, the lipid nanoparticle of the present disclosure or the pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating or preventing a disease.
[0988] The present disclosure provides a method for preparing the compound of general formula (II), comprising:
##STR00126## [0989] reacting the compound of general formula (IIb) with the compound of general formula (IIc), to give the compound of general formula (II); [0990] wherein the substituents are defined as described in general formula (I).
[0991] The present disclosure provides a compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, the compound having the structure of general formula (IIa) or general formula (IIb):
##STR00127## [0992] wherein the substituents are defined as described in general formula (I).
[0993] When the degradable group in the compound is changed, the compound of the corresponding structure can be prepared by the conventional methods in the field such as esterification and amide condensation.
[0994] The present disclosure provides the use of the compounds having the structure of general formula (IIa) or general formula (IIb), pharmaceutically acceptable salts or stereoisomers thereof in the preparation of cationic lipids.
[0995] The present disclosure also provides a lipid compound, a pharmaceutically acceptable salt, or a stereoisomer thereof, the lipid compound having the structure of general formula (I′):
##STR00128## [0996] wherein, [0997] ring A is C.sub.3-14 cycloalkyl, 3- to 14-membered heterocyclyl, C.sub.6-14 aryl or 5- to 14-membered heteroaryl; the ring A is connected to the parent structure by a C atom on the ring; the ring A is optionally further substituted; [0998] G.sub.1, G.sub.2, G.sub.3 or G.sub.4 is each independently a bond, C.sub.1-20 alkylene, C.sub.2-20 alkenylene or C.sub.2-20 alkynylene; [0999] G.sub.8 or G.sub.6 is each independently a bond or C.sub.1-8 alkylene; [1000] M.sub.1 or M.sub.2 is each independently biodegradable groups; [1001] Q is a bond or biodegradable groups; [1002] R.sub.1 or R.sub.2 is each independently C.sub.4-28 alkyl, C.sub.4-28 alkenyl or C.sub.4-28 alkynyl; [1003] R′.sub.3, R′.sub.4, R′.sub.5 or R′.sub.6 is each independently C.sub.1-8 alkyl; [1004] each of the alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, aryl or heteroaryl is each independently and optionally further substituted.
[1005] Further, the lipid compound has the structure of general formula (I′):
##STR00129## [1006] wherein, [1007] ring A is C.sub.3-14 cycloalkyl, 3- to 14-membered heterocyclyl, C.sub.6-14 aryl or 5- to 14-membered heteroaryl; the ring A is connected to the parent structure by a C atom on the ring; the ring A is optionally further substituted; [1008] G.sub.1, G.sub.2, G.sub.3 or G.sub.4 is each independently a bond, C.sub.1-20 alkylene, C.sub.2-20 alkenylene or C.sub.2-20 alkynylene; the C.sub.1-20 alkylene, C.sub.2-20 alkenylene or C.sub.2-20 alkynylene is optionally substituted with one or more substituents selected from H, OH, alkyl, hydroxyalkyl, alkoxy, amino, alkylamino, and dialkylamino; [1009] G.sub.8 or G.sub.6 is each independently a bond or C.sub.1-6 alkylene; the C.sub.1-6 alkylene is optionally substituted with one or more substituents selected from H, OH, alkyl, hydroxyalkyl, alkoxy, amino, alkylamino, and dialkylamino; [1010] M.sub.1 or M.sub.2 is each independently selected from —OC(O)—, —C(O)O—, —SC(O)—, —C(O)S—, —O—, —OC(O)O—, —SC(O)O—, —OC(O)S—, —NR.sub.a—, —C(O)NR.sub.a—, —NR.sub.aC(O)—, —NR.sub.aC(O)O—, —OC(O)NR.sub.a—, —NR.sub.aC(O)S—, —SC(O)NR.sub.a—, —NR.sub.aC(O)NR.sub.a—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR.sub.a—, —NR.sub.aC(S)O—, —S—S— and —S(O).sub.m—; [1011] Q is selected from a bond, —OC(O)—, —C(O)O—, —SC(O)—, —C(O)S—, —O—, —OC(O)O—, —SC(O)O—, —OC(O)S—, —NR.sub.b—, —C(O)NR.sub.b—, —NR.sub.bC(O)—, —NR.sub.bC(O)O—, —OC(O)NR.sub.b—, —NR.sub.bC(O)S—, —SC(O)NR.sub.b—, —NR.sub.bC(O)NR.sub.b—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR.sub.b—, —NR.sub.aC(S)O—, —S—S—, —S(O).sub.n—, phenylene and pyridylidene; the phenylene or pyridylidene group is optionally substituted with one or more substituents selected from H, hydroxy, halogen, cyano, alkyl, hydroxyalkyl, haloalkyl and alkoxy; [1012] R.sub.1 or R.sub.2 is each independently C.sub.4-28 alkyl, C.sub.4-28 alkenyl or C.sub.4-28 alkynyl; the C.sub.4-28 alkyl, C.sub.4-28 alkenyl or C.sub.4-28 alkynyl is optionally substituted with one or more substituents selected from H, OH, alkyl, hydroxyalkyl, alkoxy, amino, alkylamino, and dialkylamino; [1013] R′.sub.3, R′.sub.4, R′.sub.5 or R′.sub.6 is each independently C.sub.1-8 alkyl; [1014] each of R.sub.a or R.sub.b is each independently H, C.sub.1-28 alkyl or C.sub.3-14 cycloalkyl; the C.sub.1-28 alkyl or C.sub.3-14 cycloalkyl is optionally substituted with one or more substituents selected from H, OH, alkyl, hydroxyalkyl, alkoxy, amino, alkylamino, and dialkylamino; [1015] m or n is each independently 0, 1 or 2.
[1016] Further, the G.sub.1 and G.sub.3 are both C.sub.2-s alkylene, and G.sub.2 and G.sub.4 are both a bond; [1017] alternatively G.sub.1 and G.sub.3 are both C.sub.5 alkylene, and G.sub.2 and G.sub.4 are both a bond.
[1018] Further, the G.sub.8 is a bond.
[1019] Further, the G.sub.6 is a bond or C.sub.1-6 alkylene.
[1020] Further, the M.sub.1 or M.sub.2 is each independently —C(O)O—, —OC(O)—, —C(O)S—, —SC(O)—, —NR.sub.aC(O)— or —C(O)NR.sub.a—, the R.sub.a is H or C.sub.4-24 alkyl; alternatively M.sub.1 or M.sub.2 is each independently —C(O)O— or —C(O)S—.
[1021] Further, the Q is a bond, —O—, —OC(O)—, —C(O)O—, —OC(O)O—, —OC(O)NH—, —NHC(O)—O—, —NHC(O)NH—, —OC(O)S—, or —SC(O)O—; alternatively Q is —C(O)O—.
[1022] Further, the ring A is 3- to 8-membered heterocyclyl, the ring A is optionally substituted with one or more of R.sub.7; alternatively the ring A is
##STR00130##
[1023] Further, the R.sub.1 or R.sub.2 is each independently C.sub.4-28 alkyl, C.sub.4-28 alkenyl or C.sub.4-28 alkynyl, the C.sub.4-28 alkyl, C.sub.4-28 alkenyl or C.sub.4-28 alkynyl is optionally substituted with one or more substituents H, hydroxyl or C.sub.2-14 alkyl; alternatively R.sub.1 or R.sub.2 is each independently C.sub.4-28 alkyl, C.sub.4-28 alkenyl or C.sub.4-28 alkynyl.
[1024] Further, the R′.sub.3, R′.sub.4, R′.sub.5 or R′.sub.6 is each independently C.sub.1-3 alkyl; alternatively R′.sub.3, R′.sub.4, R′.sub.5 or R′.sub.6 are both methyl.
[1025] Further, each of the R′.sub.7 is each independently H, halogen, cyano, OH, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, —NH.sub.2, —NHC.sub.1-6 alkyl, or —N(C.sub.1-6 alkyl).sub.2; the C.sub.1-6 alkyl is optionally further substituted with a substituent selected from halogen, cyano, OH, oxo, —NH.sub.2, —NHC.sub.1-6 alkyl, and —N(C.sub.1-6 alkyl).sub.2; alternatively R′.sub.7 is C.sub.1-3 alkyl.
[1026] Further, the lipid compound is the compound of general formula (II′):
##STR00131## [1027] wherein the substituents are defined as described in general formula (I′).
[1028] The present disclosure provides a lipid compound, a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the lipid compound is selected from:
##STR00132## ##STR00133##
[1029] The present disclosure provides a composition, the composition comprises a biologically active substance and lipid compounds of the present disclosure.
[1030] Further, the biologically active substance is DNA or RNA.
[1031] Further, the composition further comprises neutral lipids, structure lipids and polymeric lipids.
[1032] Further, the neutral lipids are DSPC, DMPC, DOPC, DPPC, POPC, DOPE, DMPE, POPE or DPPE.
[1033] Further, the structure lipids are selected from one of, or a combination of cholesterol, sitosterol, coprosterol, fucosterol, brassicasterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, avenasterol, ergocalciferol and campesterol.
[1034] Further, the polymeric lipids are selected from one of, or a combination of DMPE-PEG1000, DPPE-PEG1000, DSPE-PEG1000, DOPE-PEG1000, DMG-PEG2000, Ceramide-PEG2000, DMPE-PEG2000, DPPE-PEG2000, DSPE-PEG2000, Azido-PEG2000, DSPE-PEG2000-Mannose, Ceramide-PEG5000, and DSPE-PEG5000.
[1035] The present disclosure provides a lipid nanoparticle comprising the lipid compound of the present disclosure or the composition of the present disclosure.
[1036] The present disclosure provides a pharmaceutical composition comprising the lipid compound of the present disclosure, the composition of the present disclosure or the lipid nanoparticle of the present disclosure, and pharmaceutically acceptable excipient(s).
[1037] The present disclosure provides the use of the lipid compound of the present disclosure, the composition of the present disclosure, the lipid nanoparticle of the present disclosure or the pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating or preventing a disease.
[1038] The present disclosure provides a method for preparing the compound of general formula (II′), comprising:
##STR00134## [1039] reacting the compound of general formula (II′a) with the compound of general formula (II′b), to give the compound of general formula (II′); [1040] wherein the substituents are defined as described in general formula (I′).
[1041] The compounds of the present disclosure may include one or more asymmetric centers, and thus may exist in a variety of stereoisomeric forms, for example, enantiomers and/or diastereomers. For example, the compounds of the present disclosure may be in the form of an individual enantiomer, diastereomer or geometric isomer (e.g., cis- and trans-isomers), or may be in the form of a mixture of stereoisomers, including racemic mixture and a mixture enriched in one or more stereoisomers. The isomers can be separated from the mixture by the methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or alternative isomers can be prepared by asymmetric synthesis.
[1042] The compounds of the present disclosure may exist in tautomer forms. The tautomer is a functional group isomer resulting from the rapid shift of an atom between two positions in a molecule. The tautomer is a special functional group isomer, wherein a pair of tautomers can convert between each other, but usually exist in a relatively stable isomer as its main form. The most important examples are the enol and keto tautomers.
[1043] The present disclosure also comprises compounds that are labeled with isotopes (isotope variants), which are equivalent to those described in formula (IV), but one or more atoms are replaced by atoms having an atom mass or mass number that are different from that of atoms that are common in nature. Examples of isotopes which may be introduced into the compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as .sup.2H, .sup.3H, .sup.13C, .sup.11C, .sup.14C, .sup.15N, .sup.18O, .sup.17O, .sup.31P, .sup.32p .sup.35S, .sup.18F and .sup.36C.sub.1, respectively. Compounds of the present disclosure that comprise the above isotopes and/or other isotopes of other atoms, prodrugs thereof and pharmaceutically acceptable salts of said compounds or prodrugs all are within the scope of the present disclosure. Certain isotope-labeled compounds of the present disclosure, such as those incorporating radioactive isotopes (e.g., .sup.3H and .sup.4C), can be used for the measurement of the distribution of drug and/or substrate in tissue. Tritium, which is .sup.3H and carbon-14, which is .sup.14C isotope, are yet alternative, because they are easy to prepare and detect. Furthermore, replaced by heavier isotopes, such as deuterium, which is .sup.2H, may provide therapeutic benefits due to the higher metabolic stability, such as prolonging the half-life in vivo or decreasing the dosage requirements, and thus may be alternative in some cases. Isotope-labeled compounds of formula (I) of the present disclosure and prodrugs thereof can be prepared generally by using readily available isotope-labeled reagents to replace non-isotope-labeled reagents in the following schemes and/or the procedures disclosed in the examples and preparation examples.
[1044] The present disclosure also provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (VI), or therapeutically acceptable salts thereof, and pharmaceutically acceptable carriers, diluents or excipients thereof. All of these forms belong to the present disclosure.
[1045] Pharmaceutical Compositions and Kits
[1046] In another aspect, the present disclosure provides a pharmaceutical composition comprising nanoparticle compositions of the present disclosure and pharmaceutically acceptable excipient(s), the nanoparticle composition comprises the compounds of the present disclosure.
[1047] A pharmaceutically acceptable excipient for use in the present disclosure refers to a non-toxic carrier, adjuvant or vehicle which does not destroy the pharmacological activity of the compound formulated together. Pharmaceutically acceptable carriers, adjuvants, or vehicles that may be used in the compositions of the present disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin.
[1048] The present disclosure also includes kits (e.g., pharmaceutical packs). Kits provided may include a nanoparticle composition of the present disclosure and other therapeutic, or diagnostic, or prophylactic agents, and a first and a second containers (e.g., vials, ampoules, bottles, syringes, and/or dispersible packages or other materials) containing the nanoparticle composition of the present disclosure or other therapeutic, or diagnostic, or prophylactic agents. In some embodiments, kits provided can also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending the nanoparticle composition of the present disclosure and/or other therapeutic, or diagnostic, or prophylactic agent. In some embodiments, the nanoparticle composition of the present disclosure provided in the first container and the other therapeutic, or diagnostic, or prophylactic agents provided in the second container is combined to form a unit dosage form.
[1049] Administration
[1050] The pharmaceutical composition provided by the present disclosure can be administered by a variety of routes including, but not limited to, oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration by implant or other means of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intraarterial administration, intrasynovial administration, intrasternal administration, intracerebroventricular administration, intralesional administration, and intracranial injection or infusion techniques.
[1051] Generally, the pharmaceutical compositions provided herein are administered in an effective amount. The amount of the pharmaceutical composition actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated or prevented, the chosen route of administration, the actual pharmaceutical composition administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
[1052] When used to prevent the disorder of the present disclosure, the pharmaceutical compositions provided herein will be administered to a subject at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Subjects at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
[1053] The pharmaceutical compositions provided herein can also be administered chronically (“chronic administration”). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be continued indefinitely, for example, for the rest of the subject's life. In certain embodiments, the chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time.
[1054] The pharmaceutical compositions of the present disclosure may be further delivered using a variety of dosing methods. For example, in certain embodiments, the pharmaceutical composition may be given as a bolus, e.g., in order to raise the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the systemic levels of the active ingredient desired throughout the body, e.g., an intramuscular or subcutaneous bolus dose allows a slow release of the active ingredient, while a bolus delivered directly to the veins (e.g., through an IV drip) allows a much faster delivery which quickly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, e.g., by IV drip, to provide maintenance of a steady-state concentration of the active ingredient in the subject's body. Furthermore, in still yet other embodiments, the pharmaceutical composition may be administered as first as a bolus dose, followed by continuous infusion.
[1055] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
[1056] Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the active substance is usually a minor component (from about 0.1 to about 50% by weight or alternatively from about 1 to about 40% by weight) with the remainder being various vehicles or excipients and processing aids helpful for forming the desired dosing form.
[1057] With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regimens. Using these dosing patterns, each dose provides from about 0.001 mg/kg to about 10 mg/kg of the therapeutic, or diagnostic, or prophylactic agents, with alternative doses each providing from about 0.1 mg/kg to about 10 mg/kg, and especially about 1 to about 5 mg/kg.
[1058] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses, generally in an amount ranging from about 0.01 to about 20% by weight, alternatively from about 0.1 to about 20% by weight, alternatively from about 0.1 to about 10% by weight, and still alternatively from about 0.5 to about 15% by weight.
[1059] Injection dose levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient.
[1060] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
[1061] Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable excipients known in the art. As before, the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable excipient and the like.
[1062] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s). When formulated as a ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or Formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.
[1063] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
[1064] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.
[1065] The nanoparticle compositions of the present disclosure can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.
[1066] The present disclosure also relates to the pharmaceutically acceptable formulations of a compound of the present disclosure. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ-cyclodextrins consisting of 6, 7 and 8 α-1,4-linked glucose units, respectively, optionally comprising one or more substituents on the linked sugar moieties, which include, but are not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkylether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, e.g., for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, e.g., U.S. Pat. No. 5,376,645. In certain embodiments, the formulation comprises hexapropyl-β-cyclodextrin (e.g., 10-50% in water).
EXAMPLE
[1067] In order to make the technical solutions of the present disclosure clearer and more explicit, the present disclosure is further elaborated through the following examples. The following examples are used only to illustrate specific embodiments of the present disclosure so that a person skilled in the art can understand the present disclosure, but are not intended to limit the scope of protection of the present disclosure. The technical means or methods, etc. not specifically described in the specific embodiments of the present disclosure are conventional technical means or methods, etc. in the art. The materials, reagents, etc. used in examples are commercially available if not otherwise specified.
TABLE-US-00001 TABLE 1 Abbreviation Full name THF Tetrahydrofuran DCM dichloromethane MeOH methanol DMF N, N-Dimethylformamide DMSO Dimethyl sulfoxide DCE 1, 2-Dichloroethane CDCl.sub.3 Deuterated chloroform TBAI Tetrabutylammonium iodide TSCH.sub.2CN 4-Toluenesulfonylacetonitrile TMSOK Potassium trimethylsiloxide TBDMSCl tert-Butyldimethylsily1 chloride LDA Lithium diisopropylamide DMAP 4-Dimethylaminopyridine (COCl).sub.2 Oxalyl chloride SOCl.sub.2 Thionyl dichloride NaBH.sub.4 Sodium borohydride NaH Sodium hydride K.sub.2CO.sub.3 Potassium carbonate EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide DIPEA N,N-Diisopropylethylamine Et.sub.3N Triethylamine AcOH Acetic acid NaBH.sub.3CN Sodium cyanoborohydride Imidazole Imidazole NMO 4-Methylmorpholine N-oxide BDMEP 2,6-di-tert-Butylpyridine
Example 1: Synthesis of Comound 1
[1068] ##STR00135##
[1069] A solution of compound 1-1 (100 g, 979 mmol) in tetrahydrofuran (800 mL) was cooled to −40° C. LDA (2 M, 490 mL) was added slowly dropwise to the solution and the mixture was stirred for another 1 h after completion of the dropwise addition. A solution of 1-2 (315 g, 1.37 mol) in tetrahydrofuran (100 mL) was added dropwise to the reaction system at the same temperature and the reaction system was stirred overnight. The reaction system was quenched with saturated aqueous ammonium chloride, and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give the crude product. The crude product was purified by silica gel column to give compound 1-3 (115 g). .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.06-1.11 (m, 6H), 1.13-1.22 (m, 2H), 1.29-1.39 (m, 2H), 1.42-1.49 (m, 2H), 1.73-1.82 (m, 2H), 3.28-3.40 (m, 2H), 3.55-3.66 (m, 3H).
[1070] A solution of compound 1-3 (100 g, 398 mmol), TsCH.sub.2CN (38.9 g, 199 mmol) and TBAI (14.7 g, 39.8 mmol) in dimethyl sulfoxide (800 mL) was cooled to 0° C., and sodium hydride (20.7 g, 517 mmol) was added slowly in batches. The mixture was reacted at room temperature overnight. The reaction system was quenched with saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give 115 g of crude compound 1-4, which was used directly in the next reaction without isolation and purification.
[1071] To a solution of compound 1-4 crude (110 g, 205 mmol) in dichloromethane (880 mL) was added 330 mL of concentrated hydrochloric acid, and the mixture was reacted at room temperature for 2 h. The complete reaction of the substrate was monitored by TLC. The reaction system was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give the crude product. The crude product was purified by silica gel column to give compound 1-5 (30.0 g, 80.9 mmol, yield 39.4%).
[1072] TMSOK (11.0 g, 86.4 mmol) was added to a solution of compound 1-5 (8.0 g, 21.6 mmol) in tetrahydrofuran (35.0 mL) at room temperature, and the reaction system was heated to 70° C. with stirring. The complete consumption of reaction materials was monitored by TLC. The reaction solution was cooled to room temperature, and the organic solvent was removed by rotary evaporation. The crude product was added to 20 mL of water and extracted with dichloromethane. The aqueous layer was collected, and the solution was adjusted to a pH of <5 with 1 M hydrochloric acid. The solution was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was collected and concentrated to give compound 1-6 (7.0 g). .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.03 (s, 12H), 1.08-1.17 (m, 8H), 1.34-1.45 (m, 8H), 2.21 (t, J=7.2 Hz, 4H).
[1073] Potassium carbonate (482 mg, 3.48 mmol) was added to a solution of compound 1-6 (294 mg, 0.87 mmol) and 1-7 (771 mg, 3.48 mmol) in DMF, then the reaction was warmed up to 60° C. for 6 h. The complete disappearance of reactant 1-6 was monitored. The mixture was cooled to room temperature. The reaction system was quenched with saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give the crude product. The crude was purified by silica gel column to give compound 1-8 (325 mg).
[1074] Compound 1-8 (325 mg) was dissolved in 4.0 mL of methanol and sodium borohydride (30 mg, 0.84 mmol) was added to the reaction system. The mixture was reacted at room temperature. The complete disappearance of the reactants was monitored by TLC. The reaction system was quenched with saturated aqueous sodium chloride solution and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give crude compound 1-9 (260 mg), which was used directly in the next reaction without purification.
[1075] Crude compound 1-9 (260 mg, 0.42 mmol), 1-10 (73.1 mg, 0.63 mmol), EDCI (238 mg, 1.26 mmol), triethylamine (0.17 mL, 1.26 mmol) and DMAP (51 mg, 0.42 mmol) were dissolved in 5.0 mL of dichloromethane, and the reaction solution was stirred to react at room temperature for 12 h. The reaction solution was quenched with saturated aqueous sodium chloride and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The organic phase was collected and the organic solvent was removed using a rotary-evaporator to give the crude product, which was purified by preparative high performance liquid chromatography to give compound 1 (130 mg).
[1076] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.89 (t, J=7.2 Hz, 6H), 1.15 (s, 12H), 1.27 (m, 40H), 1.49 (m, 8H), 1.61 (m, 4H), 2.26 (s, 6H), 2.44-2.52 (t, J=7.2 Hz, 2H), 2.63 (t, J=7.2 Hz, 2H), 4.04 (t, J=6.8 Hz, 4H), 4.86 (m, 1H); ESI-MS m/z: 724.7 [M+H].sup.+.
Example 2: Synthesis of Compound 2
[1077] ##STR00136##
[1078] Referring to the method of Example 1, compound 2 was prepared as an oily product: 25.7 mg.
[1079] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.89 (t, J=6.8 Hz, 6H), 1.15 (s, 12H), 1.29 (m, 32H), 1.49 (m, 8H), 1.60 (m, 4H), 2.24 (s, 6H), 2.46 (t, J=7.2 Hz, 2H), 2.61 (t, J=7.2 Hz, 2H), 4.04 (t, J=6.8 Hz, 4H), 4.86 (m, 1H); ESI-MS m/z: 668.6 [M+H].sup.+.
Example 3: Synthesis of Compound 3
[1080] ##STR00137##
[1081] Referring to the method of Example 1, compound 3 was prepared as an oily product: 31.2 mg.
[1082] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.89 (t, J=6.8 Hz, 6H), 1.16 (s, 12H), 1.28 (m, 36H), 1.49 (m, 8H), 1.62 (m, 4H), 2.25 (s, 6H), 2.47 (t, J=7.2 Hz, 2H), 2.62 (t, J=7.2 Hz, 2H), 4.05 (t, J=6.8 Hz, 4H), 4.88 (m, 1H); ESI-MS m/z: 696.6 [M+H].sup.+.
Example 4: Synthesis of Compound 4
[1083] ##STR00138##
[1084] Referring to the method of Example 1, compound 4 was prepared as an oily product: 32 mg.
[1085] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.89 (t, J=6.8 Hz, 6H), 1.16 (s, 12H), 1.28 (m, 44H), 1.49 (m, 8H), 1.52 (m, 4H), 2.51 (s, 6H), 2.53 (t, J=7.2 Hz, 2H), 3.12 (t, J=7.2 Hz, 2H), 3.91 (t, J=6.8 Hz, 4H), 4.82 (m, 1H); ESI-MS m/z: 752.7 [M+H].sup.+.
Example 5: Synthesis of Compound 5
[1086] ##STR00139##
[1087] Referring to the method of Example 1, compound 5 was prepared as an oily product: 31.4 mg.
[1088] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.88 (t, J=6.8 Hz, 6H), 1.15 (s, 12H), 1.25 (m, 48H), 1.49 (m, 8H), 1.52 (m, 4H), 2.46 (s, 6H), 2.63 (m, 2H), 2.86 (m, 2H), 4.03 (t, J=6.8 Hz, 4H), 4.84 (m, 1H); ESI-MS m/z: 780.7 [M+H].sup.+.
Example 6: Synthesis of Compound 6
[1089] ##STR00140##
[1090] Referring to the method of Example 1, compound 6 was prepared as an oily product: 30.7 mg.
[1091] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.83 (t, J=6.8 Hz, 18H), 1.00-1.28 (m, 34H), 1.31-1.62 (m, 18H), 2.21 (s, 6H), 2.36-2.46 (m, 2H), 2.51-2.62 (m, 2H), 4.02 (t, J=6.8 Hz, 4H), 4.71-4.85 (m, 1H); ESI-MS m/z: 724.6 [M+H].sup.+.
Example 7: Synthesis of Compound 7
[1092] ##STR00141##
[1093] Compound 1-6 (548 mg, 1.5 mmol) was dissolved in 5.0 mL of dichloromethane, and the reaction system was cooled to 0° C. in an ice bath. DMF (12 μL, 0.15 mmol) was added and oxalyl chloride (0.47 mL, 6.0 mmol) was added dropwise to the reaction solution. The ice bath was removed and the mixture was stirred for 1 h at room temperature. The solvent was removed using a rotary-evaporator to give acyl chloride crude product (458 mg) as an oil, which was used directly in the next reaction step.
[1094] The above obtained acyl chloride crude product (458 mg) was dissolved in 3.0 mL of 1,2-dichloroethane, and then compound 7-1 (429 mg, 3.0 mmol) was added to the reaction solution. The mixture was stirred at room temperature until the substrate was reacted completely. The solvent was removed using a rotary-evaporator to give the crude product, which was purified by silica gel column to give compound 7-2 (540 mg).
[1095] Then referring to the method of Example 1, compound 7 was prepared as an oily product: 33.2 mg.
[1096] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.89 (t, J=6.8 Hz, 6H), 1.23 (s, 12H), 1.29-1.51 (m, 32H), 1.95 (m, 8H), 2.18 (s, 6H), 2.41 (m, 2H), 2.53 (m, 2H), 3.91 (t, J=6.8 Hz, 4H), 4.78 (m, 1H), 5.25 (m, 4H); ESI-MS m/z: 692.6 [M+H].sup.+.
Example 8: Synthesis of Compound 8
[1097] ##STR00142##
[1098] Compound 1-6 (548 mg, 1.5 mmol) was dissolved in 5.0 mL of dichloromethane, and the reaction system was cooled in an ice bath. DMF (12 μL, 0.15 mmol) was added and oxalyl chloride (0.47 mL, 6.0 mmol) was added dropwise to the reaction solution. The ice bath was removed and the mixture was stirred for 1 h at room temperature. The solvent was removed using a rotary-evaporator to give acyl chloride crude product (458 mg) as an oil, which was used directly in the next reaction step.
[1099] The above obtained 458 mg of acyl chloride crude product was dissolved in 3.0 mL of 1,2-dichloroethane, and then compound 8-1 (472 mg, 3.0 mmol) was added to the reaction solution. The mixture was stirred at room temperature until the substrate was reacted completely. The solvent was removed using a rotary-evaporator to give crude product, which was purified by silica gel column to give compound 8-2 (518 mg).
[1100] 518 mg of compound 8-2 was dissolved in 5.0 mL of methanol, and sodium borohydride (48 mg, 1.25 mmol) was added to the reaction system. The mixture was reacted at room temperature. The complete disappearance of the reactants was monitored by TLC. The reaction system was quenched with saturated aqueous sodium chloride solution and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give 473 mg of crude compound 8-3, which was used directly in the next reaction without purification.
[1101] Crude compound 8-3 (270 mg, 0.43 mmol), 1-10 (76.1 mg, 0.65 mmol), EDCI (248 mg, 1.3 mmol), triethylamine (0.18 mL, 1.3 mmol) and DMAP (53 mg, 0.43 mmol) were dissolved in 5.0 mL of dichloromethane, and the reaction solution was stirred to react at room temperature for 12 h. The reaction system was quenched with saturated aqueous sodium chloride and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The organic phase was collected and the organic solvent was removed using a rotary-evaporator to give the crude product, which was purified by preparative high performance liquid chromatography to give compound 8 (39 mg).
[1102] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.89 (t, J=6.8 Hz, 6H), 1.14 (s, 12H), 1.15-1.31 (m, 40H), 1.40-1.52 (m, 12H), 2.25 (s, 6H), 2.45 (m, 2H), 2.60 (m, 2H), 3.15 (t, J=6.8 Hz, 4H), 4.77-4.89 (m, 1H), 5.51-5.67 (m, 2H); ESI-MS m/z: 722.7 [M+H].sup.+.
Example 9: Synthesis of Compound 9
[1103] ##STR00143##
[1104] Referring to the method of Example 8, compound 9 (73 mg) was prepared.
[1105] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.89 (t, J=6.8 Hz, 6H), 1.15 (s, 12H), 1.27-1.49 (m, 48H), 2.25 (s, 6H), 2.46 (t, J=7.2 Hz, 2H), 2.62 (t, J=7.2 Hz, 2H), 3.24 (m, 4H), 4.85 (m, 1H), 5.58 (m, 2H); ESI-MS m/z: 694.6 [M+H].sup.+.
Example 10: Synthesis of Compound 10
[1106] ##STR00144##
[1107] Referring to the method of Example 8, compound 10 (31.2 mg) was prepared.
[1108] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.79 (t, J=7.2 Hz, 6H), 1.07 (s, 12H), 1.27-1.49 (m, 48H), 1.41 (m, 12H), 2.18 (s, 6H), 2.41 (t, J=7.2 Hz, 2H), 2.55 (t, J=7.2 Hz, 2H), 3.16 (m, 4H), 4.78 (m, 1H), 5.51 (m, 2H); ESI-MS m/z: 778.8 [M+H].sup.+.
Example 11: Synthesis of Compound 11
[1109] ##STR00145##
[1110] Referring to the method of Example 8, compound 11 (48.1 mg) was prepared.
[1111] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.78 (t, J=7.2 Hz, 12H), 1.07 (s, 12H), 1.14-1.19 (m, 60H), 1.40 (m, 16H), 2.18 (s, 6H), 2.36-2.47 (m, 2H), 2.49-2.68 (m, 2H), 3.76-3.88 (m, 2H), 4.74-4.83 (m, 1H), 5.10-5.19 (m, 2H); ESI-MS m/z: 918.9 [M+H].sup.+.
Example 12: Synthesis of Compound 12
[1112] ##STR00146##
[1113] Referring to the method of Example 8, compound 12 (52 mg) was prepared.
[1114] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.82 (t, J=6.8 Hz, 12H), 1.15-1.32 (m, 72H), 1.54 (m, 16H), 2.31 (s, 6H), 2.51 (t, J=7.2 Hz, 2H), 2.60 (t, J=7.2 Hz, 2H), 3.14-3.33 (m, 8H), 4.75-4.83 (m, 1H); ESI-MS m/z: 946.9 [M+H].sup.+.
Example 13: Synthesis of Compound 13
[1115] ##STR00147##
[1116] Referring to the method of Example 8, compound 13 (32 mg) was prepared.
[1117] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.81 (t, J=7.2 Hz, 6H), 1.19 (m, 52H), 1.41 (m, 12H), 2.26 (s, 6H), 3.05 (s, 2H), 3.16 (m, 4H), 4.83 (m, 1H), 5.51 (m, 2H); ESI-MS m/z: 708.7 [M+H].sup.+.
Example 14: Synthesis of Compound 14
[1118] ##STR00148##
[1119] Referring to the method of Example 8, compound 14 (18 mg) was prepared.
[1120] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.81 (t, J=7.2 Hz, 6H), 1.07 (s, 12H), 1.08-1.31 (m, 44H), 1.35-1.47 (m, 8H), 1.71-1.84 (m, 2H), 2.09-2.38 (m, 10H), 3.12-3.27 (m, 4H), 4.70-4.82 (m, 1H), 5.49-5.63 (m, 2H); ESI-MS m/z: 736.7 [M+H].sup.+.
Example 15: Synthesis of Compound 15
[1121] ##STR00149##
[1122] A solution of compound 15-1 (400 mg, 1.4 mmol) in dichloromethane (3.0 mL) was cooled to 0° C., then a solution of SOCl.sub.2 (0.12 mL, 1.68 mmol) in dichloromethane (2.0 mL) was added dropwise. After the dropwise addition was completed, the mixture was stirred at 0° C. for another 1 h. After the reaction was completed, the reaction was quenched by adding saturated sodium bicarbonate solution to the reaction system, and the reaction system was extracted with dichloromethane. The organic phases were combined and the organic solvent was removed to give crude compound 15-2, which was used directly in the next reaction without purification.
[1123] Compound 1-6 (223, 0.65 mmol), 15-2 (496 mg, 1.63 mmol) and potassium carbonate (361 mg, 2.6 mmol) were dissolved in 5.0 mL of DMF and the reaction solution was heated to 70° C. to react for 6 hours. The reaction solution was cooled to room temperature, then the reaction was quenched by adding saturated sodium chloride solution to the reaction system, and the reaction system was extracted with dichloromethane. The organic phases were combined and the organic solvent was removed to give the crude product. The crude was purified by silica gel column to give compound 15-3.
[1124] Then referring to the method of Example 1, compound 15 (40 mg) was prepared.
[1125] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.89 (t, J=7.2 Hz, 12H), 1.08 (s, 12H), 1.12-1.35 (m, 46H), 1.38-1.58 (m, 22H), 2.35 (s, 6H), 2.41-2.52 (m, 10H), 2.57-2.65 (m, 2H), 2.62 (m, 4H), 4.10 (t, J=6.4 Hz, 4H), 4.86 (m, 1H); ESI-MS m/z: 978.9 [M+H].sup.+.
Example 16: Synthesis of Compound 16
[1126] ##STR00150##
[1127] DMF (11 μL, 0.14 mmol) was added to a solution of compound 1-6 (460 mg, 1.34 mmol) in dichloromethane (5.0 mL) under ice bath conditions, and oxalyl chloride (0.47 mL, 5.37 mmol) was then added dropwise to the reaction solution. The ice bath was removed, and the mixture was stirred for 1 h at room temperature. The solvent was removed using a rotary-evaporator to give 255 mg of acyl chloride crude product as an oil, which was used directly in the next reaction step.
[1128] The above obtained acyl chloride crude product (255 mg, 0.67 mmol) was dissolved in 3.0 mL of 1,2-dichloroethane, and then compound 16-1 (384 mg, 1.68 mmol) was added to the reaction solution. The mixture was stirred at room temperature until the substrate was reacted completely. The solvent was removed using a rotary-evaporator to give the crude product, which was purified by silica gel column to give 300 mg of compound 16-2.
[1129] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.78-0.83 (m, 12H), 1.07 (s, 12H), 1.13-1.22 (m, 48H), 1.49 (br s, 16H), 2.29 (t, J=7.50 Hz, 4H), 4.76 (m, 2H).
[1130] Compound 16-2 (300 mg, 0.39 mmol) was dissolved in 4.0 mL of methanol. Then NaBH.sub.4 (45 mg, 1.17 mmol) was slowly added to the reaction solution and the mixture was stirred at room temperature for 2 h. The reaction solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate. The organic phases were combined and the organic solvent was removed to give 300 mg of crude compound 16-3, which was used directly in the next reaction without purification.
[1131] Crude compound 16-3 (300 mg, 0.39 mmol) was dissolved in 2.0 mL DMF, and then 1-10 (69 mg, 0.59 mmol), EDCI (225 mg, 1.17 mmol), triethylamine (119 mg, 1.17 mmol) and DMAP (48 mg, 0.39 mmol) were added. The mixture was stirred at room temperature until the reactants was reacted completely. The reaction solution was quenched with saturated sodium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give the crude product. The crude product was purified by preparative high performance liquid chromatography to give compound 16 (32.5 mg).
[1132] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.79 (t, J=7.2 Hz, 12H), 1.07 (s, 12H), 1.19 (m, 52H), 1.40-1.46 (m, 16H), 2.15 (s, 6H), 2.34-2.58 (m, 4H), 4.74-4.81 (m, 3H); ESI-MS m/z: 864.8 [M+H].sup.+.
Example 17: Synthesis of Compound 17
[1133] ##STR00151##
[1134] Referring to the method of Example 1, compound 17 was prepared as an oily product: 41.3 mg.
[1135] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.82 (t, J=7.2 Hz, 6H), 1.08 (s, 12H), 1.14-1.20 (m, 36H), 1.40-1.64 (m, 16H), 2.32 (s, 6H), 3.08-3.21 (m, 2H), 3.97 (t, J=7.2 Hz, 4H), 4.83-4.92 (m, 1H); ESI-MS m/z: 710.6 [M+H].sup.+.
Example 18: Synthesis of Compound 18
[1136] ##STR00152##
[1137] Referring to the method of Example 1, compound 18 was prepared as an oily product: 35.4 mg.
[1138] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.79 (t, J=7.2 Hz, 6H), 1.08 (s, 12H), 1.13-1.25 (m, 36H), 1.28-1.47 (m, 10H), 1.47-1.62 (m, 6H), 1.68-1.79 (m, 2H), 2.15 (s, 6H), 2.21-2.31 (m, 4H), 3.97 (t, J=7.2 Hz, 4H), 4.73-4.82 (m, 1H); ESI-MS m/z: 738.7 [M+H].sup.+.
Example 19: Synthesis of Compound 19
[1139] ##STR00153##
[1140] Referring to the method of Example 1, compound 19 was prepared as an oily product: 33.1 mg.
[1141] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.89 (t, J=7.2 Hz, 6H), 1.15 (s, 12H), 1.29 (m, 30H), 1.50 (m, 8H), 1.60 (m, 6H), 1.64 (m, 2H), 2.23 (s, 6H), 2.33 (m, 4H), 4.05 (t, J=6.8 Hz, 4H), 4.86 (m, 1H); ESI-MS m/z: 682.6 [M+H].sup.+.
Example 20: Synthesis of Compound 20
[1142] ##STR00154##
[1143] Referring to the method of Example 1, compound 20 was prepared as an oily product: 302 mg.
[1144] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.89 (t, J=7.2 Hz, 6H), 1.15 (s, 12H), 1.27 (m, 34H), 1.47 (m, 8H), 1.51 (m, 6H), 1.79 (m, 2H), 2.23 (s, 6H), 2.33 (m, 4H), 4.04 (t, J=6.8 Hz, 4H), 4.85 (m, 1H); ESI-MS m/z: 710.7 [M+H].sup.+.
Example 21: Synthesis of Compound 21
[1145] ##STR00155##
[1146] Referring to the method of Example 1, compound 21 was prepared as an oily product: 31.2 mg.
[1147] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.79 (t, J=7.2 Hz, 6H), 1.08 (s, 12H), 1.25 (m, 44H), 1.39 (m, 8H), 1.51 (m, 4H), 1.82 (m, 2H), 2.25 (t, J=7.2 Hz, 2H), 2.32 (s, 6H), 2.41 (m, 2H), 3.96 (t, J=6.8 Hz, 4H), 4.75 (m, 1H); ESI-MS m/z: 766.7 [M+H].sup.+.
Example 22: Synthesis of Compound 22
[1148] ##STR00156##
[1149] Referring to the method of Example 1, compound 22 was prepared as an oily product: 31.8 mg.
[1150] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.79 (t, J=7.2 Hz, 6H), 1.07 (s, 12H), 1.28 (m, 48H), 1.40 (m, 8H), 1.53 (m, 4H), 1.84 (m, 2H), 2.26 (t, J=7.2 Hz, 2H), 2.35 (s, 6H), 2.48 (m, 2H), 3.98 (t, J=6.8 Hz, 4H), 4.75 (m, 1H); ESI-MS m/z: 794.7 [M+H].sup.+.
Example 23: Synthesis of Compound 23
[1151] ##STR00157##
[1152] Referring to the method of Example 7, compound 23 was prepared as an oily product: 31.0 mg.
[1153] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.87 (t, J=7.2 Hz, 6H), 1.16 (s, 12H), 1.20-1.39 (m, 28H), 1.45-1.54 (m, 12H), 1.74-1.82 (m, 2H), 2.12-2.35 (m, 14), 4.63 (t, J=2.4 Hz, 4H), 4.79-4.88 (m, 1H); ESI-MS m/z: 730.6 [M+H].sup.+.
Example 24: Synthesis of Compound 24
[1154] ##STR00158##
[1155] Referring to the method of Example 7, compound 24 was prepared as an oily product: 31.0 mg.
[1156] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.88 (t, J=7.2 Hz, 6H), 1.15 (s, 12H), 1.20-1.38 (m, 24H), 1.43-1.52 (m, 12H), 1.76-1.84 (m, 2H), 2.09-2.14 (m, 4H), 2.23 (s, 6H), 2.28-2.36 (m, 4H), 2.43-2.49 (m, 4H), 4.10 (t, J=7.2 Hz, 4H), 4.80-4.88 (m, 1H); ESI-MS m/z: 730.6 [M+H].sup.+.
Example 25: Synthesis of Compound 25
[1157] ##STR00159##
[1158] Referring to the method of Example 7, compound 25 was prepared as an oily product: 32.1 mg.
[1159] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.84 (t, J=7.2 Hz, 6H), 1.08 (s, 12H), 1.02-1.21 (m, 12H), 1.38-1.47 (m, 22H), 1.59-1.78 (m, 6H), 2.02-2.17 (m, 14H), 2.19-2.30 (m, 4H), 4.01 (t, J=6.8 Hz, 4H), 4.71-4.83 (m, 1H); ESI-MS m/z: 730.6 [M+H].sup.+.
Example 26: Synthesis of Compound 26
[1160] ##STR00160##
[1161] Compound 23 (300 mg, 0.41 mmol) and quinoline (106 mg, 0.82 mmol) were dissolved in 3.0 mL of ethyl acetate, and the air in the reaction system was replaced with nitrogen for 2-3 min at room temperature, then lindlar catalyst (16.9 mg) was added. Hydrogen gas was introduced to the reaction solution and the air was replaced with hydrogen for 2˜3 min. The reaction system was kept under hydrogen atmosphere (15 psi) at room temperature for 30 min. The complete disappearance of the reactants was monitored by LC-MS. The reaction solution was filtered, and the filter cake was rinsed with ethyl acetate 3-4 times. The combined ethyl acetate was collected and the organic solvent was removed using a rotary-evaporator to give the crude product, which was purified by preparative high performance liquid chromatography to give compound 26 (31.3 mg).
[1162] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.81 (t, J=7.2 Hz, 6H), 1.08 (s, 12H), 1.15-1.28 (m, 32H), 1.38-1.44 (m, 8H), 1.70-1.79 (m, 2H), 2.01 (m, 4H), 2.15 (s, 6H), 2.16-2.28 (m, 4H), 4.54 (d, J=12.0 Hz, 4H), 4.75 (m, 1H), 5.39-5.59 (m, 4H); ESI-MS m/z: 734.6 [M+H].sup.+.
Example 27: Synthesis of Compound 27
[1163] ##STR00161##
[1164] Referring to the method of Example 26, compound 27 was prepared as an oily product: 35.0 mg.
[1165] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.82 (m, 6H), 1.08 (s, 12H), 1.14-1.31 (m, 28H), 1.37-1.45 (m, 8H), 1.70-1.79 (m, 2H), 1.96 (m, 4H), 2.06-2.36 (m, 14H), 3.98 (t, J=7.2 Hz, 4H), 4.74-4.82 (m, 1H), 5.22-5.31 (m, 2H), 5.37-5.48 (m, 2H); ESI-MS m/z: 734.7 [M+H].sup.+.
Example 28: Synthesis of Compound 28
[1166] ##STR00162##
[1167] Referring to the method of Example 26, compound 28 was prepared as an oily product: 31.8 mg.
[1168] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.92 (t, J=6.8 Hz, 6H), 1.18 (s, 12H), 1.21-1.39 (m, 22H), 1.40-1.59 (m, 12H), 1.60-1.72 (m, 4H), 1.89-2.01 (m, 2H), 2.02-2.15 (m, 8H), 2.34-2.69 (m, 8H), 4.08 (t, J=6.4 Hz, 4H), 4.82-4.92 (m, 1H), 5.30-5.48 (m, 4H); ESI-MS m/z: 734.6 [M+H].sup.+.
Example 30: Synthesis of Compound 30
[1169] ##STR00163##
[1170] Referring to the method of Example 1, compound 30 was prepared as an oily product: 33.0 mg.
[1171] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.92 (t, J=6.8 Hz, 6H), 1.18 (s, 12H), 1.19-1.37 (m, 36H), 1.45-1.57 (m, 8H), 1.58-1.74 (m, 8H), 2.27-2.50 (m, 8H), 4.07 (t, J=6.8 Hz, 4H), 4.83-4.90 (m, 1H); ESI-MS m/z: 710.6 [M+H].sup.+.
Example 32: Synthesis of Compound 32
[1172] ##STR00164##
[1173] Referring to the method of Example 1, compound 32 was prepared as an oily product: 31.1 mg.
[1174] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.80 (t, J=6.8 Hz, 6H), 1.08 (s, 12H), 1.20-1.27 (m, 34H), 1.34-1.47 (m, 12H), 1.48-1.62 (m, 8H), 2.15 (s, 6H), 2.19-2.24 (m, 4H), 3.97 (t, J=6.8 Hz, 4H), 4.74-4.80 (m, 1H); ESI-MS m/z: 738.6 [M+H].sup.+.
Example 33: Synthesis of Compound 33
[1175] ##STR00165##
[1176] Compound 1-6 (448 mg, 1.3 mmol) was dissolved in 5.0 mL of dichloromethane, and the reaction system was cooled to 0° C. in an ice bath. DMF (10 μL, 0.13 mmol) was added, and oxalyl chloride (0.44 mL, 5.2 mmol) was then added dropwise to the reaction solution. The ice bath was removed after the dropwise addition was completed and the mixture was stirred for 1 h at room temperature. The solvent was removed using a rotary-evaporator to give acyl chloride crude product (330 mg) as an oil, which was used directly in the next reaction step.
[1177] 1-Decanethiol 33-1 (455 mg, 2.61 mmol) was added to a solution of crude acyl chloride (330 mg, 0.87 mmol) in DCE (3.0 mL), and the reaction was heated to 70° C. to react overnight. The reaction solution was cooled to room temperature and the solvent was removed using a rotary-evaporator to give the crude product, which was purified by silica gel column to give compound 33-2 (400 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.84-0.87 (m, 6H), 1.14-1.18 (m, 12H), 1.20-1.28 (m, 36H), 1.48-1.55 (m, 12H), 2.33 (t, J=7.2 Hz, 4H), 2.79 (t, J=7.2 Hz, 4H).
[1178] Compound 33-2 (300 mg, 0.46 mmol) was dissolved in 3.0 mL of methanol and NaBH.sub.4 (52.5 mg, 1.38 mmol) was added in batches. The reaction solution was stirred under nitrogen atmosphere at room temperature for 2 h. The complete disappearance of the reaction material was monitored by TLC. The reaction solution was quenched by adding saturated ammonium chloride solution, and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was collected and concentrated to give 300 mg of crude compound 33-3, which was directly used in the next reaction step without further purification.
[1179] Crude compound 33-3 (150 mg, 0.23 mmol) was dissolved in 3.0 mL of dichloromethane, and 1-10 (80.2 mg, 0.69 mmol), EDCI (131 mg, 0.69 mmol), triethylamine (0.1 mL, 0.69 mmol) and DMAP (28 mg, 0.23 mmol) were added to the reaction system. The reaction solution was stirred at room temperature for 12 h. The reaction solution was then quenched by adding saturated ammonium chloride solution, and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was collected and concentrated to give the crude product, which was passed through preparative high performance liquid chromatography to give compound 33 (28.6 mg).
[1180] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.81 (t, J=7.2 Hz, 6H), 1.15 (s, 12H), 1.31 (m, 40H), 1.48 (m, 12H), 2.23 (s, 6H), 2.42 (m, 4H), 2.80 (t, J=7.2 Hz, 4H), 4.82 (m, 1H); ESI-MS m/z: 756.6 [M+H].sup.+.
Example 34: Synthesis of Compound 34
[1181] ##STR00166##
[1182] Referring to the method of Example 33, compound 34 was prepared as an oily product: 105.2 mg.
[1183] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.85 (t, J=7.2 Hz, 6H), 1.15 (s, 12H), 1.6-1.32 (m, 40H), 1.37-1.53 (m, 14H), 1.75 (m, 2H), 2.24-2.34 (m, 8H), 2.80 (t, J=7.2 Hz, 4H), 4.72-4.82 (m, 1H); ESI-MS m/z: 770.6 [M+H].sup.+.
Example 36: Synthesis of Compound 36
[1184] ##STR00167##
[1185] Referring to the method of Example 33, compound 36 was prepared as an oily product: 33.4 mg.
[1186] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.86 (t, J=6.8 Hz, 6H), 1.16 (s, 12H), 1.18-1.38 (m, 40H), 1.41-1.59 (m, 16H), 1.61-1.67 (m, 2H), 2.19-2.33 (m, 10H), 2.82 (t, J=7.2 Hz, 4H), 4.83 (m, H); ESI-MS m/z: 798.6 [M+H].sup.+.
Example 37: Synthesis of Compound 37
[1187] ##STR00168##
[1188] Referring to the method of Example 33, compound 37 was prepared as an oily product: 33.2 mg.
[1189] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.87 (t, J=6.8 Hz, 6H), 1.20 (s, 12H), 1.19-1.37 (m, 36H), 1.39-1.56 (m, 12H), 1.75-1.84 (m, 2H), 2.24 (s, 6H), 2.28-2.34 (m, 4H), 2.81 (t, J=7.2 Hz, 4H), 4.79-4.87 (m, 1H); ESI-MS m/z: 742.6 [M+H].sup.+.
Example 39: Synthesis of Compound 39
[1190] ##STR00169##
[1191] Referring to the method of Example 33, compound 39 was prepared as an oily product: 30.7 mg.
[1192] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.91 (t, J=7.2 Hz, 6H), 1.22 (s, 12H), 1.17-1.38 (m, 32H), 1.47-1.58 (m, 12H), 1.78-1.87 (m, 2H), 2.28 (s, 6H), 2.34-2.37 (m, 4H), 2.85 (t, J=7.2 Hz, 4H), 4.81-4.90 (m, 1H); ESI-MS m/z: 714.6 [M+H].sup.+.
Example 40: Synthesis of Compound 40
[1193] ##STR00170##
[1194] Potassium carbonate (1.55 g, 11.2 mmol, 4.0 eq.) was added to a solution of compound 1-6 (959 mg, 2.8 mmol, 1.0 eq.) and 3-1 (638 mg, 3.08 mmol, 1.1 eq.) in DMF. Then the reaction was warmed up to 60° C. for 4 h. The reaction was cooled to room temperature. The reaction system was quenched with saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give the crude product, which was purified by silica gel column to give compound 40-1 (682 mg).
[1195] Compound 40-1 (324 mg, 0.69 mmol, 1.0 eq.) was dissolved in 5.0 mL of dichloromethane, and the reaction system was cooled to 0° C. in an ice bath. 2 drops of DMF were added and oxalyl chloride (0.24 mL, 2.8 mmol, 4.0 eq.) was then added dropwise to the reaction solution. The ice bath was removed after the dropwise addition was completed and the mixture was stirred for 1 h at room temperature. The solvent was removed using a rotary-evaporator to give acyl chloride crude product (309 mg) as an oil, which was used directly in the next reaction step.
[1196] 1-Decanethiol 33-1 (331 mg, 1.9 mmol, 3.0 eq) was added to a solution of crude acyl chloride (309 mg) in DCE (3.0 mL), and the reaction was heated to 70° C. to react overnight. The reaction solution was cooled to room temperature and the solvent was removed using a rotary-evaporator to give the crude product, which was purified by silica gel column to give compound 40-2 (274 mg).
[1197] Then referring to the method of Example 1, compound 40 was prepared as an oily product: 34.2 mg.
[1198] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.81 (t, J=7.2 Hz, 6H), 1.05 (s, 6H), 1.12 (s, 6H), 1.08-1.28 (m, 36H), 1.37-1.57 (m, 14H), 1.71-1.76 (m, 2H), 2.22 (s, 6H), 2.25-2.31 (m, 4H), 2.75 (t, J=7.2 Hz, 2H), 3.97 (t, J=7.2 Hz, 2H), 4.75-4.84 (m, 1H); ESI-MS m/z: 740.6 [M+H].sup.+.
Example 41: Synthesis of Compound 41
[1199] ##STR00171##
[1200] Referring to the method of Example 40, compound 41 was prepared as an oily product: 31.1 mg.
[1201] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.86-0.89 (m, 6H), 1.10 (s, 6H), 1.15 (s, 6H), 1.08-1.31 (m, 34H), 1.41-1.61 (m, 14H), 1.74-1.82 (m, 2H), 2.17-2.35 (m, 10H), 2.85 (t, J=7.2 Hz, 2H), 4.03 (t, J=7.2 Hz, 2H), 4.82-4.87 (m, 1H); ESI-MS m/z: 726.6 [M+H].sup.+.
Example 42: Synthesis of Compound 42
[1202] ##STR00172##
[1203] Referring to the method of Example 40, compound 42 was prepare as an oily product: 30.9 mg.
[1204] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.77-0.82 (m, 6H), 1.05 (s, 6H), 1.10 (s, 6H), 1.11-1.28 (m, 31H), 1.33-1.42 (m, 9H), 1.47-1.59 (m, 2H), 1.73-1.81 (m, 2H), 2.08-2.14 (m, 2H), 2.21-2.33 (m, 10H), 3.97 (t, J=7.2 Hz, 2H), 4.55 (m, 2H), 4.72-4.81 (m, 1H); ESI-MS m/z: 706.6 [M+H].sup.+.
Example 43: Synthesis of Compound 43
[1205] ##STR00173##
[1206] Referring to the method of Example 26, compound 43 was prepared as an oily product: 31.3 mg.
[1207] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.80 (m, 6H), 1.05 (s, 12H), 1.08-1.28 (m, 34H), 1.36-1.47 (m, 8H), 1.49-1.58 (m, 2H), 1.73-1.82 (m, 2H), 1.98-2.07 (m, 2H), 2.21-2.38 (m, 8H), 3.97 (t, J=7.2 Hz, 2H), 4.53 (d, J=7.2 Hz, 2H), 4.72-4.78 (m, 1H), 5.41-5.59 (m, 2H); ESI-MS m/z: 708.6 [M+H].sup.+.
Example 44: Synthesis of Compound 44
[1208] ##STR00174##
[1209] Referring to the method of Example 40, compound 44 was prepared as an oily product: 33.1 mg.
[1210] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.85 (m, 9H), 1.13 (s, 12H), 1.14-1.33 (m, 46H), 1.37-1.59 (m, 16H), 1.78-1.87 (m, 2H), 2.17-2.35 (m, 10H), 4.03 (t, J=6.8 Hz, 2H), 4.79-4.88 (m, 2H); ESI-MS m/z: 822.8 [M+H].sup.+.
Example 45: Synthesis of Compound 45
[1211] ##STR00175##
[1212] n-Nonanoic acid (3.0 g, 19 mmol) was added to 50 mL of anhydrous tetrahydrofuran and the reaction solution was cooled to 0° C. in an ice bath. Sodium hydride (836 mg, 20.9 mmol) and LDA (49.4 mL, 24.7 mmol) were added to the reaction solution, and the reaction solution was stirred at 0° C. for 1 hour. Then 1-iodoheptane was added dropwise to the reaction system. The ice bath was removed, then the mixture was reacted at room temperature for 12 h. The reaction solution was quenched by pouring the reaction solution into saturated ammonium chloride solution, and extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was collected, and concentrated to remove the solvent to give the crude product, which was purified by silica gel column to give 2.0 g of compound 2-heptylnonanoic acid.
[1213] The 2-heptylnonanoic acid (2.0 g, 7.8 mmo) obtained in the previous step was dissolved in 30 mL of anhydrous tetrahydrofuran, and lithium tetrahydroaluminum (593 mg, 15.6 mmol) was added to the reaction solution. The reaction system was heated to 80° C. to react for 2 hours. The reaction solution was cooled to room temperature, quenched by pouring the reaction solution into saturated ammonium chloride solution, and extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was collected, and concentrated to remove the solvent to give the crude product, which was purified by silica gel column to give 1.3 g of compound 45-1.
[1214] Then referring to the method of Example 40, compound 45 was prepared as an oily product: 31.6 mg.
[1215] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.88 (t, J=6.8 Hz, 9H), 1.14 (s, 12H), 1.15-1.26 (m, 47H), 1.47-1.50 (m, 8H), 1.57-1.62 (m, 4H), 1.79-1.81 (m, 2H), 2.25 (s, 6H), 2.32 (t, J=7.2 Hz, 4H), 3.93 (d, J=5.6 Hz, 2H), 4.03 (t, J=7.2 Hz, 2H), 4.81-4.87 (m, 1H); ESI-MS m/z: 808.7 [M+H].sup.+.
Example 46: Synthesis of Compound 46
[1216] ##STR00176##
[1217] Referring to the method of Example 40, compound 46 was prepared as an oily product: 32.6 mg.
[1218] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.88 (t, J=7.2 Hz, 9H), 1.14 (s, 12H), 1.15-1.28 (m, 37H), 1.47-1.59 (m, 18H), 1.75-1.84 (m, 2H), 2.24-2.35 (m, 10H), 3.95 (d, J=5.6 Hz, 2H), 4.03 (t, J=6.8 Hz, 2H), 4.80-4.87 (m, 1H); ESI-MS m/z: 780.7 [M+H].sup.+.
Example 47: Synthesis of Compound 47
[1219] ##STR00177##
[1220] Referring to the method of Example 7, compound 47 was prepared as an oily product: 33.1 mg.
[1221] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.81 (t, J=6.8 Hz, 12H), 1.08 (s, 12H), 1.09-1.24 (m, 56H), 1.40-1.61 (m, 14H), 1.67-1.72 (m, 2H), 2.17 (s, 6H), 2.19-2.28 (m, 4H), 3.88 (d, J=5.6 Hz, 4H), 4.74-4.80 (m, 1H); ESI-MS m/z: 906.8 [M+H].sup.+.
Example 48: Synthesis of Compound 48
[1222] ##STR00178##
[1223] Referring to the method of Example 7, compound 48 was prepared as an oily product: 34.8 mg.
[1224] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.81 (t, J=7.2 Hz, 12H), 1.08 (s, 12H), 1.09-1.23 (m, 48H), 1.37-1.64 (m, 14H), 1.67-1.73 (m, 2H), 2.15 (s, 6H), 2.20-2.37 (m, 4H), 3.88 (d, J=5.6 Hz, 4H), 4.74-4.89 (m, 1H); ESI-MS m/z: 850.8 [M+H].sup.+.
[1225] The compounds of Table 2 were synthesized using the methods of the above examples, or similar methods using the corresponding intermediates.
TABLE-US-00002 TABLE 2
Example 90: Synthesis of Compound 90
[1226] ##STR00219##
[1227] Referring to the method of Example 1, compound 90 was prepared as an oily product: 40.5 mg.
[1228] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.81 (t, J=6.8 Hz, 6H), 1.08 (s, 12H), 1.10-1.28 (m, 36H), 1.38-1.47 (m, 12H), 1.50-1.58 (m, 4H), 2.40 (m, 6H), 2.58 (t, J=6.8 Hz, 2H), 3.59-3.65 (m, 4H), 3.97 (t, J=6.8 Hz, 4H), 4.75-4.83 (m, 1H); ESI-MS m/z: 766.7 [M+H].sup.+.
Example 91: Synthesis of Compound 91
[1229] ##STR00220##
[1230] Referring to the method of Example 1, compound 91 was prepared as an oily product: 32.2 mg.
[1231] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.88 (t, J=6.8 Hz, 6H), 1.15 (s, 12H), 1.16-1.38 (m, 40H), 1.46 (m, 8H), 1.60 (m, 4H), 2.59 (m, 4H), 3.19 (s, 2H), 3.76 (t, J=4.8 Hz, 4H), 4.04 (t, J=6.8 Hz, 4H), 4.91 (m, 1H); ESI-MS m/z: 752.7 [M+H].sup.+.
Example 92: Synthesis of Compound 92
[1232] ##STR00221##
[1233] Referring to the method of Example 1, compound 92 was prepared as an oily product: 32 mg.
[1234] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.87 (t, J=6.8 Hz, 6H), 1.13 (s, 12H), 1.28 (m, 42H), 1.46 (m, 8H), 1.45 (m, 4H), 1.76 (m, 4H), 2.50 (m, 4H), 2.76 (m, 2H), 4.01 (t, J=6.8 Hz, 4H), 4.84 (m, 1H); ESI-MS m/z: 750.9 [M+H].sup.+.
Example 93: Synthesis of Compound 93
[1235] ##STR00222##
[1236] 3-Bromopropanol (20 g, 144 mmol), trifluoromethanesulfonic anhydride (26.6 mL, 158 mmol) and pyridine (14.0 mL, 173 mmol) were added to a round bottom flask containing 500 mL of dichloromethane. The mixture was stirred at room temperature until the reaction materials were completely consumed by TLC monitoring. The reaction solution was quenched with 1 M hydrochloric acid solution, and extracted with dichloromethane. The organic phase were combined, dried over anhydrous sodium sulfate, and filtered to remove the sodium sulfate. The filtrate was collected. The solvent was removed using a rotary-evaporator to give 25 g of crude compound 93-2, which was used directly for subsequent reactions without further purification.
[1237] 3-3 (6.0 g, 10 mmol) and crude compound 93-2 (3.0 g, 11 mmol) were added to a round bottom flask containing 50 mL of nitromethane, then 2,6-di-tert-butylpyridine (3.37 mL, 15 mmol) was added to the reaction solution. The reaction solution was warmed up to 95° C. to react overnight. The reaction solution was cooled to room temperature. The solvent was removed using a rotary-evaporator to give the crude product. The crude product was then dissolved in dichloromethane, extracted after adding saturated aqueous ammonium chloride. The organic phase were collected and combined, dried over anhydrous sodium sulfate, and filtered to remove the sodium sulfate. The filtrate was collected. The solvent was removed using a rotary-evaporator and then purified by silica gel column to give compound 93-3 (2.3 g).
[1238] Compound 93-3 (251 mg, 0.35 mmol) and 2-ethylpiperidine (71 μL, 0.53 mmol) were dissolved in 3.0 mL of anhydrous acetonitrile and anhydrous potassium carbonate (73 mg, 0.53 mmol) was added to the reaction solution. The mixture was warmed up to 80° C. to react for 6 hours. The reaction solution was cooled to room temperature, quenched by adding saturated aqueous ammonium chloride, and extracted with dichloromethane. The organic phase were collected and combined, dried over anhydrous sodium sulfate, and filtered to remove the sodium sulfate. The filtrate was collected. The solvent was removed using a rotary-evaporator and then purified by preparative high performance liquid chromatography to give compound 93 (82 mg).
[1239] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.72-0.91 (m, 9H), 1.08 (s, 12H), 1.11-1.75 (m, 60H), 1.87-2.25 (m, 3H), 2.57-2.93 (m, 4H), 3.04-3.15 (m, 2H), 3.32-3.45 (m, 2H), 3.98 (d, J=6.8 Hz, 4H); ESI-MS m/z: 750.6 [M+H].sup.+.
Example 94: Synthesis of Compound 94
[1240] ##STR00223##
[1241] Referring to the method of Example 93, compound 94 was prepared as an oily product: 79.2 mg.
[1242] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.82 (t, J=7.2 Hz, 6H), 1.09 (s, 12H), 1.11-1.34 (m, 44H), 1.52 (m, 14H), 2.45-2.74 (m, 6H), 3.07 (m, 1H), 3.38 (m, 2H), 3.94 (t, J=6.8 Hz, 4H); ESI-MS m/z: 736.6 [M+H].sup.+.
[1243] The compounds of Table 3 were synthesized using the methods of the above examples, or similar methods using the corresponding intermediates.
TABLE-US-00003 TABLE 3
Example 97: Synthesis of Compound 97
[1244] ##STR00226##
[1245] To a round bottom flask were added CuCl (989 mg, 9.99 mmol) and 160 mL THF, and the reaction system was cooled to −30° C. Then 3-butenylmagnesium bromide (1 M, 299 mL) was added. 160 mL of solution of compound 97-1 (40.0 g, 199 mmol) in tetrahydrofuran was slowly added to the reaction system. After the dropwise addition was completed, the reaction system was warmed up to room temperature and stirred to react for another 2 hours. After the reaction material 97-1 was reacted completely by TLC monitoring, the reaction solution was quenched with 300 mL of saturated aqueous ammonium chloride, and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give the crude product. The crude was purified by silica gel column to give compound 97-2 (45.0 g).
[1246] Compound 97-2 (42.0 g, 164 mmol) was dissolved in 400 mL of DMSO, and 4 mL of water and LiCl (27.8 g, 655 mmol) were added to the reaction solution. Then the reaction system was heated to 180° C. and stirred until the reactant 97-2 was reacted completely by TLC monitoring. The reaction system was cooled to room temperature, then poured into water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give the crude product 97-3 (31.0 g), which was used directly in the next reaction without further purification.
[1247] Crude product 97-3 (30.0 g, 163 mmol) was dissolved in 240 mL of tetrahydrofuran and BH.sub.3.Math.THF (1 M, 244 mL) was added dropwise to the reaction solution in an ice bath. Then the mixture was warmed up to room temperature and stirred for 2 h. The reaction system was then cooled to 0° C. in an ice bath and methanol (13.2 mL, 325 mmol), Br.sub.2 (8.39 mL, 163 mmol) and sodium methoxide (43.9 g, 244 mmol) were added sequentially.
[1248] The mixture was warmed up to room temperature and stirred for another 1 h. The reaction solution was quenched with cold saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give the crude product, which was purified by silica gel column to give compound 97-4 (14.0 g).
[1249] Then referring to the method of Example 1, compound 97 was prepared as an oily product: 31.6 mg.
[1250] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.84-0.90 (m, 6H), 0.93-1.01 (m, 12H), 1.20-1.31 (m, 32H), 1.45-1.62 (m, 16H), 2.17 (s, 4H), 2.19-2.44 (m, 8H), 3.99-4.08 (m, 4H), 4.81-4.91 (m, 1H); ESI-MS m/z: 710.7 [M+H].sup.+.
Example 98: Synthesis of Compound 98
[1251] ##STR00227##
[1252] Referring to the method of Example 97, compound 98 was prepared as an oily product: 31.0 mg.
[1253] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.88 (t, J=6.8 Hz, 9H), 0.97 (s, 12H), 1.25-1.39 (m, 38H), 1.45-1.59 (m, 10H), 1.79 (m, 2H), 2.06-2.13 (m, 2H), 2.18 (m, 4H), 2.20-2.39 (m, 9H), 3.94 (d, J=5.6 Hz, 2H), 4.59 (d, J=6.8 Hz, 2H), 4.82-4.87 (m, 1H), 5.48-5.53 (m, 1H), 5.60-5.64 (m, 1H); ESI-MS m/z: 792.7 [M+H].sup.+.
Example 99: Synthesis of Compound 99
[1254] ##STR00228##
[1255] A solution of compound 1-1 (100 g, 979 mmol) in tetrahydrofuran (800 mL) was cooled to −40° C. LDA (2 M, 490 mL) was added slowly dropwise to the solution and the mixture was stirred for another 1 h after completion of the dropwise addition. A solution of 1-2 (315 g, 1.37 mol) in tetrahydrofuran (100 mL) was added dropwise to the reaction system at the same temperature and the reaction system was stirred overnight. The reaction system was quenched with saturated aqueous ammonium chloride, and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give the crude product. The crude product was purified by silica gel column to give compound 1-3 (115 g). .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.06-1.11 (m, 6H), 1.13-1.22 (m, 2H), 1.29-1.39 (m, 2H), 1.42-1.49 (m, 2H), 1.73-1.82 (m, 2H), 3.28-3.40 (m, 2H), 3.55-3.66 (m, 3H).
[1256] A solution of compound 1-3 (100 g, 398 mmol), TsCH.sub.2CN (38.9 g, 199 mmol) and TBAI (14.7 g, 39.8 mmol) in dimethyl sulfoxide (800 mL) was cooled to 0° C., and sodium hydride (20.7 g, 517 mmol, 60% purity) was added slowly in batches. The mixture was reacted at room temperature overnight. The reaction system was quenched with saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give 115 g of crude compound 1-4, which was used directly in the next reaction without isolation and purification.
[1257] To a solution of compound 1-4 crude (110 g, 205 mmol) in dichloromethane (880 mL) was added 330 mL of concentrated hydrochloric acid, and the mixture was reacted at room temperature for 2 h. The complete reaction of the substrate was monitored by TLC. The reaction system was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give the crude product. The crude product was purified by silica gel column to give compound 1-5 (30.0 g, 80.9 mmol, 39.4%).
[1258] TMSOK (11.0 g, 86.4 mmol) was added to a solution of compound 1-5 (8.0 g, 21.6 mmol) in tetrahydrofuran (35.0 mL) at room temperature, and the reaction system was heated to 70° C. with stirring. The complete consumption of reaction materials was monitored by TLC. The reaction solution was cooled to room temperature, and the organic solvent was removed by rotary evaporation. The crude product was added to 20 mL of water and extracted with dichloromethane. The aqueous layer was collected, and the solution was adjusted to a pH of <5 with 1 M hydrochloric acid. The solution was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was collected and concentrated to give compound 1-6 (7.0 g). .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.03 (s, 12H), 1.08-1.17 (m, 8H), 1.34-1.45 (m, 8H), 2.21 (t, J=7.2 Hz, 4H).
[1259] Potassium carbonate (482 mg, 3.48 mmol) was added to a solution of compound 1-6 (294 mg, 0.87 mmol) and 1-7 (771 mg, 3.48 mmol) in DMF, then the reaction was warmed up to 60° C. for 6 h. The complete disappearance of reactant 1-6 was monitored. The mixture was cooled to room temperature. The reaction system was quenched with saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give the crude product. The crude was purified by silica gel column to give compound 1-8 (325 mg).
[1260] Compound 1-8 (325 mg) was dissolved in 4.0 mL of methanol and sodium borohydride (30 mg, 0.84 mmol) was added to the reaction system. The mixture was reacted at room temperature. The complete disappearance of the reactants was monitored by TLC. The reaction system was quenched with saturated aqueous sodium chloride solution and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give crude compound 1-9 (260 mg), which was used directly in the next reaction without purification.
[1261] Crude compound 1-9 (250 mg, 0.40 mmol), 1-11 (35.9 mg, 0.60 mmol), EDCI (230 mg, 1.20 mmol), triethylamine (0.17 mL, 1.20 mmol) and DMAP (49 mg, 0.40 mmol) were dissolved in 5.0 mL of dichloromethane, and the reaction solution was stirred to react at room temperature for 12 h. The reaction solution was quenched with saturated aqueous sodium chloride and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The organic phase was collected and the organic solvent was removed using a rotary-evaporator to give the crude product, which was purified by preparative high performance liquid chromatography to give compound 99 (31.6 mg)
[1262] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.86 (t, J=6.8 Hz, 6H), 1.13 (s, 12H), 1.25 (m, 43H), 1.46 (m, 8H), 1.57 (m, 4H), 1.84 (m, 4H), 2.33 (s, 3H), 2.86 (m, 2H), 4.01 (m, 4H), 4.81 (m, 1H); ESI-MS m/z: 751.0 [M+H].sup.+.
Example 100: Synthesis of Compound 100
[1263] ##STR00229##
[1264] Referring to the method of Example 99, compound 100 was prepared as an oily product: 33.5 mg.
[1265] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.81 (t, J=6.8 Hz, 6H), 1.08 (s, 12H), 1.11-1.31 (m, 30H), 1.41 (m, 9H), 1.54 (m, 5H), 1.65-1.77 (m, 2H), 1.78-1.98 (m, 4H), 2.20 (m, 4H), 2.74 (m, 2H), 3.97 (t, J=6.8 Hz, 4H), 4.71-4.85 (m, 1H); ESI-MS m/z: 694.6 [M+H].sup.+.
Example 101: Synthesis of Compound 101
[1266] ##STR00230##
[1267] Referring to the method of Example 99, compound 101 was prepared as an oily product: 30.8 mg.
[1268] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.81 (t, J=6.8 Hz, 6H), 0.96 (d, J=6.8 Hz, 6H), 1.08 (s, 12H), 1.11-1.31 (m, 32H), 1.35-1.46 (m, 8H), 1.54 (m, 4H), 1.59-1.74 (m, 4H), 2.01-2.13 (m, 3H), 2.62 (m, 1H), 2.77 (m, 2H), 3.97 (t, J=6.8 Hz, 4H), 4.71-4.83 (m, 1H); ESI-MS m/z: 722.6 [M+H].sup.+.
Example 102: Synthesis of Compound 102
[1269] ##STR00231##
[1270] Referring to the method of Example 99, compound 102 was prepared as an oily product: 32.4 mg.
[1271] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.90 (t, J=6.8 Hz, 6H), 1.17 (s, 12H), 1.20-1.41 (m, 34H), 1.44-1.55 (m, 8H), 1.57-1.69 (m, 5H), 1.73-1.86 (m, 3H), 1.92 (m, 2H), 2.02 (m, 2H), 2.21-2.33 (m, 4H), 2.82-2.85 (m, 2H), 4.06 (t, J=6.8 Hz, 4H), 4.84-4.90 (m, 1H); ESI-MS m/z: 722.6 [M+H].sup.+.
Example 103: Synthesis of Compound 103
[1272] ##STR00232##
[1273] Referring to the method of Example 99, compound 103 was prepared as an oily product: 32.8 mg.
[1274] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.81 (t, J=6.8 Hz, 6H), 0.96 (d, J=6.8 Hz, 6H), 1.08 (s, 12H), 1.11-1.33 (m, 34H), 1.34-1.47 (m, 8H), 1.54 (m, 5H), 1.60-1.75 (m, 3H), 1.83 (m, 2H), 2.03-2.24 (m, 3H), 2.56-2.79 (m, 3H), 3.97 (t, J=6.8 Hz, 4H), 4.74-4.81 (m, 1H); ESI-MS m/z: 750.6 [M+H].sup.+.
Example 104: Synthesis of Compound 104
[1275] ##STR00233##
[1276] Compound 1-6 (448 mg, 1.3 mmol) was dissolved in 5.0 mL of dichloromethane, and the reaction system was cooled to 0° C. in an ice bath. DMF (10 μL, 0.13 mmol) was added and oxalyl chloride (0.44 mL, 5.2 mmol) was then added dropwise to the reaction solution. The ice bath was removed after the dropwise addition was completed and the mixture was stirred for 1 h at room temperature. The solvent was removed using a rotary-evaporator to give acyl chloride crude product (330 mg) as an oil, which was used directly in the next reaction step.
[1277] 1-Decanethiol 33-1 (455 mg, 2.61 mmol) was added to a solution of crude acyl chloride (330 mg, 0.87 mmol) in DCE (3.0 mL), and the reaction was heated to 70° C. to react overnight. The reaction solution was cooled to room temperature and the solvent was removed using a rotary-evaporator to give the crude product, which was purified by silica gel column to give compound 33-2 (400 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.84-0.87 (m, 6H), 1.14-1.18 (m, 12H), 1.20-1.28 (m, 36H), 1.48-1.55 (m, 12H), 2.33 (t, J=7.2 Hz, 4H), 2.79 (t, J=7.2 Hz, 4H).
[1278] Compound 33-2 (300 mg, 0.46 mmol) was dissolved in 3.0 mL of methanol and NaBH.sub.4 (52.5 mg, 1.38 mmol) was added in batches. The reaction solution was stirred under nitrogen atmosphere at room temperature for 2 h. The complete disappearance of the reaction material was monitored by TLC. The reaction solution was quenched by adding saturated ammonium chloride solution, and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was collected and concentrated to give 300 mg of crude compound 33-3, which was directly used in the next reaction step without further purification.
[1279] Crude compound 33-3 (300 mg, 0.46 mmol), 1-11 (98.8 mg, 0.69 mmol), EDCI (264.5 mg, 1.38 mmol), triethylamine (0.19 mL, 1.38 mmol) and DMAP (56.2 mg, 0.46 mmol) were dissolved in 8.0 mL of dichloromethane, and the reaction solution was stirred at room temperature until the reaction material 33-3 was completely consumed. The reaction solution was quenched with saturated aqueous sodium chloride and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The organic phase was collected, and the organic solvent was removed using a rotary-evaporator. The crude product was purified by preparative high performance liquid chromatography to give the compound 104 (67.3 mg).
[1280] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.81 (t, J=6.8 Hz, 6H), 1.08 (s, 12H), 1.09-1.31 (m, 42H), 1.35-1.51 (m, 14H), 1.61-2.25 (m, 8H), 2.73 (t, J=7.2 Hz, 4H), 4.77 (m, 1H); ESI-MS m/z: 782.7 [M+H].sup.+.
Example 105: Synthesis of Compound 105
[1281] ##STR00234##
[1282] Referring to the method of Example 104, compound 105 was prepared as an oily product: 27.1 mg.
[1283] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.85-0.89 (m, 6H), 1.02 (br d, J=6.4 Hz, 6H), 1.18 (s, 12H), 1.20-1.40 (m, 40H), 1.42-1.59 (m, 12H), 1.64-1.83 (m, 3H), 1.87-1.93 (m, 2H), 2.11-2.23 (m, 3H), 2.66-2.94 (m, 6H), 4.72-4.94 (m, 1H); ESI-MS m/z: 810.6 [M+H].sup.+.
Example 106: Synthesis of Compound 106
[1284] ##STR00235##
[1285] Referring to the method of Example 104, compound 106 was prepared as an oily product: 38.4 mg.
[1286] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.88 (t, J=7.2 Hz, 6H), 1.17 (s, 12H), 1.15-1.34 (m, 36H), 1.43-1.57 (m, 15H), 1.69-2.09 (m, 5H), 2.27-2.34 (m, 3H), 2.77-2.86 (m, 5H), 4.78-4.85 (m, 1H); ESI-MS m/z: 754.6 [M+H].sup.+.
Example 107: Synthesis of Compound 107
[1287] ##STR00236##
[1288] Referring to the method of Example 104, compound 107 was prepared as an oily product: 39 mg.
[1289] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.88 (t, J=6.8 Hz, 6H), 1.05 (d, J=6.8 Hz, 6H), 1.16 (s, 12H), 1.12-1.35 (m, 34H), 1.37-1.55 (m, 15H), 1.62-1.92 (m, 4H), 2.15-2.19 (m, 3H), 2.71-2.93 (m, 6H), 4.78-4.85 (m, 1H); ESI-MS m/z: 782.6 [M+H].sup.+.
Example 108: Synthesis of Compound 108
[1290] ##STR00237##
[1291] Referring to the method of Example 104, compound 108 was prepared as an oily product: 43.8 mg.
[1292] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.88 (t, J=6.80 Hz, 6H), 1.18 (s, 12H), 1.20-1.39 (m, 38H), 1.40-1.62 (m, 14H), 1.66-1.86 (m, 3H), 1.89-2.10 (m, 2H), 2.19-2.27 (m, 3H), 2.28 (br s, 2H), 2.79-2.83 (m, 4H), 4.79-4.88 (m, 1H); ESI-MS m/z: 768.5 [M+H].sup.+.
Example 109: Synthesis of Compound 109
[1293] ##STR00238##
[1294] Referring to the method of Example 104, compound 109 was prepared as an oily product: 44.8 mg.
[1295] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.86-0.89 (m, 6H), 1.18 (s, 15H), 1.23-1.37 (m, 36H), 1.46-1.54 (m, 14H), 1.76-1.93 (m, 4H), 2.11-2.20 (m, 1H), 2.24-2.28 (m, 2H), 2.54-2.71 (m, 2H), 2.81 (d, J=7.2 Hz, 4H), 3.08-3.24 (m, 2H), 4.79-4.88 (m, 1H); ESI-MS m/z: 782.6 [M+H].sup.+.
Example 110: Synthesis of Compound 110
[1296] ##STR00239##
[1297] Referring to the method of Example 104, compound 110 was prepared as an oily product: 34.4 mg.
[1298] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.81 (t, J=7.2 Hz, 6H), 1.12 (s, 12H), 1.14-1.27 (m, 34H), 1.44-1.48 (m, 12H), 1.66-1.77 (m, 7H), 2.05-2.24 (m, 4H), 2.53 (m, 2H), 2.75 (t, J=7.2 Hz, 4H), 2.90-2.92 (m, 2H), 3.57 (t, J=5.2 Hz, 2H), 4.74-4.80 (m, 1H); ESI-MS m/z: 798.6 [M+H].sup.+.
Example 111: Synthesis of Compound 111
[1299] ##STR00240##
[1300] Referring to the method of Example 104, compound 111 was prepared as an oily product: 31.4 mg.
[1301] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.92 (t, J=6.8 Hz, 9H), 1.19 (s, 12H), 1.20-1.35 (m, 43H), 1.47-1.55 (m, 9H), 1.54-1.82 (m, 12H), 2.07-2.37 (m, 7H), 2.94-3.01 (m, 2H), 3.98 (d, J=6.8 Hz, 2H), 4.07 (t, J=6.8 Hz, 2H), 4.84-4.91 (m, 1H); ESI-MS m/z: 806.7 [M+H].sup.+.
Example 112: Synthesis of Compound 112
[1302] ##STR00241##
[1303] Referring to the method of Example 104, compound 112 was prepared as an oily product: 24.4 mg.
[1304] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.80-0.83 (m, 9H), 1.08 (s, 12H), 1.10-1.35 (m, 28H), 1.41-1.57 (m, 28H), 1.65-1.75 (m, 4H), 1.95-2.10 (m, 2H), 2.16 (d, J=6.4 Hz, 2H), 2.30 (s, 3H), 2.73-2.91 (m, 4H), 3.87 (d, J=5.6 Hz, 2H), 4.75-4.79 (m, 1H); ESI-MS m/z: 822.7 [M+H].sup.+.
Example 113: Synthesis of Compound 113
[1305] ##STR00242##
[1306] Referring to the method of Example 110, compound 113 was prepared as an oily product: 31.1 mg.
[1307] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.81 (t, J=7.2 Hz, 6H), 1.08 (s, 12H), 1.10-1.24 (m, 36H), 1.36-1.43 (m, 8H), 1.48-1.54 (m, 6H), 1.64-1.72 (m, 6H), 2.05 (t, J=6.8 Hz, 1H), 2.15 (d, J=6.8 Hz, 2H), 2.47 (t, J=5.6 Hz, 2H), 2.82-2.89 (m, 2H), 3.54 (t, J=5.6 Hz, 2H), 3.97 (t, J=6.8 Hz, 4H), 4.73-4.79 (m, 1H); ESI-MS m/z: 766.6 [M+H].sup.+.
Example 114: Synthesis of Compound 114
[1308] ##STR00243##
[1309] Referring to the method of Example 110, compound 114 was prepared as an oily product: 32.7 mg.
[1310] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.85-0.88 (m, 9H), 1.07 (s, 12H), 1.09-1.35 (m, 46H), 1.41-1.58 (m, 13H), 1.97-2.25 (m, 3H), 2.32 (d, J=5.6 Hz, 2H), 2.83-2.86 (m, 2H), 3.17-3.19 (m, 2H), 3.78-3.81 (d, J=7.2 Hz, 2H), 3.92 (d, J=5.6 Hz, 2H), 4.01 (t, J=6.4 Hz, 2H), 4.10 (m, 1H), 4.81-4.86 (m, 1H); ESI-MS m/z: 836.7 [M+H].sup.+.
Example 115: Synthesis of Compound 115
[1311] ##STR00244##
[1312] Referring to the method of Example 104, compound 115 was prepared as an oily product: 31.0 mg.
[1313] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.87-0.91 (m, 9H), 1.14-1.37 (m, 51H), 1.49-1.60 (m, 12H), 1.75-1.81 (m, 2H), 2.21-2.26 (m, 2H), 2.28 (s, 6H), 2.32-2.36 (m, 4H), 4.03 (t, J=6.4 Hz, 2H), 4.65 (s, 2H), 4.82-4.88 (m, 1H); ESI-MS m/z: 790.6 [M+H].sup.+.
Example 116: Synthesis of Compound 116
[1314] ##STR00245##
[1315] Referring to the method of Example 104, compound 116 was prepared as an oily product: 31.3 mg.
[1316] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.80-0.83 (m, 9H), 1.07-1.27 (m, 51H), 1.40-1.45 (m, 12H), 1.70-1.81 (m, 2H), 2.13-2.36 (m, 12H), 3.87 (d, J=5.6 Hz, 2H), 4.57 (s, 2H), 4.74-4.80 (m, 1H); ESI-MS m/z: 790.6 [M+H].sup.+.
Example 117: Synthesis of Compound 117
[1317] ##STR00246##
[1318] Referring to the method of Example 104, compound 117 was prepared as an oily product: 35.9 mg.
[1319] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.90 (t, J=6.8 Hz, 12H), 1.15 (s, 12H), 1.16-1.33 (m, 38H), 1.48-1.53 (m, 8H), 1.82-1.86 (m, 2H), 2.18-2.20 (m, 4H), 2.30-2.42 (m, 10H), 4.65 (m, 4H), 4.82-4.88 (m, 1H); ESI-MS m/z: 814.6 [M+H].sup.+.
Example 118: Synthesis of Compound 118
[1320] ##STR00247##
[1321] Referring to the method of Example 104, compound 118 was prepared as an oily product: 32.0 mg.
[1322] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.87-0.90 (m, 9H), 1.15-1.32 (m, 50H), 1.40-1.61 (m, 16H), 1.76-1.84 (m, 2H), 2.23 (s, 6H), 2.29-2.34 (m, 6H), 4.04 (t, J=6.8 Hz, 2H), 4.66 (d, J=2.0 Hz, 1H), 4.83-4.87 (m, 1H); ESI-MS m/z: 804.6 [M+H].sup.+.
Example 119: Synthesis of Compound 119
[1323] ##STR00248##
[1324] Referring to the method of Example 104, compound 119 was prepared as an oily product: 34.8 mg.
[1325] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.91-0.94 (m, 9H), 1.21-1.40 (m, 48H), 1.51-1.57 (m, 12H), 1.61-1.86 (m, 5H), 2.23 (m, 2H), 2.31 (s, 6H), 2.35-2.39 (m, 2H), 2.85 (t, J=7.2 Hz, 2H), 4.67 (t, J=2.0 Hz, 1H), 4.84-4.90 (m, 1H); ESI-MS m/z: 792.6 [M+H].sup.+.
Example 120: Synthesis of Compound 120
[1326] ##STR00249##
[1327] Referring to the method of Example 104, compound 120 was prepared as an oily product: 34.5 mg.
[1328] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.89 (t, J=6.8 Hz, 9H), 1.15-1.31 (m, 48H), 1.47-1.57 (m, 16H), 1.75-1.85 (m, 4H), 2.19-2.41 (m, 11H), 4.07 (t, J=6.8 Hz, 2H), 4.65 (t, J=2.0 Hz, 2H), 4.27-4.88 (m, 1H); ESI-MS m/z: 804.6 [M+H].sup.+.
Example 121: Synthesis of Compound 121
[1329] ##STR00250##
[1330] Referring to the method of Example 104, compound 121 was prepared as an oily product: 33.8 mg.
[1331] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.91-0.95 (m, 9H), 1.20-1.43 (m, 46H), 1.47-1.57 (m, 10H), 1.63-1.85 (m, 6H), 2.29-2.40 (m, 12H), 2.85 (t, J=7.2 Hz, 2H), 4.68 (s, 2H), 4.84-4.90 (m, 1H); ESI-MS m/z: 764.6 [M+H].sup.+.
Example 122: Synthesis of Compound 122
[1332] ##STR00251##
[1333] Referring to the method of Example 104, compound 122 was prepared as an oily product: 33.7 mg.
[1334] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.81 (t, J=6.8 Hz, 9H), 1.08-1.31 (m, 46H), 1.40-1.58 (m, 17H), 1.68-1.73 (m, 2H), 2.17 (s, 6H), 2.25 (t, J=7.2 Hz, 4H), 3.87 (d, J=5.6 Hz, 2H), 3.97 (t, J=6.8 Hz, 2H), 4.73-4.80 (m, 1H); ESI-MS m/z: 752.7 [M+H].sup.+.
Example 123: Synthesis of Compound 123
[1335] ##STR00252##
[1336] Referring to the method of Example 104, compound 123 was prepared as an oily product: 35.2 mg.
[1337] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.81 (t, J=6.8 Hz, 9H), 1.08 (s, 12H), 1.10-1.33 (m, 36H), 1.40-1.57 (m, 17H), 1.68-1.73 (m, 2H), 2.17 (s, 6H), 2.25 (t, J=7.2 Hz, 4H), 3.87 (d, J=5.6 Hz, 2H), 3.97 (t, J=6.8 Hz, 2H), 4.73-4.79 (m, 1H); ESI-MS m/z: 766.7 [M+H].sup.+.
Example 124: Synthesis of Compound 124
[1338] ##STR00253##
[1339] Referring to the method of Example 104, compound 124 was prepared as an oily product: 33.4 mg.
[1340] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.89 (t, J=6.8 Hz, 9H), 1.15 (s, 12H), 1.18-1.37 (m, 39H), 1.47-1.65 (m, 16H), 2.28 (s, 6H), 2.29-2.35 (m, 4H), 3.95 (d, J=5.6 Hz, 2H), 4.04 (t, J=6.8 Hz, 2H), 4.79-4.86 (m, 1H); ESI-MS m/z: 766.6 [M+H].sup.+.
Example 125: Synthesis of Compound 125
[1341] ##STR00254##
[1342] Referring to the method of Example 104, compound 125 was prepared as an oily product: 31.1 mg.
[1343] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.89 (t, J=6.8 Hz, 9H), 1.15 (s, 12H), 1.18-1.37 (m, 48H), 1.48-1.51 (m, 8H), 1.60-1.63 (m, 3H), 1.80-1.88 (m, 2H), 2.32-2.41 (m, 10H), 3.95 (d, J=5.6 Hz, 2H), 4.04 (t, J=6.8 Hz, 2H), 4.81-4.88 (m, 1H); ESI-MS m/z: 808.7 [M+H].sup.+.
Example 126 Synthesis of Compound 126
[1344] ##STR00255##
[1345] Referring to the method of Example 104, compound 126 was prepared as an oily product: 35.1 mg.
[1346] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.89 (t, J=6.8 Hz, 9H), 1.16 (s, 12H), 1.18-1.37 (m, 48H), 1.48-1.65 (m, 15H), 2.32-2.43 (m, 10H), 3.95 (d, J=5.6 Hz, 2H), 4.05 (t, J=6.8 Hz, 2H), 4.81-4.89 (m, 1H); ESI-MS m/z: 822.7 [M+H].sup.+.
Example 127: Synthesis of Compound 127
[1347] ##STR00256##
[1348] A solution of compound 127-1 (100 g, 552.4 mmol) in anhydrous ether (800 mL) was cooled to 0° C. in an ice bath, and methylmagnesium bromide (3 M in ether, 737 mL) was slowly added dropwise to the solution. After the dropwise addition was completed, the ice bath was removed and the mixture was stirred to react for 4 h at room temperature. The reaction system was quenched with saturated ammonium chloride aqueous solution, and extracted with ether. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give the crude product. The crude product was purified by silica gel column to give compound 127-2 (100 g).
[1349] Compound 127-2 (42 g, 232 mmol), compound 127-3 (30.3 mL, 278 mmol), Cp*TiCl.sub.3 (5.09 g, 23.2 mmol), zinc powder (45.5 g, 696 mmol), and triethylchlorosilane (116.8 mL, 696 mmol) were added to a round bottom flask. Then anhydrous tetrahydrofuran (1200 mL) was added to the reaction system and the reaction was carried out under the protection of argon gas. The reaction system was heated to 60° C. and stirred to react for 1 hour. The reaction system was quenched with saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give crude product 1-4, which was purified by silica gel column to give compound 127-4 (21 g).
[1350] Compound TosMIC (7.03 g, 36 mmol) was dissolved in DMSO (200 mL), and NaH (4.32 g, 60%, 108 mmol) was added to the reaction system in batches under ice bath conditions. After the addition was completed, the ice bath was removed and the mixture was reacted at room temperature for another 1 h. Compound 127-4 (21 g, 79 mmol) and TBAI (1.33 g, 3.6 mmol) were added to the reaction system, and the mixture was stirred at room temperature overnight. The reaction system was quenched with saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give crude compound 127-5 (21.9 g), which was used directly in the next reaction step without purification.
[1351] To a solution of crude compound 127-5 (21.9 g, 38.8 mmol) in dichloromethane (350 mL) was added 200 mL of concentrated hydrochloric acid, and the mixture was reacted at room temperature for 2 h. The complete reaction of the substrate was monitored by TLC. The reaction system was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give the crude product, which was purified by silica gel column to give compound 127-6 (12.5 g).
[1352] Compound 127-6 (12.5 g, 31.4 mmol) was dissolved in ethanol (20 mL)-water (40 mL), and NaOH (3.77 g, 94.2 mmol) was added to the mixed solution in batches under ice bath conditions. After the addition was completed, the ice bath was removed and the mixture was stirred at room temperature. The complete consumption of the reaction materials was monitored by TLC. The organic solvent was removed by rotary evaporation, and the residue was extracted with dichloromethane. The aqueous layer was collected, and the solution was adjusted to a pH of <5 with 1 M hydrochloric acid. The solution was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was collected and concentrated to give compound 127-7 (9.7 g).
[1353] DMF (17 μL, 0.22 mmol) was added to a solution of compound 127-7 (750 mg, 2.19 mmol) in dichloromethane (10.0 mL) under ice bath conditions, and oxalyl chloride (0.77 mL, 8.76 mmol) was then added dropwise to the reaction solution. The ice bath was removed, and the mixture was stirred for 1 h at room temperature. The solvent was removed using a rotary-evaporator to give acyl chloride crude product, which was used directly in the next reaction step.
[1354] The above obtained acyl chloride crude product was dissolved in 10.0 mL of 1,2-dichloroethane, and then compound 127-8 (693 mg, 4.38 mmol) was added to the reaction solution. The mixture was stirred at room temperature until the substrate was reacted completely. The solvent was removed using a rotary-evaporator. The crude was purified by silica gel column to give compound 127-9 (800 mg).
[1355] Compound 127-9 (800 mg, 1.29 mmol) was dissolved in 5.0 mL of methanol and sodium borohydride (146 mg, 3.87 mmol) was added to the reaction system. The mixture was reacted at room temperature. The complete disappearance of the reactants was monitored by TLC. The reaction system was quenched with saturated aqueous sodium chloride solution and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give crude compound 127-10 (800 mg), which was used directly in the next reaction without purification.
[1356] Crude compound 127-10 (300 mg, 0.48 mmol), 4-dimethylaminobutyric acid (94.4 mg, 0.72 mmol), EDCI (276 mg, 1.44 mmol), triethylamine (0.21 mL, 1.44 mmol) and DMAP (59 mg, 0.48 mmol) were dissolved in 5.0 mL of dichloromethane, and the reaction solution was stirred to react at room temperature for 12 h. The reaction solution was quenched with saturated aqueous sodium chloride and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The organic phase was collected, and the organic solvent was removed using a rotary-evaporator. The crude product was purified by preparative high performance liquid chromatography to give the compound 127 (43.6 mg)
[1357] .sup.1H NMR (400 MHz, CD.sub.3OD): δ ppm 0.77-0.93 (m, 28H), 1.08-1.74 (m, 38H), 1.76-1.84 (m, 2H), 1.22-2.27 (m, 10H), 2.33-2.37 (m, 4H), 4.03-4.12 (m, 4H), 4.92-4.97 (m, 1H); ESI-MS m/z: 738.6 [M+H].sup.+.
Example 128: Synthesis of Compound 128
[1358] ##STR00257##
[1359] Referring to the method of Example 127, compound 128 was prepared as an oily product: 64.2 mg.
[1360] .sup.1H NMR (400 MHz, CD.sub.3OD): δ ppm 0.86 (s, 12H), 0.91 (t, J=6.8 Hz, 12H), 1.22-1.37 (m, 48H), 1.51-1.61 (m, 14H), 1.78-1.86 (m, 2H), 2.24 (t, J=8.0 Hz, 4H), 2.30 (s, 6H), 2.37 (t, J=7.2 Hz, 2H), 2.43 (t, J=8.0 Hz, 2H), 4.10 (t, J=6.8 Hz, 4H), 4.92-4.97 (m, 1H); ESI-MS m/z: 878.7 [M+H].sup.+.
Example 129: Synthesis of Compound 129
[1361] ##STR00258##
[1362] Referring to the method of Example 127, compound 129 was prepared as an oily product: 67.0 mg.
[1363] .sup.1H NMR (400 MHz, CD.sub.3OD): δ ppm 0.86 (s, 12H), 0.88-0.93 (m, 12H), 1.12-1.40 (m, 52H), 1.49-1.56 (m, 8H), 1.59-1.66 (m, 4H), 1.77-1.84 (m, 4H), 2.22-2.27 (m, 10H), 2.34-2.38 (m, 4H), 4.01 (t, J=6.8 Hz, 4H), 4.91-4.97 (m, 1H); ESI-MS m/z: 906.8 [M+H].sup.+.
COMPARATIVE EXAMPLES
Synthesis of Comparative Compound 1 (D1)
[1364] D1 was prepared according to the method of Example 20, [M+H].sup.+: 654.6. .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.77-0.86 (t, J=7.2 Hz, 6H), 1.15-1.30 (m, 38H), 1.40-1.59 (m, 12H), 1.87-1.96 (m, 2H), 2.21 (t, J=7.2 Hz, 4H), 2.28-2.37 (m, 2H), 2.40-2.50 (m, 5H), 2.56-2.67 (m, 2H), 3.92-4.07 (m, 4H), 4.72-4.90 (m, 1H).
##STR00259##
Synthesis of Comparative Compound 2 (D2)
[1365] ##STR00260##
[1366] D2 was prepared according to the method of Example 46, [M+H].sup.+: 724.6. .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.89 (t, J=7.2 Hz, 9H), 1.21-1.30 (m, 44H), 1.50-1.63 (m, 11H), 1.77-1.92 (m, 2H), 2.27-2.36 (m, 14H), 3.97 (d, J=5.6 Hz, 2H), 4.06 (t, J=6.8 Hz, 2H), 4.85-4.92 (m, 1H).
[1367] Pharmacological Assay
Assay Example 1: Preparation of Nanoparticles
[1368] Materials used for lipid nanoparticle assembly include: (1) ionizable lipid compounds: e.g., ionizable lipids designed and synthesized in the present disclosure or DLin-MC3-DMA (purchased from AVT) as a control; (2) structure lipids: e.g., Cholesterol (purchased from Sigma-Aldrich); (3) phospholipids: e.g., DSPC i.e., 1,2-distearoyl-SN-glycero-3-phosphocholine (Distearoylphosphatidylcholine, purchased from AVT); (4) polyethylene glycolated lipids: e.g. DMG-PEG2000 i.e., dimyristoylglycero-polyethylene glycol 2000 (1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000, purchased from AVT); (5) active ingredients of nucleic acid fragments: e.g. Luciferase mRNA, siRNA, CRISPR Cas 9 mRNA, etc. (manufactured in-house). The names of materials of the lipid nanoparticle assembly and their structural formulae are detailed in Table 4.
TABLE-US-00004 TABLE 4 No. Name Structural formula 1 DLin-MC3- DMA
[1369] Lipid nanoparticles were prepared by (1) dissolving and mixing ionizable lipid compounds, cholesterol, phospholipids and polyethylene glycolated lipids in ethanol at (molar percentages) 50%, 38.5%, 10% and 1.5%, respectively; (2) dissolving the mRNA active ingredient in 25 mM sodium acetate solution (pH=4.5); (3) using an automated high-throughput microfluidic system to mix the organic phase containing the lipid mixture and the aqueous phase containing the mRNA component in the flow ratio range of 1:1 to 1:4 at a mixing speed of 10 mL/min to 18 mL/min; (4) the prepared lipid nanoparticles (N/P ratio of 6) were diluted with phosphate buffer solution and the nanoparticle solutions were ultrafiltered to the original preparation volume using ultrafiltration tubes (purchased from Millipore) with a cut-off molecular weight of 30 kDa; and (5) the obtained nanoparticles were filtered through a sterile 0.2 μm filter membrane and then stored in a sealed glass vial at low temperature.
[1370] The preparation method of lipid nanoparticles includes microfluidic mixing systems, but is not limited to this method, which also includes T-type mixers and ethanol injection method, and the like.
Assay Example 2: Characterization of Physical Properties of Lipid Nanoparticles
[1371] The particle size and particle size dispersity index (PDI) of the prepared lipid nanoparticles were measured using a Zetasizer Pro (purchased from Malvern Instruments Ltd) and a DynaPro NanoStar (purchased from Wyatt) dynamic light scattering instrument. The degree of RNA encapsulation by lipid nanoparticles was characterized by the Encapsulation Efficiency %, which reflects the degree of binding of lipid nanoparticles to RNA fragments. This parameter was measured by the method of Quant-It™ RiboGreen RNA Assay (purchased from Invitrogen). Lipid nanoparticle samples were diluted in TE buffer (10 mM Tris-HCl, 1 mM EDTA, pH=7.5). A portion of the sample solution was removed, to which 0.5% Triton (Triton X-100) was added, and then allowed to stand at 37° C. for 30 minutes. Immediately after the addition of RIBOGREEN® reaction solution, the fluorescence values were read on a Varioskan LUX multifunctional microplate reader (purchased from Thermofisher) at 485 nm for absorption and 528 nm for emission to give the encapsulation efficiency values.
Assay Example 3: Animal Experiment
[1372] The delivery effect and safety of nanoparticles encapsulated with luciferase mRNA (Trilink, L-7202) in mice were evaluated. The test mice were SPF-grade C57BL/6 mice, female, 6-8 weeks old, weighing 18-22 g, and were purchased from SPF (Beijing) Biotechnology Co., Ltd. All animals were acclimatized for more than 7 days prior to the experiment, and had free access to food and water during the experiment. The conditions include alternating light and dark for 12/12 h, the indoor temperature of 20-26° C. and the humidity of 40-70%. The mice were randomly grouped. The lipid nanoparticles encapsulated with luciferase mRNA prepared above were injected into mice by intravenous administration at a single dose of 0.5 mg/kg mRNA, and the mice were subjected to in vivo bioluminescence assay using a Small Animal In Vivo Imaging System (IVIS LUMINA III, purchased from PerkinElmer) at 6 h after administration. The assay was performed as follows: D-luciferin solution was prepared in saline at a concentration of 15 mg/mL, and each mouse was given the substrate by intraperitoneal injection. At ten minutes after administration of the substrate, the mice were anesthetized in an anesthesia chamber with isoflurane at a concentration of 2.5%. The anesthetized mice were placed in IVIS for fluorescence imaging, and data acquisition and analysis were performed on the concentrated distribution area of fluorescence.
[1373] The in vivo delivery efficiency of lipid nanoparticle carriers was expressed as the mean values of fluorescence intensity and total photon count in different animals within the same subject group, as shown in Table 5. Higher values of fluorescence intensity and total photon count indicate higher in vivo delivery efficiency of this mRNA fragment by lipid nanoparticles. The lipid nanoparticles containing the cationic lipids of the present disclosure have good in vivo delivery efficiency. Unexpectedly, compared with the molecule without tetramethyl, the corresponding lipid nanoparticles of the present disclosure have significantly increased in vivo delivery efficiency, e.g., compound 20 vs. D1, compound 46 vs. D2.
TABLE-US-00005 TABLE 5 Total photon Particle Encap- count in vivo Cationic Particle size sulation at 6 hours after lipid size dispersity efficiency administration compound (nm) (PDI) (%) (Total Flux) 1 80.07 0.06 91.54 6.43E+08 2 229.35 0.03 79.14 4.23E+08 3 133.80 0.04 86.88 1.75E+09 6 106.18 0.05 90.26 2.25E+09 7 203.67 0.04 69.51 1.16E+08 8 127.82 0.07 60.36 3.26E+07 9 352.82 0.07 19.41 6.05E+06 10 118.59 0.07 53.83 1.26E+09 11 46.49 0.03 95.61 4.42E+06 12 89.34 0.07 85.02 1.10E+09 13 157.10 0.08 56.65 1.08E+06 14 306.07 0.08 45.66 6.34E+07 15 91.68 0.06 84.78 4.89E+08 16 55.39 0.05 96.52 3.97E+07 17 81.43 0.12 30.95 6.77E+05 18 161.29 0.05 87.86 1.14E+10 19 135.15 0.19 67.96 3.20E+09 20 99.61 0.10 71.93 2.40E+10 23 151.35 0.07 70.22 1.43E+10 24 133.72 0.04 60.98 5.56E+09 25 236.90 0.06 32.43 1.89E+08 26 96.69 0.05 81.29 >4.00E+10 27 105.70 0.05 88.99 2.20E+10 28 138.16 0.06 80.36 3.21E+09 32 116.61 0.07 99.02 7.30E+09 33 105.84 0.04 88.67 2.12E+08 34 104.71 0.04 90.29 1.26E+10 36 88.33 0.07 97.52 4.84E+09 37 92.18 0.03 89.07 7.88E+09 40 83.90 0.05 97.06 4.22E+09 41 104.27 0.05 93.91 2.19E+10 42 152.04 0.07 71.95 5.32E+09 46 97.30 0.09 95.68 >4.00E+10 90 18.17 0.05 83.21 1.04E+07 91 32.61 0.05 102.99 1.29E+06 92 107.56 0.05 91.66 2.13E+09 97 157.00 0.25 93.72 3.37E+09 98 107.87 0.13 93.28 2.12E+10 99 139.99 0.05 90.69 5.30E+09 100 118.19 0.07 83.29 1.18E+10 101 152.45 0.06 76.09 5.19E+09 102 102.18 0.03 90.03 2.03E+10 103 148.67 0.04 90.97 5.69E+09 104 71.14 0.06 85.54 2.61E+10 105 78.80 0.05 94.67 3.33E+09 106 83.09 0.05 85.65 1.85E+10 107 99.54 0.05 83.74 1.36E+10 108 121.41 0.05 92.63 1.21E+10 109 101.04 0.06 87.11 1.32E+10 110 97.59 0.01 92.65 2.06E+08 111 141.30 0.06 95.12 1.79E+10 112 121.05 0.08 94.41 3.53E+10 113 112.65 0.03 94.77 3.59E+08 114 72.32 0.04 93.41 1.06E+08 115 77.12 0.04 91.76 2.56E+10 116 88.62 0.05 89.36 >4.00E+10 117 127.31 0.06 95.29 4.48E+09 118 88.33 0.07 93.87 3.14E+10 119 80.98 0.05 86.92 3.25E+10 120 98.99 0.07 95.55 3.15E+10 121 103.57 0.06 93.62 >4.00E+10 122 96.72 0.07 91.76 >4.00E+10 123 84.98 0.05 92.27 >4.00E+10 125 95.69 0.07 89.45 1.99E+10 126 133.76 0.06 94.35 1.77E+10 127 83.01 0.05 62.35 3.59E+10 128 83.10 0.05 79.88 1.00E+10 129 112.08 0.06 57.87 7.82E+09 DLin- 96.83 0.04 95.62 8.04E+09 MC3-D MA D1 131.2 0.18 97.08 4.45E+07 D2 245.33 0.20 79.63 1.57E+09
Assay Example 4: Evaluation of Delivery Efficiency and Safely In Vitro
[1374] The delivery effect and safety of nanoparticles encapsulated with luciferase mRNA were evaluated at the cellular level in vitro. The cells used in the assay were human embryonic kidney cells 293 (HEKi293T cells) cultured in DMEM (Dulbecco's Modified Eagle Medium) (purchased from Thermo Fisher) containing 1000 fetal bovine serum and 500 penicillin-streptomycin double antibiotics at a indoor temperature of 37° C. and a CO.sub.2 concentration of 500. The cells were uniformly dispersed and spread in 48-well plates, and incubated in the incubator for 24 h. Then a solution of the lipid nanoparticles encapsulated with luciferase mRNA were added. After 24 h, the cells were lysed, and the intracellular expression intensity and relative light units (RLU) of luciferase in each type of lipid nanoparticles were measured with a luciferase detection reagent (purchased from Promega). The higher the intensity of expression, the higher the delivery efficiency of the lipid material at the cellular level. Meanwhile, CCK-8 reagent (purchased from DOJINDO) was used in cytotoxicity testing for the parallel lipid nanoparticle-treated cell groups after 24 hours. In the test, the group of cells to which only PBS was added was used as a negative control. The procedure was as follows: after the addition of CCK-8 solution, the cells were left to stand in an incubator at 37° C. for 4 h. The absorbance values were read on a multifunctional microplate reader at an absorbance band of 450 nm. The ratio of the absorbance value of the nanoparticle-treated cells to that of the negative control was used as a characterization parameter for cell viability.
[1375] The delivery effects and the toxicity data of nanoparticles at the cellular level in vitro are shown in Table 6.
TABLE-US-00006 TABLE 6 Cell fluorescence Cationic lipids intensity (RLU) Cell viability (%) 32 6.99E+06 96.25 37 1.04E+07 97.48 41 1.23E+07 104.91 100 1.98E+06 104.67 DLin-MC3-DMA 2.95E+06 97.84
[1376] While the present disclosure has been fully described by way of its embodiments, it is worth noting that various variations and modifications are apparent to those skilled in the art. Such variations and modifications should all be included within the scope of the claims appended to this disclosure.