LSD1 inhibitor and preparation method and application thereof

1. A compound of formula (I), a pharmaceutically acceptable salt thereof or a tautomer thereof,

wherein,

f is 1 or 2;

r is 0, 1 or 2;

e is 0, 1, or 2;

p is 0 or 1;

m is 0, 1 or 2; n is 1 or 2; or the structural unit

each of R 1 and R 2 is independently selected from the group consisting of H, F, Cl, Br, I, OH, CN, NH 2 and —COOH, or is a C 1-3 alkyl optionally substituted by 1, 2 or 3 of R; or, R 1 and R 2 are connected together to form a 3-6-membered ring;

R 3 is -L-R 5 , or selected from the group consisting of a 5-12 membered heteroaryl, a C 3-7 cycloalkyl and a 4-8 membered heterocycloalkyl, each of which is optionally substituted by 1, 2 or 3 of R;

R 4 is H, or selected from the group consisting of a C 1-6 alkyl and a C 1-6 heteroalkyl, each of which is optionally substituted by 1, 2 or 3 of R;

R 5 is selected from the group consisting of cyclohexyl-CH 2 —, phenyl, a 5-10 membered heteroaryl, a C 3-10 cycloalkyl, a 4-10 membered heterocycloalkyl, a 5-6 membered heterocycloalkyl-C(═O)— and a 5-6 membered heterocycloalkyl-C 1-3 alkyl-, each of which is optionally substituted by 1, 2 or 3 of R;

R 6 is H, or selected from the group consisting of a C 1-6 alkyl and a C 1-6 heteroalkyl, each of which is optionally substituted by 1, 2 or 3 of R;

L is —C(═O)—, or selected from the group consisting of —C 1-6 alkyl- and -5-9 membered heteroaryl-, -4-8 membered heterocycloalkyl-, -phenyl- and —C 3-6 cycloalkyl-, each of which is optionally substituted by 1, 2 or 3 of R;

R is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, —COOH and NH 2 —C(═O)—, or selected from the group consisting of C 1-6 alkyl, C 1-6 heteroalkyl, phenyl-C 1-6 alkyl-, phenyl, 5-6 membered heteroaryl, phenyl-C(═O)—, C 3-6 cycloalkyl-C(═O)—, C 3-6 cycloalkyl-C(═O)—NH, C 3-6 cycloalkyl-NH—C(═O)— and C 3-6 cycloalkyl-C 1-3 alkyl-, each of which is optionally substituted by 1, 2 or 3 of R′;

R′ is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , COOH, C 1-3 alkyl, C 1-3 alkyl substituted by 1-3 halogen(s), C 1-3 alkyl-NH—, N,N-di(C 1-3 alkyl)-amino, C 1-3 alkyl-O—C(═O)—, C 3-6 cycloalkyl and C 1-3 alkoxyl;

each of the “hetero” in the 5-12 membered heteroaryl, 4-8 membered heterocycloalkyl, C 1-6 heteroalkyl, 5-10 membered heteroaryl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, 4-10 membered heterocycloalkyl is independently selected from the group consisting of —NH—, —S—, N, —O—, ═O, —C(═O)—, —NH—C(═O)—, —O—C(═O)—, —S(═O) 2 —, —S(═O)—, —C(═O)—NH—;

in any above cases, the number of the heteroatom or the heteroatomic group in the 5-12 membered heteroaryl, 4-8 membered heterocycloalkyl, C 1-6 heteroalkyl, 5-10 membered heteroaryl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, 4-10 membered heterocycloalkyl is independently 1, 2, 3 or 4.

2. The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 1 , wherein R′ is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , Me, Et, CF 3 , CHF 2 , CH 2 F, NHCH 3 , N(CH 3 ) 2 , COOH, —C(═O)—O—CH 3 , —O—CH 3 and

3. The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 1 , wherein R is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, COOH, NH 2 —C(═O)—, or selected from the group consisting of methyl, ethyl, propyl, isobutyl, tert-butyl, C 1-6 alkoxyl, phenyl-C 1-3 alkyl-, phenyl, pyridyl, 1,2,4-triazolyl, phenyl-C(═O)—, C 1-3 alkyl-C(═O)—, C 1-3 alkyl-NH—, cyclopropyl-C(═O)—, C 1-3 alkyl-O—C(═O)—C 1-3 alkyl-, C 1-3 alkyl-O—C(═O)—, C 1-3 alkyl-S(═O) 2 —, cyclopropyl-C(═O)—NH—, cyclopropyl-NH—C(═O)—, C 1-3 alkyl-NH—C(═O)—, cyclobutane-CH 2 — and C 1-3 alkyl-C(═O)—NH—, each of which is optionally substituted by 1, 2 or 3 of R′.

4. The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 1 , wherein each of R 1 and R 2 is independently selected from the group consisting of H, F, Cl, Br, I, OH, CN, NH 2 , —COOH, Me and Et.

5. The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 1 , wherein L is —C(═O)—, or selected from the group consisting of -1,2,4-oxadiazolyl-, -methylene-, -ethyl-, -1,3,4-oxadiazolyl-, -isoxazolyl-, -oxazolyl-, -piperidyl-, -1,2,3-triazolyl-, -cyclopropanyl- and -phenyl-, each of which is optionally substituted by 1, 2 or 3 of R.

6. The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 1 , wherein R 5 is selected from the group consisting of phenyl, pyridyl, piperidinyl, pyrrolidinyl, azetidinyl, cyclohexyl, cyclobutyl, benzo[d][1,3] m-dioxacyclopentenyl, piperidyl-2-keto, 7-azaspiro[3.5]nonyl, cyclohexyl-CH 2 —, 3a,7a-dihydro-1H-indolyl, pyrazolyl, 3a,7a-dihydrobenzo[d]thiazolyl, pyrimidinyl, cyclopentyl, spiro[3.3]heptanyl, bicyclo[2.2.2]octyl, octahydrocyclopenta[c]pyrrolyl, 2-azaspiro[3.5]nonyl, piperidinyl-C(═O)—, 4,5,6,7-tetrahydro-1H-benzo [d]imidazolyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridyl, piperidinyl-CH 2 —, bicyclo[1.1.1]pentyl and piperazinyl, each of which is optionally substituted by 1, 2 or 3 of R.

7. The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 5 , wherein -L-R 5 is selected from the group consisting of

each of which is optionally substituted by 1, 2 or 3 of R.

8. The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 1 , wherein R 3 is -L-R 5 , or selected from the group consisting of pyrrolidinyl, 1H-imidazolyl, 1H-1,2,4-triazolyl, pyridyl, thiazolyl, thienyl, pyrrolyl, 2H-tetrazolyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl, imidazo[1,5-a]pyridyl, oxazolyl, benzo[d]isoxazolyl, benzo[d]oxazolyl, 1,2,3,4-4H-2,7-naphthyridinyl, 1,2,3,4-tetrahydroisoquinolinyl, 2,3,4,5-tetrahydro-1H-benzo[d]azepinyl, azetidinyl, isoindolyl, piperidinyl, 2,3,4,5-tetrahydro-1H-benzo [b]azepinyl, 2,3-dihydro-1H-pyrrolo [3,4-c]pyridyl, benzoisoxazolyl, 5,6,7,8-tetrahydropyridopyrimidinyl, 3a,7a-dihydrobenzo[d]thiazolyl, 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, piperazinyl, morpholinyl, octahydropyrrolo[3,4-c]pyrrolyl, 1,4-diazepine, cyclohexyl and 1,2,4-oxadiazolyl, each of which is optionally substituted by 1, 2 or 3 of R.

9. The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 1 , wherein R 4 is selected from the group consisting of H, Me, Et and

10. The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 1 , wherein R 6 is selected from the group consisting of H, Me, Et and

11. The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 1 , wherein the structural unit

is selected from the group consisting of

12. The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 1 , which is selected from the group consisting of

wherein,

e, f, m and n are as defined in claim 1 ;

R is as defined in claim 1 ;

R 5 is as defined in claim 1 ;

each of q 1 and q 2 is independently 1 or 2.

13. A compound, pharmaceutically acceptable salt or tautomer thereof selected from the group consisting of

14. A pharmaceutical composition, comprising a therapeutically effective amount of the compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 1 as an active ingredient, and a pharmaceutically acceptable carrier.

15. A method for treating LSD1-related disease in a subject in need thereof, comprising administering the compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 1 to the subject.

16. A method for treating LSD1-related disease in a subject in need thereof, comprising administering the pharmaceutical composition as defined in claim 14 to the subject.

17. A method for treating LSD1-related disease in a subject in need thereof, comprising administering the compound, the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 13 to the subject.

18. A pharmaceutical composition, comprising a therapeutically effective amount of the compound, the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 13 as an active ingredient, and a pharmaceutically acceptable carrier.

19. A method for treating LSD1-related disease in a subject in need thereof, comprising administering the pharmaceutical composition as defined in claim 18 to the subject.

20. The method as defined in claim 15 , wherein the LSD1-related disease is small cell lung cancer.

21. The method as defined in claim 16 , wherein the LSD1-related disease is small cell lung cancer.

22. The method as defined in claim 17 , wherein the LSD1-related disease is small cell lung cancer.

23. The method as defined in claim 19 , wherein the LSD1-related disease is small cell lung cancer.

24. A pharmaceutical composition, comprising the compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 1 and Cisplatin.

25. A pharmaceutical composition, comprising the compound, the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 13 and Cisplatin.

26. The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 3 , wherein R is selected from the group consisting of

or R is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , Me, Et, —CF 3 , CN, COOH,

27. The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 5 , wherein L is —C(═O)—, or selected from the group consisting of

each of which is optionally substituted by 1, 2 or 3 of R.

28. The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 6 , wherein R 5 is selected from the group consisting of

or, R 5 is selected from the group consisting of

29. The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 7 , wherein -L-R 5 is selected from the group consisting of

30. The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 8 , wherein R 3 is selected from the group consisting of

or, R 3 is selected from the group consisting of