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CN-122029157-A - Bilobalide derivatives for the treatment of neurological diseases and cancers

CN122029157ACN 122029157 ACN122029157 ACN 122029157ACN-122029157-A

Abstract

Provided herein are bilobalide derivative compounds, processes for their preparation, methods of use, and uses for the prevention or treatment of neurological diseases and cancers.

Inventors

  • WU WEILONG
  • Stephen Yu Ergen Wolfgang Sheffield
  • Josephine Seck Amada
  • JIANG XIAODING
  • HE XU

Assignees

  • 香港中文大学

Dates

Publication Date
20260512
Application Date
20240803
Priority Date
20230804

Claims (20)

  1. 1. A compound having formula I: (formula I) Or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, Wherein the method comprises the steps of X is-O- -NR 1 -、-N=CR 1 -NH-or-NR 1 -NH-; wherein when X is-O-, R 1 is absent; Bond Y 1 is between R 4 and R 5 and is a single bond or a double bond; R 1 is H, R 1B or- (L 1 ) u -(Z 1 ) v ), wherein L 1 is a C 1 -C 10 aliphatic wherein up to three carbon atoms of the C 1 -C 10 aliphatic are optionally substituted with N, O OR S, wherein L 1 is optionally substituted with 1-3 occurrences of halo, CN, R, OR', OR R 1C ; u is 0 or 1; v is 0 or 1; Z 1 is a 5-16 membered aromatic or non-aromatic monocyclic, bicyclic or tricyclic ring system having 0-7 heteroatoms selected from O, N or S, wherein Z 1 is optionally substituted with 1-5 occurrences of R 1A 、R 1C or a combination thereof; R 1A is- (L 2 ) m -(Z 2 ) w ; wherein L 2 is C 1- C 10 aliphatic, wherein up to three carbon atoms of the C 1 -C 10 aliphatic are optionally substituted with N, NR, O, S, C = O, SO 2 , s=o, (c=o) N, N (c=o) N, (c=o) O OR Si, wherein L 2 is optionally substituted with 1-3 occurrences of halo, CN, R, OR' OR R 1C ; m is 0 or 1; w is 0 or 1; z 2 is C 1 -C 10 aliphatic, or a 3-to 16-membered aromatic or non-aromatic monocyclic, bicyclic or tricyclic ring system having 0 to 7 heteroatoms selected from O, N or S, wherein Z 2 is optionally substituted with 1 to 5 occurrences of R 1B ; r 1B is H, halo, CN, R 、OR 、NRR Or two R 1B taken together with the atoms to which they are attached form a 3-6 membered ring having 0-4 heteroatoms; R 1C is H, halo, CN, a 5-10 membered aromatic or non-aromatic monocyclic or bicyclic ring system having 0-5 heteroatoms selected from O, N or S, R ,OR ,NRR OR two R 1C together with the atom OR atoms to which they are attached optionally form a 3-16 membered ring having 0-4 heteroatoms, wherein R 1C is optionally substituted with 1-3 occurrences of halo, CN, R 'OR OR'; R Is a C 1 -C 6 aliphatic, wherein up to three methylene units of the C 1 -C 6 aliphatic are optionally substituted with N, NR, O, S, C =o, SO 2 OR Si, and wherein the C 1 -C 6 aliphatic is optionally substituted with 1-3 occurrences of halo, CN, R ', OR'; R 2 is R 2A OR OR 2A , wherein R 2A is H, C 1 -C 16 an aliphatic, a 5-10 membered aromatic OR non-aromatic mono-OR bi-cyclic system, OR a- (C 1 -C 16 aliphatic) - (5-10 membered aromatic OR non-aromatic mono-OR bi-cyclic system), wherein up to five carbon atoms of the C 1 -C 16 aliphatic OR the 5-10 membered aromatic OR non-aromatic mono-OR bi-cyclic system are optionally replaced by N, NR, O, S, C = O, SO 2 , S = O, (C = O) N, N (C = O) N, (C = O) O OR Si, wherein R 2A is optionally substituted by 1-5 occurrences of R 2B , wherein R 2B is halo, R 'OR OR'; R 3 is OH, R 3A OR OR 3A , wherein R 3A is C 1 -C 10 aliphatic optionally substituted with 1-3 occurrences of halo, R OR OR'; R 4 is OH, R 4A 、OR 4A , OR R 4 is absent when the bond Y 1 between R 4 and R 5 is a double bond, wherein R 4A is C 1 -C 7 aliphatic and R 4A is optionally substituted with 1-3 occurrences of halo, R 'OR OR'; r 5 is H or OH; R 6 is H, or R 6 is absent when the bond Y 1 between R 4 and R 5 is a double bond; R is H or C 1 -C 6 aliphatic optionally substituted with 1-3 occurrences of F, or two R's together with the atom or atoms to which they are attached form a 3-6 membered ring having 0-4 heteroatoms, and Wherein said C 1 -C 6 aliphatic is optionally substituted with 1-3 occurrences of F, OR, NH 2 , NHR ' OR NR ' 2 wherein R ' is a C 1 -C 6 aliphatic OR a 5-10 membered aromatic OR non-aromatic mono-OR bi-cyclic system having 0-5 heteroatoms selected from O, N OR S; wherein when R 2 is OH, R 3 is tert-butyl, R 4 is OH, R 5 is H and R 6 is H, X is not-O-.
  2. 2. The compound of claim 1, wherein X is-NR 1 -、-N=CR 1 -NH-or-NR 1 -NH-.
  3. 3. The compound of claim 1, having formula Ia: (formula Ia).
  4. 4. The compound of claim 1, having formula Ib: (formula Ib).
  5. 5. The compound of any one of claims 2-4, wherein R 2 is R 2A OR 2A , wherein R 2A is H, C =o (C 1-10 aliphatic), SO 2 (C 1-10 aliphatic), SO 2 (phenyl), phenyl, si (C 1-10 aliphatic) 1-2 , si (phenyl) 1-2 、 - (C 1-10 aliphatic) O (C 1-10 aliphatic) -, (c=o) (phenyl), NH (c=o) (C 1-10 aliphatic) 、 OR NH (C=O) O (C 1-10 aliphatic), wherein each R 2A is independently and optionally substituted with 1-5 occurrences of R 2B , wherein R 2B is halo, R 'OR OR'; R 3 is C 1-10 aliphatic; the bond Y 1 between R 4 and R 5 is a single bond; r 4 is OH OR OR 4A ; And R 5 is H or OH.
  6. 6. The compound of any one of claims 2-4, wherein R 2 is R 2A OR 2A , wherein R 2A is H、(C=O)CH 3 、SO 2 CH 3 、SO 2 C 6 H 4 CH 3 、SO 2 CF 3 、 phenyl 、Si(CH 3 ) 2 C(CH 3 ) 3 、Si(CH 2 CH 3 ) 3 、Si(CH 3 ) 3 、Si(C 6 H 5 ) 2 C(CH 3 ) 3 、Si(iPr) 3 、CH 2 OCH 3 、CH 2 CH 2 OCH 3 、(C=O)C 6 H 5 、 、 OR NH (c=o) OC (CH 3 ) 3 ; wherein phenyl, C 6 H 4 and C 6 H 5 are each independently and optionally substituted with 1-5 occurrences of R 2B , wherein R 2B is halo, R 'OR'; r 3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; the bond Y 1 between R 4 and R 5 is a single bond; r 4 is OH OR OR 4A ; And R 5 is H or OH.
  7. 7. The compound of any one of claims 2-4, wherein R 1 is H.
  8. 8. The compound of any one of claims 2-4, wherein R 1 is- (L 1 ) u -(Z 1 ) v ; Wherein the method comprises the steps of L 1 is a C 1 -C 10 aliphatic, wherein up to three carbon atoms of the C 1 -C 10 aliphatic are optionally replaced by N, O or S; Z 1 is phenyl, 1-methyl-1, 2,3, 4-tetrahydronaphthalen-2-yl, 1-methyl-2H-isoindol-2-yl, imidazole, indolyl, naphthyl, adamantyl, azetidinyl, bicyclo [1.1.1] pentyl, 1-oxa-8-azaspiro [4.5] dec-3-yl, cyclobutyl, cyclohexenyl, cyclopentyl, cyclopropanyl, norbornyl, oxetanyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, or C 3 -C 12 cycloaliphatic having 0 to 5 heteroatoms selected from O, N or S; u is 0 or 1, and V is 0 or 1, wherein Z 1 is optionally substituted with 1-5 occurrences of R 1C , morpholinyl, -OCH 2 O-, - (C=O) - (pyrazinyl) -R 1B , - (C=O) - (phenyl) -R 1B , or- (SO 2 ) - (phenyl) -R 1B , wherein each independently occurrence of R 1B is H, halo, R 、OR Or NRR Wherein each independently occurring R 1C is H, halo, R 、OR Or NRR And wherein each independently occurring R Is H、=N、-C≡CH、-N=N-、-CH 3 、-CH 2 F、-CHF 2 、-CF 3 、-CN、-CH 2 O-、-CF 2 O-、-CH 2 CH 2 O- or-Boc (- (c=o) OC (CH 3 ) 3 ).
  9. 9. The compound of claim 7, wherein when Z 1 is phenyl, Z 1 is optionally substituted with 1-5 occurrences of morpholinyl or R 1C , wherein R 1C is halo 、CH 3 、-CH 2 F、-CHF 2 、-CF 3 、-CN、-OCH 3 、-OCH 2 O-、-OCF 2 O-、-OCH 2 CH 2 O-、-NH 2 、-NH(C=O)CH 3 or-NH (Boc) (NH (c=o) OC (CH 3 ) 3 ).
  10. 10. The compound of claim 7, wherein when Z 1 is piperidinyl, Z 1 is optionally substituted with 1-2 occurrences of R 1C , wherein R 1C is t-butoxycarbonyl, 5- (difluoromethyl) pyrazine-2-carbonyl, 2-difluoro-2H-1, 3-benzodioxole-5-carbonyl, 2, 3-dihydro-1, 4-benzodioxine-6-carbonyl, 2, 3-dihydro-1-benzofuran-5-sulfonyl, 4-chlorobenzoyl, 2, 3-dihydro-1-benzofuran-5-carbonyl, or prop-2-enoyl.
  11. 11. The compound of claim 7, wherein when Z 1 is pyrrolidinyl, Z 1 is optionally substituted with 1-2 occurrences of R 1C , wherein R 1C is t-butoxycarbonyl.
  12. 12. The compound of claim 7, wherein R 1 is H, 2, 4-Dimethoxybenzyl group, [1- (Tert-butoxycarbonyl) piperidin-4-yl ] methyl, Piperidin-4-ylmethyl group, the amino group, 2- [1- (Tert-butoxycarbonyl) piperidin-4-yl ] ethyl group, 2- (Piperidin-4-yl) ethyl group, 3- [1- (Tert-butoxycarbonyl) piperidin-4-yl ] propyl, 3- (Piperidin-4-yl) propyl group, 2- [4- (Tert-butoxycarbonyl) piperazin-1-yl ] ethyl, 2- (Piperazin-1-yl) ethyl group, 2- (3-Methyl-1H-indol-2-yl) ethyl, 3- (1H-imidazol-1-yl) propyl, [1- (Tert-butoxycarbonyl) pyrrolidin-3-yl ] methyl, (Pyrrolidin-3-yl) methyl group, (Bicyclo [2.2.1] hept-5-en-2-yl) methyl, A phenyl group, 4-Acetamidophenyl group, the amino group, 4- [ (Tert-butoxycarbonyl) amino ] phenyl group, A 4-aminophenyl group, a derivative thereof, 4- (Morpholin-4-yl) phenyl, Benzo [ d ] [1,3] dioxol-5-yl, Pyridin-3-yl group is used as a base, A benzyl group, a hydroxyl group, a carboxyl group, A methyl group, Bicyclo [1.1.1] pentyl group, Oxetan-3-yl group is used as a base, A cyclobutylmethyl group, a cyclic-methyl group, A cyclopropylmethyl group, (Oxetan-3-yl) methyl, Adamantan-2-ylmethyl group, the amino group, NH 2 , A cyclopropyl group, a cyclic amine group, A 3-methoxyphenyl group, wherein the 3-methoxyphenyl group, 4-Methoxyphenyl group, wherein the amino group is a 4-methoxyphenyl group, A naphthalene-2-yl group and a derivative thereof, 3- (Trifluoromethyl) phenyl group, a hydroxyl group, A 4-cyanophenyl group, a derivative thereof, 2- [3- (But-3-yn-1-yl) -3H-bisaziridin-3-yl ] ethyl, A cyclohexyl group, A 4-fluorophenyl group, wherein the fluorine atom is a fluorine atom, 4- (Trifluoromethyl) phenyl group, a derivative thereof, 4-Toluoyl group, which is a group of a double-chain alkyl, 3-Toluoyl group, which is a group of 3-toluoyl, 2-Toluoyl group, which is a group of a 2-toluoyl group, (Oxacyclopentane-2-yl) methyl, 2-Methoxy-2-oxoethyl group, (1- (5- (Difluoromethyl) pyrazine-2-carbonyl) piperidin-4-yl) methyl, [1- (2, 3-Dihydro-1-benzofuran-5-sulfonyl) piperidin-4-yl ] methyl, (1- (2, 2-Difluorobenzo [ d ] [1,3] dioxol-5-carbonyl) piperidin-4-yl) methyl, (1- (2, 3-Dihydrobenzo [ b ] [1,4] dioxin-6-carbonyl) piperidin-4-yl) methyl, (1- (4-Chlorobenzoyl) piperidin-4-yl) methyl, (1- (2, 3-Dihydrobenzofuran-5-carbonyl) piperidin-4-yl) methyl, (1-Propenylpiperidin-4-yl) methyl, (1- (Quinoxaline-6-carbonyl) piperidin-4-yl) methyl, (Tetrahydro-2H-pyran-4-yl) methyl, (Tetrahydro-2H-thiopyran-4-yl) methyl, 2- (1-Methyl-1, 2,3, 4-tetrahydronaphthalen-2-yl) ethyl, 2- (1-Methyl-2H-isoindol-2-yl) ethyl, 2- (Azetidin-1-yl) ethyl, 2- (Trifluoromethyl) phenyl group, a radical of which is the amino acid, A 2-fluorophenyl group, wherein the fluorine atom is a fluorine atom, 2-Methoxyphenyl group, wherein the amino group is a 2-methoxyphenyl group, 3, 4-Difluorophenyl group having a hydroxyl group, 3, 4-Dichlorophenyl group, the reaction product of which is, 3, 5-Difluorophenyl group, A 3-fluorophenyl group, wherein the 3-fluorophenyl group, A 4-hydroxyphenyl group, a hydroxyl group and a hydroxyl group, 8- (Tert-butoxycarbonyl) -1-oxa-8-azaspiro [4.5] dec-3-yl, An anilino group, Benzo [ d ] [1,3] dioxol-4-yl, A cyclobutyl group, a cyclic group, A cyclohexylmethyl group, Naphthalen-1-yl group is used as a base, Pyridin-2-yl groups are used as the starting materials, Pyridin-4-yl group is used as a base, Adamantan-1-ylmethyl group, the amino group, 1- (Tert-butoxycarbonyl) -1H-indol-5-yl, 1H-indol-5-yl group, 3- [ (Tert-butoxycarbonyl) amino ] phenyl group, 4-Hydroxyphenylethyl group, which is a group of the amino acids, 1H-indol-3-ethyl group, ((1R, 4aS,10 aR) -7-isopropyl-1, 4 a-dimethyl-1, 2,3, 4a,9,10 a-octahydrophenanthren-1-yl) methyl, [ ((Tert-butoxycarbonyl) aminomethyl) adamantan-1-yl ] methyl group, (Aminomethyl) adamantan-1-yl) methyl group, 3, 5-Di-tert-butylphenyl group, 3, 4-Dihydroxyphenyl group, 3-Methoxy-4-hydroxyphenylethyl group, 1H-indol-5-hydroxy-3-ethyl, 1H-indole-5-methoxy-3-ethyl group, 1H-indole-4-hydroxy-3-ethyl group, A pepper base, wherein the pepper base is a black pepper base, 2- (4-Imidazolyl) ethyl (histamine), 2, 2-Diphenylethyl group, 3-Hydroxy-4-methoxyphenylethyl group, 3, 4-Methylenedioxyphenyl ethyl, 1H-indol-5-hydroxy-3-ethyl (serotonin), 3, 4-Dihydroxyphenylethyl (dopamine), 1H-indol-3-ethyl (tryptamine), 3-Methoxy-4-hydroxyphenylethyl (3-O-methyldopamine), or Methylenedioxyphenyl.
  13. 13. The compound of claim 11, wherein R 2 is R 2A OR OR 2A , wherein R 2A is H、(C=O)CH 3 、SO 2 CH 3 、SO 2 C 6 H 4 CH 3 、SO 2 CF 3 、 phenyl 、Si(CH 3 ) 2 C(CH 3 ) 3 、Si(CH 2 CH 3 ) 3 、Si(CH 3 ) 3 、Si(C 6 H 5 ) 2 C(CH 3 ) 3 、Si(iPr) 3 、CH 2 OCH 3 、CH 2 CH 2 OCH 3 、(C=O)C 6 H 5 、 、 OR NH (c=o) OC (CH 3 ) 3 ; wherein phenyl is optionally substituted with 1-5 occurrences of halo, R 'OR'; r 3 is tert-butyl; the bond Y 1 between R 4 and R 5 is a single bond; r 4 is OH; R 5 is H; X is-NR 1 -、-N=CR 1 -NH-or-NR 1 -NH-; and, moreover, the method comprises the steps of. R 1 is selected from , , , , 2- (4-Imidazolyl) ethyl (histamine), 1H-indol-5-hydroxy-3-ethyl (serotonin), 3, 4-Dihydroxyphenylethyl (dopamine), 1H-indol-3-ethyl (tryptamine), or 3-Methoxy-4-hydroxyphenylethyl (3-O-methyldopamine).
  14. 14. The compound of claim 1, selected from the group consisting of the compounds of table 1 d.
  15. 15. The compound of claim 1, wherein the compound is DW192、P-29、P-21、P-30、P-33、JW093、XBB-023、P-28、JW107、XBB-039、JW094、P-34、XBB-045、JW081、XBB-028、XBB-038、XBB-037、XBB-054、XBB-025、XBB-029、XBB-024、DW172、XBB-004、XBB-042、XBB-068、XBB-040、XBB-006、JW072、DW189、P-8、DW191、DW168、XBB-013、XBB-037'、XBB-009、XBB-060、XBB-016、DW182、XBB-010、SCC506、SCC363 or SXQ087-1.
  16. 16. The compound of claim 1, wherein bond Y 1 is a double bond having formula I': (formula I').
  17. 17. The compound of claim 15, wherein X is-O-and R 1 is absent; R 2 is R 2A OR OR 2A , wherein R 2A is H、(C=O)CH 3 、SO 2 CH 3 、SO 2 C 6 H 4 CH 3 、SO 2 CF 3 、 phenyl 、Si(CH 3 ) 2 C(CH 3 ) 3 、Si(CH 2 CH 3 ) 3 、Si(CH 3 ) 3 、Si(C 6 H 5 ) 2 C(CH 3 ) 3 、Si(iPr) 3 、CH 2 OCH 3 、CH 2 CH 2 OCH 3 、(C=O)C 6 H 5 、 、 Or NH (c=o) OC (CH 3 ) 3 ; wherein phenyl is optionally substituted with 1-5 occurrences of halo, R 'OR OR'; r 3 is tert-butyl; r 4 is absent; R 5 is H, and R 6 is absent.
  18. 18. The compound of claim 1, having the formula I' a: (formula I' a).
  19. 19. The compound of claim 1, having formula I' b: (formula I' b).
  20. 20. The compound of claim 1, wherein X is-O-and R 1 is absent; Bond Y 1 is a single bond; R 2 is OR 2A , wherein R 2A is H、(C=O)CH 3 、SO 2 CH 3 、SO 2 C 6 H 4 CH 3 、SO 2 CF 3 、 phenyl 、Si(CH 3 ) 2 C(CH 3 ) 3 、Si(CH 2 CH 3 ) 3 、Si(CH 3 ) 3 、Si(C 6 H 5 ) 2 C(CH 3 ) 3 、Si(iPr) 3 、CH 2 OCH 3 、(C=O)C 6 H 5 、 、 CH 2 CH 2 OCH 3 or NH (c=o) OC (CH 3 ) 3 ; wherein phenyl is optionally substituted with 1-5 occurrences of halo, R 'OR OR'; R 3 is isopropenyl; R 4 is CH 3 ; R 5 is H, and R 6 is H.

Description

Bilobalide derivatives for the treatment of neurological diseases and cancers Cross Reference to Related Applications The present application claims the benefit of U.S. c. ≡119 (e) from U.S. provisional application serial No. 63/517,627 filed on month 8 and 4 of 2023 and U.S. provisional application serial No. 63/610,394 filed on month 12 and 14 of 2023, the entire contents of which are hereby incorporated by reference. Technical Field The present application relates to bilobalide derivative compounds, processes for the preparation of the compounds, methods of using the compounds, and the use of the compounds for the prevention or treatment of cancer and neurological disorders. Background High throughput screening of chemical libraries is a common starting point for modern drug development. Unfortunately, many existing libraries are composed of planar molecules of very low structural or stereochemical complexity, thus hampering the drug development process. Terpene Trilactones (TTLs), such as ginkgolides and bilobalide, are polyoxyditerpene compounds isolated from ginkgo trees. Bilobalide has no acute toxicity and has been shown to exhibit a wide range of biological activities. However, bilobalide has limited therapeutic potential and its effect on mammalian central nervous system, nervous system disorders or cancers has not been fully demonstrated due to its instability. Due to the synthetic challenges of bilobalide structure modification, there is currently no synthetic pathway that can easily obtain bilobalide analogs for use in systematic structure-activity relationship (SAR) studies. Thus, no effective bilobalide compounds have been identified that can be used to treat the disease. Disclosure of Invention Disclosed herein are novel compounds useful for cancer, processes for preparing the novel compounds, methods of using the novel compounds, and intermediates used in the preparation of the novel compounds. In some embodiments, a compound having formula I is provided: (formula I) Or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, Wherein the method comprises the steps of X is-O- -NR 1-、-N=CR1 -NH-or-NR 1 -NH-; wherein when X is-O-, R 1 is absent; Bond Y 1 is between R 4 and R 5 and is a single bond or a double bond; R 1 is H, R 1B or- (L 1)u-(Z1)v), wherein L 1 is a C 1-C10 aliphatic wherein up to three carbon atoms of the C 1-C10 aliphatic are optionally replaced by N, O OR S, wherein L 1 is optionally substituted by 1-3 occurrences of halo, CN, R, OR' OR R 1C; u is 0 or 1; v is 0 or 1; Z 1 is a 5-16 membered aromatic or non-aromatic monocyclic, bicyclic or tricyclic ring system having 0-7 heteroatoms selected from O, N or S, wherein Z 1 is optionally substituted with 1-5 occurrences of R 1A、R1C or a combination thereof; R 1A is- (L 2)m-(Z2)w; wherein L 2 is C 1-C10 aliphatic, wherein up to three carbon atoms of the C 1-C10 aliphatic are optionally substituted with N, NR, O, S, C = O, SO 2, s=o, (c=o) N, N (c=o) N, (c=o) O OR Si, wherein L 2 is optionally substituted with 1-3 occurrences of halo, CN, R, OR' OR R 1C; m is 0 or 1; w is 0 or 1; z 2 is C 1-C10 aliphatic, or a 3-to 16-membered aromatic or non-aromatic monocyclic, bicyclic or tricyclic ring system having 0 to 7 heteroatoms selected from O, N or S, wherein Z 2 is optionally substituted with 1 to 5 occurrences of R 1B; r 1B is H, halo, CN, R 、OR、NRROr two R 1B taken together with the atoms to which they are attached form a 3-6 membered ring having 0-4 heteroatoms; R 1C is H, halo, CN, a 5-10 membered aromatic or non-aromatic monocyclic or bicyclic ring system having 0-5 heteroatoms selected from O, N or S, R ,OR,NRROR two R 1C together with the atom OR atoms to which they are attached optionally form a 3-16 membered ring having 0-4 heteroatoms, wherein R 1C is optionally substituted with 1-3 occurrences of halo, CN, R 'OR OR'; R Is a C 1-C6 aliphatic, wherein up to three methylene units of the C 1-C6 aliphatic are optionally replaced with N, NR, O, S, C =o, SO 2 OR Si, and wherein the C 1-C6 aliphatic is optionally substituted with 1-3 occurrences of halo, CN, R ', OR'; R 2 is R 2A OR OR 2A, wherein R 2A is a H, C 1-C16 aliphatic, 5-10 membered aromatic OR non-aromatic mono-OR bicyclic ring system, OR- (C 1-C16 aliphatic) - (5-10 membered aromatic OR non-aromatic mono-OR bicyclic ring system), wherein up to five carbon atoms of the C 1-C16 aliphatic OR 5-10 membered aromatic OR non-aromatic mono-OR bicyclic ring system are optionally replaced by N, NR, O, S, C = O, SO 2, S = O, (C = O) N, N (C = O) N, (C = O) O OR Si, wherein R 2A is optionally replaced by 1-5 occurrences of R 2B, wherein R 2B is halo, R 'OR OR'; R 3 is OH, R 3A OR OR 3A, wherein R 3A is C 1-C10 aliphatic optionally substituted with 1-3 occurrences of halo, R OR OR'; R 4 is OH, R 4A、OR4A, OR R 4 is absent when the bond Y 1 between R 4 and R 5 is a double bond, wherein R 4A is C 1-C7 aliphatic and R 4A is optionally substituted with 1-3 occurrences of hal