Hydrophobically tagged small molecules as inducers of protein degradation
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-031/519
C07D-487/04
출원번호
US-0436657
(2013-10-18)
등록번호
US-9758522
(2017-09-12)
국제출원번호
PCT/US2013/065698
(2013-10-18)
국제공개번호
WO2014/063061
(2014-04-24)
발명자
/ 주소
Gray, Nathanael
Xie, Ting
Lim, Sang Min
Janne, Pasi A.
Crews, Craig M.
출원인 / 주소
Dana-Farber Cancer Institute, Inc.
대리인 / 주소
Wolf, Greenfield & Sacks, P.C.
인용정보
피인용 횟수 :
3인용 특허 :
62
초록▼
Provided are bifunctional small molecules of Formula (I): or pharmaceutically acceptable salts thereof, wherein M represents a small organic molecule which binds, covalently or non-covalently, a kinase, such as Her3 protein kinase; L1 represents a linker; and RH represents a hydrophobic group. An ex
Provided are bifunctional small molecules of Formula (I): or pharmaceutically acceptable salts thereof, wherein M represents a small organic molecule which binds, covalently or non-covalently, a kinase, such as Her3 protein kinase; L1 represents a linker; and RH represents a hydrophobic group. An example of a compound of Formula (I) is a compound of Formula (II): Also provided are pharmaceutical compositions comprising a compound of Formula (I) or (II) and methods of using such compounds for treating proliferative diseases.
대표청구항▼
1. A compound of Formula (II): or a pharmaceutically acceptable salt thereof; wherein: Ring A is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;each occurrence of RB is independently
1. A compound of Formula (II): or a pharmaceutically acceptable salt thereof; wherein: Ring A is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;each occurrence of RB is independently hydrogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group, or two RB groups are joined to form an substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;each instance of RC is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —ORC1, —N(RC1)2, —SRC1, —C(═O)RC1, —C(═O)ORC1, —C(═O)SRC1, —C(═O)N(RC1)2, —NRC1C(═O)RC1, —NRC1C(═O)ORC1, —NRC1C(═O)SRC1, or —NRC1C(═O)N(RC1)2, wherein each occurrence of RC1 is independently hydrogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RC1 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;a is 0, 1, 2, 3, or 4;b is 1;L1 represents a linker of 4 to 20, inclusive, consecutive, covalently bonded atoms in length, selected from the group consisting of substituted and unsubstituted alkylene; substituted and unsubstituted alkenylene; substituted and unsubstituted alkynylene; substituted and unsubstituted heteroalkylene; substituted and unsubstituted heteroalkenylene; substituted and unsubstituted heteroalkynylene; substituted and unsubstituted heterocyclylene; substituted and unsubstituted carbocyclylene; substituted and unsubstituted arylene; substituted and unsubstituted heteroarylene; and combinations thereof;L2 represents a bond or a linker selected from the group consisting of substituted and unsubstituted alkylene; substituted and unsubstituted alkenylene; substituted and unsubstituted alkynylene; substituted and unsubstituted heteroalkylene; substituted and unsubstituted heteroalkenylene; substituted and unsubstituted heteroalkynylene; substituted and unsubstituted heterocyclylene; substituted and unsubstituted carbocyclylene; substituted and unsubstituted arylene; substituted and unsubstituted heteroarylene; and combinations thereof;RH represents a hydrophobic group selected from the group consisting of substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroarylalkyl, substituted and unsubstituted carbocycylalkyl, and substituted and unsubstituted heterocyclylalkyl;wherein the hydrophobic group refers to a group comprising zero hydrogen bond donors; andRD is of formula: wherein: RD1 is hydrogen, halogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —CN, —NO2, —ORD1a, —N(RD1a)2, —SRD1a, —CH2ORD1a, —CH2N(RD1a)2, —CH2SRD1a, —C(═O)RD1a, —C(═O)ORD1a, —C(═O)SRD1a, —C(═O)N(RD1a)2, —C(═S)RD1a, —C(═S)ORD1a, —C(═S)SRD1a, —C(═S)N(RD1a)2, —C(═NRD1a)RD1a, —C(═NRD1a)ORD1a, —C(═NRD1a)SRD1a, or —C(═NRD1a)N(RD1a)2, wherein each occurrence of RD1a is independently hydrogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two RD1a groups are joined to form an substituted or unsubstituted heterocyclic ring;RD2 is hydrogen, halogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —CN, —NO2, —ORD2a, —N(RD2a)2, —SRD2a, —CH2ORD2a, —CH2N(RD2a)2, —CH2SRD2a, —C(═O)RD2a, —C(═O)ORD2a, —C(═O)SRD2a, —C(═O)N(RD2a)2, —C(═S)RD2a, —C(═S)ORD2a, —C(═S)SRD2a, —C(═S)N(RD2a)2, —C(═NRD2a)RD2a, —C(═NRD2a)ORD2a, —C(═NRD2a)SRD2a, or —C(═NRD2a)N(RD2a)2, wherein each occurrence of RD2a is independently hydrogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two RD2a groups are joined to form an substituted or unsubstituted heterocyclic ring;RD3 is hydrogen, halogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —ORD3a, —N(RD3a)2, —SRD3a, —CH2ORD3a, —CH2N(RD3a)2, —CH2SRD3a, —C(═O)RD3a, —C(═O)ORD3a, —C(═O)SRD3a, —C(═O)N(RD3a)2, —C(═S)RD3a, —C(═S)ORD3a, —C(═S)SRD3a, —C(═S)N(RD3a)2, —C(═NRD3a)RD3a, —C(═NRD3a)ORD3a, —C(═NRD3a)SRD3a, or —C(═NRD3a)N(RD3a)2 wherein eachoccurrence of RD3a is independently hydrogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two RD3a groups are joined to form an substituted or unsubstituted heterocyclic ring;optionally RD1 and RD3, or RD2 and RD3, or RD1 and RD2 are joined to form an substituted or unsubstituted carbocyclic or substituted or unsubstituted heterocyclic ring;RD4 is a leaving group selected from the group consisting of —Br, —Cl, —I, and —OS(═O)wRD4a, wherein w is 1 or 2, and RD4a is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;X1 is a bond or NRD5, wherein RD5 is hydrogen, C1-6 alkyl, or a nitrogen protecting group;each instance of Y is independently O, S, or NRD6, wherein RD6 is hydrogen, C1-6 alkyl, or a nitrogen protecting group; andz is 0, 1, 2, 3, 4, 5, or 6. 2. The compound of claim 1, wherein Ring A is substituted or unsubstituted phenyl. 3. The compound of claim 1, wherein Ring A is a substituted or unsubstituted 5- to 6-membered heteroaryl ring. 4. The compound of claim 1, wherein Ring A is a substituted or unsubstituted C3-8carbocyclyl ring. 5. The compound of claim 1, wherein Ring A is a substituted or unsubstituted 3- to 8-membered heterocyclyl ring. 6. The compound of claim 1 of Formula (II-g): or a pharmaceutically acceptable salt thereof, wherein: each occurrence of RA is, independently, hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —ORA1, —N(RA1)2, —SRA1, —C(═O)RA1, or —C(═O)ORA1, wherein each occurrence of RA1 is independently hydrogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RA1 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; andc is 0 or 1. 7. The compound of claim 1 of Formula (II-e4): or a pharmaceutically acceptable salt thereof, wherein: each occurrence of RA is, independently, hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —ORA1, —N(RA1)2, —SRA1, —C(═O)RA1, or —C(═O)ORA1, wherein each occurrence of RA1 is independently hydrogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RA1 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; andc is 0 or 1. 8. The compound of claim 1, wherein RH is a hydrophobic substituted or unsubstituted aryl, or a hydrophobic substituted or unsubstituted aralkyl. 9. The compound of claim 8, wherein RH is a group of formula: wherein each occurrence of RH1, RH2, and RH3 is independently halogen, alkyl, haloalkyl, alkoxy, or dialkylamino; and p, q, and r are independently 0, 1, 2, or 3. 10. The compound of claim 1, wherein RH is a hydrophobic substituted or unsubstituted carbocyclyl, or a hydrophobic substituted or unsubstituted carbocyclylalkyl. 11. The compound of claim 10, wherein RH is a group of formula: wherein each occurrence of RH1 and RH2 is independently halogen, alkyl, haloalkyl, alkoxy, or dialkylamino; and p and q are independently 0, 1, 2, or 3. 12. The compound of claim 1, wherein RH is a hydrophobic substituted or unsubstituted heterocyclyl, or a hydrophobic substituted or unsubstituted heterocyclylalkyl. 13. The compound of claim 12, wherein RH is a group of formula: wherein each occurrence of RH1 and RH2 is independently halogen, alkyl, haloalkyl, alkoxy, or dialkylamino; and p and q are independently 0, 1, 2, or 3. 14. The compound of claim 1, wherein L1 represents a linker consisting of one group, or a combination of 2 to 20 consecutive covalently bonded groups, of the formula: wherein: each instance of n is independently an integer between 1 to 10, inclusive;each instance of m is independently 0, 1 or 2;each instance of Q is independently —NRW1—; —NRW1—NRW1—; —O—NRW1—; —NRW1—O—; —S—; or —O—;each instance of W is independently O, S, or NRW1;each instance of G1 and G2 are independently N or CH;each instance of RW1 is independently hydrogen; substituted or unsubstituted alkyl;substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; a nitrogen protecting group if attached to a nitrogen atom, or an oxygen protecting group if attached to an oxygen atom;each instance of RW2 is independently hydrogen; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or two RW2 groups are joined to form a 5-6 membered ring; andeach instance of RW3 is independently hydrogen; halogen; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl, or two RW3 groups are joined to form a 3-6 membered ring;or RW1 and RW3 are joined to form a 5-6 membered heterocyclic ring; provided L1 is a linker of 4 to 20, inclusive, consecutive, covalently bonded atoms in length. 15. The compound of claim 14, wherein -L1-RH represents a group of the formula: 16. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 17. A method of treating breast cancer, ovarian cancer, or lung cancer, the method comprising administering a compound of claim 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof in an amount sufficient to treat the breast cancer, ovarian cancer, or lung cancer. 18. The compound of claim 1 selected from the group consisting of: and pharmaceutically acceptable salts thereof. 19. A compound selected from the group consisting of: and pharmaceutically acceptable salts thereof. 20. A compound selected from the group consisting of: and pharmaceutically acceptable salts thereof. 21. The compound of claim 1, wherein L1 represents a linker of 5 to 15, inclusive, consecutive, covalently bonded atoms in length. 22. The compound of claim 1, wherein L1 represents a linker of 5 to 11, inclusive, consecutive, covalently bonded atoms in length.
Buchanan,John L.; Chaffee,Stuart; Harmange,Jean Christophe; Novak,Perry M.; Zhu,Xiaotian, Amino-substituted pyrimidinyl derivatives and methods of use.
Hubbard Vance M. (Bedford) Brunson Welton K. (Bedford) Saied V. C. (Wichita Falls TX), Apparatus and method for raising a skin wheal and anesthetizing skin.
Hochlowski Jill E. (Green Oaks IL) Jackson Marianna (Waukegan IL) Kadam Sunil K. (Kenosha WI) Karwowski James P. (Mundelein IL) McAlpine James B. (Libertyville IL), Dorrigocin antitumor agents.
Bolton Gary L. (Ann Arbor MI) Hodges John C. (Ann Arbor MI) Wilson Michael W. (Ann Arbor MI), Histidine and homohistidine derivatives as inhibitors of protein farnesyltransferase.
Monaghan Richard L. (Somerset NJ) Alberts Alfred W. (Short Hills NJ) Hoffman Carl H. (Scotch Plains NJ) Albers-Schonberg George (Princeton NJ), Hypocholesteremic fermentation products and process of preparation.
Lilley Stephen J. (Sawston GBX) Taylor Hugh F. (Sawston GBX) Theobald David R. (Huntingdon GBX) Carlson Craig J. (Andover MA) Rosen David I. (Arlington MA) Johnson Thomas R. (Milford NH), Medical injection system and method, gas spring thereof and launching device using gas spring.
Roth Jack A. ; Fujiwara Toshiyoshi,JPX ; Grimm Elizabeth A. ; Mukhopadhyay Tapas ; Zhang Wei-Wei ; Owen-Schaub Laurie B., Methods and compositions comprising DNA damaging agents and p53.
McKinnon ; Jr. Charles N. (Laguna Niguel CA) Peterson Steven F. (West Linn OR) Smith Paul E. (Tualatin OR) Nakagawa Takaaki (Tigard OR) Bartholomew Victor L. (Tigard OR), Needleless hypodermic injection device.
Peterson Steven F. (West Linn OR) McKinnon ; Jr. Charles N. (Laguna Niguel CA) Smith Paul E. (Tualatin OR) Nakagawa Takaaki (Tigard OR) Bartholomew Victor L. (Tigard OR), Needleless hypodermic injection methods and device.
Marsters ; Jr. James C. (Oakland CA) Brown Michael S. (Dallas TX) Crowley Craig W. (Portola Valley CA) Goldstein Joseph L. (Dallas TX) James Guy L. (Dallas TX) McDowell Robert S. (San Francisco CA) O, Ras farnesyl transferase inhibitors.
Harmange, Jean-Christophe; Buchanan, John L.; Chaffee, Stuart; Novak, Perry M.; Van Der Plas, Simon; Zhu, Xiaotian, Substituted pyrimidinyl derivatives and methods of use.
Bishop W. Robert (Pompton Plains NJ) Doll Ronald J. (Maplewood NJ) Mallams Alan K. (Long Valley NJ) Njoroge F. George (Union NJ) Petrin Joanne M. (Cedar Grove NJ) Piwinski John J. (Clinton Township N, Tricyclic sulfonamide compounds useful for inhibition of G-protein function and for treatment of proliferative diseases.
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