CAMPTOTHECIN PEPTIDE CONJUGATES

1 . A Camptothecin Conjugate having a formula:

L-(Q-D) p   (I)

or a pharmaceutically acceptable salt thereof, wherein

L is a Ligand Unit;

Q is a Linker Unit having a formula selected from:

—Z-A-S*-RL-; —Z-A-L P (S*)-RL-; —Z-A-S*-RL-Y—; or —Z-A-L P (S*)-RL-Y—,

wherein Z is a Stretcher Unit, A is a bond or a Connector Unit; L P is a Parallel Connector Unit; S* is a bond or a Partitioning Agent;

RL is a peptide comprising from 2 to 8 amino acids; and

Y is a Spacer Unit,

D is a Drug Unit selected from:

wherein

R B is a member selected from the group consisting of H, —(C 1 -C 4 )alkyl-OH, —(C 1 -C 4 )alkyl-O—(C 1 -C 4 )alkyl-NH 2 , —C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 4 alkyl, phenyl and phenylC 1 -C 4 alkyl;

each R F and R F′ is a member independently selected from the group consisting of H, C 1 -C 8 alkyl, C 1 -C 8 hydroxyalkyl, C 1 -C 8 aminoalkyl, C 1 -C 4 alkylaminoC 1 -C 8 alkyl, (C 1 -C 4 hydroxyalkyl)(C 1 -C 4 alkyl)aminoC 1 -C 8 alkyl, di(C 1 -C 4 alkyl)aminoC 1 -C 8 alkyl, C 1 -C 4 hydroxyalkylC 1 -C 8 aminoalkyl, C 2 -C 6 heteroalkyl, C 1 -C 8 alkylC(O)—, C 1 -C 8 hydroxyalkylC(O)—, C 1 -C 8 aminoalkylC(O)—, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylC 1 -C 4 alkyl, C 3 -C 10 heterocycloalkyl, C 3 -C 10 heterocycloalkylC 1 -C 4 alkyl, phenyl, phenylC 1 -C 4 alkyl, diphenylC 1 -C 4 alkyl, heteroaryl and heteroarylC 1 -C 4 alkyl; or R F and R F′ are combined with the nitrogen atom to which each is attached to form a 5-, 6- or 7-membered ring having 0 to 3 substituents selected from halogen, C 1 -C 4 alkyl, OH, OC 1 -C 4 alkyl, NH 2 , NHC 1 -C 4 alkyl and N(C 1 -C 4 alkyl) 2 ;

and wherein cycloalkyl, heterocycloalkyl, phenyl and heteroaryl portions of R B , R F and R F′ are substituted with from 0 to 3 substituents selected from halogen, C 1 -C 4 alkyl, OH, OC 1 -C 4 alkyl, NH 2 , NHC 1 -C 4 alkyl and N(C 1 -C 4 alkyl) 2 ; and

p is from about 1 to about 16;

wherein Q is attached through any one of the hydroxyl or amine groups present on CPT2 or CPT5.

2 . The Camptothecin Conjugate of claim 1 , wherein D has formula CPT2.

3 - 6 . (canceled)

7 . The Camptothecin Conjugate of claim 1 , wherein D has formula CPT5.

8 . The Camptothecin Conjugate of claim 7 , wherein the -Q-D component of the Conjugate has a formula selected from (CPT5iN), (CPT5iiN), (CPT5iiiN), (CPT5ivN), (CPT5vN), (CPT5viN), (CPT5iO), (CPT5iiO), (CPT5iiiO), (CPT5ivO), (CPT5vO), and (CPT5viO):

9 - 11 . (canceled)

12 . The Camptothecin Conjugate of claim 8 , wherein the -Q-D component of the Camptothecin Conjugate has a formula selected from (CPT5iN), (CPT5iiN), (CPT5iiiN), (CPT5ivN), (CPT5vN), and (CPT5viN).

13 . (canceled)

14 . The Camptothecin Conjugate of claim 12 , wherein R F is selected from the group consisting of —H, C 1 -C 8 alkyl, C 1 -C 8 hydroxyalkyl, C 1 -C 8 aminoalkyl, C 1 -C 4 alkylaminoC 1 -C 8 alkyl, (C 1 -C 4 hydroxyalkyl)(C 1 -C 4 alkyl)aminoC 1 -C 8 alkyl, di(C 1 -C 4 alkyl)aminoC 1 -C 8 alkyl, C 1 -C 4 hydroxyalkylC 1 -C 8 aminoalkyl, C 1 -C 8 alkylC(O)—, C 1 -C 8 hydroxyalkylC(O)—, and C 1 -C 8 aminoalkylC(O)—;

and wherein cycloalkyl, heterocycloalkyl, phenyl and heteroaryl portions of R F are substituted with from 0 to 3 substituents selected from halogen, C 1 -C 4 alkyl, OH, OC 1 -C 4 alkyl, NH 2 , NHC 1 -C 4 alkyl and N(C 1 -C 4 alkyl) 2 .

15 . (canceled)

16 . The Camptothecin Conjugate of claim 1 , wherein S* is a bond and Q is —Z-A-RL- or —Z-A-RL-Y—.

17 . The Camptothecin Conjugate of claim 1 , wherein S* is a PEG Unit, and Q is

—Z-A-S*-RL-; —Z-A-L P (S*)-RL-; —Z-A-S*-RL-Y—; or —Z-A-L P (S*)—RL-Y—.

18 . (canceled)

19 . The Camptothecin Conjugate of claim 18 , the PEG Unit has the formula:

wherein the wavy line on the left indicates the site of attachment to A, the wavy line on the right indicates the site of attachment to RL, and b is an integer from 2 to 20, or is 2, 4, 8, or 12.

20 . The Camptothecin Conjugate of claim 19 , wherein the PEG Unit has the formula:

wherein the wavy line on the left indicates the site of attachment to A, the wavy line on the right indicates the site of attachment to RL, and b is an integer from 2 to 20, or is 2, 4, 8, or 12.

21 . The Camptothecin Conjugate of 17, wherein Q is of formula —Z-A-L P (S*)—RL- or —Z-A-L P (S*)—RL-Y— and S* is a PEG Unit which comprises 2, 4, 8, or 12 —CH 2 CH 2 O— subunits and a PEG Unit terminal cap group that is C 1-4 alkyl or C 1-4 alkyl-CO 2 H.

22 . The Camptothecin Conjugate of claim 21 , wherein S* is of formula:

wherein the wavy line indicates the site of attachment to the Parallel Connector Unit (L P ), and b is an integer from 2 to 20, or is 2, 4, 8, or 12.

23 . The Camptothecin Conjugate of claim 22 , wherein S* is of formula:

wherein the wavy line indicates the site of attachment to the Parallel Connector Unit (L P ), and b is an integer from 2 to 20, or is 2, 4, 8, or 12.

24 . (canceled)

25 . The Camptothecin Conjugate of claim 24 , wherein L P is of formula:

wherein the wavy line indicates the position of attachment to the Partitioning Agent and asterisks indicate positions of attachment to A and RL.

26 . The Camptothecin Conjugate of claim 1 , wherein Z has Formula Za:

wherein the asterisk indicates the position of attachment to the Ligand Unit (L);

the wavy line indicates the position of attachment to the Connector Unit (A); and

R 17 is —C 1 -C 10 alkylene-, C 1 -C 10 heteroalkylene-, —C 3 -C 8 carbocyclo-, —O—(C 1 -C 8 alkylene)-, -arylene-, —C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-, —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-, —C 3 -C 8 heterocyclo-, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-, —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-C(═O)—, C 1 -C 10 heteroalkylene-C(═O)—, —C 3 -C 8 carbocyclo-C(═O)—, —O—(C 1 -C 8 alkylene)-C(═O)—, -arylene-C(═O)—, —C 1 -C 10 alkylene-arylene-C(═O)—, -arylene-C 1 -C 10 alkylene-C(═O)—, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-C(═O)—, —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-C(═O)—, —C 3 -C 8 heterocyclo-C(═O)—, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-C(═O)—, —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-C(═O)—, —C 1 -C 10 alkylene-NH—, C 1 -C 10 heteroalkylene-NH—, —C 3 -C 8 carbocyclo-NH—, —O—(C 1 -C 8 alkylene)-NH—, -arylene-NH—, —C 1 -C 10 alkylene-arylene-NH—, -arylene-C 1 -C 10 alkylene-NH—, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-NH—, —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-NH—, —C 3 -C 8 heterocyclo-NH—, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-NH—, —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-NH—, —C 1 -C 10 alkylene-S—, C 1 -C 10 heteroalkylene-S—, —C 3 -C 8 carbocyclo-S—, —O—(C 1 -C 8 alkylene)-S—, -arylene-S—, —C 1 -C 10 alkylene-arylene-S—, -arylene-C 1 -C 10 alkylene-S—, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-S—, —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-S—, —C 3 -C 8 heterocyclo-S—, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-S—, or —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-S—;

wherein R 17 is optionally substituted with a Basic Unit (BU) that is —(CH 2 ) x NH 2 , —(CH 2 ) x NHR a , or —(CH 2 ) x NR a 2 ;

wherein x is an integer of from 1-4; and

each R a is independently selected from the group consisting of C 1-6 alkyl and C 1-6 haloalkyl, or two R a groups are combined with the nitrogen to which they are attached to form a 4- to 6-membered heterocycloalkyl ring, or an azetidinyl, pyrrolidinyl or piperidinyl group.

27 . (canceled)

28 . The Camptothecin Conjugate of claim 26 , wherein Z is:

29 . The Camptothecin Conjugate of claim 28 , wherein Z is:

30 . (canceled)

31 . The Camptothecin Conjugate of claim 1 , wherein A is a bond.

32 . The Camptothecin Conjugate of claim 1 , wherein RL is a dipeptide, tripeptide, or tetrapeptide.

33 . (canceled)

34 . (canceled)

35 . The Camptothecin Conjugate of claim 32 , wherein RL is gly-gly, gly-gly-gly, gly-gly-gly-gly, val-gly-gly, val-cit-gly, val-gln-gly, val-glu-gly, phe-lys-gly, leu-lys-gly, gly-val-lys-gly, val-lys-gly-gly, val-lys-gly, val-lys-ala, val-lys-leu, leu-leu-gly, gly-gly-phe-gly, gly-gly-phe-gly-gly, val-gly, or val-lys-β-ala.

36 . The Camptothecin Conjugate of claim 32 , wherein RL is a tripeptide having the formula: AA 1 -AA 2 -AA 3 , wherein AA 1 , AA 2 and AA 3 are each independently an amino acid, wherein AA 1 attaches to —NH— and AA 3 attaches to S*.

37 . The Camptothecin Conjugate of claim 36 , wherein wherein AA 3 is gly or β-ala.

38 . The Camptothecin Conjugate of claim 37 , wherein RL is val-lys-gly, wherein val attaches to —NH— and gly attaches to S*.

39 . The Camptothecin Conjugate of claim 1 , wherein Y is of the formula:

40 . The Camptothecin Conjugate of claim 1 , wherein p is 1 to 16.

41 - 46 . (canceled)

47 . The Camptothecin Conjugate of claim 1 , having the Formula (IC):

or a pharmaceutically acceptable salt thereof;

wherein

y is 1, 2, 3, or 4; and

z is 2, 4, 8, or 12;

and p is 1-16.

48 . The Camptothecin Conjugate of claim 47 , wherein p is 4 or 8.

49 - 52 . (canceled)

53 . The Camptothecin Conjugate of claim 1 , wherein the Ligand Unit is an antibody or an antigen-binding fragment thereof.

54 . (canceled)

55 . (canceled)

56 . A Camptothecin-Linker Compound of the formula:

Q′-D,

or a pharmaceutically acceptable salt thereof, wherein

Q′ is a Linker Unit Precursor having a formula selected from the group consisting of:

Z′-A-S*-RL-; Z′-A-L P (S*)—RL-; Z′-A-S*-RL-Y—; Z′-A-L P (S*)—RL-Y—;

wherein

Z′ is a Stretcher Unit Precursor;

A is a bond or a Connector Unit;

S* is a bond or a Partitioning Agent;

L P is a Parallel Connector Unit;

RL is a Peptide Releasable Linker comprising a peptide comprising 2 to 8 amino acids; and

Y is a Spacer Unit,

D is a Drug Unit selected from:

wherein

R B is a member selected from the group consisting of H, —(C 1 -C 4 )alkyl-OH, —(C 1 -C 4 )alkyl-O—(C 1 -C 4 )alkyl-NH 2 , —C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 4 alkyl, phenyl and phenylC 1 -C 4 alkyl;

each R F and R F′ is a member independently selected from the group consisting of H, C 1 -C 8 alkyl, C 1 -C 8 hydroxyalkyl, C 1 -C 8 aminoalkyl, C 1 -C 4 alkylaminoC 1 -C 8 alkyl, (C 1 -C 4 hydroxyalkyl)(C 1 -C 4 alkyl)aminoC 1 -C 8 alkyl, di(C 1 -C 4 alkyl)aminoC 1 -C 8 alkyl, C 1 -C 4 hydroxyalkylC 1 -C 8 aminoalkyl, C 1 -C 8 alkylC(O)—, C 1 -C 8 hydroxyalkylC(O)—, C 1 -C 8 aminoalkylC(O)—, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylC 1 -C 4 alkyl, C 3 -C 10 heterocycloalkyl, C 3 -C 10 heterocycloalkylC 1 -C 4 alkyl, phenyl, phenylC 1 -C 4 alkyl, diphenylC 1 -C 4 alkyl, heteroaryl and heteroarylC 1 -C 4 alkyl; or R F and R F′ are combined with the nitrogen atom to which each is attached to form a 5-, 6- or 7-membered ring having 0 to 3 substituents selected from halogen, C 1 -C 4 alkyl, OH, OC 1 -C 4 alkyl, NH 2 , NHC 1 -C 4 alkyl and N(C 1 -C 4 alkyl) 2 ;

and wherein cycloalkyl, heterocycloalkyl, phenyl and heteroaryl portions of R B , R F and R F′ are substituted with from 0 to 3 substituents selected from halogen, C 1 -C 4 alkyl, OH, OC 1 -C 4 alkyl, NH 2 , NHC 1 -C 4 alkyl and N(C 1 -C 4 alkyl) 2 ,

wherein Q is attached through any one of the hydroxyl or amine groups present on CPT2 or CPT5.

57 . The Camptothecin-Linker Compound of claim 56 , wherein D has formula CPT2.

58 - 61 . (canceled)

62 . The Camptothecin-Linker Compound of claim 56 , wherein D has formula CPT5.

63 - 110 . (canceled)

111 . A Camptothecin Compound of formula:

wherein each R F and R F′ is independently H, glycyl, hydroxyacetyl, ethyl, or 2-(2-(2-aminoethoxy)ethoxy)ethyl, or wherein R F and R F′ are combined with the nitrogen atom to which each is attached to form a 5-, 6-, or 7-membered heterocycloalkyl ring.

112 . The Camptothecin Compound of claim 111 , wherein R F and R F′ are combined with the nitrogen atom to which each is attached to form a 6-membered ring.

113 . (canceled)

114 . The Camptothecin Compound of claim 111 , wherein R F′ is H and R F is glycyl, hydroxyacetyl, ethyl, or 2-(2-(2-aminoethoxy)ethoxy)ethyl, an aliphatic group, an aryl group, an amide group, or an ethylene oxide group.

115 - 118 . (canceled)

119 . The Camptothecin Compound of claim 111 , wherein the compound is selected from the group selected from Compound 4, Compound 5, and compounds in Tables I and II.

120 . A Camptothecin Compound of formula:

or a pharmaceutically acceptable salt thereof,

wherein R B is —(C 1 -C 4 )alkyl-OH, —(C 1 -C 4 )alkyl-O—(C 1 -C 4 )alkyl-NH 2 , —C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 4 alkyl, phenyl or phenylC 1 -C 4 alkyl.

121 . (canceled)

122 . (canceled)

123 . The Camptothecin Compound of claim 120 , wherein the compound is selected from the group consisting of Compound 6 and compounds in Table III.

124 . The Camptothecin Conjugate of claim 53 , wherein the antibody or antigen-binding fragment thereof comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively.

125 . The Camptothecin Conjugate of claim 124 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 8.

126 . The Camptothecin Conjugate of claim 124 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8.

127 . The Camptothecin Conjugate of claim 124 , wherein the antibody or comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 10 and a light chain comprising the amino acid sequence of SEQ ID NO: 11.

128 . The Camptothecin Conjugate of claim 124 , having Formula(IC):

or a pharmaceutically acceptable salt thereof;

wherein

y is 1, 2, 3, or 4, or is 1 or 4; and

z is an integer from 2 to 12, or is 2, 4, 8, or 12;

and p is 1-16.

129 . The Camptothecin Conjugate of claim 128 , wherein p is 2, 4 or 8.

130 . The Camptothecin Conjugate of claim 53 , having formula:

or a pharmaceutically acceptable salt thereof;

wherein

p is 2, 4, or 8.

131 . (canceled)

132 . A method of treating cancer or an autoimmune disease in a subject in need thereof, comprising administering to the subject an effective amount of a Camptothecin Conjugate of claim 1 .

133 - 136 . (canceled)

137 . A method of treating cancer in a subject in need thereof, comprising contacting the cancer cells with the Camptothecin Compound of claim 111 .

138 . (canceled)

139 . A method of preparing a Camptothecin Conjugate of claim 1 , comprising reacting an antibody or antigen-binding fragment thereof with a Camptothecin-Linker Compound of claim 56 .

140 . A pharmaceutical composition comprising the Camptothecin Conjugate of claim 1 and a pharmaceutically acceptable carrier.

141 - 143 . (canceled)