Cytotoxic and antimitotic compounds, and methods of use thereof

Abstract

The present invention relates to cytotoxic and anti-mitotic compounds and methods of using the same. The present invention discloses compounds having cytotoxic and / or anti-mitotic activity. The present invention also discloses methods related to the preparation and use of such compounds, and pharmaceutical compositions comprising such compounds. Also disclosed is a composition having the following structure: (T)-(L)-(D), wherein (T) is a targeting moiety, (L) is an optional linker, and (D) is a compound having cytotoxic and / or anti-mitotic activity.

Description

[0001] This application is a divisional application of Chinese patent application No. 201580057324.1, filed on September 17, 2015, entitled "Cytotoxic and antimitotic compounds, and methods of use thereof." Technical Field

[0002] The present invention relates to biologically active compounds, compositions containing the same, and methods of using such biologically active compounds and compositions to treat cancer and other diseases. Background Art

[0003] Promising new cancer therapeutics include dolastatins and synthetic dolastatin analogs such as auristatins (U.S. Patent Nos. 5,635,483, 5,780,588, 6,323,315, and 6,884,869; Shnyder et al. (2007) Int. J. Oncol. 31: 353-360; Otani, M. et al. Jpn. J. Cancer Res. 2000, 91, 837-844; PCT International Publication Nos. WO 01 / 18032 A3, WO 2005 / 039492, WO 2006 / 132670, and WO 2009 / 095447; Fennell, BJ et al. J. Antimicrob. Chemther. 2003, 51, 833-841). Dolastatins and auristatins have been shown to interfere with microtubule dynamics, thereby disrupting cell division (Woyke et al. (2001) Antimicrob. Agents Chemother. 45(12):3580-3584) and have anticancer (U.S. Patent No. 5,663,149) and antifungal activity (Pettit et al. (1998) Antimicrob. Agents Chemother. 42:2961-2965). Unfortunately, despite early enthusiasm, dolastatin 10 showed poor results as a single agent in a Phase II clinical trial (Shnyder (2007), supra). Certain compounds in the auristatin family have shown greater promise as clinical candidates with improved efficacy and pharmacological profiles than dolastatins (Pettit et al. (1995) Anti-Cancer Drug Des. 10:529-544; Pettit et al. (1998) Anti-Cancer Drug Des. 13:243-277; Shnyder (2007), supra). Various synthetic analogs of this structural class have been described (U.S. Pat. No. 6,569,834; U.S. Pat. No. 6,124,431; and Pettit et al. (2011) J. Nat. Prod. 74:962-968).

[0004] Auristatins have several properties that make them attractive for drug development. First, these compounds are extremely potent. Second, their preparation is straightforward because of the peptide backbone. Third, they have favorable pharmacokinetic and metabolic profiles compared to peptides in general or other classes of cancer drugs in particular. Finally, the peptide structure of auristatins is similar to that of antibodies, so when these compounds are used as part of an antibody-drug conjugate (ADC), they are less likely to cause precipitation or formation of high molecular weight aggregates (Doronina et al. (2003) Nat. Biotechnology 21(7):778-784).

[0005] Effective cytotoxic and anti-mitotic compositions are highly desirable for treating many devastating conditions, including cancer. Although a wide variety of auristatin analogs have been developed, many exhibit reduced efficacy, which limits their utility in medical treatment methods. For the above reasons, despite advances in the art, there remains a need for additional effective anti-mitotic and cytotoxic compounds with preferred characteristics that make them suitable for treating a variety of conditions, including cancer. The present disclosure addresses these needs and also provides related advantages. Summary of the Invention

[0006] Briefly, the present disclosure relates to biologically active compounds, compositions comprising the same, and methods of using such compounds and compositions. Provided are compounds of formula I:

[0007]

[0008] and pharmaceutically acceptable salts thereof, wherein:

[0009] R 1 is selected from the group consisting of amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heterocyclyl and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of aryl, aryl-C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkylthio, carboxyl, carboxamide, C3-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, guanidino, halo, C1-C6 haloalkyl, heterocyclyl, heterocyclyl-C1-C6 alkyl, hydroxyl and thio; or

[0010] R 1 R a R b NCH(R c )-;

[0011] R a Selected from: H and C1-C6 alkyl;

[0012] R bis a C1-C6 alkyl group; and

[0013] R c R d -C(CH3)2-; and

[0014] R d is selected from the group consisting of: H, aryl, C3-C7 cycloalkyl and heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: C1-C4 acylthio, C2-C4 alkenyl, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkoxy, amino, amino-C1-C4 alkyl, halo, C1-C4 haloalkyl, hydroxy, hydroxy-C1-C4 alkyl and thio, wherein C2-C4 alkenyl, C1-C4 alkylamino and C1-C4 alkoxy are further optionally substituted with one substituent selected from the group consisting of: C1-C4 alkylaryl, hydroxy and thio; or

[0015] R b and R c together with the atoms to which they are respectively bonded, form a heterocyclyldiyl;

[0016] R 2 is selected from the group consisting of: C2-C6 alkyl, aryl, aryl-C1-C6 alkyl, C4-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloacyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio, and thio-C1-C6 alkyl; and

[0017] X is -C(O)NHCH(CH2R 3 )-, or X does not exist; and

[0018] R 3 is selected from the group consisting of aryl, heteroaryl and C3-C7 cycloalkyl, each optionally substituted with one substituent selected from the group consisting of amino and hydroxy.

[0019] In one embodiment, the present invention provides a process for preparing a compound described herein or a pharmaceutically acceptable salt thereof.

[0020] In another embodiment, a pharmaceutical composition is provided, comprising a compound described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0021] In another embodiment, a method of using a compound as described herein or a pharmaceutically acceptable salt thereof in therapy is provided. Specifically, the present disclosure provides a method of treating cancer in a mammal, comprising administering to a mammal in need thereof an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound as described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0022] In another embodiment, the present disclosure provides a method of inhibiting tumor growth in a mammal, comprising administering to a mammal in need thereof an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound as described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0023] In another embodiment, the present disclosure provides a method of killing cancer cells in vitro using a compound as described herein or a pharmaceutically acceptable salt thereof. In another embodiment, the present disclosure provides a method of killing cancer cells in a mammal in vivo, the method comprising administering to a mammal in need thereof an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound as described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0024] In another embodiment, the present disclosure provides a method of increasing the survival time of a mammal suffering from cancer, comprising administering to such mammal an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound as described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0025] In another embodiment, the present disclosure provides a use of a compound as described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer in a mammal.

[0026] In another embodiment, the present disclosure provides a use of a compound described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting tumor growth in a mammal.

[0027] In another embodiment, the present disclosure provides a use of a compound as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for prolonging survival in a mammal having cancer.

[0028] In another embodiment, the present disclosure provides a compound or pharmaceutical composition as described herein for use in a method of treatment of the human or animal body by therapy.

[0029] In another embodiment, the present disclosure provides a compound or pharmaceutical composition as described herein for use in treating cancer in a mammal.

[0030] In another embodiment, the present disclosure provides a compound or pharmaceutical composition as described herein for use in inhibiting tumor growth in a mammal.

[0031] In another embodiment, the present disclosure provides a compound or pharmaceutical composition as described herein for use in prolonging survival of a mammal suffering from cancer.

[0032] In one embodiment, a composition comprising a biologically active compound as described herein, or a pharmaceutically acceptable salt thereof, directly or indirectly linked to a targeting moiety is provided.

[0033] In one embodiment, the present invention provides a composition of formula II:

[0034] (T)-(L)-(D)

[0035] II

[0036] wherein (T) is a targeting moiety, (L) is an optional linker, and (D) is a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, or Ik, or a pharmaceutically acceptable salt thereof. If (L) is present, then (D) is covalently linked to (L); or if (L) is absent, then (D) is covalently linked to (T).

[0037] In one embodiment, the targeting moiety is an antibody. Thus, in one embodiment, an antibody-drug conjugate (ADC) is provided, comprising a compound as described herein, or a pharmaceutically acceptable salt or prodrug thereof.

[0038] In one embodiment, the present invention provides a method for preparing the composition of formula II.

[0039] In another embodiment, a pharmaceutical composition is provided, comprising a composition of Formula II or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[0040] In another embodiment, a method of using a composition of Formula II in therapy is provided. Specifically, the present disclosure provides a method of treating cancer in a mammal, comprising administering to a mammal in need thereof an effective amount of a composition of Formula II or a pharmaceutical composition comprising a composition of Formula II and a pharmaceutically acceptable carrier, diluent, or excipient.

[0041] In another embodiment, the present disclosure provides a method of inhibiting tumor growth in a mammal, comprising administering to a mammal in need thereof an effective amount of a composition of Formula II or a pharmaceutical composition comprising a composition of Formula II and a pharmaceutically acceptable carrier, diluent, or excipient.

[0042] In another embodiment, the present disclosure provides a method for killing cancer cells in vitro using a composition of Formula II. In another embodiment, the present disclosure provides a method for killing cancer cells in a mammal in vivo, the method comprising administering to a mammal in need thereof an effective amount of a composition of Formula II or a pharmaceutical composition comprising a composition of Formula II and a pharmaceutically acceptable carrier, diluent, or excipient.

[0043] In another embodiment, the present disclosure provides a method for increasing the survival time of a mammal suffering from cancer, comprising administering to a mammal in need thereof an effective amount of a composition of Formula II or a pharmaceutical composition comprising a composition of Formula II and a pharmaceutically acceptable carrier, diluent, or excipient.

[0044] In another embodiment, the present disclosure provides a use of a composition of Formula II or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer in a mammal.

[0045] In another embodiment, the present disclosure provides a use of a composition of Formula II in the manufacture of a medicament for inhibiting tumor growth in a mammal.

[0046] In another embodiment, the present disclosure provides a use of a composition of Formula II in the manufacture of a medicament for prolonging survival in a mammal having cancer.

[0047] In another embodiment, the present disclosure provides a composition of Formula II or a pharmaceutical composition comprising a composition of Formula II for use in a method of treating the human or animal body by therapy.

[0048] In another embodiment, the present disclosure provides a composition of Formula II or a pharmaceutical composition comprising the composition of Formula II for use in treating cancer in a mammal.

[0049] In another embodiment, the present disclosure provides a composition of Formula II or a pharmaceutical composition comprising the composition of Formula II for use in inhibiting tumor growth in a mammal.

[0050] In another embodiment, the present disclosure provides a composition of Formula II or a pharmaceutical composition comprising the composition of Formula II for use in prolonging the survival of a mammal suffering from cancer.

[0051] These and other aspects of the disclosure will become apparent upon reference to the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1 The cytotoxicity of compound 5 against the Her2-positive HCC1954 cell line is shown.

[0053] Figure 2 The cytotoxicity of compound 5 on the Her2-negative Jurkat cell line is shown.

[0054] Figure 3 The cytotoxicity of the trastuzumab ADC of compound 5 against the Her2-positive NCI-N87 cell line is shown.

[0055] Figure 4 The cytotoxicity of the trastuzumab ADC of compound 5 against the Her2-positive HCC1954 cell line is shown.

[0056] Figure 5 The cytotoxicity of the trastuzumab ADC of compound 5 on the Her2-negative Jurkat cell line is shown.

[0057] Figure 6 Shown are the results of an equilibrium native binding assay comparing the binding of certain ADCs to the MDA-MB-231 cell line.

[0058] Figure 7 The efficacy of certain ADCs in the NCI-N87 tumor model using NOD SCID gamma mice is shown.

[0059] Figure 8 Shows some ADCs using CB-17 / IcrHsd-Prkdc scid Efficacy in the Karpas 299 tumor model in mice.

[0060] Figure 9 Shown are the results of a tolerability study of trastuzumab ADC of Compound 14 in female Sprague Dawley rats.

[0061] Figure 10 Shown are the results of a tolerability study of trastuzumab ADC of Compound 5 in female Sprague Dawley rats.

[0062] Figure 11 The results of cell cycle arrest assay in Jurkat cells treated with compound 5 are shown.

[0063] Details

[0064] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the present disclosure. However, it will be understood by those skilled in the art that the present disclosure can be practiced without these details.

[0065] definition

[0066] Unless otherwise indicated, the following terms and phrases as used herein are intended to have the following meanings: When a trade name is used herein, applicants intend to include independently the trade name product formulation, the generic name, and the active pharmaceutical ingredient of the trade name product.

[0067] Throughout this specification and claims, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" are to be interpreted in an open, inclusive sense meaning "including but not limited to."

[0068] Reference throughout this specification to "one embodiment" or "an embodiment" is intended to indicate that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. It will be appreciated that certain features of the invention that are, for clarity, described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment may also be provided separately or in any suitable subcombination.

[0069] Chemical groups

[0070] With respect to the compounds represented by variables (e.g., R contained in the chemical formulae described herein (e.g., I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, In, In, II, III, IV, V, VI, VII, and VIII) a 、R b 、R c 、R d 、R e 、R f 、R g 、R h 、R i 、R j 、R k 、R m 、R l 、R 2 、R 2a 、R 3 、R 4 、R 5、R 6 、R 7 、R 8 、R 9 、R 4 、R 10 、R 11 、R 12 、R 13 、R1 4 、R 15 、R 16 All combinations of embodiments of chemical groups represented by R, X, Y, and Z are specifically encompassed by the present invention as if each and every combination were individually and explicitly recited, whereby such combinations include compounds that produce stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of chemical groups listed in the embodiments describing such variables and all subcombinations of uses and medical indications described herein are also specifically encompassed by the present invention as if each and every subcombination of chemical groups and subcombinations of uses and medical indications were individually and explicitly recited herein. In addition, if any specific R is specified in a specific embodiment and / or claim, a 、R b 、R c 、R d 、R e 、R f 、R g 、R h 、R i 、R j 、R k 、R m 、R l 、R 2 、R 2a 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 4 、R 10 、R 11 、R 12 、R 13 、R1 4 、R 15 、R 16 , X, Y, or Z lists a list of substituents, it should be understood that each individual substituent can be deleted from the specific embodiment and / or claim, and the remaining list of substituents will be considered to be within the scope of the present disclosure.

[0071] As used herein, the term "acyloxy" includes -OC(O)-alkyl, wherein alkyl is as defined herein. Examples of acyloxy include, but are not limited to, formyloxy, acetyloxy, propionyloxy, isobutyryloxy, pivaloyloxy, and the like.

[0072] As used herein, the term "acylthio" refers to -SC(O)-alkyl, wherein alkyl is as defined herein. Examples of acylthio include, but are not limited to, formylthio, acetylthio, propionylthio, isobutyrylthio, pivaloylthio, and the like.

[0073] As used herein, the term "alkoxy" refers to an -O-alkyl group, wherein alkyl is as defined herein. Examples of alkyl groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentoxy, isopentoxy, tert-pentoxy, neopentoxy, 1-methylbutoxy, 2-methylbutoxy, n-hexyloxy, and the like.

[0074] As used herein, the term "alkoxycarbonyl" refers to a -C(O)O-alkyl group. Examples of alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butoxycarbonyl, sec-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, tert-pentyloxycarbonyl, neopentyloxycarbonyl, 1-methylbutoxycarbonyl, 2-methylbutoxycarbonyl, n-hexyloxycarbonyl, and the like.

[0075] As used herein, the term "alkenyldiyl" refers to a straight-chain or branched unsaturated hydrocarbon divalent group containing a specified number of carbon atoms and one or more carbon-carbon double bonds, for example, a C2-C6 alkenyldiyl, a C2-C4 alkenyldiyl, or a C2 alkenyldiyl. Examples of alkenyldiyl include, but are not limited to, vinyldiyl, n-propenyldiyl, isopropenyldiyl, n-butenyldiyl, sec-butenyldiyl, isobutenyldiyl, tert-butenyldiyl, pentenyldiyl, isopentenyldiyl, tert-pentenyldiyl, neopentenyldiyl, 1-methylbutenyldiyl, 2-methylbutenyldiyl, n-hexenyldiyl, and the like.

[0076] As used herein, the term "alkyl" refers to a straight or branched chain saturated hydrocarbon group containing the specified number of carbon atoms, such as C1-C6 alkyl, C1-C4 alkyl, or C2 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl, 1-methylbutyl, 2-methylbutyl, n-hexyl, and the like.

[0077] As used herein, the term "alkyldiyl" refers to a straight-chain or branched saturated hydrocarbon divalent group containing the specified number of carbon atoms, for example, a C1-C6 alkyldiyl, a C1-C4 alkyldiyl, or a C2 alkyldiyl. Examples of alkyldiyl groups include, but are not limited to, methyldiyl, ethyldiyl, n-propyldiyl, isopropyldiyl, n-butyldiyl, sec-butyldiyl, isobutyldiyl, tert-butyldiyl, pentyldiyl, isopentyldiyl, tert-pentyldiyl, neopentyldiyl, 1-methylbutyldiyl, 2-methylbutyldiyl, n-hexyldiyl, and the like.

[0078] As used herein, the term "alkylamino" refers to -NH-alkyl, wherein alkyl is as defined herein. Examples of alkylamino include, but are not limited to, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, sec-butylamino, isobutylamino, tert-butylamino, pentylamino, isopentylamino, tert-pentylamino, neopentylamino, 1-methylbutylamino, 2-methylbutylamino, n-hexylamino, and the like.

[0079] As used herein, the term "alkylthio" refers to -S-alkyl, wherein alkyl is as defined herein. Examples of alkylthio include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, sec-butylthio, isobutylthio, tert-butylthio, pentylthio, isopentylthio, tert-pentylthio, neopentylthio, 1-methylbutylthio, 2-methylbutylthio, n-hexylthio, and the like.

[0080] The term "amino" as used herein refers to -NH2.

[0081] As used herein, the term "amino-cycloalkyl" refers to a cycloalkyl group substituted with an amino substituent, as those terms are defined herein. Examples of amino-cycloalkyl groups include, but are not limited to, aminocyclopropyl, aminocyclobutyl, aminocyclopentyl, aminocyclohexyl, and the like.

[0082] As used herein, the term "amino-alkyl" refers to an alkyl group substituted with an amino substituent, as those terms are defined herein. Examples of amino-alkyl groups include, but are not limited to, aminomethyl, aminoethyl, amino-n-propyl, amino-isopropyl, amino-n-butyl, amino-sec-butyl, amino-isobutyl, amino-tert-butyl, amino-pentyl, amino-isopentyl, amino-tert-pentyl, amino-neopentyl, amino-1-methylbutyl, amino-2-methylbutyl, amino-n-hexyl, and the like.

[0083] As used herein, the term "amino-aryl" refers to an aryl group substituted with an amino substituent, as those terms are defined herein. Examples of amino-aryl groups include, but are not limited to, amino-phenyl, amino-naphthyl, and the like.

[0084] As used herein, the term "amino-heterocyclyl" refers to a heterocyclyl group substituted with an amino substituent, as those terms are defined herein. Examples of amino-heterocyclyl groups include, but are not limited to, amino-pyrrolidinyl, amino-piperidinyl, and the like.

[0085] As used herein, the term "aryl" refers to a group derived from a 6- to 12-membered monocyclic or bicyclic hydrocarbon ring system, wherein at least one ring is aromatic. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, indanyl, and the like.

[0086] As used herein, the term "aryl-alkyl" refers to an alkyl group substituted with an aryl substituent, as those terms are defined herein. Examples of aryl-alkyl groups include, but are not limited to, benzyl, phenethyl, phenylpropyl, naphthylmethyl, and the like.

[0087] As used herein, the term "aryldiyl" refers to a divalent group derived from a 6- to 12-membered monocyclic or bicyclic hydrocarbon ring system, wherein at least one ring is aromatic. Examples of aryldiyl include, but are not limited to, phenyldiyl, naphthyldiyl, 1,2,3,4-tetrahydro-naphthyldiyl, 5,6,7,8-tetrahydro-naphthyldiyl, indanyldiyl, and the like.

[0088] As used herein, the term "carboxamide" refers to -C(O)NH2.

[0089] The term "carboxy" as used herein refers to -C(O)OH.

[0090] The term "cyano" as used herein refers to -CN.

[0091] As used herein, the term "cycloalkyl" refers to a cyclic saturated hydrocarbon group containing a specified number of carbon atoms, such as a C3-C7 alkyl or a C4-C7 alkyldiyl. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0092] As used herein, the term "cycloalkyl-alkyl" refers to an alkyl group substituted with a cycloalkyl substituent, as those terms are defined herein. Examples of cycloalkyl-alkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, and the like.

[0093] As used herein, the term "cycloalkyldiyl" refers to a divalent cyclic saturated hydrocarbon group containing a specified number of carbon atoms, for example, a C3-C7 cycloalkyldiyl or a C4-C7 alkyldiyl. Examples of cycloalkyldiyl groups include, but are not limited to, cyclopropyldiyl, cyclobutyldiyl, cyclopentyldiyl, cyclohexyldiyl, and the like.

[0094] As used herein, the term "guanidino" refers to -NH-C(=NH)-NH2.

[0095] The term "halo" as used herein refers to -F, -Cl, -Br and -I.

[0096] As used herein, the term "haloacyl" refers to -C(O)-haloalkyl, wherein haloalkyl is as defined herein. Examples of haloacyl include, but are not limited to, difluoroacetyl, trifluoroacetyl, 3,3,3-trifluoropropionyl, pentafluoropropionyl, and the like.

[0097] As used herein, the term "haloalkoxy" refers to -O-haloalkyl, wherein haloalkyl is as defined herein. Examples of haloalkoxy include, but are not limited to, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, and the like.

[0098] As used herein, the term "haloalkyl" refers to an alkyl group as defined herein that is substituted with one or more halogens. A fully substituted haloalkyl group can be represented by the formula C n L 2n+1 = represents, wherein L is a halogen. When more than one halogen is present, they may be the same or different and are selected from the group consisting of F, Cl, Br, and I. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and the like.

[0099] As used herein, the term "heteroaryl" refers to a radical derived from a 6- to 12-membered monocyclic or bicyclic ring system in which at least one ring atom is a heteroatom and at least one ring is aromatic. Examples of heteroatoms include, but are not limited to, O, S, N, and the like. Examples of heteroaryl radicals include, but are not limited to, pyridyl, benzofuranyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, quinolinyl, benzoxazolyl, benzothiazolyl, 1H-benzimidazolyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pyrrolyl, indolyl, 1H-benzimidazol-2-yl, benzo[1,3]dioxol-5-yl, 3,4-dihydro-2H-benzo[1,4]oxazin-7-yl, 2,3-dihydro-benzofuran-7-yl, 2,3-dihydroindole-1-yl, and the like.

[0100] As used herein, the term "heteroaryl-alkyl" refers to an alkyl group substituted with a heteroaryl substituent, as those terms are defined herein. Examples of heteroaryl-alkyl groups include, but are not limited to, pyridylmethyl, benzofuranylmethyl, pyrazinylmethyl, pyridazinylmethyl, pyrimidinylmethyl, triazinylmethyl, quinolylmethyl, benzoxazolylmethyl, benzothiazolylmethyl, 1H-benzimidazolylmethyl, isoquinolylmethyl, quinazolinylmethyl, quinoxalinylmethyl, pyrrolylmethyl, indolylmethyl, 1H-benzimidazol-2-ylmethyl, benzo[1,3]dioxol-5-ylmethyl, 3,4-dihydro-2H-benzo[1,4]oxazin-7-ylmethyl, 2,3-dihydro-benzofuran-7-ylmethyl, 2,3-dihydro-indol-1-ylmethyl, and the like.

[0101] As used herein, the term "heteroaryldiyl" refers to a divalent radical derived from a 6- to 12-membered monocyclic or bicyclic ring system in which at least one ring atom is a heteroatom and at least one ring is aromatic. Examples of heteroatoms include, but are not limited to, O, S, N, and the like. Examples of heteroaryldiyls include, but are not limited to, thiazolyldiyl, 2,4-thiazolyldiyl, triazolyldiyl, 1,2,3-triazolyl-1,4-diyl, pyridyldiyl, benzofuranyldiyl, pyrazinyldiyl, pyridazinyldiyl, pyrimidinyldiyl, triazinyldiyl, quinolinyldiyl, benzoxazolyldiyl, benzothiazolyldiyl, 1H-benzimidazolyldiyl, isoquinolinyldiyl, 1-H-benzo[1,3]dioxol-5-yldiyl, 3,4-dihydro-2H-benzo[1,4]oxazin-7-yldiyl, 2,3-dihydro-benzofuran-7-yldiyl, 2,3-dihydro-indol-1-yldiyl, etc. Examples include, but are not limited to, benzo[1,3]dioxol-5-yldiyl, 1H-benzimidazol-2-yldiyl, 1H-benzimidazol-2-yldiyl, 1H-benzimidazol-3 ...

[0102] As used herein, the term "heterocyclyl" refers to a group derived from a 3- to 12-membered monocyclic or bicyclic non-aromatic ring system, wherein at least one ring atom is a heteroatom. Examples of heteroatoms include, but are not limited to, O, S, N, and the like. Heterocyclyl substituents may be attached via any of their available ring atoms, such as a ring carbon or ring nitrogen. In some embodiments, a heterocyclyl is a ring containing 3-, 4-, 5-, 6-, or 7-members. Examples of heterocyclic groups include, but are not limited to, aziridine-1-yl, aziridine-2-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, piperazin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, [1,3]-dioxolane-2-yl, thiomorpholin-4-yl, [1,4]oxazepan-4-yl, 1,1-dioxo-1λ ... 6 -thiomorpholin-4-yl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, octahydro-quinolin-1-yl, octahydro-isoquinolin-2-yl, and the like.

[0103] As used herein, the term "heterocyclyl-alkyl" refers to an alkyl group substituted with a heterocyclyl substituent, those terms being as defined herein. Examples of heterocyclyl-alkyl groups include, but are not limited to, azetidin-3-ylmethyl, piperidin-1-ylmethyl, piperidin-2-ylmethyl, piperidin-3-ylmethyl, piperidin-4-ylmethyl, morpholin-2-ylmethyl, morpholin-3-ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl, piperazin-2-ylmethyl, piperazin-3-ylmethyl, piperazin-4-ylmethyl, pyrrolidin-1-ylmethyl, pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, [1,3]-dioxolane-2-ylmethyl, thiomorpholin-4-ylmethyl, [1,4]oxazepane-4-ylmethyl, 1,1-dioxo-1λ ... 6 -thiomorpholin-4-ylmethyl, azepan-1-ylmethyl, azepan-2-ylmethyl, azepan-3-ylmethyl, azepan-4-ylmethyl, octahydro-quinolin-1-ylmethyl, octahydro-isoquinolin-2-yl and the like.

[0104] As used herein, the term "heterocyclyldiyl" refers to a divalent group derived from a 3- to 12-membered monocyclic or bicyclic non-aromatic ring system, wherein at least one ring atom is a heteroatom. Examples of heteroatoms include, but are not limited to, O, S, N, and the like. Heterocyclyldiyl substituents may be attached via any two of their available ring atoms, such as ring carbon or ring nitrogen. In some embodiments, heterocyclyldiyl is a ring containing 3-, 4-, 5-, 6-, or 7-members. Examples of heterocyclyldiyl include, but are not limited to, aziridine-1-yldiyl, aziridine-2-yldiyl, azetidin-1-yldiyl, azetidin-2-yldiyl, azetidin-3-yldiyl, piperidin-1-yldiyl, piperidin-2-yldiyl, piperidin-3-yldiyl, piperidin-4-yldiyl, morpholin-2-yldiyl, morpholin-3-yldiyl, morpholin-4-yldiyl, piperazin-1-yldiyl, piperazin-2-yldiyl, piperazin-3-yldiyl, piperazin-4-yldiyl, pyrrolidine-2-yldiyl, pyrrolidine-3-yldiyl, pyrrolidine-4-yldiyl, pyrrolidine-1-yldiyl, pyrrolidine-2-yldiyl, pyrrolidine-3-yldiyl, pyrrolidine ...1-yldiyl, pyrrolidine-2-yldiyl, pyrrolidine-3-yldiyl, pyrrolidine-4-yldiyl, pyrrolidine-4-yldiyl, pyrrolidine-1-yldiyl, pyrrolidine-2-yldiyl, pyrrolidine-3-yldiyl, pyrrolidine-4-yldiyl, pyrrolidine-4-yldiyl, pyrrolidine-1-yldiyl, pyrrolidine-2-yldiyl, pyrrolidine-3-yldiyl, pyrrolidine-4 -1-yldiyl, pyrrolidin-2-yldiyl, pyrrolidin-3-yldiyl, [1,3]-dioxolane-2-yldiyl, thiomorpholin-4-yldiyl, [1,4]oxazepan-4-yldiyl, 1,1-dioxo-1λ6-thiomorpholin-4-yldiyl, azepan-1-yldiyl, azepan-2-yldiyl, azepan-3-yldiyl, azepan-4-yldiyl, octahydro-quinolin-1-yldiyl, octahydro-isoquinolin-2-yldiyl, and the like.

[0105] The term "hydroxy" as used herein refers to -OH.

[0106] As used herein, the term "hydroxy-alkyl" refers to an alkyl group substituted with one hydroxy substituent, as those terms are defined herein. Examples of hydroxy-alkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxy-isopropyl, hydroxy-n-butyl, hydroxy-sec-butyl, hydroxy-isobutyl, hydroxy-tert-butyl, hydroxy-pentyl, hydroxy-isopentyl, hydroxy-tert-pentyl, hydroxy-neopentyl, hydroxy-1-methylbutyl, hydroxy-2-methylbutyl, hydroxy-n-hexyl, and the like.

[0107] As used herein, the term "nitro" refers to -NO2.

[0108] The term "oxo" as used herein refers to =0.

[0109] The term "thio" as used herein refers to -SH.

[0110] As used herein, the term "thioalkyl" refers to an -S-alkyl group, wherein alkyl is as defined herein. Examples include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, sec-butylthio, isobutylthio, tert-butylthio, pentylthio, isopentylthio, tert-pentylthio, neopentylthio, 1-methylbutylthio, 2-methylbutylthio, n-hexylthio, and the like.

[0111] As used herein, "substituted" means that at least one hydrogen atom of a chemical group is replaced by a non-hydrogen substituent or group, which can be monovalent or divalent. When a substituent or group is divalent, it is understood that this group is further substituted by another substituent or group. When a chemical group herein is "substituted", it can have substitutions up to a full valence; for example, a methyl group can be substituted by 1, 2 or 3 substituents, a methylene group (methyldiyl) can be substituted by 1 or 2 substituents, a phenyl group can be substituted by 1, 2, 3, 4 or 5 substituents, a naphthyl group can be substituted by 1, 2, 3, 4, 5, 6 or 7 substituents, etc. Similarly, "substituted by one or more substituents" means that a group is substituted by one substituent to the total number of substituents physically allowed by the group. In addition, when a group is substituted by more than one group, they can be the same or they can be different.

[0112] The compounds described herein may also include tautomeric forms, such as keto-enol tautomers, etc. Tautomeric forms may be in equilibrium or sterically locked into one form by appropriate substitution. It should be understood that various tautomeric forms are within the scope of the compounds of the present invention.

[0113] It should be understood and appreciated that compounds of Formula I and related formulae may have one or more chiral centers and may therefore exist as enantiomers and / or diastereoisomers. It should be understood that the present invention extends to and includes all such enantiomers, diastereoisomers, and mixtures thereof, including but not limited to racemates. It should be understood that unless otherwise indicated or shown, compounds of Formula I and formulae used throughout this disclosure are intended to represent all individual enantiomers and mixtures thereof.

[0114] As used herein, the term "protecting group" refers to an unstable chemical moiety that is known in the art to protect reactive groups (including but not limited to hydroxyl and amino) to avoid undesirable reactions during the synthesis process. Hydroxyl and amino groups protected with protecting groups are referred to as "protected hydroxyl" and "protected amino" in this article. Protecting groups are typically used selectively and / or relatively to protect sites at other reactive sites during the reaction and can be subsequently removed to leave unprotected groups, which are undisturbed or can be used for other reactions. Protecting groups as known in the art are generally described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Groups can be optionally incorporated into compounds of the present disclosure as precursors. For example, amino groups can be placed in compounds described herein as azido groups, which can be chemically converted to amino groups at the desired moment in the synthesis. In general, groups are protected or present as precursors that are inert to the reactions of other parts of the modified parent molecule so that they are converted into their final groups at the appropriate time. Other representative protecting or pro-groups are discussed in Agrawal, et al., Protocols for Oligonucleotide Conjugates, eds., Humana Press; New Jersey, 1994; Vol. 26, p. 172. Examples of hydroxy protecting groups include, but are not limited to, tert-butyl, tert-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, 2,6-dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, trityl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl (TBDPS), triphenylsilyl, benzoylformate, acetate, chloroacetate, trichloroacetate, trifluoroacetate, pivalate, benzoate, p-phenylbenzoate, 9-fluorenylmethyl carbonate, mesylate, and tosylate. Examples of “amino protecting groups” include, but are not limited to, carbamate protecting groups such as 2-trimethylsilylethoxycarbonyl (Teoc), 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc), tert-butyloxycarbonyl (BOC), allyloxycarbonyl (Alloc), 9-fluorenylmethoxycarbonyl (Fmoc), and benzyloxycarbonyl (Cbz); amide protecting groups such as formyl, acetyl, trihaloacetyl, benzoyl, and nitrophenylacetyl; sulfonamide protecting groups such as 2-nitrobenzenesulfonyl; and imine and cyclic imine protecting groups such as phthalimido and dithiasuccinoyl.

[0115] As used herein, "prodrug" refers to a compound that can be converted into a biologically active compound as described herein under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound as described herein. A prodrug may be inactive when administered to a subject in need thereof, but is converted into an active compound as described herein in vivo. In one embodiment, the prodrug is rapidly converted in vivo to produce the parent compound as described herein, for example, by hydrolysis in the blood. In one embodiment, the prodrug may be stable in plasma or blood. In one embodiment, the prodrug may be a targeted form of a compound as described herein. Prodrug compounds often provide advantages in solubility, tissue compatibility, or delayed release in mammalian organisms (see Bundgard, H., Design of Prodrugs (1985), 79, 2124 pages (Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi, T. et al., ACS Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0116] The term "prodrug" includes any covalently bonded carrier that releases the active compound described herein in vivo when such prodrug is administered to a mammalian subject. Conjugates (including ADCs as disclosed herein) are such prodrugs of the compounds described herein. Prodrugs of the compounds described herein can be prepared by modifying the functional groups present in the compounds described herein in a manner that the modifier is cleaved into the parent compound described herein during conventional manipulation or in vivo. Prodrugs include compounds described herein in which a hydroxyl, amino, or sulfhydryl group is bonded to any group that, when a prodrug of a compound described herein is administered to a mammalian subject, is cleaved to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol functional groups, and amide derivatives of amine functional groups in the compounds described herein.

[0117] The present disclosure also includes all compounds described herein that are isotopically labeled by replacing one or more atoms with atoms having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2 H. 3 H. 11 C. 13 C. 14 C.13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 Cl, 123 I and 125 I. These radioactive isotope-labeled compounds are useful in helping to determine or measure the effectiveness of a compound by characterizing, for example, the site or mode of action or binding affinity to a pharmacologically important site of action. Certain isotope-labeled compounds described herein (e.g., those to which a radioactive isotope has been incorporated) are useful in drug and / or substrate tissue distribution studies. Given their ease of incorporation and readily available assays, the radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) is particularly suitable for this purpose.

[0118] Using heavier isotopes such as deuterium (i.e. 2 H) may offer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and thus may be preferred in some circumstances.

[0119] Using positron-emitting isotopes such as 11 C. 18 F. 15 O and 13 Substitution of N can be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds described herein can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the preparations and examples set forth below, using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously used.

[0120] The present disclosure is also intended to include in vivo metabolites of the disclosed compounds. Such products can be produced by, for example, oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, primarily due to enzymatic processes. Therefore, the present disclosure includes compounds produced by a method comprising administering a compound of the present disclosure to a mammal for a period of time sufficient to produce its metabolites. Such products are typically identified by administering a radiolabeled compound as described herein to an animal such as a rat, mouse, guinea pig, monkey, or human in a detectable dose, allowing sufficient time for metabolism to occur, and isolating its conversion products from urine, blood, or other biological samples.

[0121] As used herein, "stable compound" and "stable structure" are intended to refer to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0122] Other definitions

[0123] The term "antibody" is used in a broad sense herein and specifically includes complete monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) and antibody fragments formed by at least two complete antibodies, as long as they exhibit the desired biological activity. The term "antibody" refers to a full-length immunoglobulin molecule or a functionally active portion of a full-length immunoglobulin molecule, i.e., a molecule containing an antigen binding site that immunospecifically binds to a target antigen or a portion thereof. The immunoglobulins disclosed herein can be immunoglobulin molecules of any type (e.g., IgG, IgE, IgM, IgD, and IgA), category (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass. Immunoglobulins can be derived from any species. In one aspect, the immunoglobulin has human, mouse, or rabbit origin. In another aspect, the antibody is a polyclonal, monoclonal, multispecific (e.g., bispecific), human, humanized or chimeric antibody, a linear antibody, a single-chain antibody, a diabody, a maxibodies, a minibody, an Fv, a Fab fragment, a F(ab') fragment, a F(ab')2 fragment, a fragment produced by a Fab expression library, an anti-idiotypic (anti-Id) antibody, a CDR, and an epitope-binding fragment of any of the foregoing that immunospecifically binds to a target antigen.

[0124] The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., individual antibodies that are identical in population except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies include "chimeric" antibodies, in which a portion of the heavy and / or light chain is identical or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain is identical or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as antibody fragments of such species (see, e.g., U.S. Patent No. 4,816,567; and Morrison et al., 1984, Proc. Natl. Acad. Sci. USA 81: 6851-6855). Monoclonal antibodies also include humanized antibodies, which may contain fully human constant regions and CDRs from non-human sources.

[0125] An “intact” antibody is one that comprises an antigen-binding variable region and a light chain constant domain (CL) and a heavy chain constant domain (C). H1 、C H2 and C H3The constant domain may be a native sequence constant domain (eg, a human native sequence constant domain) or an amino acid sequence variant thereof.

[0126] An intact antibody may have one or more "effector functions," which refers to those biological activities attributable to the Fc region (a native sequence Fc region or an amino acid sequence variant Fc region) of an antibody. Examples of antibody effector functions include C1q binding; complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B cell receptor; BCR), etc. In some embodiments, the antibody lacks effector functions.

[0127] "Antibody fragments" comprise a portion of an intact antibody, preferably comprising the antigen-binding region or its variable region. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules; macrobodies; minibodies; and multispecific antibodies formed from antibody fragments.

[0128] "Isolated" antibodies are antibodies that have been identified and separated and / or recovered from components of their natural environment. The contaminating components of their natural environment are materials that will interfere with the diagnostic or therapeutic use of the antibody and may include enzymes, hormones, and other proteins or non-protein solutes. In some embodiments, the antibody will be purified (1) to greater than 95% by weight, as determined by the Lowry method, and most preferably to greater than 99% by weight, (2) by utilizing a spinning cup sequencer to a degree sufficient to obtain at least 15 residues of the N-terminal or internal amino acid sequence, or (3) by SDS-PAGE to homogeneity under reducing or non-reducing conditions using Coomassie blue or preferably silver stain. Isolated antibodies include antibodies in situ within recombinant cells because at least one component of the antibody's natural environment will not be present. However, typically, isolated antibodies will be prepared by at least one purification step.

[0129] An antibody that "binds" an antigen of interest is one that is capable of binding that antigen with sufficient affinity to render the antibody suitable for targeting cells expressing the antigen.

[0130] A "native sequence" polypeptide is a polypeptide having an amino acid sequence identical to a polypeptide derived from nature. Such native sequence polypeptides can be isolated from nature or produced by recombinant or synthetic means. Thus, a native sequence polypeptide can have the amino acid sequence of a naturally occurring human polypeptide, a murine polypeptide, or a polypeptide from any other mammalian species.

[0131] The term "intracellular metabolite" refers to a compound produced by a metabolic process or reaction within a cell of a composition described herein, e.g., an antibody drug conjugate (ADC). The metabolic process or reaction can be an enzymatic process, such as proteolytic cleavage of a peptide linker of the subject composition, or hydrolysis of a functional group such as a hydrazone, ester, or amide within the subject composition. In the case of conjugates (including ADCs), intracellular metabolites include, but are not limited to, antibodies and free drug that have been isolated within the cell, i.e., after entry, diffusion, uptake, or transport into the cell (e.g., by enzymatic cleavage of the ADC by intracellular enzymes).

[0132] In the context of conjugates (including ADCs), the terms "intracellularly cleaved" and "intracellular cleavage" refer to a metabolic process or reaction within a cell of a composition described herein whereby the covalent bond (e.g., linker (L)) between the drug moiety (D) and the targeting moiety (T) (e.g., antibody) is broken to produce free drug. In one embodiment, the cleaved moieties of the subject compositions are thus intracellular metabolites (e.g., T, TL fragments, DL fragments, and D). Thus, in one embodiment, the invention provides compositions that are cleavage products of a composition of Formula II, including compositions comprising a compound of Formula I.

[0133] The term "extracellular cleavage" refers to a metabolic process or reaction of a composition described herein outside of a cell whereby the covalent bond (e.g., linker (L)) between the drug moiety (D) and the targeting moiety (T) (e.g., an antibody) is broken, resulting in free drug that dissociates from (T) outside the cell. In one embodiment, the cleaved portion of the subject composition is thus the initial extracellular metabolite (e.g., T, TL fragments, DL fragments, and D), which can move within the cell by diffusion and cell permeability or transport. Thus, in one embodiment, the present invention provides a composition that is a cleavage product of a composition of Formula II, including a composition comprising a compound of Formula I.

[0134] "Mammal" includes humans and domestic animals, such as laboratory animals and household pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and non-domestic animals, such as wild animals, etc.

[0135] "Optional" or "optionally" means that the subsequently described event or circumstances may or may not occur, and that the description includes instances where the event or circumstances described below occur and instances where it does not. For example, "optionally substituted aryl" means that the aryl substituent may or may not be substituted, and that the description includes substituted aryl substituents as well as unsubstituted aryl substituents.

[0136] "Pharmaceutically acceptable carrier, diluent or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved by the U.S. Food and Drug Administration (or other similar regulatory agency in another jurisdiction) as acceptable for use in humans or veterinary animals.

[0137] "Pharmaceutically acceptable salts" include both acid and base addition salts.

[0138] "Pharmaceutically acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases, which are biologically or otherwise desirable, and which are formed from inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, Formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, dodecanoic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc.

[0139] "Pharmaceutically acceptable base addition salts" refers to those salts that retain the biological effectiveness and properties of the free acids, which are biologically or otherwise desirable. These salts are prepared by the addition of inorganic or organic bases to the free acids. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines; substituted amines, including naturally occurring substituted amines; cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, denanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrazine, choline, betaine, benzylethylamine, benzophenone, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0140] Crystallization often produces solvates of the compounds described herein. As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of a compound described herein and one or more molecules of a solvent. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present disclosure may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvate forms. The compounds described herein may be true solvates, while in other cases, the compounds described herein may retain only adventitious water or a mixture of water plus some adventitious solvent.

[0141] A "pharmaceutical composition" refers to a formulation of a compound described herein with a medium generally accepted in the art for delivering the biologically active compound to a mammal, such as a human. Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients.

[0142] Non-limiting examples of conditions to be treated herein include benign and malignant tumors; leukemias and lymphoid malignancies, in particular breast cancer, ovarian cancer, gastric cancer, endometrial cancer, salivary gland cancer, lung cancer, kidney cancer, colon cancer, thyroid cancer, pancreatic cancer, prostate cancer, or bladder cancer; neuronal, glial, astrocyte, hypothalamic and other glandular, macrophage, epithelial, mesenchymal and blastocoel disorders, autoimmune diseases, inflammatory diseases, fibrosis, and infectious diseases. Considering the characteristics and, in particular, the efficacy of the subject compositions, it will be apparent to the skilled artisan that the compounds described herein can be shown to be useful in treating any disease in which it is desired to exert a cytotoxic or cytotoxic effect on target cells.

[0143] In one embodiment, the compositions described herein are used to treat autoimmune diseases. Antibodies that are immunospecific for the antigens of cells responsible for producing autoimmune antibodies can be obtained from any institution (e.g., university scientists or companies such as Genentech) or produced by any method known to those skilled in the art (e.g., chemical synthesis or recombinant expression technology). In another embodiment, useful ligand antibodies that are immunospecific for the treatment of autoimmune diseases include, but are not limited to, antinuclear antibodies; anti-double-stranded DNA; anti-single-stranded DNA, anti-cardiolipin antibodies IgM, IgG; anti-phospholipid antibodies IgM, IgG; anti-SM antibodies; anti-mitochondrial antibodies; thyroid antibodies; microsomal antibodies; thyroglobulin antibodies; anti-SCL-70; anti-Jo; anti-U1RNP; anti-La / SSB; anti-SSA; anti-SSB; anti-parietal cell antibodies; anti-histone; anti-RNP; C-ANCA; P-ANCA; anti-centromere; anti-fibrin and anti-GBM antibodies. In certain preferred embodiments, the antibodies suitable for use in this method can bind to receptors or receptor complexes expressed on activated lymphocytes.

[0144] The receptor or receptor complex may comprise an immunoglobulin gene superfamily member, a TNF receptor superfamily member, an integrin, a cytokine receptor, a chemokine receptor, a major histocompatibility protein, a lectin, or a complement regulatory protein. Non-limiting examples of suitable immunoglobulin superfamily members are CD2, CD3, CD4, CD8, CD19, CD22, CD28, CD79, CD90, CD152 / CTLA-4, PD-1, and ICOS.

[0145] Non-limiting examples of suitable TNF receptor superfamily members are CD27, CD40, CD95 / Fas, CD134 / OX40, CD137 / 4-1BB, TNF-R1, TNFR-2, RANK, TACI, BCMA, osteoprotegerin, Apo2 / TRAIL-R1, TRAIL-R2, TRAIL-R3, TRAIL-R4, and APO-3. Non-limiting examples of suitable integrins are CD11a, CD11b, CD11c, CD18, CD29, CD41, CD49a, CD49b, CD49c, CD49d, CD49e, CD49f, CD103, and CD104. Non-limiting examples of suitable lectins are C-type, S-type, and I-type lectins.

[0146] In one embodiment, the ligand is an antibody that binds to activated lymphocytes associated with an autoimmune disease.

[0147] Immune diseases characterized by the inappropriate activation of immune cells and which can be treated or prevented by the methods described herein can be classified, for example, by the type of hypersensitivity reaction underlying the condition. These reactions are generally divided into four types: allergic reaction, cytotoxic (cytolytic) reaction, immune complex reaction, or cell-mediated immunity (CMI) reaction (also referred to as delayed-type hypersensitivity (DTH) reaction). (See, for example, Fundamental Immunology (William E. Paul, ed., Raven Press, NY, 3rd edition 1993)).

[0148] Specific examples of such immune diseases include the following: rheumatoid arthritis, autoimmune demyelinating diseases (e.g., multiple sclerosis, allergic encephalomyelitis), endocrine eye diseases, uveoretinitis, systemic lupus erythematosus, myasthenia gravis, Graves' disease, glomerulonephritis, autoimmune blood diseases, inflammatory bowel diseases (e.g., Crohn's disease), hypersensitivity, allergic reactions, Sjögren's syndrome, type I diabetes, primary biliary cirrhosis, Wegener's granulomatosis, fibromyalgia, polymyositis, dermatomyositis, polyendocrine gland failure, Schmidt's syndrome, autoimmune uveitis, Addison's disease, adrenalitis, thyroiditis, Hashimoto's thyroiditis, thyroiditis), autoimmune thyroid disease, pernicious anemia, gastric atrophy, chronic hepatitis, lupus hepatitis, atherosclerosis, subacute cutaneous lupus erythematosus, hypoparathyroidism, post-myocardial infarction syndrome (Dressler's syndrome), autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, hemolytic anemia, pemphigus vulgaris, pemphigus, dermatitis herpetiformis, alopecia areata, pemphigoid, scleroderma, progressive systemic sclerosis, CREST syndrome (calcification, Raynaud's phenomenon, esophageal dysmotility, digital scleroderma, and telangiectasia), male and female autoimmune infertility, ankylosing spondylitis, ulcerative colitis, mixed connective tissue disease, polyarteritis nodosa, systemic necrotizing vasculitis, atopic dermatitis, atopic rhinitis, Goodpasture's syndrome syndrome), Chagas' disease, sarcoidosis, rheumatic fever, asthma, recurrent miscarriage, antiphospholipid syndrome, farmer's lung, erythema multiforme, postcardiotomy syndrome, Cushing's syndrome, autoimmune chronic active hepatitis, bird farmer's lung, toxic epidermal necrolysis, Alport's syndrome, alveolitis, allergic alveolitis, fibrosing alveolitis, interstitial lung disease, erythema nodosum, pyoderma gangrenosum, transfusion reaction, Takayasu's arteritis, polymyalgia rheumatica, temporal arteritis, schistosomiasis, giant cell arteritis, ascariasis, aspergillosis, Sampter's syndromesyndrome), eczema, lymphomatoid granulomatosis, Behçet's disease, Caplan's syndrome, Kawasaki's disease, dengue fever, encephalomyelitis, endocarditis, endomyocardial fibrosis, endophthalmitis, erythema elevate perstans, psoriasis, erythroblastosis fetalis, eosinophilic fasciitis, Shulman's syndrome, Felty's syndrome, filariasis, cyclitis, chronic cyclitis, metachronous cyclitis, Fuch's cyclitis, IgA nephropathy, Henoch-Schonlein purpura, graft-versus-host disease, transplant rejection, cardiomyopathy, Eaton-Lambert myasthenic syndrome syndrome), relapsing polychondritis, cryoglobulinemia, Waldenstrom's macroglobulemia, Evan's syndrome, and autoimmune dysgonadotropin. Thus, the methods described herein include treating the following conditions: B lymphocytes (e.g., systemic lupus erythematosus, Goodpasture's syndrome, rheumatoid arthritis, and type 1 diabetes), Th1 lymphocytes (e.g., rheumatoid arthritis, multiple sclerosis, psoriasis, Sjögren's syndrome, Hashimoto's thyroiditis, Graves' disease, primary biliary cirrhosis, Wegener's granulomatosis, tuberculosis, or acute graft-versus-host disease), or Th2 lymphocytes (e.g., atopic dermatitis, systemic lupus erythematosus, allergic asthma, rhinitis conjunctivitis, allergic rhinitis, Omenn's syndrome, systemic sclerosis, or chronic graft-versus-host disease). Generally speaking, disorders involving dendritic cells include disorders of Th1 lymphocytes or Th2 lymphocytes.

[0149] In certain embodiments, the immune disorder is T cell mediated, which may include activated T cells. ADC or ADC derivatives may be administered to deplete such activated T cells.

[0150] In one embodiment, the compositions described herein can be used to treat fibrosis. Fibrosis can occur in many tissues in the body, usually due to inflammation or injury, examples include, but are not limited to: lungs, pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis; liver, cirrhosis; heart, endomyocardial fibrosis, old myocardial infarction, atrial fibrosis; others, mediastinal fibrosis (soft tissue of the mediastinum), myelofibrosis (bone marrow), retroperitoneal fibrosis (soft tissue of the retroperitoneum), progressive massive fibrosis (lung); complications of coal workers' pneumoconiosis, nephrogenic systemic fibrosis (skin), Crohn's disease (intestine), keloids (skin), scleroderma / systemic sclerosis (skin, lung), arthrofibrosis (knees, shoulders, other joints), Peyronie's disease (penis), Dupuytren's contracture (hands, fingers), and certain forms of adhesive capsulitis (shoulder).

[0151] With respect to infectious diseases, the compositions described herein may act directly on certain infectious agents or pathogens, or may be used to exert a cytostatic or cytotoxic effect on host cells that carry or otherwise provide infectious agents or pathogens.

[0152] "Effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein that is sufficient to achieve treatment of a particular indication, such as cancer or tumor cells in a mammal, preferably a human, when administered to a mammal, preferably a human, as defined below. The amount of a compound described herein that constitutes a "therapeutically effective amount" will vary depending on the compound, the condition and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their knowledge and in light of this disclosure.

[0153] As used herein, "Treating" or "treatment" includes treating a target disease or condition in a mammal, preferably a human, having the target disease or condition, and includes:

[0154] (i) preventing the occurrence of the disease or condition in a mammal, particularly where such mammal is susceptible to the disease but has not yet been diagnosed as having the disease;

[0155] (ii) inhibiting the disease or condition, i.e., preventing its development;

[0156] (iii) alleviate the disease or condition, i.e., cause regression of the disease or condition; or

[0157] (iv) Alleviation of symptoms resulting from the disease or condition, i.e., relief of pain without resolution of the underlying disease or condition.

[0158] A therapeutically effective amount of a compound for cancer treatment may reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slow down to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow down to some extent and preferably stop) tumor metastasis; inhibit tumor growth to some extent; increase survival time; and / or alleviate to some extent one or more symptoms associated with the cancer. A drug may be cytostatic and / or cytotoxic if it prevents growth and / or kills existing cancer cells. The compounds of the present invention are preferably cytotoxic. For cancer therapy, efficacy may be measured, for example, by evaluating the time to disease progression (TTP) and / or determining the response rate (RR).

[0159] An "effective amount" with respect to a specific result to be achieved is an amount sufficient to achieve the desired result. For example, an "effective amount" of a drug when referring to killing cancer cells refers to an amount of the drug sufficient to produce the killing effect.

[0160] Solid tumors contemplated for treatment using the compounds of the present disclosure include, but are not limited to, sarcomas, fibrosarcomas, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, renal cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer (e.g., gastrointestinal cancer), oral cancer, nasal cancer, laryngeal cancer, squamous cell carcinoma (e.g., of the lung), basal cell carcinoma, adenocarcinoma (e.g., of the lung), sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatocarcinoma, bile duct cancer, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, tumor), cervical cancer, uterine cancer, testicular cancer, small cell lung cancer, bladder cancer, lung cancer, non-small cell lung cancer, epithelial cancer, glioma, glioblastoma, multiforme astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, skin cancer, melanoma, neuroblastoma, and retinoblastoma. Blood-related cancers that are expected to be treated using the compounds of the present disclosure include, but are not limited to, acute lymphoblastic leukemia "ALL", acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblastic leukemia "AML", acute promyelocytic leukemia "APL", acute monocytic leukemia, acute erythroleukemic leukemia, acute megakaryocytic leukemia, acute myelomonocytic leukemia, acute non-lymphocytic leukemia, acute undifferentiated leukemia, chronic myeloid leukemia "CML", chronic lymphocytic leukemia "CLL", hairy cell leukemia, and multiple myeloma. Acute and chronic leukemias that are expected to be treated using the compounds of the present disclosure include, but are not limited to, lymphoblastic leukemia, myeloid leukemia, lymphocytic leukemia, and myeloid leukemia. Lymphomas contemplated for treatment using the compounds of the present disclosure include, but are not limited to, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, and polycythemia vera. Other cancers contemplated for treatment using the compounds of the present disclosure include, but are not limited to, peritoneal cancer, hepatocellular carcinoma, liver cancer, salivary gland cancer, vulvar cancer, thyroid cancer, penile cancer, anal cancer, head and neck cancer, renal cell carcinoma, acute anaplastic large cell carcinoma, and cutaneous anaplastic large cell carcinoma.

[0161] Cancer, including but not limited to tumors, metastases, or other diseases or conditions characterized by uncontrolled or unwanted cell growth, can be treated or prevented by administering the compounds of the present disclosure.

[0162] In other embodiments, methods for treating or preventing cancer are provided, comprising administering to a patient in need thereof an effective amount of a compound disclosed herein in combination with another therapeutic method. In one embodiment, the additional therapeutic method comprises treatment with a chemotherapeutic agent. In one embodiment, the chemotherapeutic agent is one whereby the cancer is not considered refractory to treatment. In another embodiment, the chemotherapeutic agent is one whereby the cancer is considered refractory to treatment. The compounds described herein can be administered before, after, or simultaneously with the chemotherapeutic agent.

[0163] In one embodiment, the additional treatment method is radiation therapy.The compounds described herein can be administered before, after, or simultaneously with radiation.

[0164] The compounds described herein can also be administered to patients who have undergone or will undergo surgery for cancer treatment.

[0165] In a specific embodiment, the compounds described herein are administered concurrently with a chemotherapeutic agent or radiation therapy. In another specific embodiment, the chemotherapeutic agent or radiation therapy is administered before or after the administration of the compounds described herein, in one aspect, at least one hour, five hours, 12 hours, a day, a week, a month, and in other aspects several months (e.g., up to three months) before or after the administration of the compounds described herein.

[0166] The chemotherapeutic agent may be administered over a series of time periods. Any one or combination of chemotherapeutic agents listed herein or otherwise known in the art may be administered. With respect to radiation, any radiation therapy regimen may be used depending on the type of cancer to be treated. For example, but not by way of limitation, x-ray radiation may be administered; specifically, high-energy giant voltage (radiation with energy greater than 1 MeV) may be used for deep-seated tumors, and electron beam and orthovoltage x-ray radiation may be used for skin cancers. Gamma-emitting radioisotopes, such as radioisotopes of radium, cobalt, and other elements, may also be administered.

[0167] In addition, cancer treatment methods using the compounds described herein are provided as an alternative to chemotherapy or radiation therapy, where the chemotherapy or radiation therapy has proven or can be proven to be too toxic, e.g., produces unacceptable or intolerable side effects in the subject being treated. In addition, cancer treatment methods using the compounds described herein are provided as an alternative to surgery, where surgery has proven or can be proven to be unacceptable or intolerable in the subject being treated.

[0168] The compounds described herein can also be used in vitro or ex vivo, such as for the treatment of certain cancers, including but not limited to leukemias and lymphomas, such treatments include autologous stem cell transplantation. This can include a multi-step process in which the animal's autologous hematopoietic stem cells are collected and all cancer cells are eliminated, and then the animal's remaining bone-bone marrow cell population is eradicated by administering high doses of the compounds described herein with or without high doses of radiation therapy, and the stem cell transplant is infused back into the animal. Supportive care is then provided as bone marrow function is restored and the animal recovers.

[0169] Methods for treating cancer also include administering to a patient in need thereof an effective amount of a compound as described herein and another therapeutic agent as an anticancer agent. Suitable anticancer agents include, but are not limited to, methotrexate, paclitaxel, L-asparaginase, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine, procarbazine, topotecan, nitrogen mustard, cyclophosphamide, etoposide, 5-fluorouracil, BCNU, irinotecan, camptothecin, bleomycin, doxorubicin, idarubicin, daunorubicin, actinomycin D, dactinomycin, plicamycin, mitoxantrone, asparaginase, vinblastine, vincristine, vindesine, vinorelbine, paclitaxel, and docetaxel.

[0170] Other examples of chemotherapeutic agents include alkylating agents such as thiotepa and Cyclophosphamide; alkyl sulfonates, such as busulfan, thiosulfan, improsulfan, and bupropion; aziridines, such as benzodopa, carboquinone, meturedopa, and uredopa; ethyleneimines and methylamelamines, including hexamethylmelamine, trothamide, triethylenephosphamide, triethylenethiophosphamide, and trimethylolmelamine; TLK 286 (TELCYTA TM ); polyacetyl (especially bratacin and bratacinone); delta-9-tetrahydrocannabinol (dronabinol, ); β-lapachone; lapachol; colchicine; betulinic acid; camptothecin (including the synthetic analogue topotecan CPT-11 (irinotecan, ), acetylcamptothecin, scopolectin, and 9-aminocamptothecin); bryostatin; callystatin; CC-1065 (including its synthetic analogs of adolesin, carzelesin, and biszelesin); podophyllotoxin; podophyllic acid; teniposide; cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycins (including synthetic analogs, KW-2189, and CB1-TM1); ilimycin; hyoscyamine; sarcodictyin; halichondrin; nitrogen mustards, such as chlorambucil, naphthiazolin, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, methoxychlor hydrochloride, melphalan, nembixin, cholesterol phenylacetic acid mustard, chlorambucil, cyclophosphamide, and uracil mustard; triazines, such as dacarbazine; nitrosoureas, such as carmustine, chlorozolin, fotemustine, lomustine, nimustine, and ranimnustine; epipodophyllins, such as etoposide, teniposide, topotecan, 9-aminocamptothecin, camptothecin, and chloramphenicol. Bisphosphonates, such as clodronate; antibiotics, such as enediyne antibiotics (e.g., calicheamicins, particularly calicheamicin gamma 1I and calicheamicin omega 11 (see, e.g., Agnew, Chem. Intl. Ed. Engl., 33:183-186 (1994)) and anthracyclines, such as anthracenemycin, AD32, aclarubicin, daunorubicin, dexrazoxane, DX-52-1, epirubicin, GPX-100, idarubicin, KRN5500, menocril, danemycins including danemycin chloramphenicol, ... Doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, liposomal doxorubicin and deoxydoxorubicin), esorubicin, mesilomycin, mitomycins such as mitomycin C, mycophenolic acid, nogamycin, olivomycin, peplomycin, potfiromycin, puromycin, triferric doxorubicin, rhodorubicin, streptozotocin, streptozotocin, tuberculin, ubenimex, zostatin and daunorubicin; phototherapy Methods, such as benzoporphyrin derivative monoacid (BPD-MA), phthalocyanine, photosensitizer Pc4 and demethoxy-hypocrellin A (2BA-2-DMHA); folic acid analogs, such as dimethylfolate, pteropterin and trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thiopurine and thioguanine; pyrimidine analogs, such as cyclocytidine, azacitidine, 6-azauridine, carmofur, cytarabine, cytosine arabinoside ... arabinoside), dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens, such as dimethyltestosterone, drostanolone propionate, cyclothiocarbamate, melastane, and testolactone; antiadreners, such as aminoglutethimide, mitotane, and trilostane; folic acid supplements, such as folinic acid (leucovorin); acetoglucuronolide; antifolate antineoplastic agents, such as LY231514 pemetrexed, dihydrofolate reductase inhibitors such as methotrexate and trimetrexate; antimetabolites such as 5-fluorouracil (5-FU) and its prodrugs such as UFT, S-1, and capecitabine, floxuridine, doxifluridine, and raltitrexed; and thymidylate synthase inhibitors and glycinamide nucleotide formyltransferase inhibitors such as raltitrexed Dihydropyrimidine dehydrogenase inhibitors, such as eniluracil; aldophosphamide glycoside; aminoethyllevulinic acid; amsacrine; amustine; bisantrene; edatrexate; defofamine; colcemid; diacrazoxane; elformithine; hydroxypyrrolidone acetate; epothilone; ethoxydimidine; gallium nitrate; hydroxyurea; mushroom polysaccharides; lonidainine; maytansine alkaloids, such as maytansine and maytansine; mitoxantrone; mitoxantrone; mopidanmol; nitraerine; pentostatin; methamidine; pirarubicin; losoxantrone; 2-acetylhydrazine; procarbazine; Polysaccharide complex (JHS Natural Products, Eugene, OR); aproximine; lisoxine; sizoran; spirogermanamine; tenuisporic acid; triiminoquinone; 2,2',2"-trichlorotriethylamine; trichothecenes (particularly T-2 toxin, verracurin A, baculozolin A, and serpentin); urethane; vindesine dacarbazine; mannitol mustard; dibromomannitol; dibromodulcitol; dibromopropylpiperazine; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; paclitaxel and taxanes, e.g. Paclitaxel (Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE TM Albumin-engineered nanoparticle formulation of paclitaxel without Cremophor oil (American Pharmaceutical Partners, Schaumberg, Ill.) and Docetaxel (Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine 6-Thioguanine; mercaptopurine; platinum; platinum analogs or platinum-based analogs, such as cisplatin, oxaliplatin, and carboplatin; vinblastine Etoposide (VP-16); ifosfamide; mitoxantrone; vincristine Vinca alkaloid; Vinorelbine Velcade; lenalidomide; thalidomide; IMiD3; lovastatin; verapamil; thapsigargin; 1-methyl-4-phenylpyridine; cell cycle inhibitors such as staurosporine; novantrone; edatrexate; daunorubicin; mitoxantrone; aminopterin; capecitabine; ibandronate; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); vitamin D3 analogs such as EB 1089, CB 1093 and KH 1060; retinoids such as retinoic acid; pharmaceutically acceptable salts, acids or derivatives of any of the above; and combinations of two or more of the above, such as CHOP, which is an abbreviation for combination therapy of cyclophosphamide, doxorubicin, vincristine and prednisolone; and FOLFOX, which is an abbreviation for oxaliplatin (ELOXATIN OXOP). TM ) in combination with 5-FU and leucovorin.

[0171] Antihormonal agents used to modulate or inhibit hormonal effects on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), include, for example, tamoxifen (including Tamoxifen), raloxifene, megestrol acetate, droloxifene, 4-hydroxytamoxifen, troloxifene, raloxifene, LY117018, onapristone, and Toremifene; aromatase inhibitors that inhibit aromatase, which regulates estrogen production in the adrenal glands, such as 4(5)-imidazole, aminoglutethimide, Megestrol acetate, Exeguantan, formestanie, fadrozole, Fuclozole, Letrozole and Anastrozole; and antiandrogens, such as flutamide, bicalutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); antisense oligonucleotides, particularly those that inhibit the expression of genes in signaling pathways involved in abnormal cell proliferation, such as, for example, PKC-α, Raf, H-Ras, and epidermal growth factor receptor (EGF-R); vaccines, such as gene therapy vaccines, such as, for example, vaccine, Vaccines and vaccine; rIL-2: Topoisomerase 1 inhibitors; rmRH; and pharmaceutically acceptable salts, acids or derivatives of any of the above.

[0172] New compounds

[0173] Provided are compounds of formula I:

[0174]

[0175] and pharmaceutically acceptable salts thereof, wherein:

[0176] R 1 is selected from the group consisting of amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heterocyclyl and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of aryl, aryl-C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkylthio, carboxyl, carboxamide, C3-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, guanidino, halo, C1-C6 haloacyl, C1-C6 haloalkyl, heterocyclyl, heterocyclyl-C1-C6 alkyl, hydroxyl and thio; or

[0177] R 1 R a R b NCH(R c )-;

[0178] R a Selected from: H and C1-C6 alkyl;

[0179] R b is a C1-C6 alkyl group; and

[0180] R c R d -C(CH3)2-; and

[0181] R d is selected from the group consisting of: H, aryl, C3-C7 cycloalkyl and heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: C1-C4 acylthio, C2-C4 alkenyl, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkoxy, amino, amino-C1-C4 alkyl, halo, C1-C4 haloalkyl, hydroxy, hydroxy-C1-C4 alkyl and thio, wherein C2-C4 alkenyl, C1-C4 alkylamino and C1-C4 alkoxy are further optionally substituted with one substituent selected from the group consisting of: C1-C4 alkylaryl, hydroxy and thio; or

[0182] R b and R c together with the atoms to which they are respectively bonded, form a heterocyclyldiyl;

[0183] R 2 is selected from the group consisting of: C2-C6 alkyl, aryl, aryl-C1-C6 alkyl, C4-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloacyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio, and thio-C1-C6 alkyl; and

[0184] X is -C(O)NHCH(CH2R 3 )-, or X does not exist; and

[0185] R 3 is selected from the group consisting of aryl, heteroaryl and C3-C7 cycloalkyl, each optionally substituted with one substituent selected from the group consisting of amino and hydroxy.

[0186] In some embodiments, when R 1 When it is 2-methyl-1-(methylamino)propyl and X is -C(O)NHCH(CH2Ph)-, R 2 Not ethyl, isopropyl, n-butyl and phenyl.

[0187] Also provided are compounds of formula I:

[0188]

[0189] and pharmaceutically acceptable salts thereof, wherein:

[0190] R 1is selected from the group consisting of amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heterocyclyl and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of aryl, aryl-C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkylthio, carboxyl, carboxamide, C3-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, guanidino, halo, C1-C6 haloacyl, C1-C6 haloalkyl, heterocyclyl, heterocyclyl-C1-C6 alkyl, hydroxyl and thio; or

[0191] R 1 R a R b NCH(R c )-;

[0192] R a Selected from: H and C1-C6 alkyl;

[0193] R b is a C1-C6 alkyl group; and

[0194] R c R d -C(CH3)2-; and

[0195] R d is selected from the group consisting of: H, aryl, C3-C7 cycloalkyl and heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: C1-C4 acylthio, C2-C4 alkenyl, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkoxy, amino, amino-C1-C4 alkyl, halo, C1-C4 haloalkyl, hydroxy, hydroxy-C1-C4 alkyl and thio, wherein C2-C4 alkenyl, C1-C4 alkylamino and C1-C4 alkoxy are further optionally substituted with one substituent selected from the group consisting of: C1-C4 alkylaryl, hydroxy and thio; or

[0196] R b and R c together with the atoms to which they are respectively bonded, form a heterocyclyldiyl;

[0197] R 2is selected from the group consisting of: C1-C6 alkyl, aryl, aryl-C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloacyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio, and thio-C1-C6 alkyl; and

[0198] X is -C(O)NHCH(CH2R 3 )-, or X does not exist; and

[0199] R 3 is selected from the group consisting of aryl, heteroaryl and C3-C7 cycloalkyl, each optionally substituted with one substituent selected from the group consisting of chloro and hydroxy.

[0200] In some embodiments, when R 1 When it is 2-methyl-1-(methylamino)propyl and X is -C(O)NHCH(CH2Ph)-, R 2 It is not methyl, ethyl, isopropyl, n-butyl, cyclopropyl or phenyl.

[0201] Also provided are compounds of formula I:

[0202]

[0203] and pharmaceutically acceptable salts thereof, wherein:

[0204] R 1 is selected from the group consisting of amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heterocyclyl and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of aryl, aryl-C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkylthio, carboxyl, carboxamide, C3-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, guanidino, halo, C1-C6 haloacyl, C1-C6 haloalkyl, heterocyclyl, heterocyclyl-C1-C6 alkyl, hydroxyl and thio; or

[0205] R 1 R a R b NCH(R c )-;

[0206] R a Selected from: H and C1-C6 alkyl;

[0207] Rb is a C1-C6 alkyl group; and

[0208] R c R d -C(CH3)2-; and

[0209] R d is selected from the group consisting of: H, aryl, C3-C7 cycloalkyl and heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: C1-C4 acylthio, C2-C4 alkenyl, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkoxy, amino, amino-C1-C4 alkyl, halo, C1-C4 haloalkyl, hydroxy, hydroxy-C1-C4 alkyl and thio, wherein C2-C4 alkenyl, C1-C4 alkylamino and C1-C4 alkoxy are further optionally substituted with one substituent selected from the group consisting of: C1-C4 alkylaryl, hydroxy and thio; or

[0210] R b and R c together with the atoms to which they are respectively bonded, form a heterocyclyldiyl;

[0211] R 2 is selected from the group consisting of: C2-C6 alkyl, aryl, aryl-C1-C6 alkyl, C4-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloacyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio, and thio-C1-C6 alkyl; and

[0212] X does not exist.

[0213] variable R 1

[0214] In some embodiments, R 1 Selected from: amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heterocyclyl and heterocyclyl, each optionally substituted with one or more substituents selected from the following: aryl, aryl-C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkylthio, carboxyl, carboxamide, C3-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, guanidino, halo, C1-C6 haloalkyl, heterocyclyl, heterocyclyl-C1-C6 alkyl, hydroxyl and thio.

[0215] In some embodiments, R 1Selected from: amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heterocyclyl and heterocyclyl, each optionally substituted with one or more substituents selected from C1-C6 alkyl and halo.

[0216] In some embodiments, R 1 selected from the group consisting of: 1-(dimethylamino)-2-methylpropyl, 2-methyl-1-(methylamino)propyl, 1-aminocyclopentyl, 1-aminocyclopropyl, 4-aminophenyl, 2-aminopropyl-2-yl, 1-aminocyclohexyl, 3-aminooxetan-3-yl, 2-(methylamino)propyl-2-yl, 1-amino-2-methylpropyl-2-yl, 2-methylpyrrolidin-2-yl, 2-amino-3-methylbutan-2-yl, 2-aminobutan-2-yl, 2-methyl-1-(methylamino)propyl-2-yl, 1-methylpiperidin-2-yl, 3-fluoropyrrolidin-3-yl, 1,2-dimethylpyrrolidin-2-yl and 2-(dimethylamino)propyl-2-yl).

[0217] In some embodiments, R 1 Selected from: 1-(dimethylamino)-2-methylpropyl, 2-methyl-1-(methylamino)propyl, 1-aminocyclopentyl, 1-aminocyclopropyl, 4-aminophenyl, 2-aminopropyl-2-yl, 1-aminocyclohexyl, 3-aminooxetan-3-yl, 2-(methylamino)propyl-2-yl, 1-amino-2-methylpropyl-2-yl, 2-methylpyrrolidin-2-yl, 2-amino-3-methylbutyl-2-yl, 2-aminobutyl- 1-methylpiperidin-2-yl, 3-fluoropyrrolidin-3-yl, 1,2-dimethylpyrrolidin-2-yl, 2-(dimethylamino)propan-2-yl), 2-methyl-1-(methylamino)-2-phenylpropyl, 1-isopropylpiperidin-2-yl, 2-azabicyclo[2.2.1]heptan-3-yl and 2-methyl-2-azabicyclo[2.2.1]heptan-3-yl.

[0218] In some embodiments, R 1 It is 1-(dimethylamino)-2-methylpropyl.

[0219] In some embodiments, R 1 It is 2-methyl-1-(methylamino)propyl.

[0220] In some embodiments, R 1 It is 1-aminocyclopentyl.

[0221] In some embodiments, R 1 It is 1-aminocyclopropyl.

[0222] In some embodiments, R1 It is 4-aminophenyl.

[0223] In some embodiments, R 1 It is 2-aminopropane-2-yl.

[0224] In some embodiments, R 1 It is 1-aminocyclohexyl.

[0225] In some embodiments, R 1 It is 3-aminooxetane-3-yl.

[0226] In some embodiments, R 1 It is 2-(methylamino)propan-2-yl.

[0227] In some embodiments, R 1 It is 1-amino-2-methylpropane-2-yl.

[0228] In some embodiments, R 1 It is 2-methylpyrrolidin-2-yl.

[0229] In some embodiments, R 1 It is 2-amino-3-methylbutan-2-yl.

[0230] In some embodiments, R 1 It is 2-aminobutan-2-yl.

[0231] In some embodiments, R 1 It is 2-methyl-1-(methylamino)propan-2-yl.

[0232] In some embodiments, R 1 It is 1-methylpiperidin-2-yl.

[0233] In some embodiments, R 1 It is 3-fluoropyrrolidin-3-yl.

[0234] In some embodiments, R 1 It is 2-methyl-1-(methylamino)propyl.

[0235] In some embodiments, R 1 It is (R)-1-(dimethylamino)-2-methylpropyl.

[0236] In some embodiments, R 1 is (R)-2-methyl-1-(methylamino)propyl.

[0237] In some embodiments, R 1 R a R bNCH(R c )-.

[0238] In some embodiments, R 1 It is 2-methyl-1-(methylamino)-2-phenylpropyl.

[0239] In some embodiments, R 1 It is 1-isopropylpiperidin-2-yl.

[0240] In some embodiments, R 1 It is 2-azabicyclo[2.2.1]heptan-3-yl.

[0241] In some embodiments, R 1 It is 2-methyl-2-azabicyclo[2.2.1]heptan-3-yl.

[0242] variable R a

[0243] In some embodiments, R a Selected from: H and C1-C6 alkyl;

[0244] In some embodiments, R b Selected from: H, methyl and isopropyl.

[0245] In some embodiments, R c For H.

[0246] In some embodiments, R d It is a methyl group.

[0247] In some embodiments, R e It is isopropyl.

[0248] variable R b

[0249] In some embodiments, R b It is a C1-C6 alkyl group.

[0250] In some embodiments, R b It is a methyl group.

[0251] variable R c

[0252] In some embodiments, R c R d -C(CH3)2-.

[0253] variable R d

[0254] In some embodiments, R dis selected from the group consisting of: H, aryl, C3-C7 cycloalkyl and heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: C1-C4 acylthio, C2-C4 alkenyl, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkoxy, amino, amino-C1-C4 alkyl, halo, C1-C4 haloalkyl, hydroxy, hydroxy-C1-C4 alkyl and thio, wherein C2-C4 alkenyl, C1-C4 alkylamino and C1-C4 alkoxy are further optionally substituted with one substituent selected from the group consisting of C1-C4 alkylaryl, hydroxy and thio.

[0255] In some embodiments, R d Selected from: H, aryl, C3-C7 cycloalkyl and heteroaryl, each of which is optionally substituted with one or more substituents selected from the following: C1-C4 acylthio, C2-C4 alkenyl, C1-C4 alkyl, C1-C4 alkylchloro, C1-C4 alkoxy, amino, amino-C1-C4 alkyl, halo, C1-C4 haloalkyl, hydroxy, hydroxy-C1-C4 alkyl and thio, wherein C2-C4 alkenyl, C1-C4 alkylamino and C1-C4 alkoxy are further optionally substituted with one substituent selected from p-tolyl, hydroxy and thio.

[0256] In some embodiments, R d Selected from: H, aryl, C3-C7 cycloalkyl and heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: (2-hydroxyethyl)amino, (2-mercaptoethyl)amino, 2-(acetylthio)ethoxy, 2-aminoethoxy, 2-hydroxyethoxy, 2-mercaptoethoxy, 3-methoxy, 4-methylstyryl, amino, aminomethyl, chloro, fluoro, hydroxy, hydroxymethyl, methyl, thio, trifluoromethyl.

[0257] In some embodiments, R d is selected from the group consisting of: H, cyclohexyl, 1H-indol-3-yl, phenyl, and thiophen-2-yl, each of which is optionally substituted with one or more substituents selected from the group consisting of: (2-hydroxyethyl)amino, (2-mercaptoethyl)amino, 2-(acetylthio)ethoxy, 2-aminoethoxy, 2-hydroxyethoxy, 2-mercaptoethoxy, 3-methoxy, 4-methylstyryl, amino, aminomethyl, chloro, fluoro, hydroxy, hydroxymethyl, methyl, thio, and trifluoromethyl.

[0258] In some embodiments, R dSelected from: H, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 2-methoxyphenyl, 3-((2-hydroxyethyl)amino)phenyl, 3-((2-mercaptoethyl)amino)phenyl, 3-(2-(acetylthio)ethoxy)phenyl, 3-(2-hydroxyethoxy)phenyl, 3-(2-mercaptoethoxy)phenyl, 3-(4-methylphenyl)phenyl, 3-(aminomethyl)phenyl, 3-(hydroxymethyl)phenyl, 3-hydroxyphenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl, 3-aminophenyl, 3-chlorophenyl phenyl, 3-mercaptophenyl, 3-methoxyphenyl, 3-trifluoromethylphenyl, 4-((2-hydroxyethyl)amino)phenyl, 4-((2-mercaptoethyl)amino)phenyl, 4-(2-(acetylthio)ethoxy)phenyl, 4-(2-aminoethoxy)phenyl, 4-(2-hydroxyethoxy)phenyl, 4-(2-mercaptoethoxy)phenyl, 4-(aminomethyl)phenyl, 4-(hydroxymethyl)phenyl, 4-aminophenyl, 4-hydroxyphenyl, 4-mercaptophenyl, 4-methoxyphenyl, cyclohexyl, thien-2-yl, m-tolyl, and phenyl.

[0259] In some embodiments, R d Selected from the group consisting of: H, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 2-methoxyphenyl, 3-((2-hydroxyethyl)amino)phenyl, 3-((2-mercaptoethyl)amino)phenyl, 3-(2-hydroxyethoxy)phenyl, 3-(2-mercaptoethoxy)phenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl, 3-chlorophenyl, 3-mercaptophenyl, 3-methoxyphenyl, 3-trifluoromethylphenyl, 4-((2-hydroxyethyl)amino)phenyl, 4-((2-mercaptoethyl)amino)phenyl, 4-4-(2-hydroxyethoxy)phenyl, 4-(2-mercaptoethoxy)phenyl, 4-mercaptophenyl, 4-methoxyphenyl, cyclohexyl, thien-2-yl, m-tolyl and phenyl.

[0260] In some embodiments, R d It is phenyl.

[0261] In some embodiments, R d It is 1H-indol-3-yl.

[0262] In some embodiments, R d It is 1-methyl-1H-indol-3-yl.

[0263] In some embodiments, R d It is 2-methoxyphenyl.

[0264] In some embodiments, R d It is 3-((2-hydroxyethyl)amino)phenyl.

[0265] In some embodiments, R d It is 3-((2-mercaptoethyl)amino)phenyl.

[0266] In some embodiments, R d It is 3-(2-hydroxyethoxy)phenyl.

[0267] In some embodiments, R d It is 3-(2-mercaptoethoxy)phenyl.

[0268] In some embodiments, R d It is 3,5-difluorophenyl.

[0269] In some embodiments, R d It is 3,5-dimethylphenyl.

[0270] In some embodiments, R d It is 3-chlorophenyl.

[0271] In some embodiments, R d It is 3-mercaptophenyl.

[0272] In some embodiments, R d It is 3-methoxyphenyl.

[0273] In some embodiments, R d It is 3-trifluoromethylphenyl.

[0274] In some embodiments, R d It is 4-((2-hydroxyethyl)amino)phenyl.

[0275] In some embodiments, R d It is 4-((2-mercaptoethyl)amino)phenyl.

[0276] In some embodiments, R d It is 4-4-(2-hydroxyethoxy)phenyl.

[0277] In some embodiments, R d It is 4-(2-mercaptoethoxy)phenyl.

[0278] In some embodiments, R d It is 4-mercaptophenyl.

[0279] In some embodiments, R d It is 4-methoxyphenyl.

[0280] In some embodiments, R d It is cyclohexyl.

[0281] In some embodiments, R dIt is thiophen-2-yl.

[0282] In some embodiments, R d It is m-tolyl.

[0283] variable R 2

[0284] In some embodiments, R 2 Selected from: C2-C6 alkyl, aryl, aryl-C1-C6 alkyl, C4-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl and heterocyclyl, each optionally substituted with one or more substituents selected from the following: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloacyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio and thio-C1-C6 alkyl.

[0285] In some embodiments, R 2 is selected from the group consisting of: C2-C6 alkyl, aryl, aryl-C1-C6 alkyl, C4-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of: 1-aminocyclopropyl, 4-aminophenyl, amino, aminomethyl, bromo, tert-butyl, carboxamide, carboxyl, chloro, cyano, ethyl, fluoro, hydroxy, isopropyl, methoxy, methyl, nitro, phenyl, thio, thiomethyl, trifluoromethoxy and trifluoromethyl.

[0286] In some embodiments, R 2 selected from the group consisting of: 5,6,7,8-tetrahydronaphthalen-1-yl, benzyl, cyclohexyl, ethyl, hexane-2-yl, methyl, naphthalen-2-yl, piperidin-1-yl, phenyl, propyl, pyridin-3-yl and thiophen-2-yl, each optionally substituted with one or more substituents selected from the group consisting of: 1-aminocyclopropyl, 4-aminophenyl, amino, aminomethyl, bromo, tert-butyl, carboxamide, carboxyl, chloro, cyano, ethyl, fluoro, hydroxy, isopropyl, methoxy, methyl, nitro, phenyl, thio, thiomethyl, trifluoromethoxy and trifluoromethyl.

[0287] In some embodiments, R 2Selected from: 5,6,7,8-tetrahydronaphthalen-1-yl, benzyl, cyclohexyl, ethyl, hexane-2-yl, naphthalen-2-yl, piperidin-1-yl, phenyl, propyl, pyridin-3-yl and thiophen-2-yl, each optionally substituted with one or more substituents selected from: 1-aminocyclopropyl, 4-aminophenyl, amino, aminomethyl, bromo, tert-butyl, carboxamide, carboxyl, chloro, cyano, ethyl, fluoro, hydroxy, isopropyl, methoxy, methyl, nitro, phenyl, thio, thiomethyl, trifluoromethoxy and trifluoromethyl.

[0288] In some embodiments, R 2 Selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, benzyl, 3-mercaptopropyl, 2-mercaptoethyl, 4-(mercaptomethyl)phenyl, p-tolyl, 2,4,6-trimethylphenyl, 4-(trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl, 4-chlorophenyl, 3-cyanophenyl, 2-nitrophenyl, 4-methoxy-2-nitrophenyl, 4- aminocarbonyl-2-nitrophenyl, 4-methoxyphenyl, phenyl, 2-fluorobenzyl, piperidin-1-yl, o-tolyl, 4-bromophenyl, naphth-2-yl, 4-methoxycarbonylphenyl, 2-(trifluoromethyl)benzyl, hexan-2-yl, 2-methoxyethyl, cyclopentylmethyl, cyclohexyl, pyridin-3-ylmethyl, 4-carboxyphenyl, 3-aminophenyl, pyridin-3-yl, thiophen-2-yl, 4-hydroxyphenyl, 4-(1-aminocyclopropyl) benzyl, 4-(1-aminocyclopropyl)phenyl, 2-methylbenzyl, 4-nitrobenzyl, 4-chlorobenzyl, phenethyl, 4-bromobenzyl, 4-cyanobenzyl, 3-nitrobenzyl, 4-tert-butylbenzyl, 2-nitrobenzyl, 4-nitrophenethyl, 2-chloro-3-methoxycarbonylphenyl, 2-aminophenyl, [1,1′-biphenyl]-4-yl, 4′-amino-[1,1′-biphenyl]-4-yl, 4-fluorobenzyl, 3-(trifluoromethyl) benzyl, 3-(trifluoromethoxy)benzyl, 3,4-dichlorobenzyl, 2-cyanobenzyl, 3-chlorobenzyl, 4-amino-2-ethylphenyl, 4-amino-3-(trifluoromethoxy)phenyl, 4-amino-2,3-dimethylphenyl, 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl, 4-amino-3-methylphenyl, 4-amino-3-fluorophenyl, 4-amino-3-ethylphenyl and 4-amino-3-(trifluoromethyl)phenyl.

[0289] In some embodiments, R 2Selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, benzyl, 3-mercaptopropyl, 2-mercaptoethyl, 4-(mercaptomethyl)phenyl, p-tolyl, 2,4,6-trimethylphenyl, 4-(trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl, 4-chlorophenyl, 3-cyanophenyl, 2-nitrophenyl, 4-methoxy-2-nitrophenyl, 4-aminocarbonyl phenyl, 2-nitrophenyl, 4-methoxyphenyl, phenyl, 2-fluorobenzyl, piperidin-1-yl, o-tolyl, 4-bromophenyl, naphth-2-yl, 4-methoxycarbonylphenyl, 2-(trifluoromethyl)benzyl, hexane-2-yl, 2-methoxyethyl, cyclopentylmethyl, cyclohexyl, pyridin-3-ylmethyl, 4-carboxyphenyl, 3-aminophenyl, pyridin-3-yl, thiophen-2-yl, 4-hydroxyphenyl, 4-(1-aminocyclopropyl)benzyl, 4-( 1-aminocyclopropyl)phenyl, 2-methylbenzyl, 4-nitrobenzyl, 4-chlorobenzyl, phenethyl, 4-bromobenzyl, 4-cyanobenzyl, 3-nitrobenzyl, 4-tert-butylbenzyl, 2-nitrobenzyl, 4-nitrophenethyl, 2-chloro-3-methoxycarbonylphenyl, 2-aminophenyl, [1,1′-biphenyl]-4-yl, 4′-amino-[1,1′-biphenyl]-4-yl, 4-fluorobenzyl, 3-(trifluoromethyl)benzyl, 3-(trifluoromethyl)benzyl, phenyl, 4-amino-3-(trifluoromethoxy)phenyl, 4-amino-2,3-dimethylphenyl, 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl, 4-amino-3-methylphenyl, 4-amino-3-fluorophenyl, 4-amino-3-ethylphenyl, 4-amino-3-(trifluoromethyl)phenyl and 4-(methoxycarbonyl)phenyl.

[0290] In some embodiments, wherein R 2 Selected from: aryl and aryl-C1-C6 alkyl, each optionally substituted with one or more substituents selected from: amino and amino-C1-C6 alkyl.

[0291] In some embodiments, R 2 Selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl and benzyl.

[0292] In some embodiments, R 2 It is 4-aminobenzyl.

[0293] In some embodiments, R 2 It is 4-(aminomethyl)benzyl.

[0294] In some embodiments, R 2 It is 4-(aminomethyl)phenyl.

[0295] In some embodiments, R 2 It is 4-aminophenyl.

[0296] In some embodiments, R 2 It is benzyl.

[0297] In some embodiments, R 2 It is 3-mercaptopropyl.

[0298] In some embodiments, R 2 It is 2-mercaptoethyl.

[0299] In some embodiments, R 2 It is 4-(mercaptomethyl)phenyl.

[0300] In some embodiments, R 2 It is p-tolyl.

[0301] In some embodiments, R 2 It is 2,4,6-trimethylphenyl.

[0302] In some embodiments, R 2 It is 4-(trifluoromethoxy)phenyl.

[0303] In some embodiments, R 2 It is 2,4,6-triisopropylphenyl.

[0304] In some embodiments, R 2 It is 4-tert-butylphenyl.

[0305] In some embodiments, R 2 It is 4-chlorophenyl.

[0306] In some embodiments, R 2 It is 3-cyanophenyl.

[0307] In some embodiments, R 2 It is 2-nitrophenyl.

[0308] In some embodiments, R 2 It is 4-methoxy-2-nitrophenyl.

[0309] In some embodiments, R 2 It is 4-aminocarbonyl-2-nitrophenyl.

[0310] In some embodiments, R 2 It is 4-methoxyphenyl.

[0311] In some embodiments, R 2 It is a phenyl group.

[0312] In some embodiments, R 2 It is 2-fluorobenzyl.

[0313] In some embodiments, R 2 It is piperidin-1-yl.

[0314] In some embodiments, R 2 It is o-tolyl.

[0315] In some embodiments, R 2 It is 4-bromophenyl.

[0316] In some embodiments, R 2 It is naphthalene-2-yl.

[0317] In some embodiments, R 2 It is 4-methoxycarbonylphenyl.

[0318] In some embodiments, R 2 is -(trifluoromethyl)benzyl.

[0319] In some embodiments, R 2 It is hexane-2-yl.

[0320] In some embodiments, R 2 It is 2-methoxyethyl.

[0321] In some embodiments, R 2 It is cyclopentylmethyl.

[0322] In some embodiments, R 2 It is cyclohexyl.

[0323] In some embodiments, R 2 It is pyridin-3-ylmethyl.

[0324] In some embodiments, R 2 It is 4-carbonylphenyl.

[0325] In some embodiments, R 2 It is 3-aminophenyl.

[0326] In some embodiments, R 2 It is pyridin-3-yl.

[0327] In some embodiments, R 2 It is thiophen-2-yl.

[0328] In some embodiments, R 2 It is 4-hydroxyphenyl.

[0329] In some embodiments, R 2 It is 4-(1-aminocyclopropyl)benzyl.

[0330] In some embodiments, R 2 It is 4-(1-aminocyclopropyl)phenyl.

[0331] In some embodiments, R 2 It is 2-methylbenzyl.

[0332] In some embodiments, R 2 It is 4-nitrobenzyl.

[0333] In some embodiments, R 2 It is 4-chlorobenzyl.

[0334] In some embodiments, R 2 It is phenethyl.

[0335] In some embodiments, R 2 It is 4-bromobenzyl.

[0336] In some embodiments, R 2 It is 4-cyanobenzyl.

[0337] In some embodiments, R 2 It is 3-nitrobenzyl.

[0338] In some embodiments, R 2 It is 4-tert-butylbenzyl.

[0339] In some embodiments, R 2 It is 2-nitrobenzyl.

[0340] In some embodiments, R 2 It is -nitrophenethyl.

[0341] In some embodiments, R 2 It is 2-chloro-3-methoxycarbonylphenyl.

[0342] In some embodiments, R 2 It is 2-aminophenyl.

[0343] In some embodiments, R 2 It is [1,1'-biphenyl]-4-yl.

[0344] In some embodiments, R 2 It is 4'-amino-[1,1'-biphenyl]-4-yl.

[0345] In some embodiments, R 2 It is 4-fluorobenzyl.

[0346] In some embodiments, R 2 It is 3-(trifluoromethyl)benzyl.

[0347] In some embodiments, R 2 It is 3-(trifluoromethoxy)benzyl.

[0348] In some embodiments, R 2 It is 3,4-dichlorobenzyl.

[0349] In some embodiments, R 2 It is 2-cyanobenzyl.

[0350] In some embodiments, R 2 It is 3-chlorobenzyl.

[0351] In some embodiments, R 2 It is 4-amino-2-ethylphenyl.

[0352] In some embodiments, R 2 It is 4-amino-3-(trifluoromethoxy)phenyl.

[0353] In some embodiments, R 2 It is 4-amino-2,3-dimethylphenyl.

[0354] In some embodiments, R 2 It is 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl.

[0355] In some embodiments, R 2 It is 4-amino-3-methylphenyl.

[0356] In some embodiments, R 2 It is 4-amino-3-fluorophenyl.

[0357] In some embodiments, R 2 It is 4-amino-3-ethylphenyl.

[0358] In some embodiments, R 2 It is 4-amino-3-(trifluoromethyl)phenyl.

[0359] In some embodiments, R 2 It is 4-(methoxycarbonyl)phenyl.

[0360] variable R 3

[0361] In some embodiments, R 3 is selected from the group consisting of aryl, heteroaryl and C3-C7 cycloalkyl, each optionally substituted with one substituent selected from the group consisting of amino and hydroxy.

[0362] In some embodiments, R 3 Selected from: 1H-indol-3-yl, 4-aminophenyl, 4-hydroxyphenyl, 5-hydroxypyridin-2-yl, cyclohexyl and phenyl.

[0363] In some embodiments, R 3 It is 1H-indol-3-yl.

[0364] In some embodiments, R 3 It is 4-aminophenyl.

[0365] In some embodiments, R 3 It is 4-hydroxyphenyl.

[0366] In some embodiments, R 3 It is 5-hydroxypyridin-2-yl.

[0367] In some embodiments, R 3 It is cyclohexyl.

[0368] In some embodiments, R 3 It is a phenyl group.

[0369] variable R 4

[0370] In some embodiments, R 4 Selected from: H and C1-C6 alkyl.

[0371] In some embodiments, R 4 For H.

[0372] In some embodiments, R 4 It is a C1-C6 alkyl group.

[0373] In some embodiments, R 4 It is a methyl group.

[0374] variable R 5

[0375] In some embodiments, R 5 Selected from: H and C1-C6 alkyl.

[0376] In some embodiments, R 5 For H.

[0377] In some embodiments, R 5 It is a C1-C6 alkyl group.

[0378] In some embodiments, R 5 It is a methyl group.

[0379] VARIABLE X

[0380] In some embodiments, X is -C(O)NHCH(CH2R 3 )-, or X does not exist.

[0381] In some embodiments, X is -C(O)NHCH(CH2R 3 )-

[0382] In some embodiments, X is absent.

[0383] Certain combinations

[0384] In some embodiments, R b is a C1-C6 alkyl group; and R c R d -C(CH3)2-.

[0385] In some embodiments, R b and R c Together with the atoms to which they are respectively bonded they form a heterocyclyldiyl.

[0386] In some embodiments, R b and R c Together with the atoms to which they are respectively bonded, they form a heterocyclyldiyl selected from the group consisting of pyrrolidinyldiyl, piperidinyldiyl and azepanyldiyl.

[0387] In some embodiments, R b and R c Together with the atoms to which they are respectively bonded, they form a pyrrolidinyl group.

[0388] In some embodiments, R b and R c Together with the atoms to which they are respectively bonded, they form piperidinyldiyl.

[0389] In some embodiments, R b and R c Together with the atoms to which they are respectively bonded, they form an azepanyldiyl group.

[0390] In some embodiments, R 4 and R 5 Each is independently selected from: H and C1-C6 alkyl.

[0391] In some embodiments, R 4 and R 5 are each independently selected from: H and methyl.

[0392] In some embodiments, R 4 and R 5 Each is a methyl group.

[0393] In some embodiments, R 4 H and R 5 It is a methyl group.

[0394] Also provided are compounds of formula Ia:

[0395]

[0396] and pharmaceutically acceptable salts thereof, wherein:

[0397] R 2 is selected from the group consisting of: C2-C6 alkyl, aryl, aryl-C1-C6 alkyl, C4-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio, and thio-C1-C6 alkyl; and

[0398] R 4 and R 5 Each is independently selected from: H and C1-C6 alkyl.

[0399] Also provided are compounds of formula Ia:

[0400]

[0401] and pharmaceutically acceptable salts thereof, wherein:

[0402] R 2Selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, benzyl, 3-mercaptopropyl, 2-mercaptoethyl, 4-(mercaptomethyl)phenyl, p-tolyl, 2,4,6-trimethylphenyl, 4-(trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl, 4-chlorophenyl, 3-cyanophenyl, 2-nitrophenyl, 4-methoxy-2-nitrophenyl, 4-aminophenyl phenyl, 2-nitrophenyl, 4-methoxyphenyl, phenyl, 2-fluorobenzyl, piperidin-1-yl, o-tolyl, 4-bromophenyl, naphth-2-yl, 4-methoxycarbonylphenyl, 2-(trifluoromethyl)benzyl, hexane-2-yl, 2-methoxyethyl, cyclopentylmethyl, cyclohexyl, pyridin-3-ylmethyl, 4-carboxyphenyl, 3-aminophenyl, pyridin-3-yl, thiophen-2-yl, 4-hydroxyphenyl, 4-(1-aminocyclopropyl)benzyl , 4-(1-aminocyclopropyl)phenyl, 2-methylbenzyl, 4-nitrobenzyl, 4-chlorobenzyl, phenethyl, 4-bromobenzyl, 4-cyanobenzyl, 3-nitrobenzyl, 4-tert-butylbenzyl, 2-nitrobenzyl, 4-nitrophenethyl, 2-chloro-3-methoxycarbonylphenyl, 2-aminophenyl, [1,1′-biphenyl]-4-yl, 4′-amino-[1,1′-biphenyl]-4-yl, 4-fluorobenzyl, 3-(trifluoromethyl)benzyl, 3-(trifluoromethoxy)benzyl, 3,4-dichlorobenzyl, 2-cyanobenzyl, 3-chlorobenzyl, 4-amino-2-ethylphenyl, 4-amino-3-(trifluoromethoxy)phenyl, 4-amino-2,3-dimethylphenyl, 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl, 4-amino-3-methylphenyl, 4-amino-3-fluorophenyl, 4-amino-3-ethylphenyl, and 4-amino-3-(trifluoromethyl)phenyl; and

[0403] R 4 and R 5 are each independently selected from: H and methyl.

[0404] Also provided are compounds of formula Ib:

[0405]

[0406] and pharmaceutically acceptable salts thereof, wherein:

[0407] R 2selected from the group consisting of: C2-C6 alkyl, aryl, aryl-C1-C6 alkyl, C4-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio, and thio-C1-C6 alkyl;

[0408] R 3 is selected from the group consisting of: aryl, heteroaryl, and C3-C7 cycloalkyl, each optionally substituted with a substituent selected from amino and hydroxy; and

[0409] R 4 and R 5 Each is independently selected from: H and C1-C6 alkyl.

[0410] Also provided are compounds of formula Ib:

[0411]

[0412] and pharmaceutically acceptable salts thereof, wherein:

[0413] R 2Selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, benzyl, 3-mercaptopropyl, 2-mercaptoethyl, 4-(mercaptomethyl)phenyl, p-tolyl, 2,4,6-trimethylphenyl, 4-(trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl, 4-chlorophenyl, 3-cyanophenyl, 2-nitrophenyl, 4-methoxy-2-nitrophenyl, 4-aminophenyl phenyl, 2-fluorobenzyl, piperidin-1-yl, o-tolyl, 4-bromophenyl, naphth-2-yl, 4-methoxycarbonylphenyl, 2-(trifluoromethyl)benzyl, hexane-2-yl, 2-methoxyethyl, cyclopentylmethyl, cyclohexyl, pyridin-3-ylmethyl, 4-carboxyphenyl, 3-aminophenyl, pyridin-3-yl, thiophen-2-yl, 4-hydroxyphenyl, 4-(1-aminocyclopropyl)benzyl phenyl, 2-methylbenzyl, 4-nitrobenzyl, 4-chlorobenzyl, phenethyl, 4-bromobenzyl, 4-cyanobenzyl, 3-nitrobenzyl, 4-tert-butylbenzyl, 2-nitrobenzyl, 4-nitrophenethyl, 2-chloro-3-methoxycarbonylphenyl, 2-aminophenyl, [1,1′-biphenyl]-4-yl, 4′-amino-[1,1′-biphenyl]-4-yl, 4-fluorobenzyl, 3-(trifluoromethyl)benzyl phenyl, 4-amino-3-(trifluoromethoxy)phenyl, 4-amino-2,3-dimethylphenyl, 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl, 4-amino-3-methylphenyl, 4-amino-3-fluorophenyl, 4-amino-3-ethylphenyl, and 4-amino-3-(trifluoromethyl)phenyl;

[0414] R 3 is selected from the group consisting of: 1H-indol-3-yl, 4-aminophenyl, 4-hydroxyphenyl, 5-hydroxypyridin-2-yl, cyclohexyl, and phenyl; and

[0415] R 4 and R 5 are each independently selected from: H and methyl.

[0416] Also provided are compounds of formula Ic:

[0417]

[0418] and pharmaceutically acceptable salts thereof, wherein:

[0419] R 2is selected from the group consisting of: C2-C6 alkyl, aryl, aryl-C1-C6 alkyl, C4-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio, and thio-C1-C6 alkyl; and

[0420] X is -C(O)NHCH(CH2R 3 )-, or X does not exist; and

[0421] R 3 is selected from the group consisting of: aryl, heteroaryl, and C3-C7 cycloalkyl, each optionally substituted with a substituent selected from amino and hydroxy; and

[0422] R 4 and R 5 Each is independently selected from: H and C1-C6 alkyl.

[0423] Also provided are compounds of formula Ic:

[0424]

[0425] or a pharmaceutically acceptable salt thereof,

[0426] in:

[0427] R 2Selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, benzyl, 3-mercaptopropyl, 2-mercaptoethyl, 4-(mercaptomethyl)phenyl, p-tolyl, 2,4,6-trimethylphenyl, 4-(trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl, 4-chlorophenyl, 3-cyanophenyl, 2-nitrophenyl, 4-methoxy-2-nitrophenyl, 4-aminophenyl phenyl, 2-nitrophenyl, 4-methoxyphenyl, phenyl, 2-fluorobenzyl, piperidin-1-yl, o-tolyl, 4-bromophenyl, naphth-2-yl, 4-methoxycarbonylphenyl, 2-(trifluoromethyl)benzyl, hexane-2-yl, 2-methoxyethyl, cyclopentylmethyl, cyclohexyl, pyridin-3-ylmethyl, 4-carboxyphenyl, 3-aminophenyl, pyridin-3-yl, thiophen-2-yl, 4-hydroxyphenyl, 4-(1-aminocyclopropyl)benzyl , 4-(1-aminocyclopropyl)phenyl, 2-methylbenzyl, 4-nitrobenzyl, 4-chlorobenzyl, phenethyl, 4-bromobenzyl, 4-cyanobenzyl, 3-nitrobenzyl, 4-tert-butylbenzyl, 2-nitrobenzyl, 4-nitrophenethyl, 2-chloro-3-methoxycarbonylphenyl, 2-aminophenyl, [1,1′-biphenyl]-4-yl, 4′-amino-[1,1′-biphenyl]-4-yl, 4-fluorobenzyl, 3-(trifluoromethyl)benzyl, 3-(trifluoromethoxy)benzyl, 3,4-dichlorobenzyl, 2-cyanobenzyl, 3-chlorobenzyl, 4-amino-2-ethylphenyl, 4-amino-3-(trifluoromethoxy)phenyl, 4-amino-2,3-dimethylphenyl, 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl, 4-amino-3-methylphenyl, 4-amino-3-fluorophenyl, 4-amino-3-ethylphenyl, and 4-amino-3-(trifluoromethyl)phenyl; and

[0428] X is -C(O)NHCH(CH2R 3 )-, or X does not exist; and

[0429] R 3 is selected from the group consisting of: 1H-indol-3-yl, 4-aminophenyl, 4-hydroxyphenyl, 5-hydroxypyridin-2-yl, cyclohexyl, and phenyl; and

[0430] R 4 and R 5 are each independently selected from: H and methyl.

[0431] Also provided are compounds of formula Id:

[0432]

[0433] and pharmaceutically acceptable salts thereof, wherein:

[0434] R 2is selected from the group consisting of: C2-C6 alkyl, aryl, aryl-C1-C6 alkyl, C4-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio, and thio-C1-C6 alkyl; and

[0435] R 4 and R 5 Each is independently selected from: H and C1-C6 alkyl.

[0436] Also provided are compounds of formula Id:

[0437]

[0438] and pharmaceutically acceptable salts thereof, wherein:

[0439] R 2Selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, benzyl, 3-mercaptopropyl, 2-mercaptoethyl, 4-(mercaptomethyl)phenyl, p-tolyl, 2,4,6-trimethylphenyl, 4-(trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl, 4-chlorophenyl, 3-cyanophenyl, 2-nitrophenyl, 4-methoxy-2-nitrophenyl, 4-aminophenyl phenyl, 2-nitrophenyl, 4-methoxyphenyl, phenyl, 2-fluorobenzyl, piperidin-1-yl, o-tolyl, 4-bromophenyl, naphth-2-yl, 4-methoxycarbonylphenyl, 2-(trifluoromethyl)benzyl, hexane-2-yl, 2-methoxyethyl, cyclopentylmethyl, cyclohexyl, pyridin-3-ylmethyl, 4-carboxyphenyl, 3-aminophenyl, pyridin-3-yl, thiophen-2-yl, 4-hydroxyphenyl, 4-(1-aminocyclopropyl)benzyl , 4-(1-aminocyclopropyl)phenyl, 2-methylbenzyl, 4-nitrobenzyl, 4-chlorobenzyl, phenethyl, 4-bromobenzyl, 4-cyanobenzyl, 3-nitrobenzyl, 4-tert-butylbenzyl, 2-nitrobenzyl, 4-nitrophenethyl, 2-chloro-3-methoxycarbonylphenyl, 2-aminophenyl, [1,1′-biphenyl]-4-yl, 4′-amino-[1,1′-biphenyl]-4-yl, 4-fluorobenzyl, 3-(trifluoromethyl)benzyl, 3-(trifluoromethoxy)benzyl, 3,4-dichlorobenzyl, 2-cyanobenzyl, 3-chlorobenzyl, 4-amino-2-ethylphenyl, 4-amino-3-(trifluoromethoxy)phenyl, 4-amino-2,3-dimethylphenyl, 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl, 4-amino-3-methylphenyl, 4-amino-3-fluorophenyl, 4-amino-3-ethylphenyl, and 4-amino-3-(trifluoromethyl)phenyl; and

[0440] R 4 and R 5 are each independently selected from: H and methyl.

[0441] Also provided are compounds of Formula Ie:

[0442]

[0443] and pharmaceutically acceptable salts thereof, wherein:

[0444] R 2is selected from the group consisting of: C2-C6 alkyl, aryl, aryl-C1-C6 alkyl, C4-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio, and thio-C1-C6 alkyl; and

[0445] R 3 is selected from the group consisting of: aryl, heteroaryl, and C3-C7 cycloalkyl, each optionally substituted with a substituent selected from amino and hydroxy; and

[0446] R 4 and R 5 Each is independently selected from: H and C1-C6 alkyl.

[0447] Also provided are compounds of Formula Ie:

[0448]

[0449] and pharmaceutically acceptable salts thereof, wherein:

[0450] R 2Selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, benzyl, 3-mercaptopropyl, 2-mercaptoethyl, 4-(mercaptomethyl)phenyl, p-tolyl, 2,4,6-trimethylphenyl, 4-(trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl, 4-chlorophenyl, 3-cyanophenyl, 2-nitrophenyl, 4-methoxy-2-nitrophenyl, 4-aminophenyl phenyl, 2-nitrophenyl, 4-methoxyphenyl, phenyl, 2-fluorobenzyl, piperidin-1-yl, o-tolyl, 4-bromophenyl, naphth-2-yl, 4-methoxycarbonylphenyl, 2-(trifluoromethyl)benzyl, hexane-2-yl, 2-methoxyethyl, cyclopentylmethyl, cyclohexyl, pyridin-3-ylmethyl, 4-carboxyphenyl, 3-aminophenyl, pyridin-3-yl, thiophen-2-yl, 4-hydroxyphenyl, 4-(1-aminocyclopropyl)benzyl , 4-(1-aminocyclopropyl)phenyl, 2-methylbenzyl, 4-nitrobenzyl, 4-chlorobenzyl, phenethyl, 4-bromobenzyl, 4-cyanobenzyl, 3-nitrobenzyl, 4-tert-butylbenzyl, 2-nitrobenzyl, 4-nitrophenethyl, 2-chloro-3-methoxycarbonylphenyl, 2-aminophenyl, [1,1′-biphenyl]-4-yl, 4′-amino-[1,1′-biphenyl]-4-yl, 4-fluorobenzyl, 3-(trifluoromethyl)benzyl, 3-(trifluoromethoxy)benzyl, 3,4-dichlorobenzyl, 2-cyanobenzyl, 3-chlorobenzyl, 4-amino-2-ethylphenyl, 4-amino-3-(trifluoromethoxy)phenyl, 4-amino-2,3-dimethylphenyl, 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl, 4-amino-3-methylphenyl, 4-amino-3-fluorophenyl, 4-amino-3-ethylphenyl, and 4-amino-3-(trifluoromethyl)phenyl; and

[0451] R 3 is selected from the group consisting of: 1H-indol-3-yl, 4-aminophenyl, 4-hydroxyphenyl, 5-hydroxypyridin-2-yl, cyclohexyl, and phenyl; and

[0452] R 4 and R 5 are each independently selected from: H and methyl.

[0453] Also provided are compounds of formula If:

[0454]

[0455] and pharmaceutically acceptable salts thereof, wherein:

[0456] R 2is selected from the group consisting of: C2-C6 alkyl, aryl, aryl-C1-C6 alkyl, C4-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, chloro-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio, and thio-C1-C6 alkyl; and

[0457] X is -C(O)NHCH(CH2R 3 )-, or X does not exist; and

[0458] R 3 is selected from the group consisting of aryl, heteroaryl and C3-C7 cycloalkyl, each optionally substituted with one substituent selected from the group consisting of amino and hydroxy.

[0459] Also provided are compounds of formula If:

[0460]

[0461] and pharmaceutically acceptable salts thereof, wherein:

[0462] R 2 is selected from the group consisting of: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl; and

[0463] X is -C(O)NHCH(CH2R 3 )-, or X does not exist; and

[0464] R 3 Selected from: 1H-indol-3-yl, 4-aminophenyl, 4-hydroxyphenyl, 5-hydroxypyridin-2-yl, cyclohexyl and phenyl.

[0465] Also provided are compounds of formula Ig:

[0466]

[0467] and pharmaceutically acceptable salts thereof, wherein:

[0468] R 2Selected from: C2-C6 alkyl, aryl, aryl-C1-C6 alkyl, C4-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl and heterocyclyl, each optionally substituted with one or more substituents selected from the following: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio and thio-C1-C6 alkyl.

[0469] Also provided are compounds of formula Ig:

[0470]

[0471]

[0472] and pharmaceutically acceptable salts thereof, wherein:

[0473] R 2 Selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl.

[0474] Also provided are compounds of formula Ih:

[0475]

[0476] and pharmaceutically acceptable salts thereof, wherein:

[0477] R 2 is selected from the group consisting of: C2-C6 alkyl, aryl, aryl-C1-C6 alkyl, C4-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio, and thio-C1-C6 alkyl; and

[0478] R 3 is selected from the group consisting of aryl, heteroaryl and C3-C7 cycloalkyl, each optionally substituted with one substituent selected from the group consisting of amino and hydroxy.

[0479] Also provided are compounds of formula Ih:

[0480]

[0481] and pharmaceutically acceptable salts thereof, wherein:

[0482] R 2 is selected from the group consisting of: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl; and

[0483] R 3 Selected from: 1H-indol-3-yl, 4-aminophenyl, 4-hydroxyphenyl, 5-hydroxypyridin-2-yl, cyclohexyl and phenyl.

[0484] Also provided are compounds of formula Ii:

[0485]

[0486] and pharmaceutically acceptable salts thereof, wherein:

[0487] R 2 selected from the group consisting of: C2-C6 alkyl, aryl, aryl-C1-C6 alkyl, C4-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio, and thio-C1-C6 alkyl;

[0488] X is -C(O)NHCH(CH2R 3 )-, or X does not exist; and

[0489] R 3 is selected from the group consisting of aryl, heteroaryl and C3-C7 cycloalkyl, each optionally substituted with one substituent selected from the group consisting of amino and hydroxy.

[0490] Also provided are compounds of formula Ii:

[0491]

[0492] and pharmaceutically acceptable salts thereof, wherein:

[0493] R 2Selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, benzyl, 3-mercaptopropyl, 2-mercaptoethyl, 4-(mercaptomethyl)phenyl, p-tolyl, 2,4,6-trimethylphenyl, 4-(trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl, 4-chlorophenyl, 3-cyanophenyl, 2-nitrophenyl, 4-methoxy-2-nitrophenyl, 4-aminophenyl phenyl, 2-fluorobenzyl, piperidin-1-yl, o-tolyl, 4-bromophenyl, naphth-2-yl, 4-methoxycarbonylphenyl, 2-(trifluoromethyl)benzyl, hexane-2-yl, 2-methoxyethyl, cyclopentylmethyl, cyclohexyl, pyridin-3-ylmethyl, 4-carboxyphenyl, 3-aminophenyl, pyridin-3-yl, thiophen-2-yl, 4-hydroxyphenyl, 4-(1-aminocyclopropyl)benzyl phenyl, 2-methylbenzyl, 4-nitrobenzyl, 4-chlorobenzyl, phenethyl, 4-bromobenzyl, 4-cyanobenzyl, 3-nitrobenzyl, 4-tert-butylbenzyl, 2-nitrobenzyl, 4-nitrophenethyl, 2-chloro-3-methoxycarbonylphenyl, 2-aminophenyl, [1,1′-biphenyl]-4-yl, 4′-amino-[1,1′-biphenyl]-4-yl, 4-fluorobenzyl, 3-(trifluoromethyl)benzyl phenyl, 4-amino-3-(trifluoromethoxy)phenyl, 4-amino-2,3-dimethylphenyl, 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl, 4-amino-3-methylphenyl, 4-amino-3-fluorophenyl, 4-amino-3-ethylphenyl, and 4-amino-3-(trifluoromethyl)phenyl;

[0494] X is -C(O)NHCH(CH2R 3 )-, or X does not exist; and

[0495] R 3 Selected from: 1H-indol-3-yl, 4-aminophenyl, 4-hydroxyphenyl, 5-hydroxypyridin-2-yl, cyclohexyl and phenyl.

[0496] Also provided are compounds of formula Ij:

[0497]

[0498] and pharmaceutically acceptable salts thereof, wherein:

[0499] R 2Selected from: C2-C6 alkyl, aryl, aryl-C1-C6 alkyl, C4-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl and heterocyclyl, each optionally substituted with one or more substituents selected from the following: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio and thio-C1-C6 alkyl.

[0500] Also provided are compounds of formula Ij:

[0501]

[0502] or a pharmaceutically acceptable salt thereof,

[0503] in:

[0504] R 2Selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, benzyl, 3-mercaptopropyl, 2-mercaptoethyl, 4-(mercaptomethyl)phenyl, p-tolyl, 2,4,6-trimethylphenyl, 4-(trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl, 4-chlorophenyl, 3-cyanophenyl, 2-nitrophenyl, 4-methoxy-2-nitrophenyl, 4- aminocarbonyl-2-nitrophenyl, 4-methoxyphenyl, phenyl, 2-fluorobenzyl, piperidin-1-yl, o-tolyl, 4-bromophenyl, naphth-2-yl, 4-methoxycarbonylphenyl, 2-(trifluoromethyl)benzyl, hexan-2-yl, 2-methoxyethyl, cyclopentylmethyl, cyclohexyl, pyridin-3-ylmethyl, 4-carboxyphenyl, 3-aminophenyl, pyridin-3-yl, thiophen-2-yl, 4-hydroxyphenyl, 4-(1-aminocyclopropyl) benzyl, 4-(1-aminocyclopropyl)phenyl, 2-methylbenzyl, 4-nitrobenzyl, 4-chlorobenzyl, phenethyl, 4-bromobenzyl, 4-cyanobenzyl, 3-nitrobenzyl, 4-tert-butylbenzyl, 2-nitrobenzyl, 4-nitrophenethyl, 2-chloro-3-methoxycarbonylphenyl, 2-aminophenyl, [1,1′-biphenyl]-4-yl, 4′-amino-[1,1′-biphenyl]-4-yl, 4-fluorobenzyl, 3-(trifluoromethyl) benzyl, 3-(trifluoromethoxy)benzyl, 3,4-dichlorobenzyl, 2-cyanobenzyl, 3-chlorobenzyl, 4-amino-2-ethylphenyl, 4-amino-3-(trifluoromethoxy)phenyl, 4-amino-2,3-dimethylphenyl, 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl, 4-amino-3-methylphenyl, 4-amino-3-fluorophenyl, 4-amino-3-ethylphenyl and 4-amino-3-(trifluoromethyl)phenyl.

[0505] Also provided are compounds of formula Ik:

[0506]

[0507] and pharmaceutically acceptable salts thereof, wherein:

[0508] R 2 is selected from the group consisting of: C2-C6 alkyl, aryl, aryl-C1-C6 alkyl, C4-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio, and thio-C1-C6 alkyl; and

[0509] R 3 is selected from the group consisting of aryl, heteroaryl and C3-C7 cycloalkyl, each optionally substituted with one substituent selected from the group consisting of amino and hydroxy.

[0510] Also provided are compounds of formula Ik:

[0511]

[0512] and pharmaceutically acceptable salts thereof, wherein:

[0513] R 2 Selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, benzyl, 3-mercaptopropyl, 2-mercaptoethyl, 4-(mercaptomethyl)phenyl, p-tolyl, 2,4,6-trimethylphenyl, 4-(trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl, 4-chlorophenyl, 3-cyanophenyl, 2-nitrophenyl, 4-methoxy-2-nitrophenyl, 4-aminophenyl phenyl, 2-nitrophenyl, 4-methoxyphenyl, phenyl, 2-fluorobenzyl, piperidin-1-yl, o-tolyl, 4-bromophenyl, naphth-2-yl, 4-methoxycarbonylphenyl, 2-(trifluoromethyl)benzyl, hexane-2-yl, 2-methoxyethyl, cyclopentylmethyl, cyclohexyl, pyridin-3-ylmethyl, 4-carboxyphenyl, 3-aminophenyl, pyridin-3-yl, thiophen-2-yl, 4-hydroxyphenyl, 4-(1-aminocyclopropyl)benzyl , 4-(1-aminocyclopropyl)phenyl, 2-methylbenzyl, 4-nitrobenzyl, 4-chlorobenzyl, phenethyl, 4-bromobenzyl, 4-cyanobenzyl, 3-nitrobenzyl, 4-tert-butylbenzyl, 2-nitrobenzyl, 4-nitrophenethyl, 2-chloro-3-methoxycarbonylphenyl, 2-aminophenyl, [1,1′-biphenyl]-4-yl, 4′-amino-[1,1′-biphenyl]-4-yl, 4-fluorobenzyl, 3-(trifluoromethyl)benzyl, 3-(trifluoromethoxy)benzyl, 3,4-dichlorobenzyl, 2-cyanobenzyl, 3-chlorobenzyl, 4-amino-2-ethylphenyl, 4-amino-3-(trifluoromethoxy)phenyl, 4-amino-2,3-dimethylphenyl, 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl, 4-amino-3-methylphenyl, 4-amino-3-fluorophenyl, 4-amino-3-ethylphenyl, and 4-amino-3-(trifluoromethyl)phenyl; and

[0514] R 3 Selected from: 1H-indol-3-yl, 4-aminophenyl, 4-hydroxyphenyl, 5-hydroxypyridin-2-yl, cyclohexyl and phenyl.

[0515] Also provided are compounds of formula Im:

[0516]

[0517] and pharmaceutically acceptable salts thereof, wherein:

[0518] R 1 is selected from the group consisting of amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heterocyclyl and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of aryl, aryl-C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkylthio, carboxyl, carboxamide, C3-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, guanidino, halo, C1-C6 haloacyl, C1-C6 haloalkyl, heterocyclyl, heterocyclyl-C1-C6 alkyl, hydroxyl and thio; or

[0519] R 1 R a R b NCH(R c )-;

[0520] R a Selected from: H and C1-C6 alkyl;

[0521] R b is a C1-C6 alkyl group; and

[0522] R c R d -C(CH3)2-; and

[0523] R d is selected from the group consisting of: H, aryl, C3-C7 cycloalkyl and heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: C1-C4 acylthio, C2-C4 alkenyl, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkoxy, amino, amino-C1-C4 alkyl, halo, C1-C4 haloalkyl, hydroxy, hydroxy-C1-C4 alkyl and thio, wherein C2-C4 alkenyl, C1-C4 alkylamino and C1-C4 alkoxy are further optionally substituted with one substituent selected from the group consisting of: C1-C4 alkylaryl, hydroxy and thio; or

[0524] R b and R c together with the atoms to which they are respectively bonded, form a heterocyclyldiyl;

[0525] R 2Selected from: C2-C6 alkyl, aryl, aryl-C1-C6 alkyl, C4-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl and heterocyclyl, each optionally substituted with one or more substituents selected from the following: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloacyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio and thio-C1-C6 alkyl.

[0526] Also provided are compounds of formula Im:

[0527]

[0528] and pharmaceutically acceptable salts thereof, wherein:

[0529] R 1 selected from the group consisting of: 1-(dimethylamino)-2-methylpropyl, 2-methyl-1-(methylamino)propyl, 1-aminocyclopentyl, 1-aminocyclopropyl, 4-aminophenyl, 2-aminopropyl-2-yl, 1-aminocyclohexyl, 3-aminooxetan-3-yl, 2-(methylamino)propyl-2-yl, 1-amino-2-methylpropyl-2-yl, 2-methylpyrrolidin-2-yl, 2-amino-3-methylbutan-2-yl, 2-aminobutan-2-yl, 2-methyl-1-(methylamino)propyl-2-yl, 1-methylpiperidin-2-yl, 3-fluoropyrrolidin-3-yl, 1,2-dimethylpyrrolidin-2-yl, and 2-(dimethylamino)propyl-2-yl); and

[0530] R 2Selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, benzyl, 3-mercaptopropyl, 2-mercaptoethyl, 4-(mercaptomethyl)phenyl, p-tolyl, 2,4,6-trimethylphenyl, 4-(trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl, 4-chlorophenyl, 3-cyanophenyl, 2-nitrophenyl, 4-methoxy-2-nitrophenyl, 4- aminocarbonyl-2-nitrophenyl, 4-methoxyphenyl, phenyl, 2-fluorobenzyl, piperidin-1-yl, o-tolyl, 4-bromophenyl, naphth-2-yl, 4-methoxycarbonylphenyl, 2-(trifluoromethyl)benzyl, hexan-2-yl, 2-methoxyethyl, cyclopentylmethyl, cyclohexyl, pyridin-3-ylmethyl, 4-carboxyphenyl, 3-aminophenyl, pyridin-3-yl, thiophen-2-yl, 4-hydroxyphenyl, 4-(1-aminocyclopropyl) benzyl, 4-(1-aminocyclopropyl)phenyl, 2-methylbenzyl, 4-nitrobenzyl, 4-chlorobenzyl, phenethyl, 4-bromobenzyl, 4-cyanobenzyl, 3-nitrobenzyl, 4-tert-butylbenzyl, 2-nitrobenzyl, 4-nitrophenethyl, 2-chloro-3-methoxycarbonylphenyl, 2-aminophenyl, [1,1′-biphenyl]-4-yl, 4′-amino-[1,1′-biphenyl]-4-yl, 4-fluorobenzyl, 3-(trifluoromethyl) benzyl, 3-(trifluoromethoxy)benzyl, 3,4-dichlorobenzyl, 2-cyanobenzyl, 3-chlorobenzyl, 4-amino-2-ethylphenyl, 4-amino-3-(trifluoromethoxy)phenyl, 4-amino-2,3-dimethylphenyl, 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl, 4-amino-3-methylphenyl, 4-amino-3-fluorophenyl, 4-amino-3-ethylphenyl and 4-amino-3-(trifluoromethyl)phenyl.

[0531] Also provided are compounds of formula Im:

[0532]

[0533] and pharmaceutically acceptable salts thereof, wherein:

[0534] R 1 is selected from the group consisting of amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heterocyclyl and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of aryl, aryl-C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkylthio, carboxyl, carboxamide, C3-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, guanidino, halo, C1-C6 haloacyl, C1-C6 haloalkyl, heterocyclyl, heterocyclyl-C1-C6 alkyl, hydroxyl and thio; or

[0535] R 1 R a Rb NCH(R c )-;

[0536] R a Selected from: H and C1-C6 alkyl;

[0537] R b is a C1-C6 alkyl group; and

[0538] R c R d -C(CH3)2-; and

[0539] R d is selected from the group consisting of: H, aryl, C3-C7 cycloalkyl and heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: C1-C4 acylthio, C2-C4 alkenyl, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkoxy, amino, amino-C1-C4 alkyl, halo, C1-C4 haloalkyl, hydroxy, hydroxy-C1-C4 alkyl and thio, wherein C2-C4 alkenyl, C1-C4 alkylamino and C1-C4 alkoxy are further optionally substituted with one substituent selected from the group consisting of: C1-C4 alkylaryl, hydroxy and thio; or

[0540] R b and R c together with the atoms to which they are respectively bonded, form a heterocyclyldiyl;

[0541] R 2 Selected from: C1-C6 alkyl, aryl, aryl-C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl and heterocyclyl, each optionally substituted with one or more substituents selected from the following: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloacyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio and thio-C1-C6 alkyl.

[0542] Also provided are compounds of formula Im:

[0543]

[0544] and pharmaceutically acceptable salts thereof, wherein:

[0545] R 1Selected from: 1-(dimethylamino)-2-methylpropyl, 2-methyl-1-(methylamino)propyl, 1-aminocyclopentyl, 1-aminocyclopropyl, 4-aminophenyl, 2-aminopropyl-2-yl, 1-aminocyclohexyl, 3-aminooxetan-3-yl, 2-(methylamino)propyl-2-yl, 1-amino-2-methylpropyl-2-yl, 2-methylpyrrolidin-2-yl, 2-amino-3-methylbutyl-2-yl, 2-aminobutyl-2-yl -yl, 2-methyl-1-(methylamino)propan-2-yl, 1-methylpiperidin-2-yl, 3-fluoropyrrolidin-3-yl, 1,2-dimethylpyrrolidin-2-yl, 2-(dimethylamino)propan-2-yl), 2-methyl-1-(methylamino)-2-phenylpropyl, 1-isopropylpiperidin-2-yl, 2-azabicyclo[2.2.1]heptan-3-yl, and 2-methyl-2-azabicyclo[2.2.1]heptan-3-yl; and

[0546] R 2 Selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, benzyl, 3-mercaptopropyl, 2-mercaptoethyl, 4-(mercaptomethyl)phenyl, p-tolyl, 2,4,6-trimethylphenyl, 4-(trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl, 4-chlorophenyl, 3-cyanophenyl, 2-nitrophenyl, 4-methoxy-2-nitrophenyl, 4-aminocarbonyl phenyl, 2-nitrophenyl, 4-methoxyphenyl, phenyl, 2-fluorobenzyl, piperidin-1-yl, o-tolyl, 4-bromophenyl, naphth-2-yl, 4-methoxycarbonylphenyl, 2-(trifluoromethyl)benzyl, hexane-2-yl, 2-methoxyethyl, cyclopentylmethyl, cyclohexyl, pyridin-3-ylmethyl, 4-carboxyphenyl, 3-aminophenyl, pyridin-3-yl, thiophen-2-yl, 4-hydroxyphenyl, 4-(1-aminocyclopropyl)benzyl, 4-( 1-aminocyclopropyl)phenyl, 2-methylbenzyl, 4-nitrobenzyl, 4-chlorobenzyl, phenethyl, 4-bromobenzyl, 4-cyanobenzyl, 3-nitrobenzyl, 4-tert-butylbenzyl, 2-nitrobenzyl, 4-nitrophenethyl, 2-chloro-3-methoxycarbonylphenyl, 2-aminophenyl, [1,1′-biphenyl]-4-yl, 4′-amino-[1,1′-biphenyl]-4-yl, 4-fluorobenzyl, 3-(trifluoromethyl)benzyl, 3-(trifluoromethyl)benzyl, phenyl, 4-amino-3-(trifluoromethoxy)phenyl, 4-amino-2,3-dimethylphenyl, 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl, 4-amino-3-methylphenyl, 4-amino-3-fluorophenyl, 4-amino-3-ethylphenyl, 4-amino-3-(trifluoromethyl)phenyl and 4-(methoxycarbonyl)phenyl.

[0547] Also provided are compounds of the formula In:

[0548]

[0549] and pharmaceutically acceptable salts thereof, wherein:

[0550] R 1 is selected from the group consisting of amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heterocyclyl and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of aryl, aryl-C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkylthio, carboxyl, carboxamide, C3-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, guanidino, halo, C1-C6 haloacyl, C1-C6 haloalkyl, heterocyclyl, heterocyclyl-C1-C6 alkyl, hydroxyl and thio; or

[0551] R 1 R a R b NCH(R c )-;

[0552] R a Selected from: H and C1-C6 alkyl;

[0553] R b is a C1-C6 alkyl group; and

[0554] R c R d -C(CH3)2-; and

[0555] R d is selected from the group consisting of: H, aryl, C3-C7 cycloalkyl and heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: C1-C4 acylthio, C2-C4 alkenyl, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkoxy, amino, amino-C1-C4 alkyl, halo, C1-C4 haloalkyl, hydroxy, hydroxy-C1-C4 alkyl and thio, wherein C2-C4 alkenyl, C1-C4 alkylamino and C1-C4 alkoxy are further optionally substituted with one substituent selected from the group consisting of: C1-C4 alkylaryl, hydroxy and thio; or

[0556] R b and R c together with the atoms to which they are respectively bonded, form a heterocyclyldiyl;

[0557] R 2is selected from the group consisting of: C2-C6 alkyl, aryl, aryl-C1-C6 alkyl, C4-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloacyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio, and thio-C1-C6 alkyl; and

[0558] R 3 is selected from the group consisting of: aryl, heteroaryl, and C3-C7 cycloalkyl, each optionally substituted with a substituent selected from amino and hydroxy;

[0559] The prerequisite is that when R 1 is 2-methyl-1-(methylamino)propyl, and R 3 When it is phenyl, R 2 Not ethyl, isopropyl, n-butyl and phenyl.

[0560] Also provided are compounds of the formula In:

[0561]

[0562] and pharmaceutically acceptable salts thereof, wherein:

[0563] R 1 selected from the group consisting of: 1-(dimethylamino)-2-methylpropyl, 2-methyl-1-(methylamino)propyl, 1-aminocyclopentyl, 1-aminocyclopropyl, 4-aminophenyl, 2-aminopropyl-2-yl, 1-aminocyclohexyl, 3-aminooxetan-3-yl, 2-(methylamino)propyl-2-yl, 1-amino-2-methylpropyl-2-yl, 2-methylpyrrolidin-2-yl, 2-amino-3-methylbutan-2-yl, 2-aminobutan-2-yl, 2-methyl-1-(methylamino)propyl-2-yl, 1-methylpiperidin-2-yl, 3-fluoropyrrolidin-3-yl, 1,2-dimethylpyrrolidin-2-yl, and 2-(dimethylchloro)propyl-2-yl); and

[0564] R 2Selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, benzyl, 3-mercaptopropyl, 2-mercaptoethyl, 4-(mercaptomethyl)phenyl, p-tolyl, 2,4,6-trimethylphenyl, 4-(trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl, 4-chlorophenyl, 3-cyanophenyl, 2-nitrophenyl, 4-methoxy-2-nitrophenyl, 4-aminophenyl phenyl, 2-nitrophenyl, 4-methoxyphenyl, phenyl, 2-fluorobenzyl, piperidin-1-yl, o-tolyl, 4-bromophenyl, naphth-2-yl, 4-methoxycarbonylphenyl, 2-(trifluoromethyl)benzyl, hexane-2-yl, 2-methoxyethyl, cyclopentylmethyl, cyclohexyl, pyridin-3-ylmethyl, 4-carboxyphenyl, 3-aminophenyl, pyridin-3-yl, thiophen-2-yl, 4-hydroxyphenyl, 4-(1-aminocyclopropyl)benzyl , 4-(1-aminocyclopropyl)phenyl, 2-methylbenzyl, 4-nitrobenzyl, 4-chlorobenzyl, phenethyl, 4-bromobenzyl, 4-cyanobenzyl, 3-nitrobenzyl, 4-tert-butylbenzyl, 2-nitrobenzyl, 4-nitrophenethyl, 2-chloro-3-methoxycarbonylphenyl, 2-aminophenyl, [1,1′-biphenyl]-4-yl, 4′-amino-[1,1′-biphenyl]-4-yl, 4-fluorobenzyl, 3-(trifluoromethyl)benzyl, 3-(trifluoromethoxy)benzyl, 3,4-dichlorobenzyl, 2-cyanobenzyl, 3-chlorobenzyl, 4-amino-2-ethylphenyl, 4-amino-3-(trifluoromethoxy)phenyl, 4-amino-2,3-dimethylphenyl, 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl, 4-amino-3-methylphenyl, 4-amino-3-fluorophenyl, 4-amino-3-ethylphenyl, and 4-amino-3-(trifluoromethyl)phenyl; and

[0565] R 3 Selected from: 1H-indol-3-yl, 4-aminophenyl, 4-hydroxyphenyl, 5-hydroxypyridin-2-yl, cyclohexyl and phenyl.

[0566] The prerequisite is that when R 1 is 2-methyl-1-(methylamino)propyl, and R 3 When it is phenyl, R 2 Not ethyl, isopropyl, n-butyl and phenyl.

[0567] Also provided are compounds of the formula In:

[0568]

[0569] and pharmaceutically acceptable salts thereof, wherein:

[0570] R 1Selected from: 1-(dimethylamino)-2-methylpropyl, 2-methyl-1-(methylamino)propyl, 1-aminocyclopentyl, 1-aminocyclopropyl, 4-aminophenyl, 2-aminopropyl-2-yl, 1-aminocyclohexyl, 3-aminooxetan-3-yl, 2-(methylamino)propyl-2-yl, 1-amino-2-methylpropyl-2-yl, 2-methylpyrrolidin-2-yl, 2-amino-3-methylbutyl-2-yl, 2-aminobutyl-2-yl -yl, 2-methyl-1-(methylamino)propan-2-yl, 1-methylpiperidin-2-yl, 3-fluoropyrrolidin-3-yl, 1,2-dimethylpyrrolidin-2-yl, 2-(dimethylamino)propan-2-yl), 2-methyl-1-(methylamino)-2-phenylpropyl, 1-isopropylpiperidin-2-yl, 2-azabicyclo[2.2.1]heptan-3-yl, and 2-methyl-2-azabicyclo[2.2.1]heptan-3-yl; and

[0571] R 2 Selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, benzyl, 3-mercaptopropyl, 2-mercaptoethyl, 4-(mercaptomethyl)phenyl, p-tolyl, 2,4,6-trimethylphenyl, 4-(trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl, 4-chlorophenyl, 3-cyanophenyl, 2-nitrophenyl, 4-methoxy-2-nitrophenyl, 4-aminocarbonyl -2-nitrophenyl, 4-methoxyphenyl, phenyl, 2-fluorobenzyl, piperidin-1-yl, o-tolyl, 4-bromophenyl, naphth-2-yl, 4-methoxycarbonylphenyl, 2-(trifluoromethyl)benzyl, hexane-2-yl, 2-methoxyethyl, cyclopentylmethyl, cyclohexyl, pyridin-3-ylmethyl, 4-carboxyphenyl, 3-aminophenyl, pyridin-3-yl, thiophen-2-yl, 4-hydroxyphenyl, 4-(1-aminocyclopropyl)benzyl, 4-(1 4-aminocyclopropyl)phenyl, 2-methylbenzyl, 4-nitrobenzyl, 4-chlorobenzyl, phenethyl, 4-bromobenzyl, 4-cyanobenzyl, 3-nitrobenzyl, 4-tert-butylbenzyl, 2-nitrobenzyl, 4-nitrophenethyl, 2-chloro-3-methoxycarbonylphenyl, 2-aminophenyl, [1,1′-biphenyl]-4-yl, 4′-amino-[1,1′-biphenyl]-4-yl, 4-fluorobenzyl, 3-(trifluoromethyl)benzyl, 3-(trifluoromethoxy)benzyl, phenyl, 4-amino-3-(trifluoromethoxy)phenyl, 4-amino-2,3-dimethylphenyl, 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl, 4-amino-3-methylphenyl, 4-amino-3-fluorophenyl, 4-amino-3-ethylphenyl, 4-amino-3-(trifluoromethyl)phenyl, and 4-(methoxycarbonyl)phenyl; and

[0572] R3 Selected from: 1H-indol-3-yl, 4-aminophenyl, 4-hydroxyphenyl, 5-hydroxypyridin-2-yl, cyclohexyl and phenyl.

[0573] The prerequisite is that when R 1 is 2-methyl-1-(methylamino)propyl, and R 3 When it is phenyl, R 2 Not ethyl, isopropyl, n-butyl and phenyl.

[0574] Also provided are compounds of formula VI:

[0575]

[0576] and pharmaceutically acceptable salts thereof, wherein:

[0577] R 6 is selected from the group consisting of amino-C1-C6 alkyl, amino-aryl, chloro-C3-C7 cycloalkyl, amino-heterocyclyl and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of aryl, aryl-C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkylthio, carboxyl, carboxamide, C3-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, guanidino, halo, C1-C6 haloacyl, C1-C6 haloalkyl, heterocyclyl, heterocyclyl-C1-C6 alkyl, hydroxyl and thio; or

[0578] R 6 R e R f NCH(R g )-;

[0579] R e Selected from: H and C1-C6 alkyl;

[0580] R f is a C1-C6 alkyl group; and

[0581] R g R h -C(CH3)2-; and

[0582] R h is selected from the group consisting of: H, aryl, C3-C7 cycloalkyl and heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: C1-C4 acylthio, C2-C4 alkenyl, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkoxy, amino, amino-C1-C4 alkyl, halo, C1-C4 haloalkyl, hydroxy, hydroxy-C1-C4 alkyl and thio, wherein C2-C4 alkenyl, C1-C4 alkylamino and C1-C4 alkoxy are further optionally substituted with one substituent selected from the group consisting of: C1-C4 alkylaryl, hydroxy and thio; or

[0583] R e and R f together with the atoms to which they are respectively bonded, form a heterocyclyldiyl;

[0584] R 7 is a C2-C4 alkyl group optionally substituted by a C1-C6 alkylthio group;

[0585] R 8 is a C2-C4 alkyl group optionally substituted by a C1-C6 alkylthio group;

[0586] R 9 Selected from: H and C1-C3 alkyl;

[0587] R 10 Selected from: C1-C6 alkyl, aryl, aryl-C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl and heterocyclyl, each optionally substituted with one or more substituents selected from: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloacyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio and thio-C1-C6 alkyl;

[0588] Y is -C(O)NHCH(CH2R 11 )-, or Y does not exist; and

[0589] R 11 is selected from the group consisting of aryl, heteroaryl and C3-C7 cycloalkyl, each optionally substituted with one substituent selected from the group consisting of amino and hydroxy.

[0590] Also provided are compounds of formula VI:

[0591]

[0592] and pharmaceutically acceptable salts thereof, wherein:

[0593] R 6Selected from: 1-(dimethylamino)-2-methylpropyl, 2-methyl-1-(methylamino)propyl, 1-aminocyclopentyl, 1-aminocyclopropyl, 4-aminophenyl, 2-aminopropyl-2-yl, 1-aminocyclohexyl, 3-aminooxetan-3-yl, 2-(methylamino)propyl-2-yl, 1-amino-2-methylpropyl-2-yl, 2-methylpyrrolidin-2-yl, 2-amino-3-methylbutyl-2-yl, 2-aminobutyl- 2-yl, 2-methyl-1-(methylamino)propan-2-yl, 1-methylpiperidin-2-yl, 3-fluoropyrrolidin-3-yl, 1,2-dimethylpyrrolidin-2-yl, 2-(dimethylamino)propan-2-yl), 2-methyl-1-(methylamino)-2-phenylpropyl, 1-isopropylpiperidin-2-yl, 2-azabicyclo[2.2.1]heptan-3-yl and 2-methyl-2-azabicyclo[2.2.1]heptan-3-yl;

[0594] R 7 Selected from: isopropyl, isobutyl, sec-butyl, tert-butyl and 2-(methylthio)ethyl;

[0595] R 8 Selected from: isopropyl, isobutyl, sec-butyl and 2-(methylthio)ethyl;

[0596] R 9 Selected from: methyl, ethyl and n-propyl;

[0597] R 10Selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, benzyl, 3-mercaptopropyl, 2-mercaptoethyl, 4-(mercaptomethyl)phenyl, p-tolyl, 2,4,6-trimethylphenyl, 4-(trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl, 4-chlorophenyl, 3-cyanophenyl, 2-nitrophenyl, 4-methoxy-2-nitrophenyl, 4-aminocarbonyl phenyl, 2-nitrophenyl, 4-methoxyphenyl, phenyl, 2-fluorobenzyl, piperidin-1-yl, o-tolyl, 4-bromophenyl, naphth-2-yl, 4-methoxycarbonylphenyl, 2-(trifluoromethyl)benzyl, hexane-2-yl, 2-methoxyethyl, cyclopentylmethyl, cyclohexyl, pyridin-3-ylmethyl, 4-carboxyphenyl, 3-aminophenyl, pyridin-3-yl, thiophen-2-yl, 4-hydroxyphenyl, 4-(1-aminocyclopropyl)benzyl, 4-( 1-aminocyclopropyl)phenyl, 2-methylbenzyl, 4-nitrobenzyl, 4-chlorobenzyl, phenethyl, 4-bromobenzyl, 4-cyanobenzyl, 3-nitrobenzyl, 4-tert-butylbenzyl, 2-nitrobenzyl, 4-nitrophenethyl, 2-chloro-3-methoxycarbonylphenyl, 2-aminophenyl, [1,1′-biphenyl]-4-yl, 4′-chloro-[1,1′-biphenyl]-4-yl, 4-fluorobenzyl, 3-(trifluoromethyl)benzyl, 3-(trifluoromethyl)benzyl, phenyl, 4-amino-3-(trifluoromethoxy)phenyl, 4-amino-2,3-dimethylphenyl, 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl, 4-amino-3-methylphenyl, 4-amino-3-fluorophenyl, 4-amino-3-ethylphenyl, 4-amino-3-(trifluoromethyl)phenyl, and 4-(methoxycarbonyl)phenyl;

[0598] Y is -C(O)NHCH(CH2R 11 )-, or Y does not exist; and

[0599] R 11 Selected from: 1H-indol-3-yl, 4-aminophenyl, 4-hydroxyphenyl, 5-hydroxypyridin-2-yl, cyclohexyl and phenyl.

[0600] Also provided are compounds of formula VII:

[0601]

[0602] and pharmaceutically acceptable salts thereof, wherein:

[0603] R 6is selected from the group consisting of amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heterocyclyl and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of aryl, aryl-C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkylthio, carboxyl, carboxamide, C3-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, guanidino, halo, C1-C6 haloacyl, C1-C6 haloalkyl, heterocyclyl, heterocyclyl-C1-C6 alkyl, hydroxyl and thio; or

[0604] R 6 R e R f NCH(R g )-;

[0605] R e Selected from: H and C1-C6 alkyl;

[0606] R f is a C1-C6 alkyl group; and

[0607] R g R h -C(CH3)2-; and

[0608] R h is selected from the group consisting of: H, aryl, C3-C7 cycloalkyl and heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: C1-C4 acylthio, C2-C4 alkenyl, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkoxy, amino, amino-C1-C4 alkyl, halo, C1-C4 haloalkyl, hydroxy, hydroxy-C1-C4 alkyl and thio, wherein C2-C4 alkenyl, C1-C4 alkylamino and C1-C4 alkoxy are further optionally substituted with one substituent selected from the group consisting of: C1-C4 alkylaryl, hydroxy and thio; or

[0609] R e and R f together with the atoms to which they are respectively bonded, form a heterocyclyldiyl;

[0610] R 7 is a C2-C4 alkyl group optionally substituted by a C1-C6 alkylthio group;

[0611] R 8 is a C2-C4 alkyl group optionally substituted by a C1-C6 alkylthio group;

[0612] R 9 Selected from: H and C1-C3 alkyl;

[0613] R 10Selected from: C1-C6 alkyl, aryl, aryl-C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl and heterocyclyl, each optionally substituted with one or more substituents selected from: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloacyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio and thio-C1-C6 alkyl;

[0614] Y is -C(O)NHCH(CH2R 11 )-, or Y does not exist; and

[0615] R 11 is selected from the group consisting of aryl, heteroaryl and C3-C7 cycloalkyl, each optionally substituted with one substituent selected from the group consisting of amino and hydroxy.

[0616] Also provided are compounds of formula VII:

[0617]

[0618] and pharmaceutically acceptable salts thereof, wherein:

[0619] R 6 Selected from: 1-(dimethylamino)-2-methylpropyl, 2-methyl-1-(methylamino)propyl, 1-aminocyclopentyl, 1-aminocyclopropyl, 4-aminophenyl, 2-aminopropyl-2-yl, 1-aminocyclohexyl, 3-aminooxetan-3-yl, 2-(methylamino)propyl-2-yl, 1-amino-2-methylpropyl-2-yl, 2-methylpyrrolidin-2-yl, 2-chloro-3-methylbutyl-2-yl, 2-aminobutyl- 2-yl, 2-methyl-1-(methylamino)propan-2-yl, 1-methylpiperidin-2-yl, 3-fluoropyrrolidin-3-yl, 1,2-dimethylpyrrolidin-2-yl, 2-(dimethylamino)propan-2-yl), 2-methyl-1-(methylamino)-2-phenylpropyl, 1-isopropylpiperidin-2-yl, 2-azabicyclo[2.2.1]heptan-3-yl and 2-methyl-2-azabicyclo[2.2.1]heptan-3-yl;

[0620] R 7 Selected from: isopropyl, isobutyl, sec-butyl, tert-butyl and 2-(methylthio)ethyl;

[0621] R 8 Selected from: isopropyl, isobutyl, sec-butyl and 2-(methylthio)ethyl;

[0622] R9 Selected from: methyl, ethyl and n-propyl;

[0623] R 10 Selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, benzyl, 3-mercaptopropyl, 2-mercaptoethyl, 4-(mercaptomethyl)phenyl, p-tolyl, 2,4,6-trimethylphenyl, 4-(trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl, 4-chlorophenyl, 3-cyanophenyl, 2-nitrophenyl, 4-methoxy-2-nitrophenyl, 4-aminocarbonyl phenyl, 2-nitrophenyl, 4-methoxyphenyl, phenyl, 2-fluorobenzyl, piperidin-1-yl, o-tolyl, 4-bromophenyl, naphth-2-yl, 4-methoxycarbonylphenyl, 2-(trifluoromethyl)benzyl, hexane-2-yl, 2-methoxyethyl, cyclopentylmethyl, cyclohexyl, pyridin-3-ylmethyl, 4-carboxyphenyl, 3-aminophenyl, pyridin-3-yl, thiophen-2-yl, 4-hydroxyphenyl, 4-(1-aminocyclopropyl)benzyl, 4-( 1-aminocyclopropyl)phenyl, 2-methylbenzyl, 4-nitrobenzyl, 4-chlorobenzyl, phenethyl, 4-bromobenzyl, 4-cyanobenzyl, 3-nitrobenzyl, 4-tert-butylbenzyl, 2-nitrobenzyl, 4-nitrophenethyl, 2-chloro-3-methoxycarbonylphenyl, 2-aminophenyl, [1,1′-biphenyl]-4-yl, 4′-amino-[1,1′-biphenyl]-4-yl, 4-fluorobenzyl, 3-(trifluoromethyl)benzyl, 3-(trifluoromethyl)benzyl, phenyl, 4-amino-3-(trifluoromethoxy)phenyl, 4-amino-2,3-dimethylphenyl, 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl, 4-amino-3-methylphenyl, 4-amino-3-fluorophenyl, 4-amino-3-ethylphenyl, 4-amino-3-(trifluoromethyl)phenyl, and 4-(methoxycarbonyl)phenyl;

[0624] Y is -C(O)NHCH(CH2R 11 )-, or Y does not exist; and

[0625] R 11 Selected from: 1H-indol-3-yl, 4-aminophenyl, 4-hydroxyphenyl, 5-hydroxypyridin-2-yl, cyclohexyl and phenyl.

[0626] Also provided are compounds of formula VIII:

[0627]

[0628] and pharmaceutically acceptable salts thereof, wherein:

[0629] R 12is selected from the group consisting of amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heterocyclyl and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of aryl, aryl-C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkylthio, carboxyl, carboxamide, C3-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, guanidino, halo, C1-C6 haloacyl, C1-C6 haloalkyl, heterocyclyl, heterocyclyl-C1-C6 alkyl, hydroxyl and thio; or

[0630] R 12 R i R j NCH(R k )-;

[0631] R i Selected from: H and C1-C6 alkyl;

[0632] R j is a C1-C6 alkyl group; and

[0633] R k R m -C(CH3)2-; and

[0634] R m is selected from the group consisting of: H, aryl, C3-C7 cycloalkyl and heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: C1-C4 acylthio, C2-C4 alkenyl, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkoxy, amino, amino-C1-C4 alkyl, halo, C1-C4 haloalkyl, hydroxy, hydroxy-C1-C4 alkyl and thio, wherein C2-C4 alkenyl, C1-C4 alkylamino and C1-C4 alkoxy are further optionally substituted with one substituent selected from the group consisting of: C1-C4 alkylaryl, hydroxy and thio; or

[0635] R i and R j together with the atoms to which they are respectively bonded, form a heterocyclyldiyl;

[0636] R 13 is a C2-C4 alkyl group optionally substituted by a C1-C6 alkylthio group;

[0637] R 14 is a C2-C4 alkyl group optionally substituted by a C1-C6 alkylthio group;

[0638] R 15selected from the group consisting of: C2-C6 alkyl, aryl, aryl-C1-C6 alkyl, C4-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloacyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio, and thio-C1-C6 alkyl;

[0639] Z is -C(O)NHCH(CH2R 16 )-, or Z does not exist; and

[0640] R 16 is selected from the group consisting of: aryl, heteroaryl, and C3-C7 cycloalkyl, each optionally substituted with a substituent selected from amino and hydroxy;

[0641] The prerequisite is that when R 12 is 2-methyl-1-(methylamino)propyl, R 13 is isopropyl, and R 14 When it is sec-butyl and Z is -C(O)NHCH(CH2Ph)-, R 15 Not ethyl, isopropyl, n-butyl and phenyl.

[0642] Also provided are compounds of formula VIII:

[0643]

[0644] and pharmaceutically acceptable salts thereof, wherein:

[0645] R 12 Selected from: 1-(dimethylamino)-2-methylpropyl, 2-methyl-1-(methylamino)propyl, 1-aminocyclopentyl, 1-aminocyclopropyl, 4-aminophenyl, 2-aminopropyl-2-yl, 1-aminocyclohexyl, 3-aminooxetan-3-yl, 2-(methylamino)propyl-2-yl, 1-amino-2-methylpropyl-2-yl, 2-methylpyrrolidin-2-yl, 2-amino-3-methylbutyl-2-yl, 2-aminobutyl- 2-yl, 2-methyl-1-(methylamino)propan-2-yl, 1-methylpiperidin-2-yl, 3-fluoropyrrolidin-3-yl, 1,2-dimethylpyrrolidin-2-yl, 2-(dimethylamino)propan-2-yl), 2-methyl-1-(methylamino)-2-phenylpropyl, 1-isopropylpiperidin-2-yl, 2-azabicyclo[2.2.1]heptan-3-yl and 2-methyl-2-azabicyclo[2.2.1]heptan-3-yl;

[0646] R 13 Selected from: isopropyl, isobutyl, sec-butyl, tert-butyl and 2-(methylthio)ethyl;

[0647] R 14 Selected from: isopropyl, isobutyl, sec-butyl and 2-(methylthio)ethyl;

[0648] R 15 Selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, benzyl, 3-mercaptopropyl, 2-mercaptoethyl, 4-(mercaptomethyl)phenyl, p-tolyl, 2,4,6-trimethylphenyl, 4-(trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl, 4-chlorophenyl, 3-cyanophenyl, 2-nitrophenyl, 4-methoxy-2-nitrophenyl, 4-aminocarbonyl phenyl, 2-nitrophenyl, 4-methoxyphenyl, phenyl, 2-fluorobenzyl, piperidin-1-yl, o-tolyl, 4-bromophenyl, naphth-2-yl, 4-methoxycarbonylphenyl, 2-(trifluoromethyl)benzyl, hexane-2-yl, 2-methoxyethyl, cyclopentylmethyl, cyclohexyl, pyridin-3-ylmethyl, 4-carboxyphenyl, 3-aminophenyl, pyridin-3-yl, thiophen-2-yl, 4-hydroxyphenyl, 4-(1-aminocyclopropyl)benzyl, 4-( 1-aminocyclopropyl)phenyl, 2-methylbenzyl, 4-nitrobenzyl, 4-chlorobenzyl, phenethyl, 4-bromobenzyl, 4-cyanobenzyl, 3-nitrobenzyl, 4-tert-butylbenzyl, 2-nitrobenzyl, 4-nitrophenethyl, 2-chloro-3-methoxycarbonylphenyl, 2-aminophenyl, [1,1′-biphenyl]-4-yl, 4′-amino-[1,1′-biphenyl]-4-yl, 4-fluorobenzyl, 3-(trifluoromethyl)benzyl, 3-(trifluoromethyl)benzyl, phenyl, 4-amino-3-(trifluoromethoxy)phenyl, 4-amino-2,3-dimethylphenyl, 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl, 4-amino-3-methylphenyl, 4-amino-3-fluorophenyl, 4-amino-3-ethylphenyl, 4-amino-3-(trifluoromethyl)phenyl, and 4-(methoxycarbonyl)phenyl;

[0649] Z is -C(O)NHCH(CH2R 16 )-, or Z does not exist; and

[0650] R 16 Selected from: 1H-indol-3-yl, 4-aminophenyl, 4-hydroxyphenyl, 5-hydroxypyridin-2-yl, cyclohexyl and phenyl;

[0651] The prerequisite is that when R 12 is 2-methyl-1-(methylamino)propyl, R13 is isopropyl, and R 14 When it is sec-butyl and Z is -C(O)NHCH(CH2Ph)-, R 15 Not ethyl, isopropyl, n-butyl and phenyl.

[0652] Also provided are compounds of formula VIIIa:

[0653]

[0654] and pharmaceutically acceptable salts thereof, wherein:

[0655] R 12 is selected from the group consisting of amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heterocyclyl and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of aryl, aryl-C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkylthio, carboxyl, carboxamide, C3-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, guanidino, halo, C1-C6 haloacyl, C1-C6 haloalkyl, heterocyclyl, heterocyclyl-C1-C6 alkyl, hydroxyl and thio; or

[0656] R 12 R i R j NCH(R k )-;

[0657] R i Selected from: H and C1-C6 alkyl;

[0658] R j is a C1-C6 alkyl group; and

[0659] R k R m -C(CH3)2-; and

[0660] R m is selected from the group consisting of: H, aryl, C3-C7 cycloalkyl and heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: C1-C4 acylthio, C2-C4 alkenyl, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkoxy, amino, amino-C1-C4 alkyl, halo, C1-C4 haloalkyl, hydroxy, hydroxy-C1-C4 alkyl and thio, wherein C2-C4 alkenyl, C1-C4 alkylamino and C1-C4 alkoxy are further optionally substituted with one substituent selected from the group consisting of: C1-C4 alkylaryl, hydroxy and thio; or

[0661] R i and R j together with the atoms to which they are respectively bonded, form a heterocyclyldiyl;

[0662] R 13 is a C2-C4 alkyl group optionally substituted by a C1-C6 alkylthio group;

[0663] R 14 is a C2-C4 alkyl group optionally substituted by a C1-C6 alkylthio group; and

[0664] R 15 Selected from: C1-C6 alkyl, aryl, aryl-C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl and heterocyclyl, each optionally substituted with one or more substituents selected from the following: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloacyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio and thio-C1-C6 alkyl.

[0665] Also provided are compounds of formula VIIIa:

[0666]

[0667] and pharmaceutically acceptable salts thereof, wherein:

[0668] R 12 Selected from: 1-(dimethylamino)-2-methylpropyl, 2-methyl-1-(methylamino)propyl, 1-aminocyclopentyl, 1-aminocyclopropyl, 4-aminophenyl, 2-aminopropyl-2-yl, 1-aminocyclohexyl, 3-aminooxetan-3-yl, 2-(methylamino)propyl-2-yl, 1-amino-2-methylpropyl-2-yl, 2-methylpyrrolidin-2-yl, 2-amino-3-methylbutyl-2-yl, 2-aminobutyl- 2-yl, 2-methyl-1-(methylamino)propan-2-yl, 1-methylpiperidin-2-yl, 3-fluoropyrrolidin-3-yl, 1,2-dimethylpyrrolidin-2-yl, 2-(dimethylamino)propan-2-yl), 2-methyl-1-(methylamino)-2-phenylpropyl, 1-isopropylpiperidin-2-yl, 2-azabicyclo[2.2.1]heptan-3-yl and 2-methyl-2-azabicyclo[2.2.1]heptan-3-yl;

[0669] R 13 Selected from: isopropyl, isobutyl, sec-butyl, tert-butyl and 2-(methylthio)ethyl;

[0670] R 14 is selected from the group consisting of isopropyl, isobutyl, sec-butyl and 2-(methylthio)ethyl; and

[0671] R 15 Selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, benzyl, 3-mercaptopropyl, 2-mercaptoethyl, 4-(mercaptomethyl)phenyl, p-tolyl, 2,4,6-trimethylphenyl, 4-(trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl, 4-chlorophenyl, 3-cyanophenyl, 2-nitrophenyl, 4-methoxy-2-nitrophenyl, 4-aminocarbonyl phenyl, 2-nitrophenyl, 4-methoxyphenyl, phenyl, 2-fluorobenzyl, piperidin-1-yl, o-tolyl, 4-bromophenyl, naphth-2-yl, 4-methoxycarbonylphenyl, 2-(trifluoromethyl)benzyl, hexane-2-yl, 2-methoxyethyl, cyclopentylmethyl, cyclohexyl, pyridin-3-ylmethyl, 4-carboxyphenyl, 3-aminophenyl, pyridin-3-yl, thiophen-2-yl, 4-hydroxyphenyl, 4-(1-aminocyclopropyl)benzyl, 4-( 1-aminocyclopropyl)phenyl, 2-methylbenzyl, 4-nitrobenzyl, 4-chlorobenzyl, phenethyl, 4-bromobenzyl, 4-cyanobenzyl, 3-nitrobenzyl, 4-tert-butylbenzyl, 2-nitrobenzyl, 4-nitrophenethyl, 2-chloro-3-methoxycarbonylphenyl, 2-aminophenyl, [1,1′-biphenyl]-4-yl, 4′-amino-[1,1′-biphenyl]-4-yl, 4-fluorobenzyl, 3-(trifluoromethyl)benzyl, 3-(trifluoromethyl)benzyl, phenyl, 4-amino-3-(trifluoromethoxy)phenyl, 4-amino-2,3-dimethylphenyl, 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl, 4-amino-3-methylphenyl, 4-amino-3-fluorophenyl, 4-amino-3-ethylphenyl, 4-amino-3-(trifluoromethyl)phenyl and 4-(methoxycarbonyl)phenyl.

[0672] Also provided are compounds of formula VIIIb:

[0673]

[0674] and pharmaceutically acceptable salts thereof, wherein:

[0675] R 12 is selected from the group consisting of amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heterocyclyl and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of aryl, aryl-C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkylthio, carboxyl, carboxamide, C3-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, guanidino, halo, C1-C6 haloacyl, C1-C6 haloalkyl, heterocyclyl, heterocyclyl-C1-C6 alkyl, hydroxyl and thio; or

[0676] R 12 R i R j NCH(R k )-;

[0677] R i Selected from: H and C1-C6 alkyl;

[0678] R j is a C1-C6 alkyl group; and

[0679] R k R m -C(CH3)2-; and

[0680] R m is selected from the group consisting of: H, aryl, C3-C7 cycloalkyl and heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: C1-C4 acylthio, C2-C4 alkenyl, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkoxy, amino, amino-C1-C4 alkyl, halo, C1-C4 haloalkyl, hydroxy, hydroxy-C1-C4 alkyl and thio, wherein C2-C4 alkenyl, C1-C4 alkylamino and C1-C4 alkoxy are further optionally substituted with one substituent selected from the group consisting of: C1-C4 alkylaryl, hydroxy and thio; or

[0681] R i and R j together with the atoms to which they are respectively bonded, form a heterocyclyldiyl;

[0682] R 13 is a C2-C4 alkyl group optionally substituted by a C1-C6 alkylthio group;

[0683] R 14 is a C2-C4 alkyl group optionally substituted by a C1-C6 alkylthio group;

[0684] R 15 is selected from the group consisting of: C2-C6 alkyl, aryl, aryl-C1-C6 alkyl, C4-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloacyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio, and thio-C1-C6 alkyl; and

[0685] R 16is selected from the group consisting of: aryl, heteroaryl, and C3-C7 cycloalkyl, each optionally substituted with a substituent selected from amino and hydroxy;

[0686] The prerequisite is that when R 12 is 2-methyl-1-(methylamino)propyl, R 13 is isopropyl, and R 14 is sec-butyl, and R 16 When it is phenyl, R 15 Not ethyl, isopropyl, n-butyl and phenyl.

[0687] Also provided are compounds of formula VIIIb:

[0688]

[0689] and pharmaceutically acceptable salts thereof, wherein:

[0690] R 12 Selected from: 1-(dimethylamino)-2-methylpropyl, 2-methyl-1-(methylamino)propyl, 1-aminocyclopentyl, 1-aminocyclopropyl, 4-aminophenyl, 2-aminopropyl-2-yl, 1-aminocyclohexyl, 3-aminooxetan-3-yl, 2-(methylamino)propyl-2-yl, 1-amino-2-methylpropyl-2-yl, 2-methylpyrrolidin-2-yl, 2-amino-3-methylbutyl-2-yl, 2-aminobutyl- 2-yl, 2-methyl-1-(methylamino)propan-2-yl, 1-methylpiperidin-2-yl, 3-fluoropyrrolidin-3-yl, 1,2-dimethylpyrrolidin-2-yl, 2-(dimethylamino)propan-2-yl), 2-methyl-1-(methylamino)-2-phenylpropyl, 1-isopropylpiperidin-2-yl, 2-azabicyclo[2.2.1]heptan-3-yl and 2-methyl-2-azabicyclo[2.2.1]heptan-3-yl;

[0691] R 13 Selected from: isopropyl, isobutyl, sec-butyl, tert-butyl and 2-(methylthio)ethyl;

[0692] R 14 Selected from: isopropyl, isobutyl, sec-butyl and 2-(methylthio)ethyl;

[0693] R 15Selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, benzyl, 3-mercaptopropyl, 2-mercaptoethyl, 4-(mercaptomethyl)phenyl, p-tolyl, 2,4,6-trimethylphenyl, 4-(trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl, 4-chlorophenyl, 3-cyanophenyl, 2-nitrophenyl, 4-methoxy-2-nitrophenyl, 4-aminocarbonyl -2-nitrophenyl, 4-methoxyphenyl, phenyl, 2-fluorobenzyl, piperidin-1-yl, o-tolyl, 4-bromophenyl, naphth-2-yl, 4-methoxycarbonylphenyl, 2-(trifluoromethyl)benzyl, hexane-2-yl, 2-methoxyethyl, cyclopentylmethyl, cyclohexyl, pyridin-3-ylmethyl, 4-carboxyphenyl, 3-aminophenyl, pyridin-3-yl, thiophen-2-yl, 4-hydroxyphenyl, 4-(1-aminocyclopropyl)benzyl, 4-(1 4-aminocyclopropyl)phenyl, 2-methylbenzyl, 4-nitrobenzyl, 4-chlorobenzyl, phenethyl, 4-bromobenzyl, 4-cyanobenzyl, 3-nitrobenzyl, 4-tert-butylbenzyl, 2-nitrobenzyl, 4-nitrophenethyl, 2-chloro-3-methoxycarbonylphenyl, 2-aminophenyl, [1,1′-biphenyl]-4-yl, 4′-amino-[1,1′-biphenyl]-4-yl, 4-fluorobenzyl, 3-(trifluoromethyl)benzyl, 3-(trifluoromethoxy)benzyl, phenyl, 4-amino-3-(trifluoromethoxy)phenyl, 4-amino-2,3-dimethylphenyl, 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl, 4-amino-3-methylphenyl, 4-amino-3-fluorophenyl, 4-amino-3-ethylphenyl, 4-amino-3-(trifluoromethyl)phenyl, and 4-(methoxycarbonyl)phenyl; and

[0694] R 16 Selected from: 1H-indol-3-yl, 4-aminophenyl, 4-hydroxyphenyl, 5-hydroxypyridin-2-yl, cyclohexyl and phenyl;

[0695] The prerequisite is that when R 12 is 2-methyl-1-(methylamino)propyl, R 13 is isopropyl, and R 14 is sec-butyl, and R 16 When it is phenyl, R 15 Not ethyl, isopropyl, n-butyl and phenyl.

[0696] Some embodiments of the present invention include every combination of one or more compounds selected from the following groups shown in Table A.

[0697] Some embodiments of the present invention include every combination of one or more compounds selected from the following groups shown in Table B.

[0698] Some embodiments of the present invention include every combination of one or more compounds selected from the following groups shown in Table C.

[0699] Table A

[0700]

[0701]

[0702]

[0703]

[0704] Table B

[0705]

[0706]

[0707]

[0708]

[0709]

[0710]

[0711]

[0712]

[0713] Table C

[0714]

[0715]

[0716]

[0717] In addition, the individual compounds and chemical species of the present invention, such as those compounds found in Table A, Table B and Table C (including diastereomers and enantiomers thereof) encompass all pharmaceutically acceptable salts. The compounds of Formula I can be prepared according to the relevant published literature methods used by those skilled in the art. Exemplary reagents and methods for these reactions are shown in the following working examples. In one embodiment, the present invention provides a method for making the compounds described herein.

[0718] Conjugates containing novel compounds

[0719] The compounds described herein can be used to form conjugates, such as antibody-drug conjugates (ADCs). Therefore, in one embodiment of the present disclosure, there is provided a conjugate composition of Formula II:

[0720] (T)-(L)-(D)

[0721] II

[0722] wherein (T) is a targeting moiety, (L) is an optional linker, and (D) is a compound of Formula I. In one embodiment, (T) is an antibody. Thus, in one embodiment, the antibody-drug conjugate (ADC) comprises a compound (D) of Formula I.

[0723] As will be appreciated by the skilled artisan, a wide variety of means can be used to covalently link (T)-(L)-(D). Any known method can be used to link the conjugate components. Any known linker technology can be used to link (T) to (D). Furthermore, (T), (L), and (D) can be modified in any suitable manner as will be appreciated by the skilled artisan to facilitate conjugate formation.

[0724] Targeting moiety (T)

[0725] The targeting moiety (T) of the compositions of the present invention includes within its scope any unit of (T) that binds to, reactively associates with, or complexes with a receptor, antigen, or other receptive moiety associated with a given target cell population. (T) is a molecule that binds to, complexes with, or reacts with a portion of the cell population to which it is sought to be targeted. In one aspect, (T) is used to deliver a drug (D) to a specific target cell population that reacts with (T). Such (T) includes, but is not limited to, large molecular weight proteins such as, for example, full-length antibodies, antibody fragments, smaller molecular weight proteins, polypeptides or peptides, lectins, glycoproteins, non-peptides, vitamins, nutrient transport molecules (such as, but not limited to, transferrin), or any other cell-binding molecule or substance.

[0726] (T) can form a bond with the Linker unit (L) or the Drug (D). (T) can form a bond with the (L) unit via a heteroatom of (T). Heteroatoms that may be present on (T) include sulfur (in one embodiment, a thiol group from (T)), oxygen (in one embodiment, a carbonyl group, a carboxyl group, or a hydroxyl group from (T)), and nitrogen (in one embodiment, a primary or secondary amino group from (T)). These heteroatoms may be present in (T) in its natural state, such as in naturally occurring antibodies, or may be introduced into (T) via chemical modification.

[0727] In one embodiment, (T) has a sulfhydryl group and (T) is bonded to (L) via the sulfur atom of the sulfhydryl group. In another embodiment, (T) has one or more lysine residues that can be chemically modified to introduce one or more sulfhydryl groups. (T) is bonded to the (L) unit via the sulfhydryl group. Reagents that can be used to modify lysine include, but are not limited to, N-succinimidyl S-acetylthioacetate (SATA) and 2-iminothiolane hydrochloride (Traut's reagent).

[0728] In another embodiment, (L) may have one or more glycosyl groups that can be chemically modified to have one or more sulfhydryl groups. (T) is bonded to (L) via the sulfur atom of the sulfhydryl group. In yet another embodiment, (T) may have one or more glycosyl groups that can be oxidized to provide an aldehyde (-CHO) group (see, e.g., Laguzza et al., 1989, J. Med. Chem. 32(3): 548-55). The corresponding aldehyde can form a bond with a reactive site on a portion of (L). Reactive sites that can react with a carbonyl group on (T) include, but are not limited to, hydrazine and hydroxylamine. Other protocols for modifying proteins for attachment or association of (D) are described in Coligan et al., Current Protocols in Protein Science, Vol. 2, John Wiley & Sons (2002), which is incorporated herein by reference.

[0729] (T) may include, for example, proteins, polypeptides, or peptides, including but not limited to transferrin, epidermal growth factor ("EGF"), bombesin, gastrin, gastrin-releasing peptide, platelet-derived growth factor, IL-2, IL-6, transforming growth factor ("TGF") such as TGF-α or TGF-β, vaccinia growth factor ("VGF"), insulin and insulin-like growth factors I and II, lectins, and apoproteins from low-density lipoprotein.

[0730] (T) may also include antibodies, such as polyclonal antibodies or monoclonal antibodies. Antibodies may be directed against specific antigenic determinants, including, for example, cancer cell antigens, viral antigens, microbial antigens, proteins, peptides, sugars, chemicals, nucleic acids, or fragments thereof. Methods for producing polyclonal antibodies are known in the art. Monoclonal antibodies (mAbs) directed against target antigens can be prepared using any technology known in the art. These technologies include, but are not limited to, the hybridoma technology initially described by Kohler and Milstein (1975, Nature 256, 495-497), human B cell hybridoma technology (Kozbor et al., 1983, Immunology Today 4: 72) and EBV-hybridoma technology (Cole et al., 1985, Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96). Selected lymphocyte antibody method (SLAM) (Babcook, JS et al., A novel strategy for generating monoclonal antibodies from single, isolated lymphocytes producing antibodies of defined specificities. Proc Natl Acad Sci USA, 1996. 93 (15): p. 7843-8) and (McLean GR, Olsen OA, Watt IN, Rathanaswami P, Leslie KB, Babcook JS, Schrader JW. Recognition of human cytomegalovirus by human primary immunoglobulins identifies an innate foundation to an adaptive immune response. J Immunol. 2005 Apr 15; 174 (8): 4768-78. Such antibodies can be any of the immunoglobulin classes, including IgG, IgM, IgE, IgA and IgD and any subclass thereof. Hybridomas producing mAbs used in the present invention can be cultured in vitro or in vivo.

[0731] Monoclonal antibodies can be, for example, human monoclonal antibodies, humanized monoclonal antibodies, antibody fragments, or chimeric antibodies (e.g., human-mouse antibodies). Human monoclonal antibodies can be made by any of a number of techniques known in the art (e.g., Teng et al., 1983, Proc. Natl. Acad. Sci. USA 80:7308-7312; Kozbor et al., 1983, Immunology Today 4:72-79; and Olsson et al., 1982, Meth. Enzymol. 92:3-16). See also Huse et al., 1989, Science 246:1275-1281 and McLean et al. J Immunol. 2005 Apr 15; 174(8):4768-78.

[0732] Antibodies can also be bispecific antibodies. Methods for making bispecific antibodies are known in the art. Traditional production of full-length bispecific antibodies is based on the co-expression of two immunoglobulin heavy chain-light chain pairs, where the two chains have different specificities (see, e.g., Milstein et al., 1983, Nature 305:537-539; International Publication No. WO 93 / 08829; Traunecker et al., 1991, EMBO J. 10:3655-3659).

[0733] According to a different approach, antibody variable domains with the desired binding specificities (antibody-antigen combining sites) are fused to immunoglobulin constant domain sequences. The fusion is preferably carried out with a ligand comprising a hinge, C H2 and C H3 In some embodiments, the present invention relates to a method for producing an immunoglobulin heavy chain fusion product comprising: first heavy chain constant region (CH1) containing at least a portion of the immunoglobulin heavy chain constant domain of the first heavy chain constant region (CH2) containing the site necessary for light chain binding, present in at least one of the fusions. A nucleic acid having a sequence encoding the immunoglobulin heavy chain fusion product and (if necessary) the immunoglobulin light chain is inserted into a separate expression vector and co-transfected into a suitable host organism. This provides flexibility in regulating the mutual ratio of the three polypeptide fragments in an embodiment when the three polypeptide chains of unequal ratios used in the construction provide the best yield. However, it is possible that the coding sequences of two or all three polypeptide chains are inserted into one expression vector when the expression of at least two polypeptide chains of equal ratios results in high yield or when the ratio is not particularly important.

[0734] For example, a bispecific antibody can have a hybrid immunoglobulin heavy chain with a first binding specificity on one arm and a hybrid immunoglobulin heavy chain-light chain pair (providing a second binding specificity) on the other arm. This asymmetric structure facilitates the separation of the desired bispecific compound from the binding of unwanted immunoglobulin chains, as the presence of the immunoglobulin light chain in only half of the bispecific molecule provides a convenient means of separation (International Publication No. WO 94 / 04690), which is incorporated herein by reference in its entirety.

[0735] For further details on the generation of bispecific antibodies, see, for example, Suresh et al., 1986, Methods in Enzymology 121:210; Rodrigues et al., 1993, J. Immunology 151:6954-6961; Carter et al., 1992, Bio / Technology 10:163-167; Carter et al., 1995, J. Hematotherapy 4:463-470; Merchant et al., 1998, Nature Biotechnology 16:677-681. Using such techniques, bispecific antibodies can be prepared for use in treating or preventing diseases as defined herein.

[0736] Bifunctional antibodies are also described in European Patent Publication No. EPA 0 105 360. As disclosed in this reference, hybrid or bifunctional antibodies can be obtained biologically, i.e., by cell fusion techniques, or chemically, in particular with cross-linking agents or disulfide bridge-forming reagents, and can comprise whole antibodies or fragments thereof. Methods for obtaining such hybrid antibodies are disclosed, for example, in International Publication No. WO 83 / 03679 and European Patent Publication No. EPA 0 217 577, both of which are incorporated herein by reference.

[0737] The antibody may also be a functionally active fragment, derivative or analog of an antibody that immunospecifically binds to a target antigen (e.g., a cancer antigen, a viral antigen, a microbial antigen, or other antibody that binds to a cell or matrix). In this context, "functional activity" means that the fragment, derivative or analog is capable of recognizing the same antigen as the antigen recognized by the antibody from which the fragment, derivative or analog is derived. Specifically, in exemplary embodiments, the antigenicity of the idiotype of an immunoglobulin molecule can be enhanced by deleting framework and CDR sequences C-terminal to the CDR sequences that specifically recognize the antigen. To determine which CDR sequence binds the antigen, synthetic peptides containing the CDR sequences can be used in a binding assay to the antigen by any binding assay known in the art (e.g., a BIA core assay) (see, e.g., Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th ed., National Institute of Health, Bethesda, Md.; Kabat et al., 1980, J. Immunology 125(3):961-969).

[0738] Other useful antibodies include fragments of antibodies, such as, but not limited to, F(ab')2 fragments, Fab fragments, Fab', Fv fragments, and antibody heavy and light chain dimers or any minimal fragment thereof, such as Fvs or single-chain antibodies (SCAs) (e.g., as described in U.S. Pat. No. 4,946,778; Bird, 1988, Science 242:423-42; Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883; and Ward et al., 1989, Nature 334:544-54).

[0739] Recombinant antibodies, such as chimeric and humanized monoclonal antibodies, comprising human and non-human portions, can also be used. (See, e.g., U.S. Patent No. 4,816,567; and U.S. Patent No. 4,816,397.) Humanized antibodies are antibody molecules from non-human species that have one or more complementarity determining regions (CDRs) from the non-human species and framework regions from a human immunoglobulin molecule. (See, e.g., U.S. Patent No. 5,585,089.) Chimeric and humanized monoclonal antibodies can be produced by recombinant DNA techniques known in the art, for example, using the methods described in International Publication No. WO 87 / 02671; European Patent Publication No. 0 184 187; European Patent Publication No. 0 171 496; European Patent Publication No. 0 173 494; International Publication No. WO 86 / 01533; U.S. Patent No. 4,816,567; European Patent Publication No. 012023; Berter et al., 1988, Science 240:1041-1043; Liu et al., 1987, Proc. Natl. Acad. Sci. USA 84:3439-3443; Liu et al., 1987, J. Immunol. 139:3521-3526; Sun et al., 1987, Proc. Natl. Acad. Sci. USA 84:214-218; Nishimura et al., 1987, Cancer. Res. 47:999-1005; Wood et al., 1985, Nature 314:446-449; Shaw et al., 1988, J. Natl. Cancer Inst. 80:1553-1559; Morrison, 1985, Science 229:1202-1207; Oi et al., 1986, BioTechniques 4:214; U.S. Patent No. 5,225,539; Jones et al., 1986, Nature 321:552-525; Verhoeyan et al., 1988, Science 239:1534; and Beidler et al., 1988, J. Immunol. 141:4053-4060.

[0740] Completely human antibodies can be used. Human antibodies can be prepared, for example, using transgenic mice that cannot express endogenous immunoglobulin heavy and light chain genes, but can express human heavy and light chain genes. Transgenic mice are immunized with a selected antigen (e.g., all or part of a polypeptide) in a normal manner. Monoclonal antibodies against antigens can be obtained using conventional hybridoma technology. The human immunoglobulin transgenes carried by transgenic mice are rearranged during B cell differentiation and subsequently undergo class switching and somatic mutation. Therefore, it is possible to produce therapeutically useful IgG, IgA, IgM, and IgE antibodies using such technology. For a review of this technology for producing human antibodies, see Lonberg and Huszar (1995, Int. Rev. Immunol. 13: 65-93). For a detailed discussion of this technology for producing human antibodies and human monoclonal antibodies and protocols for producing such antibodies. See, e.g., U.S. Patent Nos. 5,625,126; 5,633,425; 5,569,825; 5,661,016; and 5,545,806.

[0741] Human antibodies that recognize selected epitopes can also be generated using a technique called "guided selection." In this method, a selected non-human monoclonal antibody, such as a mouse antibody, is used to guide the selection of a fully human antibody that recognizes the same epitope. (See, e.g., Jespers et al., 1994, Biotechnology 12: 899-903.) Human antibodies can also be produced using various techniques known in the art, including phage display libraries (see, e.g., Hoogenboom and Winter, 1991, J. Mol. Biol. 227: 381; Marks et al., 1991, J. Mol. Biol. 222: 581; Quan and Carter, 2002, "The rise of monoclonal antibodies as therapeutics," in Anti-IgE and Allergic Disease, Jardieu, PM and Fick Jr., RB, eds., Marcel Dekker, New York, NY, Chapter 20, pp. 427-469).

[0742] In other embodiments, the antibody is a fusion protein of an antibody or a functionally active fragment thereof. For example, the antibody can be fused to the amino acid sequence of another protein (or portion thereof, such as a portion of at least 10, 20, or 50 amino acids of a protein) that is not an antibody via a covalent bond (e.g., a peptide bond) at the N-terminus or C-terminus.

[0743] Antibodies also include analogs and derivatives that are modified, i.e., by covalent attachment of any type of molecule, as long as such covalent attachment allows the antibody to retain its antigen-binding immunospecificity. For example, but not limited to, derivatives and analogs of antibodies include those that have been further modified, for example, by glycosylation, acetylation, pegylation, phosphorylation, amidation, by derivatization with known protection / blocking groups, proteolytic cleavage, bonding to cellular antibody units or other proteins. Any of the numerous chemical modifications can be performed by known techniques, including but not limited to specific chemical cleavage, acetylation, formylation, metabolic synthesis in the presence of tunicamycin, etc. In addition, analogs or derivatives may contain one or more non-natural amino acids.

[0744] The antibodies may have modifications (e.g., substitutions, deletions, or additions) in amino acid residues that interact with Fc receptors. Specifically, the antibodies include those having modifications in amino acid residues identified as being involved in the interaction between the anti-Fc domain and the FcRn receptor (see, e.g., International Publication No. WO 97 / 34631, which is incorporated herein by reference in its entirety). Antibodies immunospecific for target antigens may be obtained commercially or from other sources or produced by any method known to those skilled in the art (e.g., such as chemical synthesis or recombinant expression techniques). Nucleotide sequences encoding antibodies immunospecific for cancer cell antigens may be obtained, for example, from the GenBank database or similar databases, literature publications, or by conventional cloning and sequencing.

[0745] Examples of antibodies that can be used to treat cancer include, but are not limited to, humanized anti-HER2 monoclonal antibodies, (trastuzumab; Genentech); (rituximab; Genentech), a chimeric anti-CD20 monoclonal antibody used to treat patients with non-Hodgkin's lymphoma; OvaRex (AltaRex Corporation, MA), a murine antibody used to treat ovarian cancer; Panorex (GlaxoWellcome, NC), a murine IgG2a antibody used to treat colorectal cancer; Erbitux (Imclone Systems Inc., NY), an anti-EGFR IgG chimeric antibody used to treat epidermal growth factor-positive cancers such as head and neck cancer; Vitaxin (Med Immune, Inc., MD), a humanized antibody used to treat sarcomas; Campath I / H (Leukosite, MA), a humanized IgG1 antibody used to treat chronic lymphocytic leukemia (CLL); SmartMI95 (Protein Design Labs, Inc., CA), a humanized anti-CD33 IgG antibody for the treatment of acute myeloid leukemia (AML); LymphoCide (Immunomedics, Inc., NJ), a humanized anti-CD22 IgG antibody for the treatment of non-Hodgkin's lymphoma; Smart ID10 (Protein Design Labs, Inc., CA), a humanized anti-HLA-DR antibody for the treatment of non-Hodgkin's lymphoma; Oncolym (Techniclone, Inc., CA), a radiolabeled murine anti-HLA-Dr10 antibody for the treatment of non-Hodgkin's lymphoma; Allomune (BioTransplant, CA), a humanized anti-CD2 mAb; Avastin (Genentech, Inc., CA), an anti-VEGF humanized antibody used to treat lung and colorectal cancer; Epratuzamab (Immunomedics, Inc., NJ and Amgen, CA), an anti-CD22 antibody used to treat non-Hodgkin's lymphoma; and CEAcide (Immunomedics, NJ), a humanized anti-CEA antibody used to treat colorectal cancer.

[0746] Other antibodies useful for treating cancer include, but are not limited to, antibodies to the following antigens (exemplary cancers are shown in parentheses): CA125 (ovarian cancer), CA15-3 (carcinoma), CA19-9 (carcinoma), L6 (carcinoma), Lewis Y (carcinoma), Lewis X (carcinoma), alpha-fetoprotein (carcinoma), CA242 (colorectal cancer), placental alkaline phosphatase (carcinoma), prostate-specific membrane antigen (prostate cancer), prostatic acid phosphatase (prostate cancer), epidermal growth factor (carcinoma), MAGE-1 (carcinoma), MAGE-2 (carcinoma), MAGE-3 (carcinoma), MAGE-4 (carcinoma), anti-transferrin receptor (carcinoma), p97 (melanoma), MUC1-KLH (breast cancer), CEA (colorectal cancer), gp100 (melanomas), melanoma), MART1 (melanoma), prostate-specific antigen (PSA) (prostate cancer), IL-2 receptor (T-cell leukemia and lymphoma), CD20 (non-Hodgkin's lymphoma), CD52 (leukemia), CD33 (leukemia), CD22 (lymphoma), human chorionic gonadotropin (carcinoma), CD38 (multiple myeloma), CD40 (lymphoma), mucin (carcinoma), P21 (carcinoma), MPG (melanoma), and Neu oncogene products (carcinoma). Some specific, useful antibodies include, but are not limited to, BR96 mAb (Trail et al., 1993, Science 261:212-215), BR64 (Trail et al., 1997, Cancer Research 57:100-105), mAbs to the CD40 antigen, such as S2C6 mAb (Francisco et al., 2000, Cancer Res. 60:3225-3231) and chimeric and humanized variants thereof, mAbs to the cD33 antigen; mAbs to the EphA2 antigen; mAbs to the CD70 antigen, such as 1F6 mAb and 2F2 mAb and chimeric and humanized variants thereof; and mAbs to the CD30 antigen, such as AC10 (Bowen et al., 1993, J. Immunol. 151:5896-5906; Wahl et al., 2002, Cancer Res. 151:5896-5906). Res. 62(13):3736-42) and chimeric and humanized variants thereof. Many other internalizing antibodies that bind to tumor-associated antigens are available and have been reviewed (see, e.g., Franke et al., 2000, Cancer Biother. Radiopharm. 15:459-76; Murray, 2000, Semin. Oncol. 27:64-70; Breitling et al., Recombinant Antibodies, John Wiley, and Sons, New York, 1998).

[0747] Antibodies can also be antibodies that are bound to antigens present on target cells or target cell groups. For example, compared with one or more normal cells (e.g., non-cancerous cells), transmembrane polypeptides and other markers can be specifically expressed on the surface of one or more specific types of target cells (e.g., cancer cells). Compared with those on the surface of normal cells, such markers are often expressed on the surface of target cells in greater quantities, or exhibit greater immunogenicity. The identification of such cell surface antigen polypeptides elicits the ability to specifically target cells for destruction via antibody-based therapy. Therefore, in some embodiments, antibodies include but are not limited to antibodies for tumor-associated antigens (TAA). Such tumor-associated antigens are known in the art, and can be prepared so as to be used to generate antibodies using methods and information well known in the art.

[0748] See also EP2552957, WO / 2012 / 116453, WO / 2012 / 032080. See also Zybody TM , http: / / www.zyngenia.com / science-technology / technology-approach.asp. See also human heavy chain-only antibody technology, http: / / www.crescendobi ologics.com / . See also WO2010001251, yeast-based human antibody yeast-based platform http: / / www.adimab.com / platform-overview, mAbLogix TM Platform http: / / www.dna.com / OurApproach / ComplementaryTechnologies / AntibodyDiscovery, Monoclonal Discovery Platform http: / / www.igenica.com / science.php, WO2009 / 157771, EP2560993, WO2013004842, WO2012166560.

[0749] In addition to antibodies, the targeting portion (T) of the composition of the present invention also includes within its scope any unit of (T) that binds to or reactively associates or complexes with a receptor, antigen, or other receptive moiety associated with a given target cell population. (T) is a molecule that binds to, complexes with, or reacts with a portion of the cell population being targeted. For example, ligands of cell surface receptors derived from different sources are included in (T), including those derived from human cells, ligands derived from bacteria, and ligands derived from pathogens. A variety of suitable targeting moieties are known in the art, for example, see WO2013117705.

[0750] Connector part (L)

[0751] The compositions of the present invention optionally further comprise a linker moiety (L). (L) is a bifunctional compound that can be used to link (D) and (T) to form a conjugate composition TLD. Such conjugates allow for selective delivery of drugs to target cells (e.g., tumor cells). (L) includes divalent substituents such as alkyldiyl, aryldiyl, heteroaryldiyl, moieties such as: -(CR2) n O(CR2) n -, alkoxy (e.g., polyethyleneoxy, PEG, polymethyleneoxy) and alkylamino (e.g., polyethyleneamino, Jeffamine TM ) repeating units; and diacids and amides, including succinate, succinamide, diglycolate, malonate and caproamide.

[0752] The compositions of the present invention can be prepared using (L) units having reactive sites for binding to (D) and (T). In some embodiments, (L) has reactive sites having electrophilic groups reactive toward nucleophilic groups present on (T). Useful nucleophilic groups on (T) include, but are not limited to, sulfhydryls, hydroxyls, and amino groups. Heteroatoms of the nucleophilic groups of (T) are reactive toward and form covalent bonds with the electrophilic groups on (L). Useful electrophilic groups include, but are not limited to, maleimide and haloacetamide groups. The nucleophilic groups on (T) provide convenient sites for attachment to (L).

[0753] In another embodiment, (L) has a reactive site having a nucleophilic group that is reactive toward an electrophilic group present on (T). Useful electrophilic groups on (T) include, but are not limited to, aldehyde and ketone carbonyl groups. A heteroatom of the nucleophilic group of (L) can react with an electrophilic group on (T) and form a covalent bond with (T). Useful nucleophilic groups on (L) include, but are not limited to, hydrazides, oximes, amino groups, hydrazines, thiosemicarbazones, hydrazine carboxylates, and aromatic hydrazides. The electrophilic group on (T) provides a convenient site for attachment to (L).

[0754] Carboxylic acid functional groups and chloroformate functional groups are also useful reactive sites for (L) because they can react with the amino groups of (D) to form an amide bond. Carbonate functional groups on (L) are also suitable as reactive sites, such as, but not limited to, p-nitrophenyl carbonate, which can react with the amino groups of (D) to form a carbamate bond.

[0755] It should be understood that any linker moiety taught in the prior art, and particularly those taught in the context of drug delivery, can be used in the present invention. Without wishing to limit the scope of the previous statement, in one embodiment, (L) comprises a linker moiety disclosed in WO 2012 / 113847. In another embodiment, (L) comprises a linker moiety disclosed in US8,288,352. In another embodiment, (L) comprises a linker moiety disclosed in US5,028,697. In another embodiment, (L) comprises a linker moiety disclosed in US5,006,652. In another embodiment, (L) comprises a linker moiety disclosed in US5,094,849. In another embodiment, (L) comprises a linker moiety disclosed in US5,053,394. In another embodiment, (L) comprises a linker moiety disclosed in US5,122,368. In another embodiment, (L) comprises a linker moiety disclosed in US5,387,578. In another embodiment, (L) comprises a linker moiety disclosed in US5,547,667. In another embodiment, (L) comprises a linker moiety disclosed in US5,622,929. In another embodiment, (L) comprises a linker moiety disclosed in US5,708,146. In another embodiment, (L) comprises a linker moiety disclosed in US6,468,522. In another embodiment, (L) comprises a linker moiety disclosed in US6,103,236. In another embodiment, (L) comprises a linker moiety disclosed in US6,638,509. In another embodiment, (L) comprises a linker moiety disclosed in US6,214,345. In another embodiment, (L) comprises a linker moiety disclosed in US.6,759,509. In another embodiment, (L) comprises a linker moiety disclosed in WO 2007 / 103288. In another embodiment, (L) comprises a linker moiety disclosed in WO 2008 / 083312. In another embodiment, (L) comprises a linker moiety disclosed in WO 2003 / 068144. In another embodiment, (L) comprises a linker moiety disclosed in WO 2004 / 016801. In another embodiment, (L) comprises a linker moiety disclosed in WO 2009 / 134976. In another embodiment, (L) comprises a linker moiety disclosed in WO 2009 / 134952. In another embodiment, (L) comprises a linker moiety disclosed in WO 2009 / 134977. In another embodiment, (L) comprises a linker moiety disclosed in WO 2002 / 08180. In another embodiment, (L) comprises a linker moiety disclosed in WO 2004 / 043493.In another embodiment, (L) comprises a linker moiety disclosed in WO 2007 / 018431. In another embodiment, (L) comprises a linker moiety disclosed in WO 2003 / 026577. In another embodiment, (L) comprises a linker moiety disclosed in WO 2005 / 077090. In another embodiment, (L) comprises a linker moiety disclosed in WO 2005 / 082023. In another embodiment, (L) comprises a linker moiety disclosed in WO 2007 / 011968. In another embodiment, (L) comprises a linker moiety disclosed in WO 2007 / 038658. In another embodiment, (L) comprises a linker moiety disclosed in WO 2007 / 059404. In another embodiment, (L) comprises a linker moiety disclosed in WO 2006 / 110476. In another embodiment, (L) comprises a linker moiety disclosed in WO 2005 / 112919. In another embodiment, (L) comprises a linker moiety disclosed in WO 2008 / 103693. In another embodiment, (L) comprises a linker moiety disclosed in US6,756,037. In another embodiment, (L) comprises a linker moiety disclosed in US7,087,229. In another embodiment, (L) comprises a linker moiety disclosed in US7,122,189. In another embodiment, (L) comprises a linker moiety disclosed in US7,332,164. In another embodiment, (L) comprises a linker moiety disclosed in US5,556,623. In another embodiment, (L) comprises a linker moiety disclosed in US5,643,573. In another embodiment, (L) comprises a linker moiety disclosed in US5,665,358.

[0756] In a preferred embodiment, (L) comprises a linker moiety disclosed in U.S. Provisional Application No. 61 / 921,242, filed December 27, 2013. Thus, a conjugate composition of Formula III is provided:

[0757] (T)-(L 1 )-(D 1 )

[0758] III

[0759] Wherein (T) is the targeting moiety, wherein (D 1 ) has the following structure (IV):

[0760]

[0761] where R 1 and X as described herein above and below;

[0762] where R 2a Selected from: C2-C6 alkyldiyl, aryldiyl, C4-C7 cycloalkyldiyl, heteroaryldiyl and heterocyclyldiyl, each optionally substituted with one or more substituents selected from: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio and thio-C1-C6 alkyl;

[0763] And among them (L 1 )-(T) has the following structure (V)

[0764] (AA)1-(AA) n -(L 2 )-(T)

[0765] V

[0766] wherein R is bonded to Formula IV 2a The -NH- group of the formula V forms a peptide bond (JPB) with (AA)1, wherein the JPB is enzymatically cleavable, wherein each AA is independently an amino acid, wherein n is an integer from 0 to 25, wherein (L 2 ) is optionally a linker (L 1 ), wherein (T) is a targeting moiety, and wherein (AA)1-(AA) n In combination, they contain amino acid sequences capable of promoting enzymatic cleavage of JPB.

[0767] Linkers (L) comprising self-immolative moieties may also be used. See, for example, U.S. Pat. No. 6,214,345. An example of a self-immolative moiety is p-aminobenzylcarbamoyl (PABC).

[0768] Commercially available linkers can be used in the present invention. For example, as shown herein, the commercially available cleavable linker 6-[3'(2-pyridyldisulfanyl)-propionamido]hexanoic acid sulfosuccinimidyl ester (sulfo-LC-SPDP: Thermo Pierce Cat. No. 21650) and the non-cleavable linker 4-[N-maleimidomethyl]cyclohexane-1-carboxylic acid succinimidyl ester (SMCC: Thermo Pierce Cat. No. 22360) can be used.

[0769] See also WO2012171020, WO2010138719, a variety of commercially available linkers, for example from Concortis http: / / www.concortis.com / home. See also Kim et al., Bioconjugate Chemistry, 21(8): 1513-1519 AUG 2010. See also EP2326349. See also copper-free click chemistry linkers, Angew. Chem. Int. ed., 2010, 49, pp. 9422-9425, ChemBioChem, 2011, 12, pp. 1309-1312, http: / / www.synaffix.com / technology / .

[0770] Drug part (D)

[0771] (D) is a compound of Formula I as described herein. The skilled artisan will recognize that the compounds described herein can be appropriately modified to facilitate the conjugation reaction with (L), or if (L) is absent, with (T), and the formation of the conjugates (T)-(L)-(D) or (T)-(D). Any point of attachment on (D) can be used. In one embodiment, the C-terminus of (D) forms the point of attachment in the (T)-(L)-(D) conjugate. In another embodiment, the N-terminus of (D) forms the point of attachment in the (T)-(L)-(D) conjugate. In another embodiment, the side chain of (D) forms the point of attachment in the (T)-(L)-(D) conjugate.

[0772] Application

[0773] For the purpose of administration, the compounds of the present disclosure can be administered as raw chemicals or can be formulated as pharmaceutical compositions. The pharmaceutical compositions of the present disclosure comprise the compounds described herein and a pharmaceutically acceptable carrier, diluent, or excipient. The compounds described herein are in an amount effective to treat a specific target disease or condition, for example, in an amount sufficient to treat cancer or tumor cell growth, and are preferably present in the composition with toxicity acceptable to the patient. The activity of the compounds described herein can be determined by those skilled in the art, for example, as described in the examples below. Appropriate concentrations and dosages can be readily determined by those skilled in the art.

[0774] Compounds as described herein or their pharmaceutically acceptable salts can be administered in pure form or in the form of suitable pharmaceutical compositions via any of the modes of administration accepted for the use of agents having similar effects. Pharmaceutical compositions of the present disclosure can be prepared by combining compounds as described herein with suitable pharmaceutically acceptable carriers, diluents, or excipients, and can be formulated into solid, semisolid, liquid, or gaseous preparations such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Typical routes of administration of such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal. The term parenteral as used herein includes subcutaneous injection, intravenous, intramuscular, intrasternal injection, or infusion techniques. Pharmaceutical compositions of the present disclosure are formulated so as to allow the active ingredients contained therein to be bioavailable when the composition is administered to a patient. The composition to be administered to the subject or patient takes the form of one or more dosage units, where, for example, a tablet can be a single dosage unit, and a container of a compound described herein in aerosol form can hold multiple dosage units. Actual methods of preparing such dosage forms are known or will be apparent to those skilled in the art; for example, see Remington: The Science and Practice of Pharmacy (22nd ed.), ed. Loyd V. Allen, Jr., et al., Pharmaceutical Press, 2012. The composition to be administered will in any case contain a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, for treating the target disease or condition in accordance with the teachings of the present disclosure.

[0775] The pharmaceutical compositions described herein can be in solid or liquid form. In one aspect, the carrier is a particle, such that the composition is in tablet or powder form, for example. The carrier can be a liquid, such that the composition is in the form of, for example, an oral syrup, an injectable liquid, or an aerosol, suitable for administration, for example, by inhalation.

[0776] When intended for oral administration, the pharmaceutical compositions of the present disclosure are typically in solid or liquid form, with semi-solid, semi-liquid, suspension, and gel forms included within the forms considered herein as solid or liquid.

[0777] As a solid composition for oral administration, the pharmaceutical composition can be formulated into a powder, granules, compressed tablets, pills, capsules, chewing gum, rice paper or the like. Such solid compositions will typically contain one or more inert diluents or edible carriers. In addition, one or more of the following substances may be present: a binder such as carboxymethyl cellulose, ethyl cellulose, microcrystalline cellulose, tragacanth gum or gelatin; an excipient such as starch, lactose or dextrin; a disintegrant such as alginic acid, sodium alginate, Primogel, corn starch, etc.; a lubricant such as magnesium stearate or Sterotex; a glidant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; a flavoring such as mint, methyl salicylate or orange flavoring; and a coloring agent.

[0778] When the pharmaceutical composition is in the form of a capsule (eg, a gelatin capsule), it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.

[0779] The pharmaceutical compositions described herein can be in liquid form, such as elixirs, syrups, solutions, emulsions, or suspensions. Liquids can be used for oral administration or for delivery by injection, as two examples. When intended for oral administration, the pharmaceutical compositions described herein typically contain one or more of a sweetener, a preservative, a dye / colorant, and a flavor enhancer in addition to the present compound. In compositions intended for administration by injection, one or more of a surfactant, a preservative, a wetting agent, a dispersant, a suspending agent, a buffer, a stabilizer, and an isotonic agent can be included.

[0780] The liquid pharmaceutical compositions described herein, whether they are solutions, suspensions or other similar forms, may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solutions, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic monoglycerides or diglycerides, polyethylene glycol, glycerol, propylene glycol or other solvents that can serve as solvents or suspending media; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for regulating osmotic pressure such as sodium chloride or glucose. Parenteral formulations can be placed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. Injectable pharmaceutical compositions are preferably sterile.

[0781] Liquid pharmaceutical compositions described herein intended for parenteral or oral administration should contain an amount of a compound described herein such that a suitable dosage will be obtained.

[0782] The pharmaceutical compositions described herein can be used for topical administration, in which case the carrier can suitably comprise a solution, emulsion, ointment, or gel matrix. The matrix can, for example, comprise one or more of the following: petrolatum, lanolin, polyethylene glycol, beeswax, mineral oil, a diluent such as water and ethanol, and an emulsifier and stabilizer. A thickening agent can be present in the pharmaceutical composition for topical administration. If intended for transdermal administration, the composition can include a transdermal patch or an iontophoresis device.

[0783] The pharmaceutical compositions described herein can be intended for rectal administration, for example, in the form of suppositories that will melt in the rectum and release the drug. Compositions for rectal administration can contain an oleaginous base as a suitable non-irritating excipient. Such bases include, but are not limited to, lanolin, cocoa butter, and polyethylene glycol.

[0784] The pharmaceutical compositions described herein may include various substances that improve the physical form of a solid or liquid dosage unit. For example, the composition may include a substance that forms a coating shell around the active ingredient. The substance forming the coating shell is generally inert and may be selected from, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredient may be encapsulated in a gelatin capsule.

[0785] Pharmaceutical compositions as herein described can be prepared in dosage units, which can be used as aerosols. The term aerosol is used to represent a variety of systems ranging from those systems with colloidal properties to systems consisting of pressurized packaging. Delivery can be carried out by liquefied or compressed gas or by a suitable pump system that distributes active ingredients. The aerosol of compound as herein described can be delivered in a single-phase, two-phase or three-phase system to deliver active ingredients. The delivery of aerosols includes necessary containers, activators, valves, sub-containers, etc., which can be combined to form complete sets of devices. Those skilled in the art can determine preferred aerosols without excessive experimentation.

[0786] The pharmaceutical compositions described herein can be prepared by methods well known in the pharmaceutical art. For example, a pharmaceutical composition intended for administration by injection can be prepared by combining a compound described herein with sterile distilled water to form a solution. A surfactant can be added to promote the formation of a uniform solution or suspension. A surfactant is a compound that non-covalently interacts with a compound described herein to promote dissolution or uniform suspension of the compound in an aqueous delivery system.

[0787] The compounds described herein, or pharmaceutically acceptable salts thereof, are administered in a therapeutically effective amount, which will vary depending on a variety of factors including: the activity of the particular compound employed; the metabolic stability and length of action of the compound; the age, weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disorder or condition; and the therapy the subject is receiving.

[0788] The compounds described herein or pharmaceutically acceptable derivatives thereof may also be administered simultaneously with, before, or after the administration of one or more other therapeutic agents. Such combination therapies include the administration of a single pharmaceutical dosage formulation containing a compound as described herein and one or more additional active agents, as well as the administration of a compound as described herein with each active agent in its own separate pharmaceutical dosage formulation. For example, the compounds described herein and other active agents may be administered to the patient together in the form of a single oral dosage composition (such as a tablet or capsule), or each agent may be administered in a separate oral dosage formulation. When a separate dosage formulation is used, the compounds described herein and one or more additional active agents may be administered substantially simultaneously (i.e., simultaneously) or at separately staggered times (i.e., continuously); it should be understood that combination therapy includes all of these regimens.

[0789] The following examples illustrate various methods for preparing the compounds described herein (i.e., compounds of Formula I and related formulae). It should be understood that one skilled in the art will be able to prepare these compounds by similar methods or by combining other methods known to those skilled in the art. It should also be understood that one skilled in the art will be able to prepare other compounds of Formula I, not specifically shown below, in a similar manner as described below by using appropriate starting components and optionally modifying the parameters of the synthesis. Generally speaking, starting components can be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA or synthesized according to sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition (Wiley, December 2000)) or prepared as described herein.

[0790] The following examples are offered for purposes of illustration and not limitation. DETAILED DESCRIPTION

[0791] 1. A compound of formula I:

[0792]

[0793] or a pharmaceutically acceptable salt thereof,

[0794] in:

[0795] R 1is selected from the group consisting of amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heterocyclyl and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of aryl, aryl-C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkylthio, carboxyl, carboxamide, C3-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, guanidino, halo, C1-C6 haloalkyl, heterocyclyl, heterocyclyl-C1-C6 alkyl, hydroxyl and thio; or

[0796] R 1 R a R b NCH(R c )-;

[0797] R a Selected from: H and C1-C6 alkyl;

[0798] R b is a C1-C6 alkyl group; and

[0799] R c R d -C(CH3)2-; and

[0800] R d is selected from the group consisting of: H, aryl, C3-C7 cycloalkyl and heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: C1-C4 acylthio, C2-C4 alkenyl, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkoxy, amino, amino-C1-C4 alkyl, halo, C1-C4 haloalkyl, hydroxy, hydroxy-C1-C4 alkyl and thio, wherein C2-C4 alkenyl, C1-C4 alkylamino and C1-C4 alkoxy are further optionally substituted with one substituent selected from the group consisting of: C1-C4 alkylaryl, hydroxy and thio; or

[0801] R b and R c together with the atoms to which they are respectively bonded, form a heterocyclyldiyl;

[0802] R 2 is selected from the group consisting of: C2-C6 alkyl, aryl, aryl-C1-C6 alkyl, C4-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloacyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio, and thio-C1-C6 alkyl; and

[0803] X does not exist.

[0804] 2. The compound according to embodiment 1, wherein R 1 Selected from: amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heterocyclyl and heterocyclyl, each optionally substituted with one or more substituents selected from C1-C6 alkyl and halo.

[0805] 3. The compound according to embodiment 1, wherein R 1 selected from the group consisting of: 1-(dimethylamino)-2-methylpropyl, 2-methyl-1-(methylamino)propyl, 1-aminocyclopentyl, 1-aminocyclopropyl, 4-aminophenyl, 2-aminopropyl-2-yl, 1-aminocyclohexyl, 3-aminooxetan-3-yl, 2-(methylamino)propyl-2-yl, 1-amino-2-methylpropyl-2-yl, 2-methylpyrrolidin-2-yl, 2-amino-3-methylbutan-2-yl, 2-aminobutan-2-yl, 2-methyl-1-(methylamino)propyl-2-yl, 1-methylpiperidin-2-yl, 3-fluoropyrrolidin-3-yl, 1,2-dimethylpyrrolidin-2-yl and 2-(dimethylamino)propyl-2-yl).

[0806] 4. The compound according to embodiment 1, wherein R 1 It is 1-(dimethylamino)-2-methylpropyl.

[0807] 5. The compound according to embodiment 1, wherein R 1 It is 2-methyl-1-(methylamino)propyl.

[0808] 6. The compound according to embodiment 1, wherein R 1 It is (R)-1-(dimethylamino)-2-methylpropyl.

[0809] 7. The compound according to embodiment 1, wherein R 1 is (R)-2-methyl-1-(methylamino)propyl.

[0810] 8. A compound as described in any one of embodiments 1 to 7, wherein R 2 is selected from the group consisting of: C2-C6 alkyl, aryl, aryl-C1-C6 alkyl, C4-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of: 1-aminocyclopropyl, 4-aminophenyl, amino, aminomethyl, bromo, tert-butyl, carboxamide, carboxyl, chloro, cyano, ethyl, fluoro, hydroxy, isopropyl, methoxy, methyl, nitro, phenyl, thio, thiomethyl, trifluoromethoxy and trifluoromethyl.

[0811] 9. A compound as described in any one of embodiments 1 to 7, wherein R 2 Selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, benzyl, 3-mercaptopropyl, 2-mercaptoethyl, 4-(mercaptomethyl)phenyl, p-tolyl, 2,4,6-trimethylphenyl, 4-(trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl, 4-chlorophenyl, 3-cyanophenyl, 2-nitrophenyl, 4-methoxy-2-nitrophenyl, 4- aminocarbonyl-2-nitrophenyl, 4-methoxyphenyl, phenyl, 2-fluorobenzyl, piperidin-1-yl, o-tolyl, 4-bromophenyl, naphth-2-yl, 4-methoxycarbonylphenyl, 2-(trifluoromethyl)benzyl, hexan-2-yl, 2-methoxyethyl, cyclopentylmethyl, cyclohexyl, pyridin-3-ylmethyl, 4-carboxyphenyl, 3-aminophenyl, pyridin-3-yl, thiophen-2-yl, 4-hydroxyphenyl, 4-(1-aminocyclopropyl) benzyl, 4-(1-aminocyclopropyl)phenyl, 2-methylbenzyl, 4-nitrobenzyl, 4-chlorobenzyl, phenethyl, 4-bromobenzyl, 4-cyanobenzyl, 3-nitrobenzyl, 4-tert-butylbenzyl, 2-nitrobenzyl, 4-nitrophenethyl, 2-chloro-3-methoxycarbonylphenyl, 2-aminophenyl, [1,1′-biphenyl]-4-yl, 4′-amino-[1,1′-biphenyl]-4-yl, 4-fluorobenzyl, 3-(trifluoromethyl) benzyl, 3-(trifluoromethoxy)benzyl, 3,4-dichlorobenzyl, 2-cyanobenzyl, 3-chlorobenzyl, 4-amino-2-ethylphenyl, 4-amino-3-(trifluoromethoxy)phenyl, 4-amino-2,3-dimethylphenyl, 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl, 4-amino-3-methylphenyl, 4-amino-3-fluorophenyl, 4-amino-3-ethylphenyl and 4-amino-3-(trifluoromethyl)phenyl.

[0812] 10. A compound as described in any one of embodiments 1 to 7, wherein R 2 Selected from: aryl and aryl-C1-C6 alkyl, each optionally substituted with one or more substituents selected from: amino and amino-C1-C6 alkyl.

[0813] 11. A compound as described in any one of embodiments 1 to 7, wherein R 2 Selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl and benzyl.

[0814] 12. A compound as described in any one of embodiments 1 to 7, wherein R 2 It is 4-aminobenzyl.

[0815] 13. A compound as described in any one of embodiments 1 to 7, wherein R 2 It is 4-(aminomethyl)benzyl.

[0816] 14. A compound as described in any one of embodiments 1 to 7, wherein R 2 It is 4-(aminomethyl)phenyl.

[0817] 15. A compound as described in any one of embodiments 1 to 7, wherein R 2 It is 4-aminophenyl.

[0818] 16. A compound as described in any one of embodiments 1 to 7, wherein R 2 It is benzyl.

[0819] 17. The compound according to embodiment 1, which has formula Ia:

[0820]

[0821] or a pharmaceutically acceptable salt thereof,

[0822] in:

[0823] R 2 is selected from the group consisting of: C2-C6 alkyl, aryl, aryl-C1-C6 alkyl, C4-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio and thio-C l -C6 alkyl; and

[0824] R 4 and R 5 Each is independently selected from: H and C1-C6 alkyl.

[0825] 18. The compound according to embodiment 1, which has formula Ia:

[0826]

[0827] or a pharmaceutically acceptable salt thereof,

[0828] in:

[0829] R 2Selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, benzyl, 3-mercaptopropyl, 2-mercaptoethyl, 4-(mercaptomethyl)phenyl, p-tolyl, 2,4,6-trimethylphenyl, 4-(trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl, 4-chlorophenyl, 3-cyanophenyl, 2-nitrophenyl, 4-methoxy-2-nitrophenyl, 4-aminophenyl phenyl, 2-nitrophenyl, 4-methoxyphenyl, phenyl, 2-fluorobenzyl, piperidin-1-yl, o-tolyl, 4-bromophenyl, naphth-2-yl, 4-methoxycarbonylphenyl, 2-(trifluoromethyl)benzyl, hexane-2-yl, 2-methoxyethyl, cyclopentylmethyl, cyclohexyl, pyridin-3-ylmethyl, 4-carboxyphenyl, 3-aminophenyl, pyridin-3-yl, thiophen-2-yl, 4-hydroxyphenyl, 4-(1-aminocyclopropyl)benzyl , 4-(1-aminocyclopropyl)phenyl, 2-methylbenzyl, 4-nitrobenzyl, 4-chlorobenzyl, phenethyl, 4-bromobenzyl, 4-cyanobenzyl, 3-nitrobenzyl, 4-tert-butylbenzyl, 2-nitrobenzyl, 4-nitrophenethyl, 2-chloro-3-methoxycarbonylphenyl, 2-aminophenyl, [1,1′-biphenyl]-4-yl, 4′-amino-[1,1′-biphenyl]-4-yl, 4-fluorobenzyl, 3-(trifluoromethyl)benzyl, 3-(trifluoromethoxy)benzyl, 3,4-dichlorobenzyl, 2-cyanobenzyl, 3-chlorobenzyl, 4-amino-2-ethylphenyl, 4-amino-3-(trifluoromethoxy)phenyl, 4-amino-2,3-dimethylphenyl, 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl, 4-amino-3-methylphenyl, 4-amino-3-fluorophenyl, 4-amino-3-ethylphenyl, and 4-amino-3-(trifluoromethyl)phenyl; and

[0830] R 4 and R 5 are each independently selected from: H and methyl.

[0831] 19. The compound according to embodiment 1, which has the formula Ib:

[0832]

[0833] or a pharmaceutically acceptable salt thereof,

[0834] in:

[0835] R 2selected from the group consisting of: C2-C6 alkyl, aryl, aryl-C1-C6 alkyl, C4-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio, and thio-C1-C6 alkyl;

[0836] R 3 is selected from the group consisting of: aryl, heteroaryl, and C3-C7 cycloalkyl, each optionally substituted with a substituent selected from amino and hydroxy; and

[0837] R 4 and R 5 Each is independently selected from: H and C1-C6 alkyl.

[0838] 20. The compound according to embodiment 1, which has the formula Ib:

[0839]

[0840] or a pharmaceutically acceptable salt thereof,

[0841] in:

[0842] R 2Selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, benzyl, 3-mercaptopropyl, 2-mercaptoethyl, 4-(mercaptomethyl)phenyl, p-tolyl, 2,4,6-trimethylphenyl, 4-(trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl, 4-chlorophenyl, 3-cyanophenyl, 2-nitrophenyl, 4-methoxy-2-nitrophenyl, 4-aminophenyl phenyl, 2-fluorobenzyl, piperidin-1-yl, o-tolyl, 4-bromophenyl, naphth-2-yl, 4-methoxycarbonylphenyl, 2-(trifluoromethyl)benzyl, hexane-2-yl, 2-methoxyethyl, cyclopentylmethyl, cyclohexyl, pyridin-3-ylmethyl, 4-carboxyphenyl, 3-aminophenyl, pyridin-3-yl, thiophen-2-yl, 4-hydroxyphenyl, 4-(1-aminocyclopropyl)benzyl phenyl, 2-methylbenzyl, 4-nitrobenzyl, 4-chlorobenzyl, phenethyl, 4-bromobenzyl, 4-cyanobenzyl, 3-nitrobenzyl, 4-tert-butylbenzyl, 2-nitrobenzyl, 4-nitrophenethyl, 2-chloro-3-methoxycarbonylphenyl, 2-aminophenyl, [1,1′-biphenyl]-4-yl, 4′-amino-[1,1′-biphenyl]-4-yl, 4-fluorobenzyl, 3-(trifluoromethyl)benzyl phenyl, 4-amino-3-(trifluoromethoxy)phenyl, 4-amino-2,3-dimethylphenyl, 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl, 4-amino-3-methylphenyl, 4-amino-3-fluorophenyl, 4-amino-3-ethylphenyl, and 4-amino-3-(trifluoromethyl)phenyl;

[0843] R 3 is selected from the group consisting of: 1H-indol-3-yl, 4-aminophenyl, 4-hydroxyphenyl, 5-hydroxypyridin-2-yl, cyclohexyl, and phenyl; and

[0844] R 4 and R 5 are each independently selected from: H and methyl.

[0845] 21. The compound according to embodiment 1, which has the formula Id:

[0846]

[0847] or a pharmaceutically acceptable salt thereof,

[0848] in:

[0849] R 2is selected from the group consisting of: C2-C6 alkyl, aryl, aryl-C1-C6 alkyl, C4-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, and heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio, and thio-C1-C6 alkyl; and

[0850] R 4 and R 5 Each is independently selected from: H and C1-C6 alkyl.

[0851] 22. The compound according to embodiment 1, which has the formula Id:

[0852]

[0853]

[0854] or a pharmaceutically acceptable salt thereof,

[0855] in:

[0856] R 2Selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, benzyl, 3-mercaptopropyl, 2-mercaptoethyl, 4-(mercaptomethyl)phenyl, p-tolyl, 2,4,6-trimethylphenyl, 4-(trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl, 4-chlorophenyl, 3-cyanophenyl, 2-nitrophenyl, 4-methoxy-2-nitrophenyl, 4-aminophenyl phenyl, 2-nitrophenyl, 4-methoxyphenyl, phenyl, 2-fluorobenzyl, piperidin-1-yl, o-tolyl, 4-bromophenyl, naphth-2-yl, 4-methoxycarbonylphenyl, 2-(trifluoromethyl)benzyl, hexane-2-yl, 2-methoxyethyl, cyclopentylmethyl, cyclohexyl, pyridin-3-ylmethyl, 4-carboxyphenyl, 3-aminophenyl, pyridin-3-yl, thiophen-2-yl, 4-hydroxyphenyl, 4-(1-aminocyclopropyl)benzyl , 4-(1-aminocyclopropyl)phenyl, 2-methylbenzyl, 4-nitrobenzyl, 4-chlorobenzyl, phenethyl, 4-bromobenzyl, 4-cyanobenzyl, 3-nitrobenzyl, 4-tert-butylbenzyl, 2-nitrobenzyl, 4-nitrophenethyl, 2-chloro-3-methoxycarbonylphenyl, 2-aminophenyl, [1,1′-biphenyl]-4-yl, 4′-amino-[1,1′-biphenyl]-4-yl, 4-fluorobenzyl, 3-(trifluoromethyl)benzyl, 3-(trifluoromethoxy)benzyl, 3,4-dichlorobenzyl, 2-cyanobenzyl, 3-chlorobenzyl, 4-amino-2-ethylphenyl, 4-amino-3-(trifluoromethoxy)phenyl, 4-amino-2,3-dimethylphenyl, 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl, 4-amino-3-methylphenyl, 4-amino-3-fluorophenyl, 4-amino-3-ethylphenyl, and 4-amino-3-(trifluoromethyl)phenyl; and

[0857] R 4 and R 5 are each independently selected from: H and methyl.

[0858] 23. The compound according to embodiment 1, which has the formula Ig:

[0859]

[0860]

[0861] or a pharmaceutically acceptable salt thereof,

[0862] in:

[0863] R 2Selected from: C2-C6 alkyl, aryl, aryl-C1-C6 alkyl, C4-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl and heterocyclyl, each optionally substituted with one or more substituents selected from the following: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio and thio-C1-C6 alkyl.

[0864] 24. The compound according to embodiment 1, which has the formula Ig:

[0865]

[0866] or a pharmaceutically acceptable salt thereof,

[0867] in:

[0868] R 2 Selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl.

[0869] 25. The compound of embodiment 1, which has formula Ij:

[0870]

[0871] or a pharmaceutically acceptable salt thereof,

[0872] in:

[0873] R 2 Selected from: C2-C6 alkyl, aryl, aryl-C1-C6 alkyl, C4-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl and heterocyclyl, each optionally substituted with one or more substituents selected from the following: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylamino, amino, amino-C1-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, hydroxy, nitro, thio and thio-C1-C6 alkyl.

[0874] 26. The compound of embodiment 1, which has the formula Ij:

[0875]

[0876] or a pharmaceutically acceptable salt thereof,

[0877] in:

[0878] R 2 Selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, benzyl, 3-mercaptopropyl, 2-mercaptoethyl, 4-(mercaptomethyl)phenyl, p-tolyl, 2,4,6-trimethylphenyl, 4-(trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl, 4-chlorophenyl, 3-cyanophenyl, 2-nitrophenyl, 4-methoxy-2-nitrophenyl, 4- aminocarbonyl-2-nitrophenyl, 4-methoxyphenyl, phenyl, 2-fluorobenzyl, piperidin-1-yl, o-tolyl, 4-bromophenyl, naphth-2-yl, 4-methoxycarbonylphenyl, 2-(trifluoromethyl)benzyl, hexan-2-yl, 2-methoxyethyl, cyclopentylmethyl, cyclohexyl, pyridin-3-ylmethyl, 4-carboxyphenyl, 3-aminophenyl, pyridin-3-yl, thiophen-2-yl, 4-hydroxyphenyl, 4-(1-aminocyclopropyl) benzyl, 4-(1-aminocyclopropyl)phenyl, 2-methylbenzyl, 4-nitrobenzyl, 4-chlorobenzyl, phenethyl, 4-bromobenzyl, 4-cyanobenzyl, 3-nitrobenzyl, 4-tert-butylbenzyl, 2-nitrobenzyl, 4-nitrophenethyl, 2-chloro-3-methoxycarbonylphenyl, 2-aminophenyl, [1,1′-biphenyl]-4-yl, 4′-amino-[1,1′-biphenyl]-4-yl, 4-fluorobenzyl, 3-(trifluoromethyl) benzyl, 3-(trifluoromethoxy)benzyl, 3,4-dichlorobenzyl, 2-cyanobenzyl, 3-chlorobenzyl, 4-amino-2-ethylphenyl, 4-amino-3-(trifluoromethoxy)phenyl, 4-amino-2,3-dimethylphenyl, 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl, 4-amino-3-methylphenyl, 4-amino-3-fluorophenyl, 4-amino-3-ethylphenyl and 4-amino-3-(trifluoromethyl)phenyl.

[0879] 27. The compound according to embodiment 1, which is selected from the following:

[0880] (S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(4-aminophenylsulfonamido)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptane-14-yl)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamide; and

[0881] (S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-((4-aminophenyl)methylsulfonamido)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptane-4-yl)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamide,

[0882] or a pharmaceutically acceptable salt thereof.

[0883] 28. The compound according to embodiment 1, which is selected from the following:

[0884] (R)-N-((S)-1-(((3R,4S,5S)-1-((S)-2-((1R,2R)-3-((4-aminophenyl)sulfonamido)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)-1-isopropylpiperidine-2-carboxamide;

[0885] (S)-2-(2-amino-2-methylpropionamido)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-((4-aminophenyl)sulfonamido)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-N,3-dimethylbutanamide;

[0886] (S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-((4-aminophenyl)sulfonamido)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)-3-phenylbutanamido)butanamide;

[0887] (S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-((4-chlorophenyl)sulfonamido)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)butanamido)butanamide;

[0888] (S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-((4-(aminomethyl)phenyl)sulfonamido)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamide;

[0889] (S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((4-(aminomethyl)phenyl)methyl)sulfonamido)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamide;

[0890] (S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(4-(1-aminocyclopropyl)phenylsulfonamido)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamide;

[0891] (S)-N-((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-((phenylmethyl)sulfonamido)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)butanamido)butanamide; and

[0892] methyl 4-(N-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanoyl)sulfamoyl)benzoate,

[0893] or a pharmaceutically acceptable salt thereof.

[0894] 29. A pharmaceutical composition comprising the compound of any one of Embodiments 1 to 28 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[0895] 30. A method of treating cancer in a mammal, the method comprising administering to a mammal in need thereof an effective amount of a compound according to any one of embodiments 1 to 28 or a pharmaceutical composition according to embodiment 29.

[0896] 31. A method of inhibiting tumor growth in a mammal, the method comprising administering to a mammal in need thereof an effective amount of a compound according to any one of embodiments 1 to 28 or a pharmaceutical composition according to embodiment 29.

[0897] 32. A method of prolonging the survival of a mammal having cancer, the method comprising administering to the mammal an effective amount of a compound according to any one of embodiments 1 to 28 or a pharmaceutical composition according to embodiment 29.

[0898] 33. Use of a compound according to any one of embodiments 1 to 28, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating cancer in a mammal.

[0899] 34. Use of a compound according to any one of embodiments 1 to 28, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting tumor growth in a mammal.

[0900] 35. Use of a compound according to any one of embodiments 1 to 28, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for prolonging survival of a mammal having cancer.

[0901] 36. A compound according to any one of embodiments 1 to 28 or a pharmaceutical composition according to embodiment 29 for use in a method of treatment of the human or animal body by therapy.

[0902] 37. A compound according to any one of embodiments 1 to 28 or a pharmaceutical composition according to embodiment 29 for use in treating cancer in a mammal.

[0903] 38. A compound according to any one of embodiments 1 to 28 or a pharmaceutical composition according to embodiment 29 for use in inhibiting tumor growth in a mammal.

[0904] 39. A compound according to any one of embodiments 1 to 28 or a pharmaceutical composition according to embodiment 29 for use in prolonging survival of a mammal suffering from cancer.

[0905] 40. A composition of formula II:

[0906] (T)-(L)-(D)

[0907] II

[0908] wherein (T) is a targeting moiety, (L) is an optional linker, and (D) is a compound according to any one of embodiments 1 to 28.

[0909] 41. A pharmaceutical composition comprising the composition of embodiment 40 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[0910] 42. A method of treating cancer in a mammal, the method comprising administering to a mammal in need thereof an effective amount of the composition of embodiment 40 or the pharmaceutical composition of embodiment 41.

[0911] 43. A method of inhibiting tumor growth in a mammal, the method comprising administering to a mammal in need thereof an effective amount of the composition of embodiment 40 or the pharmaceutical composition of embodiment 41.

[0912] 44. A method of prolonging the survival of a mammal having cancer, the method comprising administering to the mammal an effective amount of the composition of embodiment 40 or the pharmaceutical composition of embodiment 41.

[0913] 45. Use of the composition of embodiment 40 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cancer in a mammal.

[0914] 46. ​​Use of the composition of embodiment 40 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting tumor growth in a mammal.

[0915] 47. Use of the composition of embodiment 40, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for prolonging survival in a mammal suffering from cancer.

[0916] 48. A composition according to embodiment 40 or a pharmaceutical composition according to embodiment 41 for use in a method of treatment of the human or animal body by therapy.

[0917] 49. The composition of embodiment 40 or the pharmaceutical composition of embodiment 41 for use in treating cancer in a mammal.

[0918] 50. The composition of embodiment 40 or the pharmaceutical composition of embodiment 41 for use in inhibiting tumor growth in a mammal.

[0919] 51. The composition of embodiment 40 or the pharmaceutical composition of embodiment 41 for use in prolonging survival of a mammal suffering from cancer.

[0920] Example

[0921] Example 1: General Synthesis Method

[0922] Synthesis Scheme A

[0923]

[0924] Synthesis Scheme B

[0925]

[0926] Plan C

[0927]

[0928] Example 1.1: General Method 1 - Trifluoroacetamide Apparatus.

[0929] To the stirred suspension of amine in 1,4-dioxane, add trifluoroacetic anhydride (1.1 equivalents).Reaction mixture is converted into solution and converted back to suspension from suspension again.The progress of reaction is monitored by TLC and / or HPLC-MS so that reaction is complete.In case starting material is consumed completely, then by reaction hexane or ether dilution, filter on Buchner funnel and dry the generated solid under reduced pressure to obtain pure trifluoroacetamide.

[0930] Example 1.2: General Method 2

[0931] Method A: DCC / DMAP-mediated N-acylsulfonamide formation.

[0932] To a stirred solution of the acid in dichloromethane is added a solution of the sulfonamide (1.3 equivalents, in dichloromethane, N,N-dimethylformamide, or a mixture thereof as desired). Dicyclohexylcarbodiimide (1.2 equivalents) is added followed by N,N-dimethylaminopyridine (1.2 equivalents). The progress of the reaction is monitored by HPLC-MS (typically 16 h) and excess by-products can be precipitated by the addition of ether. The solid is removed by filtration and washed with 1:1 ether / dichloromethane. The combined organic layers are concentrated and the residue is purified by silica gel chromatography or optionally preparative-HPLC to yield the desired N-acylsulfonamide.

[0933] Method B: DCC or EDCI / DMAP mediated N-acylsulfonamide formation.

[0934] To a stirred solution of the acid in dichloromethane, ethyl acetate, or a mixture thereof, is added a solution of the sulfonamide (1.3 equivalents in dichloromethane, ethyl acetate, or N,N-dimethylformamide, or a mixture thereof, as needed). Dicyclohexylcarbodiimide or EDCI (1.2 equivalents) is added followed by N,N-dimethylaminopyridine (1.2 equivalents). The progress of the reaction is monitored by HPLC-MS (typically 16 h) and excess by-products can be precipitated by the addition of ether. The solid is removed by filtration and washed with 1:1 ether / dichloromethane. The combined organic layers are concentrated, and the residue is purified by silica gel chromatography or optionally preparative HPLC to yield the desired N-acylsulfonamide.

[0935] Example 1.3: General Method 3 Alternative - AcBt-mediated N-acylsulfonamide formation

[0936] This method was adapted from that described in ARKIVOC 2004(xii), 14-22.

[0937] Example 1.4: General Methods 4-Trifluoroacetamide Saponification.

[0938] To a solution of trifluoroacetamide containing the construct in 1,4-dioxane or methanol was added lithium hydroxide (10 equivalents) and water (10% v / v). The reaction was allowed to stir at room temperature or optionally heated to 50° C. The reaction progress was monitored by HPLC-MS. Once complete, volatiles were removed under reduced pressure, the pH of the aqueous layer was adjusted as necessary, and washed continuously with dichloromethane or ethyl acetate. The organic phases were pooled, dried over MgSO , filtered, and concentrated. The reaction product was used “as is” or purified by silica gel chromatography as needed.

[0939] Example 1.4.1: General Method 4.1 - Amide / Ester Saponification.

[0940] To a solution of the amide / ester containing the construct in 1,4-dioxane or methanol was added lithium hydroxide (10 equivalents) and water (10% v / v). The reaction was allowed to stir at room temperature or optionally heated to 50° C. The reaction progress was monitored by HPLC-MS. Once complete, the volatiles were removed under reduced pressure, the pH of the aqueous layer was adjusted if necessary, and washed continuously with dichloromethane or ethyl acetate. The organic phases were pooled, dried over MgSO , filtered, and concentrated. The reaction product was used “as is” or purified by silica gel chromatography as needed.

[0941] Example 1.5: General Method 5 - DIC / Cu(II)-mediated Peptide Bond Formation

[0942] To a stirred solution of a carboxylic acid in a minimum amount of 30% N,N-dimethylformamide in dichloromethane are added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.95 equiv), 1-hydroxy-7-azabenzotriazole (1.0 equiv), an amine (0.33 equiv), and anhydrous copper(II) chloride (1.0 equiv) in sequence, with a brief pause between each additional reagent. Stirring is continued at room temperature and the progress of the reaction is monitored by HPLC-MS. Upon completion, the volatiles are removed under reduced pressure and the residual material is purified by silica gel chromatography or reverse phase HPLC to provide the desired amide in sufficient purity.

[0943] Example 1.6: General Methods 6-HATU-mediated peptide bond formation.

[0944] To a stirred solution of a carboxylic acid in a minimum amount of dichloromethane or N,N-dimethylformamide or a mixture thereof is added HATU (1.05-1.2 equivalents) and N,N-diisopropylamine (2-4 equivalents) or 2,4,6-collidine (2-4 equivalents) at 0°C. Stirring is continued for a brief induction period (5-20 minutes) at which time a solution of the amine in dichloromethane is charged to the reaction. The reaction is allowed to warm to room temperature and progress is monitored by HPLC-MS. Once complete, the volatiles are removed under reduced pressure and the residual material is purified by silica gel chromatography or reverse phase HPLC to provide an amide of sufficient purity.

[0945] Example 1.7: General Methods 7-Fmoc Group Removal.

[0946] The Fmoc-protected peptide construct was dissolved in 20% piperidine in N,N-dimethylformamide. The reaction progress was monitored by HPLC-MS. When complete, all volatile substances were removed under reduced pressure to give a residue which was either purified by silica gel chromatography or used directly in the next step.

[0947] Example 1.8: General Method 8 - N-acylation of Amines Using NHS-Activated Esters.

[0948] To a solution of the amine in a minimum amount of N,N-dimethylformamide is added the corresponding ester-containing N-hydroxysuccinimide (1.5 equivalents) and optionally diisopropylamine (2-4 equivalents). The reaction progress is monitored by HPLC-MS (typically about 16 hours), at which point all volatiles are removed under reduced pressure. The residue is then purified by silica gel chromatography or reverse phase HPLC to yield the desired amide product.

[0949] Example 1.9: General Methods 9-Boc Group Removal.

[0950] To a solution of the Boc-protected construct in dichloromethane was added 10% v / v trifluoroacetic acid. The reaction progress was monitored by HPLC-MS. Upon completion, all volatile substances were removed under reduced pressure. The residual material was purified by reverse phase HPLC, silica gel chromatography, or precipitation from a mixture of cold methanol / dichloromethane / ether.

[0951] Example 1.9.1: General Method 9.1 - Boc Group and tert-Butyl Ester Removal.

[0952] To a solution of the Boc-protected amine or tert-butyl ester in dichloromethane is added 10-20% v / v trifluoroacetic acid. The reaction progress is monitored by HPLC-MS. Once complete, all volatile materials are removed under reduced pressure. The residual material is purified by reverse phase HPLC, silica gel chromatography, or precipitation from a mixture of cold methanol / dichloromethane / ether.

[0953] Example 1.10: Fmoc-Val-Cit-OH: (S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)-5-ureidopentanic acid, Fmoc-valine-citrulline-OH, Fmoc-VC-OH.

[0954]

[0955] The title compound was prepared according to Dubowehik et al., Bioconjugate Chem., 2002, 13, 855-869.

[0956] 1 H NMR (400MHz, DMSO-d6) δ12.56 (s, 1H), 8.21 (d, J = 7.3Hz, 1H), 7.90 (d, J = 7.5Hz, 2H), 7.76 (t, J = 7.0Hz, 2H ), 7.49-7.39(m, 3H), 7.38-7.23(m, 2H), 5.96(t, J=5.9Hz, 1H), 5.40(s, 2H), 4.34-4.09(m, 4H), 3.93(dd , J = 9.1, 7.1 Hz, 1H), 3.39 (q, J = 7.0 Hz, 3H), 2.96 (q, J = 6.5 Hz, 2H), 1.97 (d, J = 6.9 Hz, 1H), 1.86-1.63 (m, 1H), 1.57 (dtd, J = 13.9, 9.0, 5.4 Hz, 1H), 1.41 (dhept, J = 13.2, 6.9 Hz, 2H), 0.88 (dd, J = 13.3, 6.7 Hz, 6H). Calculated for C26H32N4O6: [M+H]+ 497.23. Found: [M+H] +497.19.

[0957] Example 1.11: (S)-2-((S)-2-((tert-Butoxycarbonyl)amino)-3-methylbutanamido)-5-ureidopentanic acid, Boc-valine-citrulline-OH, Boc-VC-OH.

[0958]

[0959] The title compound was synthesized according to US 2010 / 0233190 A1 with matching spectral data.

[0960] Example 1.12: MC-NHS: 2,5-dioxopyrrolidin-1-yl 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoate.

[0961]

[0962] To the stirred solution of 6-aminocaproic acid (10.0g, 76.2mmol, 1.0eq) in acetic acid (75mL), add maleic anhydride (7.85g, 80.0mmol, 1.05eq). Solid dissolution took a few minutes, and then after about 5min, white solid began to appear. After one hour, the suspension thickened into a white cake. This material was filtered on a sinter funnel and washed with toluene and dried under heating to remove all traces of acetic acid in a vacuum.

[0963] The intermediate powder is dissolved in toluene (250mL), add triethylamine (21.3mL, 152mmol, 2.0eq), and with the Dean-Stark water trap, the mixture is heated to reflux. After reflux 5h, cooling mixture and with all the other viscous residues of clarifying toluene layer from flask decant. Remove toluene in a vacuum to produce the triethylamine salt of 6-(2,5-dioxo-2,5-dihydro-1H-pyrroles-1-yl) hexanoate. Salt is redissolved in toluene, and adds a small amount of acetic acid, then concentrates. Immediately thereafter, the mixture is dissolved in 50% saturated sodium bicarbonate, and adds 1M HCl so that pH is adjusted to 3, forms milky precipitation. It was extracted three times with EtOAc, the combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to give pure 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoate (3.08 g, 19%).

[0964] To a stirred solution of 6-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)hexanoate (3.08g, 14.6mmol, 1.0eq) and N-hydroxysuccinimide (1.76g, 15.3mmol, 1.05eq) in EtOAc (30mL) was added dicyclohexylcarbodiimide (3.16g, 15.3mmol, 1.05eq) at 0°C. The reaction was then allowed to warm to room temperature. After 20h, the reactant was filtered and washed with EtOAc and the filtrate was concentrated. The residue was purified by flash chromatography to obtain the title compound (2.16g, 48%) as a clear oil, which slowly solidified into a white waxy solid. 1 H NMR (400 MHz, chloroform-d) δ 6.71 (s, 2H), 3.56 (t, J = 7.2 Hz, 2H), 2.86 (s, 4H), 2.63 (t, J = 7.4 Hz, 2H), 1.80 (p, J = 7.4 Hz, 2H), 1.73-1.57 (m, 2H), 1.50-1.35 (m, 2H). m / z calculated: C 14 H 16 N2O6=308.10. Found: [M+H] + =309.13. R f =0.28 (50% EtOAc / Hex).

[0965] Example 1.13: MT-OH: 3-(2-(2-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)ethoxy)ethoxy)propanoic acid.

[0966]

[0967] The title compound was prepared according to Warnecke, A., Kratz, F. Bioconjugate Chemistry 2003, 14, 377-387.

[0968] 1 H NMR (400 MHz, chloroform-d) δ 6.74 (s, 2H), 3.87-3.72 (m, 4H), 3.72-3.62 (m, 10H), 2.73-2.64 (m, 2H). m / z calculated: C13H29NO7 = 301.12. Found: [M+H] + =302.14.

[0969] Example 1.14: MT-NHS: 2,5-dioxopyrrolidin-1-yl 3-(2-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)ethoxy)ethoxy)propanoate.

[0970]

[0971] MT-OH (2.6 g, 8.6 mmol, 1.0 eq) was treated with dicyclohexylcarbodiimide (1.87 g, 9.06 mmol, 1.05 eq) and N-hydroxysuccinimide (1.04 g, 6.06 mmol, 1.05 eq) in 30 mL of 5:1 EtOAc / dioxane at room temperature. After 36 h, the mixture was filtered, washed with EtOAc, and the residue was purified by flash chromatography to give the title compound (309 mg, 9.0%) as a clear oil along with starting material (1.31 g, 50% recovery).

[0972] 1 H NMR (400 MHz, chloroform-d) δ 6.72 (s, 2H), 3.87 (t, J = 6.4 Hz, 2H), 3.74 (t, J = 5.6 Hz, 2H), 3.70-3.58 (m, 10H), 2.93 (t, J = 6.4 Hz, 2H), 2.86 (s, 4H), 1.32-1.19 (m, 2H). m / z calculated: C 17 H 22 N2O9=398.13. Found: [M+H] + =399.15, [M+Na] + =421.14. R f =0.59(10%(5%AcOH / MeOH) / 10%Hex / CH2Cl2).

[0973] Example 1.15: MT-VC-OH: (14R,17R)-1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-14-isopropyl-12,15-dioxo-17-(3-ureidopropyl)-3,6,9-trioxa-13,16-diazaoctadecane-18-anoic acid.

[0974]

[0975] Method A

[0976] To (R)-2-((R)-2-(tert-butyloxycarbonyl amino)-3-methylbutyramide)-5-urea groups valeric acid (Boc-VC-OH, 0.600g, 1.602mmol) in dichloromethane (2.5mL) solution, add trifluoroacetic acid (2.5mL).Monitor the starting material consumption in the reaction process by HPLC, then under reduced pressure concentrate, be resuspended in toluene, under reduced pressure concentrate and leave standstill 4 hours under high vacuum.A part of product (H-VC-OH.TFA, 0.5g, 1.287mmol) is suspended in 1,4-dioxane (0.5mL) and disposable add MT-NHS (0.512g, 1.287mmol), then add diisopropylethylamine (0.90mL, 4 equivalents) and allow stirring reaction to spend the night.Concentration reaction is to dryness and the oil generated is dissolved in methyl alcohol, passed through preparation HPLC purifying afterwards. Lyophilization of the desired fractions gave the title compound as a white powder (0.351 g).

[0977] Method B

[0978] The title compound was prepared according to the method described in WO 2015095953 A1.

[0979] Example 1.16: (S)-2-Amino-3-phenyl-N-(4-(2,2,2-trifluoroacetamido)phenylsulfonyl)propionamide (Compound 1).

[0980]

[0981] Prepared according to General Methods 2 and 9 from Boc-phenylalanine and 2,2,2-trifluoro-N-(4-sulfamoylphenyl)acetamide. 1 H NMR (400MHz, DMSO-d6) δ11.42 (s, 1H), 7.84 (d, J = 8.7Hz, 2H), 7.73-7.64 (m, 1H), 7.69 (d, J = 8.7Hz, 2H), 7.24-7 .14 ​​(m, 3H), 7.13-7.06 (m, 2H), 3.65-3.60 (m, 1H), 3.06 (dd, J=14.2, 5.1Hz, 1H), 2.91 (dd, J=14.1, 7.1Hz, 1H). C 17 H 16 Calculated value for F3N3O4S: m / z = 415.08 Found: [M+H] + =416.5.

[0982] Example 1.17: (S)-2-Amino-3-phenyl-N-((4-(2,2,2-trifluoroacetamido)benzyl)sulfonyl)propionamide (Compound 2).

[0983]

[0984] Prepared according to General Methods 3 and 9 from Boc-phenylalanine and 2,2,2-trifluoro-N-(4-sulfamoylphenyl)acetamide (Example 1.39). 1 H NMR (400MHz, DMSO-d6) δ7.76-7.71 (m, 2H), 7.58 (d, J=8.4Hz, 2H), 7.36-7.21 (m, 8H), 4.34 (d, J=13.1Hz, 1 H), 4.30 (d, J=13.1Hz, 1H), 3.62 (dd, J=8.2, 4.6Hz, 1H), 3.21-3.09 (m, 1H), 2.89 (dd, J=14.3, 8.3Hz, 1H). C 18 H 18 Calculated value for F3N3O4S: m / z = 429.10 Found: [M+H] + =430.7.

[0985] Example 1.18: (S)-tert-Butyl 1-(((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-(4-(2,2,2-trifluoroacetamido)phenylsulfonamido)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-ylcarbamate (Compound 3).

[0986]

[0987] The title compound was synthesized using General Method 2 from commercially available Boc-Val-Dip-Dap-OH (0.08 g) and 2,2,2-trifluoro-N-(4-sulfamoylphenyl)acetamide. 37 H 58 F3N5O 10 S calculated value: m / z = 821.39 Found: [M+H] + =823.04.

[0988] Example 1.19: (S)-2-((S)-2-(Dimethylamino)-3-methylbutanamido)-N-((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-(4-(2,2,2-trifluoroacetamido)phenylsulfonamido)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)-N,3-dimethylbutanamide (Compound 4).

[0989]

[0990] The title compound was prepared from compound 3 and N,N-dimethylvaline using General Methods 9 and 6. 39 H 63 Calculated value for F3N6O9S: m / z = 848.43 Found: [M+H] + 850.11.

[0991] Example 1.20: (S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(4-aminophenylsulfonamido)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptane-4-yl)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamide (Compound 5).

[0992]

[0993] The title compound was prepared from compound 4 using General Method 4. 37 H 64 Calculated value for N6O8S: m / z = 752.45 Found: [M+H] + 754.16.

[0994] Example 1.21: (S)-tert-Butyl 1-(((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-((4-(2,2,2-trifluoroacetamido)phenyl)methylsulfonamido)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-ylcarbamate (Compound 6).

[0995]

[0996] The title compound was prepared from commercially available Boc-Val-Dil-Dap-OH by General Method 2. 38 H 60 F3N5O 10 S calculated value: m / z = 835.40 Found: [M+H] + =836.7.

[0997] Example 1.22: (S)-2-((S)-2-(Dimethylamino)-3-methylbutanamido)-N-((3R,4S,5S)-3-methoxy-1-(S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-((4-(2,2,2-trifluoroacetamido)phenyl)methylsulfonamido)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)-N,3-dimethylbutanamide (Compound 7).

[0998]

[0999] The title compound was prepared from compound 6 following General Method 6. 40 H 65 Calculated value for F3N6O9S: m / z = 862.45 Found: [M+H] + =863.2.

[1000] Example 1.23: (S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-((4-aminophenyl)methylsulfonamido)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptane-4-yl)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamide (Compound 8).

[1001]

[1002] The title compound was prepared from compound 7 following General Method 4. 38 H 66 Calculated value for N6O8S: m / z = 766.47 Found: [M-C7H8O2S+H] + = 599.0 (fragmentation of quinone methide and loss of 4-aminobenzylsulfonate).

[1003] Example 1.24: (S)-tert-Butyl 1-(((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-((S)-1-oxo-3-phenyl-1-(4-(2,2,2-trifluoroacetamido)phenylsulfonamido)propan-2-ylamino)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-ylcarbamate (Compound 9).

[1004]

[1005] The title compound was synthesized from commercially available Boc-Val-Dip-Dap-OH (0.07 g) and compound 1 using General Method 6. 46 H 67 F3N6O 11 S calculated value: m / z = 968.45 Found: [M+Na] + =992.1.

[1006] Example 1.25: (S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N-((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-((S)-1-oxo-3-phenyl-1-(4-(2,2,2-trifluoroacetamido)phenylsulfonamido)propan-2-ylamino)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)-N,3-dimethylbutanamide (Compound 10).

[1007]

[1008] The title compound was prepared from compound 9 (110 mg) and N,N-dimethylvaline using General Methods 9 and 6. 48 H 72 F3N7O 10 S calculated value: m / z = 995.50 Found: [M+H] + 997.3.

[1009] Example 1.26: (S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-((S)-1-(4-aminophenylsulfonamido)-1-oxo-3-phenylpropan-2-ylamino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptane-4-yl)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamide (Compound 11).

[1010]

[1011] The title compound was prepared from compound 10 (100 mg) using General Method 4. 46 H 73 Calculated value for N7O9S: m / z = 899.52 Found: [M+H] + 901.3.

[1012] Example 1.27: (S)-tert-Butyl 1-(((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-((S)-1-oxo-3-phenyl-1-(4-(2,2,2-trifluoroacetamido)phenylmethylsulfonamido)propan-2-ylamino)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-ylcarbamate (Compound 12).

[1013]

[1014] The title compound was prepared by General Method 6 from commercially available Boc-Val-Dil-Dap-OH and compound 2. 47 H 69 F3N6O 11 S calculated value: m / z = 982.47 Found: [M+Na] + =1006.2.

[1015] Example 1.28: (S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N-((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-((S)-1-oxo-3-phenyl-1-(4-(2,2,2-trifluoroacetamido)phenylmethylsulfonamido)propan-2-ylamino)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)-N,3-dimethylbutanamide (Compound 13).

[1016]

[1017] The title compound was prepared from compound 12 and dimethylvaline by General Method 6. 49 H 74 F3N7O 10 S calculated value: m / z = 1009.52 Found: [M+H] + =1011.0.

[1018] Example 1.29: (S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-((S)-1-(4-aminophenylmethylsulfonamido)-1-oxo-3-phenylpropan-2-ylamino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptane-4-yl)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamide (Compound 14).

[1019]

[1020] Compound C was prepared from compound 13 by general method 4. 47 H 75 N7O95 calculated value: m / z = 913.53 Found: [M-C7H a O2S+Na] + =768.1 (fragmentation of quinone methide and loss of 4-aminobenzylsulfonate).

[1021] Example 1.30: General Method 10 - Hydrogenation.

[1022] A magnetic stirrer is added to a solution of the sample to be reduced in methanol, ethanol, acetic acid, ethyl acetate, a mixture thereof or other suitable solvent. The flask containing the stirred solution is equipped with a two-way gas line adapter and evacuated and filled with nitrogen under reduced pressure. This process is repeated 3 times. 10% Pd / C is added as a solid or slurry, usually at 10 mol% palladium relative to the reactants. The container is evacuated again under reduced pressure and filled with a hydrogen balloon. The reaction is monitored for completion by HPLC-MS and, once completed, filtered through a diatomaceous earth pad on a filter funnel. The filtrate is concentrated under reduced pressure and used as is or purified by silica gel or preparative HPLC chromatography.

[1023] Example 1.31: Perfluorophenyl 3-(2-(2-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)ethoxy)ethoxy)propanoate.

[1024] To a stirred solution of 3-(2-(2-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)ethoxy)ethoxy)propanoic acid (Example 1.13) (2.28 g, 7.57 mmol) in dichloromethane (100 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.59 g, 1.1 equiv) and pentafluorophenol (1.53 g, 1.1 equiv). The reaction was allowed to stir overnight, at which point HPLC-MS showed no starting material remaining (Rt = 5.30 min, 490.4 m / z, full gradient). The crude reaction mixture was diluted with saturated sodium bicarbonate (-20 mL) and the mixture was transferred to a separatory funnel. The organic phase was washed with brine (-50 mL), dried over MgSO4, filtered and concentrated to give a light yellow oil. The oil was dissolved in a minimum amount of dichloromethane and loaded onto a 100 g silica gel column for purification (Isolera, 10-100% EtOAc in hexanes over 12 column volumes). Fractions containing the desired material were pooled and concentrated under reduced pressure to give a colorless oil (3.32 g, 94%).

[1025] Example 1.32: tert-Butyl (3R,4S,5S)-4-((S)-2-(Benzyloxycarbonylamino)-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoate, Cbz-Val-Dil-OtBu.

[1026]

[1027] The title compound was prepared following General Method 6 from commercially available Cbz-Val-OH and H-Dil-OtBu·HCl.

[1028] 1 H NMR (400 MHz, chloroform-d) δ 740-7.30 (m, 5H), 5.54 (d, J = 9.2 Hz, 1H), 5.12 (s, 2H), 4.73 (s, 1H), 4.54 (dd, J = 9.2, 5.6 Hz, 1H), 3.91 (s, 1H), 3.37 (s, 3H), 2.98 (s, 3H), 2.47 (d, J = 16.5 Hz, 1H), 2.33 ( dd, J=15.6, 9.1Hz, 1H), 2.07-1.96 (m, 1H), 1.84-1.60 (m, 1H), 1.48 (s, 9H), 1.45-1.32 (m, 2H ), 1.04 (d, J=6.8Hz, 3H), 0.98 (d, J=6.6Hz, 3H), 0.94 (d, J=6.8Hz, 3H), 0.86 (t, J=7.4Hz, 3H). C 27 H 44Calculated value for N2O6: m / z = 492.32 Found: [M+H] + =515.8[M+Na] + . R f =0.78 (50% EtOAc / Hex).

[1029] Example 1.33: (3R,4S,5S)-4-((S)-2-(((Benzyloxy)carbonyl)amino)-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoic acid, Cbz-Val-Dil-OH.

[1030]

[1031] The title compound was prepared from Cbz-Val-Dil-OtBu (Example 1.32) using General Method 9. 23 H 36 Calculated value for N2O6: m / z = 436.26 Found: [M+Na] + 459.81.1H NMR (400MHz, methanol-d4) δ7.47-7.22(m, 5H), 5.21-4.99(m, 2H), 4.83-4.54(m, 1H), 4.39 (d, J=8.0Hz, 1H), 3.96 (s, 1H), 3.43-3.33 (s, 3H), 3.07 (s, 3H), 2. 63 (dd, J=15.9, 2.9Hz, 1H), 2.38 (dd, J=15.8, 9.3Hz, 1H), 2.15-1.95 (m, 1H) , 1.83 (s, 1H), 1.52-1.30 (m, 1H), 1.07-0.91 (m, 9H), 0.85 (t, J=7.4Hz, 3H).

[1032] Example 1.34: tert-Butyl (3R,4S,5S)-4-((S)-2-amino-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoate, H-Val-Dil-OtBu.

[1033]

[1034] The title compound was generated from Cbz-Val-Dil-OtBu (438 mg, 0.889 mmol) according to General Method 10 to give the desired product (288 mg, 90%) as a clear film. 1H NMR (400 MHz, chloroform-d) δ 4.76 (s, 1H), 3.92 (s, 1H), 3.50 (d, J = 5.1 Hz, 1H), 3.38 (s, 3H), 2.92 (s, 3H), 2.48 (dd, J = 15.7, 3.1 Hz, 1H), 2.35 (dd, J = 15.6, 8.8 Hz, 1H), 1.93 (dq, J = 10.9, 6.5 Hz, 1H), 1.82-1.60 (m, 1H), 1.51-1.46 (m, 11H), 1.05-0.85 (m, 12H). 19 H 38 Calculated value for N2O4: m / z = 358.28 Found: [M+Na] + =381.8.

[1035] Example 1.35: (3R,4S,5S)-tert-Butyl 4-((S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoate, Dov-Val-Dil-OtBu.

[1036]

[1037] The title compound was prepared following General Method 6 from H-Val-Dil-OtBu and N,N-dimethylvaline.

[1038] 1 H NMR (400 MHz, chloroform-d) δ 7.09 (d, J = 8.8 Hz, 1H), 4.79 (t, J = 7.6 Hz, 1H), 4.00-3.81 (m, 1H), 3.75 (s, 1H), 3.37 (s, 3H), 3.26 (s, 1H), 3.00 (s, 3H), 2.74 (s, 6H), 2.4 9(d, J=15.9Hz, 1H), 2.38-2.20(m, 2H), 2.13-2.05(m, 1H), 1.81-1.62(m, 1H) , 1.51-1.43 (m, 10H), 1.33 (s, 1H), 1.18-0.89 (m, 15H), 0.83 (t, J=7.2Hz, 3H). C 26 H 51 Calculated value for N3O5: m / z = 485.38 Found: [M+Na] + =508.9. R f =0.36 (5% MeOH / CH2Cl2).

[1039] Example 1.36: (3R,4S,5S)-tert-Butyl 4-((S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoic acid, Dov-Val-Dil-OH.

[1040]

[1041] The title compound was prepared following General Method 9 from Dov-Val-Dil-OtBu.

[1042] 1 H NMR (400 MHz, chloroform-d) δ 4.98 (t, J = 10.0 Hz, 1H), 4.65 (dd, J = 9.3, 3.1 Hz, 1H), 4.08 (d, J = 10.6 Hz, 1H), 3.61-3.53 (m, 1H), 3.39 (s, 3H), 3.24 (s, 3H), 3.13 (s, 3H), 2.93 (s, 3H), 2.77 (dd, J = 17.0, 9.8 Hz, 1H), 2.66 (dd, J = 13.7, 11.8 Hz, 1H). =17.3, 1.9Hz, 1H), 2.31-2.26 (m, 1H), 2.07 (dt, J = 10.8, 5.5Hz, 1H), 1.97-1.85 (m, 1H), 1.29-1.24 (m, 1H ), 1.13 (d, J = 6.7Hz, 3H), 1.08-1.01 (m, 6H), 1.01-0.95 (m, 6H), 0.90-0.81 (m, 1H), 0.77 (t, J = 6.9Hz, 3H) C 22 H 43 Calculated value for N3O5: m / z = 429.32. Found: [M+H] + =430.8.

[1043] Example 1.37: (5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H-fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradec-14-oic acid tert-butyl ester, Fmoc-(Me)Val-Val-Dil-OtBu.

[1044]

[1045] The title compound was prepared from Fmoc-(Me)-(L)-Valine-OH and H-Val-Dil-OtBu according to General Method 6. 40 H 59 Calculated value for N3O7: m / z = 693.44 Found: [M+H]+ 694.98.

[1046] Example 1.38: (5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H-fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradec-14-oic acid, Fmoc-(Me)Val-Val-Dil-OH.

[1047]

[1048] The title compound was prepared from Fmoc-(Me)Val-Val-Dil-OtBu using General Method 9. 36 H 51 Calculated value for N3O7: m / z = 637.37 Found: [M+H] + 638.91.

[1049] Example 1.39: 2,2,2-Trifluoro-N-(4-sulfamoylphenyl)acetamide.

[1050]

[1051] To the stirred suspension of sulfanilamide (1.72g, 10mmol) in dioxane (20mL), trifluoroacetic anhydride (1.69mL, 1.2 equivalents) is added. Slowly dissolving solid to generate uniform solution and after a short period, a new batch of solids is formed. The reaction is diluted with ether (100mL) and the generated suspension is filtered on a Buchner funnel. Collect solid and dry under reduced pressure to provide the title compound of sufficient purity for further use (2.60g, 97%).

[1052] Example 1.40: (2R,3R)-3-Methoxy-2-methyl-3-((S)-pyrrolidin-2-yl)-N-(4-(2,2,2-trifluoroacetamido)phenylsulfonyl)propionamide.

[1053]

[1054] The title compound was prepared following General Methods 2 and 9 from commercially available Boc-Dap-OH and 2,2,2-trifluoro-N-(4-sulfamoylphenyl)acetamide.

[1055] 1H NMR (400MHz, methanol-d4) δ8.06 (d, J=8.9Hz, 2H), 7.92 (d, J=8.9Hz, 2H), 3.69 (dd, J=6.6, 3.0Hz, 1H), 3.48 (s, 3 H), 3.51-3.39 (m, 1H), 3.33-3.14 (m, 2H), 2.64 (p, J=7.0Hz, 1H), 2.06-1.68 (m, 4H), 1.19 (d, J=7.1Hz, 3H). C 17 H 22 Calculated value for F3N3O5S: m / z = 437.12 Found: [M+H] + =438.6.

[1056] Example 1.41: Benzyl ((S)-1-(((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-((4-(2,2,2-trifluoroacetamido)phenyl)sulfonamido)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate.

[1057]

[1058] The title compound was prepared from Cbz-Val-Dil-OH and the product of Example 1.40 according to General Method 2. 40 H 56 F3N5O 10 S calculated value: m / z = 855.37 Found: [M+H] + 857.07.

[1059] Example 1.42: (S)-2-Amino-N-((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-((4-(2,2,2-trifluoroacetamido)phenyl)sulfonamido)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)-N,3-dimethylbutanamide.

[1060]

[1061] The title compound was prepared from the product of Example 1.41 according to General Method 10. 32 H 50 Calculated value for F3N5O8S: m / z = 721.33 Found: [M+H] + 722.70.

[1062] Example 1.43: (3R,4S,5S)-tert-Butyl 4-((S)-2-((R)-1-isopropylpiperidine-2-carboxamido)-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoate.

[1063]

[1064] The title compound was prepared from (R)-1-isopropylpiperidine-2-carboxylic acid and H-Val-Dil-OtBu according to General Method 6. 28 H 53 Calculated value for N3O5: m / z = 511.40 Found: [M+H] + 512.77.

[1065] Example 1.44: (3R,4S,5S)-4-((S)-2-((R)-1-isopropylpiperidine-2-carboxamido)-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoic acid.

[1066]

[1067] The title compound was prepared from the tert-butyl product of Example 1.43 according to General Method 9. 24 H 45 Calculated value for N3O5: m / z = 455.34 Found: [M+H] + 456.70.

[1068] Example 1.45: (R)-1-Isopropyl-N-((S)-1-(((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-((4-(2,2,2-trifluoroacetamido)phenyl)sulfonamido)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)piperidine-2-carboxamide (Compound 15).

[1069]

[1070] The title compound was prepared from the product of Example 1.40 and the product of Example 1.44 according to General Method 6. 41 H 65 Calculated value for F3N6O9S: m / z = 874.45 Found: [M+H] + 876.0.

[1071] Example 1.46: (R)-N-((S)-1-(((3R,4S,5S)-1-((S)-2-((1R,2R)-3-((4-aminophenyl)sulfonamido)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)-1-isopropylpiperidine-2-carboxamide (Compound 16).

[1072]

[1073] The title compound was prepared from compound 15 according to General Method 4. 39 H 66 Calculated value for N6O85: m / z = 778.47 Found: [M+H] + 780.06.

[1074] Example 1.47: tert-Butyl (1-(((S)-1-(((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-((4-(2,2,2-trifluoroacetamido)phenyl)sulfonamido)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-2-methyl-1-oxopropan-2-yl)carbamate.

[1075]

[1076] The title compound was prepared from the product of Example 1.42 and commercially available α-(Boc-amino)isobutyric acid according to General Method 6. 41 H 65 F3N6O 11 S calculated value: m / z = 906.44 Found: [M+H] + 907.80.

[1077] Example 1.48: Tert-butyl (1-(((S)-1-(((3R,4S,5S)-1-((S)-2-((1R,2R)-3-((4-aminophenyl)sulfonamido)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-2-methyl-1-oxopropan-2-yl)carbamate.

[1078]

[1079] The title compound was prepared from the product of Example 1.47 according to General Method 4. 39 H 66 N6O 10 S calculated value: m / z = 810.46 Found: [M+H] + 811.84.

[1080] Example 1.49: (S)-2-(2-Amino-2-methylpropionamido)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-((4-aminophenyl)sulfonamido)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-N,3-dimethylbutanamide (Compound 17).

[1081]

[1082] The title compound was prepared from the product of Example 1.48 according to General Method 9. 34 H 58 Calculated value for N6O8S: m / z = 710.40 Found: [M+H] + 711.77.

[1083] Example 1.50 (6S,9S,12S,13R)-12-((S)-sec-butyl)-9-isopropyl-13-methoxy-2,2,5,11-tetramethyl-4,7,10-trioxo-6-(2-phenylpropan-2-yl)-3-oxa-5,8,11-triazapentadecan-15-oic acid tert-butyl ester.

[1084]

[1085] The title compound was prepared from (S)-2-((tert-Butyloxycarbonyl)(methyl)amino)-3-methyl-3-phenylbutanoic acid (prepared according to WO 2015095953 A1) and H-Val-Dil-OtBu using General Method 6. 36 H 61 Calculated value for N3O7: m / z = 647.45 Found: [M+H] + 649.12.

[1086] Example 1.51: (3R,4S,5S)-4-((S)-N,3-Dimethyl-2-((S)-3-methyl-2-(methylamino)-3-phenylbutanamido)butanamido)-3-methoxy-5-methylheptanoic acid.

[1087]

[1088] The title compound was prepared from the product of Example 1.50 according to General Method 9. 27 Calculated value for H45N3O5: m / z = 491.34 Found: [M+H] + 492.73.

[1089] Example 1.52: tert-Butyl (1-(((S)-1-(((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-((4-(2,2,2-trifluoroacetamido)phenyl)sulfonamido)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-2-methyl-1-oxopropan-2-yl)carbamate (Compound 18).

[1090]

[1091] The title compound was prepared from the product of Example 1.51 and the product of Example 1.42 according to General Method 6. 44 H 65 Calculated value for F3N6O9S: m / z = 910.45 Found: [M+H] + 911.91.

[1092] Example 1.53 (S)-N-((3R,4S,5S)-1-((S)-2-(((1R,2R)-3-((4-aminophenyl)sulfonamido)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)-3-phenylbutanamido)butanamide (Compound 19).

[1093]

[1094] The title compound was prepared from the product of Example 1.52 using General Method 4. 42 H 66 Calculated value for N6O8S: m / z = 814.47 Found: [M+H] + 816.08.

[1095] Example 1.54: tert-Butyl ((S)-1-(((S)-1-(((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-((4-(2,2,2-trifluoroacetamido)phenyl)sulfonamido)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamate.

[1096]

[1097] The title compound was prepared from the product of Example 1.42 and commercially available Boc-(Me)-(L)-Valine-OH using General Method 6. 43 H 69 F3N6O 11 S calculated value: m / z = 934.47 Found: [M+H] + 935.87.

[1098] Example 1.55: tert-Butyl ((S)-1-(((S)-1-(((3R,4S,5S)-1-((S)-2-((1R,2R)-3-((4-aminophenyl)sulfonamido)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamate.

[1099]

[1100] The title compound was prepared from the product of Example 1.54 using General Method 4. 41 H 70 N6O 10 S calculated value: m / z = 838.49 Found: [M+H] + 839.85.

[1101] Example 1.56: (S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-((4-aminophenyl)sulfonamido)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)butanamido)butanamide (Compound 20).

[1102]

[1103] The title compound was prepared from the product of Example 1.54 using General Method 9. 36 H 62 Calculated value for N6O8S: m / z = 738.43 Found: [M+H] + 739.84.

[1104] Example 1.57: 2,2,2-Trifluoro-N-(4-(sulfamoylmethyl)phenyl)acetamide.

[1105]

[1106] The title compound was prepared according to WO 2015095953 A1.

[1107] Example 1.58: 2,2,2-Trifluoro-N-(4-sulfamoylbenzyl)acetamide.

[1108]

[1109] The title compound was prepared according to WO 2015095953 A1.

[1110] Example 1.59: (S)-tert-Butyl 2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-((4-((2,2,2-trifluoroacetamido)methyl)phenyl)sulfonamido)propyl)pyrrolidine-1-carboxylate.

[1111]

[1112] The title compound was prepared from commercially available Boc-dolaproline-OH and 2,2,2-trifluoro-N-(4-sulfamoylbenzyl)acetamide using General Method 2. 23 H 32 Calculated value for F3N3O7S: m / z = 551.19 Found: [M+Na] + 574.92.

[1113] Example 1.60: (2R,3R)-3-Methoxy-2-methyl-3-((S)-pyrrolidin-2-yl)-N-((4-((2,2,2-trifluoroacetamido)methyl)phenyl)sulfonyl)propanamide.

[1114]

[1115] The title compound was prepared from the product of Example 1.59 using General Method 9. 18 H 24Calculated value for F3N3O5S: m / z = 451.14 Found: [M+H] + 452.71.

[1116] Example 1.61: (S)-2-((S)-2-(Dimethylamino)-3-methylbutanamido)-N-((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-((4-((2,2,2-trifluoroacetamido)methyl)phenyl)sulfonamido)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)-N,3-dimethylbutanamide (Compound 21).

[1117]

[1118] The title compound was prepared from Dov-Val-Dil-OH (Example 1.36) and the product of Example 1.60 using General Method 6. 40 H 65 Calculated value for F3N6O9S: m / z = 862.45 Found: [M+H] + 863.80.

[1119] Example 1.62: (S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-((4-(aminomethyl)phenyl)sulfonamido)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamide (Compound 22).

[1120]

[1121] The title compound was prepared from compound 51 according to General Method 4. 38 H 66 Calculated value for N6O8S: m / z = 766.47 Found: [M+H] + 767.85.

[1122] Example 1.63: tert-Butyl (S)-(1-oxo-3-phenyl-1-((4-((2,2,2-trifluoroacetamido)methyl)phenyl)sulfonamido)propan-2-yl)carbamate (Compound 63)

[1123]

[1124] The title compound was prepared from Boc-(L)-Phe-OH and 2,2,2-trifluoro-N-(4-sulfamoylbenzyl)acetamide (Example 1.58) using General Method 2. 23 H 26 Calculated value for F3N3O6S: m / z = 529.15 Found: [M+Na] + 552.52.

[1125] Example 1.64: (S)-2-Amino-3-phenyl-N-((4-((2,2,2-trifluoroacetamido)methyl)phenyl)sulfonyl)propionamide.

[1126]

[1127] The title compound was prepared from the product of Example 1.63 using General Method 9. 18 H 18 Calculated value for F3N3O4S: m / z = 429.10 Found: [M+H] + 430.51. 1 H NMR (400 MHz, methanol-d4) δ 8.05-7.98 (m, 2H), 7.56 (d, J = 8.2 Hz, 2H), 7.33-7.22 (m, 3H), 7.09 (d, J = 6.7 Hz, 2H), 4.59 (d, J = 4.4 Hz, 2H), 4.06 (t, J = 6.8 Hz, 1H), 3.15 (dd, J = 14.1, 6.3 Hz, 1H), 3.03 (dd, J = 14.2, 7.4 Hz, 1H).

[1128] Example 1.65: (S)-tert-Butyl 2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-(((S)-1-oxo-3-phenyl-1-((4-((2,2,2-trifluoroacetamido)methyl)phenyl)sulfonamido)propan-2-yl)amino)propyl)pyrrolidine-1-carboxylate.

[1129]

[1130] The title compound was prepared according to General Method 6 from commercially available Boc-dolaproline-OH and the product of Example 1.64. 32 H 41 Calculated value for F3N4O8S: m / z = 698.26 Found: [M+Na] + 721.62.

[1131] Example 1.66: (2R,3R)-3-Methoxy-2-methyl-N-((S)-1-oxo-3-phenyl-1-((4-((2,2,2-trifluoroacetamido)methyl)phenyl)sulfonamido)propan-2-yl)-3-((S)-pyrrolidin-2-yl)propanamide.

[1132]

[1133] The title compound was prepared from the product of Example 1.65 using General Method 9. 27 H 33 Calculated value for F3N4O6S: m / z = 598.21 Found: [M+H] + 599.62.

[1134] Example 1.67: (S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N-((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-(((S)-1-oxo-3-phenyl-1-((4-((2,2,2-trifluoroacetamido)methyl)phenyl)sulfonamido)propan-2-yl)amino)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)-N,3-dimethylbutanamide (Compound 23).

[1135]

[1136] The title compound was prepared from Dov-Val-Dil-OH (Example 1.36) and the product of Example 1.66 according to General Method 6. 49 H 74 F3N7O 10 S calculated value: m / z = 1009.52 Found: [M+H] + 1011.04.

[1137] Example 1.68: (S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((S)-1-((4-(aminomethyl)phenyl)sulfonamido)-1-oxo-3-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptane-4-yl)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamide (Compound 24).

[1138]

[1139] The title compound was prepared from the product of Example 1.67 according to General Method 4. 47 H 75 Calculated value for N7O9S: m / z = 913.53 Found: [M+H] + 915.09.

[1140] Example 1.69: 2,2,2-Trifluoro-N-(4-(sulfamoylmethyl)benzyl)acetamide.

[1141]

[1142] The title compound was prepared according to WO 2015095953 A1.

[1143] Example 1.70: (S)-tert-Butyl 2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-(((4-((2,2,2-trifluoroacetamido)methyl)phenyl)methyl)sulfonamido)propyl)pyrrolidine-1-carboxylate.

[1144]

[1145] The title compound was prepared using General Method 2 from commercially available Boc-dolaproline-OH and 2,2,2-trifluoro-N-(4-(sulfamoylmethyl)benzyl)acetamide (Example 1.69). 24 H 34 Calculated value for F3N3O7S: m / z = 565.21 Found: [M+Na] + 588.75.

[1146] Example 1.71: (2R,3R)-3-Methoxy-2-methyl-3-((S)-pyrrolidin-2-yl)-N-((4-((2,2,2-trifluoroacetamido)methyl)benzyl)sulfonyl)propionamide.

[1147]

[1148] The title compound was prepared from the product of Example 1.69 according to General Method 9. 19 Calculated value for H26F3N3O5S: m / z = 465.15 Found: [M+H] + 466.77.

[1149] Example 1.72: (S)-2-((S)-2-(Dimethylamino)-3-methylbutanamido)-N-((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-(((4-((2,2,2-trifluoroacetamido)methyl)phenyl)methyl)sulfonamido)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)-N,3-dimethylbutanamide (Compound 25).

[1150]

[1151] The title compound was prepared from the product of Example 1.36 and the product of Example 1.71 according to General Method 6. 41 H 67 Calculated value for F3N6O9S: m / z = 876.46 Found: [M+H] + 878.22.

[1152] Example 1.73: (S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((4-(aminomethyl)phenyl)methyl)sulfonamido)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamide (Compound 26).

[1153]

[1154] The title compound was prepared from the product of Example 1.72 according to General Method 4. 39 H 68 Calculated value for N6O8S: m / z = 780.48 Found: [M+H] + 782.20.

[1155] Example 1.74: (S)-tert-Butyl(1-oxo-3-phenyl-1-(((4-((2,2,2-trifluoroacetamido)methyl)phenyl)methyl)sulfonamido)propan-2-yl)carbamate.

[1156]

[1157] The title compound was prepared according to General Method 2 from Boc-(L)-Phe-OH and 2,2,2-trifluoro-N-(4-(sulfamoylmethyl)benzyl)acetamide (Example 1.69). 24 Calculated value for H28F3N3O6S: m / z = 543.17 Found: [M+Na]+ 566.78.

[1158] Example 1.75: (S)-2-Amino-3-phenyl-N-((4-((2,2,2-trifluoroacetamido)methyl)benzyl)sulfonyl)propionamide.

[1159]

[1160] The title compound was prepared from the product of Example 1.74 using General Method 9. 19 H 20 Calculated value for F3N3O4S: m / z = 443.11 Found: [M+H] + 444.55. 1 H NMR (400 MHz, Methanol-d4) δ 7.46-7.27 (m, 9H), 4.51 (s, 2H), 4.46 (s, 2H), 3.84 (dd, J = 9.3, 4.3 Hz, 1H), 3.29 (dd, 1H), 2.95 (dd, J = 14.5, 9.4 Hz, 1H).

[1161] Example 1.76: (S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-(((S)-1-oxo-3-phenyl-1-(((4-((2,2,2-trifluoroacetamido)methyl)phenyl)methyl)sulfonamido)propan-2-yl)amino)propyl)pyrrolidine-1-carboxylate.

[1162]

[1163] The title compound was prepared according to General Method 6 from commercially available Boc-dolaproline-OH and the product of Example 1.75. 33 H 43 Calculated value for F3N4O8S: m / z = 712.28 Found: [M+Na] + 735.65.

[1164] Example 1.77: (2R,3R)-3-Methoxy-2-methyl-N-((S)-1-oxo-3-phenyl-1-(((4-((2,2,2-trifluoroacetamido)methyl)phenyl)methyl)sulfonamido)propan-2-yl)-3-((S)-pyrrolidin-2-yl)propanamide.

[1165]

[1166] The title compound was prepared from the product of Example 1.76 using General Method 9. 28 H 35Calculated value for F3N4O6S: m / z = 612.22 Found: [M+H] + 613.58.

[1167] Example 1.78: (S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N-((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-(((S)-1-oxo-3-phenyl-1-(((4-((2,2,2-trifluoroacetamido)methyl)phenyl)methyl)sulfonamido)propan-2-yl)amino)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)-N,3-dimethylbutanamide (Compound 27).

[1168]

[1169] The title compound was prepared from Dov-Val-Dil-OH (Example 1.36) and the product of Example 1.77 using General Methods 9 and 6. 50 H 76 F3N7O 10 S calculated value: m / z = 1023.53 Found: [M+H] + 1024.94.

[1170] Example 1.79: (S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((S)-1-(((4-(aminomethyl)phenyl)methyl)sulfonamido)-1-oxo-3-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamide (Compound 28)

[1171]

[1172] The title compound was prepared from the product of Example 1.78 using General Method 4. 48 H 77 Calculated value for N7O9S: m / z = 927.55 Found: [M+H] + 928.92.

[1173] Example 1.80: 2,2,2-Trifluoro-N-(1-(4-sulfamoylphenyl)cyclopropyl)acetamide.

[1174]

[1175] The title compound was prepared according to WO 2015095953 A1.

[1176] Example 1.81: (2R,3R)-3-Methoxy-2-methyl-3-((S)-pyrrolidin-2-yl)-N-(4-(1-(2,2,2-trifluoroacetamido)cyclopropyl)phenylsulfonyl)propanamide.

[1177]

[1178] The title compound was prepared following General Methods 2 and 9 from commercially available Boc-Dap-OH and 2,2,2-trifluoro-N-(1-(4-sulfamoylphenyl)cyclopropyl)acetamide (Example 1.80). 1 H NMR (400 MHz, DMSO-d 6 ) δ12.19 (s, 1H), 10.32 (s, 1H), 7.86 (d, J = 8.6Hz, 2H), 7.35 (d, J = 8.6Hz, 2H), 7.31 (s, 1H), 3.58 (dd, J = 5.7, 3.7Hz, 1H), 3.28 (s, 3H), 3.11 (t, J=6.8Hz, 2H), 2.59 (dq, J=13.0, 6.5Hz, 1H), 1.90-1.68 (m, 3H), 1.63-1.56 (m, 1H), 1.44-1.35 (m, 4H), 1.04 (d, J=7.0Hz, 3H). C20H 26 Calculated value for F3N3O5S: m / z = 477.15 Found: [M+H] + =478.6.

[1179] Example 1.82: (S)-2-((S)-2-(Dimethylamino)-3-methylbutanamido)-N-((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-(4-(1-(2,2,2-trifluoroacetamido)cyclopropyl)phenylsulfonamido)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)-N,3-dimethylbutanamide (Compound 29).

[1180]

[1181] The title compound was prepared from Dov-Val-Dil-OH (Example 1.36) and the product of Example 1.81 according to General Method 6. 42 H 67 Calculated value for F3N6O9S: m / z = 888.46 Found: [M+H]+ =889.3.

[1182] Example 1.83: (S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(4-(1-aminocyclopropyl)phenylsulfonamido)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamide (Compound 30).

[1183]

[1184] The title compound was prepared from the product of Example 1.82 according to General Method 4. 40 H 68 Calculated value for N6O8S: m / z = 792.48 Found: [M+Na] + =815.9.

[1185] Example 1.84: (S)-2-Amino-3-phenyl-N-(4-(1-(2,2,2-trifluoroacetamido)cyclopropyl)phenylsulfonyl)propionamide.

[1186]

[1187] The title compound was prepared following General Methods 2 and 9 from Boc-Phe-OH and 2,2,2-trifluoro-N-(1-(4-sulfamoylphenyl)cyclopropyl)acetamide (Example 1.80). 1 H NMR (400 MHz, DMSO-d 6 )δ10.30 (s, 1H), 7.87 (b, 3H), 7.79 (d, J=8.3Hz, 2H), 7.25 (d, J=8.2Hz, 2H), 7.23-7.16 (m, 3H), 7.08 (dd, J=6.6, 2 .9Hz, 2H), 3.78 (s, 1H), 3.06 (dd, J=14.2, 5.3Hz, 1H), 2.93 (dd, J=14.1, 7.2Hz, 1H), 1.36 (dd, J=6.6, 3.0Hz, 4H). C 20 H 20 Calculated value for F3N3O4S: m / z = 455.11 Found: [M+H] + =456.6.

[1188] Example 1.85: (S)-tert-Butyl 1-(((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-((S)-1-oxo-3-phenyl-1-(4-(1-(2,2,2-trifluoroacetamido)cyclopropyl)phenylsulfonamido)propan-2-ylamino)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-ylcarbamate.

[1189]

[1190] The title compound was prepared according to General Method 2 from commercially available Boc-Val-Dil-Dap-OH and the product of Example 1.84. 49 H 71 F3N6O 11 S calculated value: m / z = 1008.49 Found: [M+Na] + =1031.9.

[1191] Example 1.86: (S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N-((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-((S)-1-oxo-3-phenyl-1-(4-(1-(2,2,2-trifluoroacetamido)cyclopropyl)phenylsulfonamido)propan-2-ylamino)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)-N,3-dimethylbutanamide (Compound 31).

[1192]

[1193] The title compound was prepared from the product of Example 1.85 and N,N-dimethylvaline following General Methods 9 and 6. 51 H 76 F3N7O 10 S calculated value: m / z = 1035.53 Found: [M+H] + =1036.5.

[1194] Example 1.87: (S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-((S)-1-(4-(1-aminocyclopropyl)phenylsulfonamido)-1-oxo-3-phenylpropan-2-ylamino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamide (Compound 32).

[1195]

[1196] The title compound was prepared from the product of Example 1.86 according to General Method 4. 49 H 77 Calculated value for N7O9S: m / z = 939.55 Found: [M+H] + =940.5.

[1197] Example 1.88: (S)-tert-Butyl 2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-((phenylmethyl)sulfonamido)propyl)pyrrolidine-1-carboxylate.

[1198]

[1199] The title compound was prepared from commercially available Boc-dolaproline-OH and benzylsulfonamide using General Method 2. 21 H 32 Calculated value for N2O6S: m / z = 440.20 Found: [M+H] + 463.71.

[1200] Example 1.89: (2R,3R)-N-(Benzylsulfonyl)-3-methoxy-2-methyl-3-((S)-pyrrolidin-2-yl)propanamide.

[1201]

[1202] The title compound was prepared from the product of Example 1.88 using General Method 9. 16 H 24 Calculated value for N2O4S: m / z = 340.15 Found: [M+H] + 341.75.

[1203] Example 1.90: (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-(((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-((phenylmethyl)sulfonamido)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamate.

[1204]

[1205] The title compound was prepared from the product of Example 1.89 and the product of Example 1.38 according to General Method 6. 52 H 73 N5O 10 S calculated value: m / z = 959.51 Found: [M+H] + 961.15.

[1206] Example 1.91: (S)-N-((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-((phenylmethyl)sulfonamido)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)butanamido)butanamide (Compound 33).

[1207]

[1208] The title compound was prepared from the product of Example 1.90 according to General Method 7. 37 H 63 Calculated value for N5O8S: m / z = 737.44 Found: [M+H] + 739.07.

[1209] Example 1.92: (S)-tert-Butyl 2-((1R,2R)-1-methoxy-3-((4-(methoxycarbonyl)phenyl)sulfonamido)-2-methyl-3-oxopropyl)pyrrolidine-1-carboxylate.

[1210]

[1211] The title compound was prepared from methyl 4-sulfamoylbenzoate and Boc-Dap-OH according to General Method 2. 22 H 32 Calculated value for N2O8S: m / z = 484.19. Found: [M+Na] +=507.6.

[1212] Example 1.93: Methyl 4-(N-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanoyl)sulfamoyl)benzoate (Compound 34).

[1213]

[1214] The title compound was prepared from the product of Example 1.92 and Dov-Val-Dil-OH (Example 1.36) according to General Methods 9 and 6. 22 H 32 Calculated value for N2O8S: m / z = 795.45. Found: [M+Na] + =818.8.

[1215] Example 1.94: (S,E)-4-((S)-2-((tert-Butoxycarbonyl)amino)-N,3,3-trimethylbutanamido)-2,5-dimethylhexan-2-anoic acid (Compound 83)

[1216]

[1217] The title compound was prepared from ethyl (S,E)-4-((S)-2-((tert-butoxycarbonyl)amino)-N,3,3-trimethylbutanamido)-2,5-dimethylhexan-2-anoate according to General Method 4. 20 H 36 Calculated value for N2O5: m / z = 384.26 Found: [M+H] + =407.71. 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.80 (dd, J = 9.6, 1.8 Hz, 1H), 5.29 (d, J = 10.1 Hz, 1H), 5.16 (t, J = 10.0 Hz, 1H), 4.46 (d, J = 10.1 Hz, 1H), 3.03 (s, 3H), 1.95 (d, J = 1.5 Hz, 3H), 1.44 (s, 9H), 0.99 (s, 9H), 0.92 (d, J = 6.5 Hz, 3H), 0.88 (d, J = 6.5 Hz, 3H).

[1218] Example 1.95: Methyl (2R,3R)-3-methoxy-2-methyl-3-((S)-pyrrolidin-2-yl)propanoate.

[1219]

[1220] To a stirred solution of Boc-Dap-OH (0.635 g, 2.21 mmol) in dichloromethane / methanol (95:5, v / v, 10 mL) was added TMS-diazomethane (2 M in hexanes, 1.35 mL, 1.2 equiv). The reaction was monitored and when bubbling ceased, HPLC-MS analysis showed complete conversion to the ester. The remaining TMS-diazomethane was quenched by the addition of acetic acid and once all yellow color disappeared, the reaction was concentrated under reduced pressure. The residue was dissolved in dichloromethane and the Boc-protecting group was removed according to General Method 9.1. The material was used "as is" without further purification. 10 H 19 NO3 calculated value: m / z = 201.14 Found: [M+H] + =202.56. 1 H NMR (400 M IHz, methanol-d4) δ 3.88 (dd, J = 6.0, 3.6 Hz, 1H), 3.74 (s, 3H), 3.73-3.62 (m, 1H), 3.52 (s, 3H), 3.32-3.26 (m, 2H), 2.88-2.74 (m, 1H), 2.15-1.87 (m, 4H), 1.29 (d, J = 7.2 Hz, 3H).

[1221] Example 1.96: Methyl (2R,3R)-3-((S)-1-((S,E)-4-((S)-2-((tert-Butoxycarbonyl)amino)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanoate.

[1222]

[1223] The title compound was prepared from the product of Example 1.94 and the product of Example 1.95 according to General Method 6. 30 H 53 Calculated value for N3O7: m / z = 567.39 Found: [M+Na] + =590.85. 1H NMR (400 MHz, chloroform-d) δ 5.53 (dd, J = 9.0, 1.8 Hz, 1H), 5.18 (d, J = 10.1 Hz, 1H), 5.02 (dd, J = 10.6, 8.8 Hz, 1H), 4.37 (d, J = 10.1 Hz, 1H), 4.11-4.01 (m, 1H), 3.92 (dd, J = 8.2, 2.8 Hz, 1H), 3.66 (s, 3H), 3.51-3.42 (m, 1H), 3 .39(s, 3H), 3.34-3.23(m, 1H), 2.89(s, 3H), 2.54-2.43(m, 1H), 1.86(s, 3H), 1.95-1.77(m, 3H), 1.70-1. 52 (m, 1H), 1.36 (s, 9H), 1.21 (d, J=6.9Hz, 3H), 0.92 (s, 9H), 0.88 (d, J=6.6Hz, 3H), 0.78 (d, J=6.6Hz, 3H).

[1224] Example 1.97: (2R,3R)-3-((S)-1-((S,E)-4-((S)-2-((tert-Butoxycarbonyl)amino)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanoic acid.

[1225]

[1226] The title compound was prepared from the product of Example 1.96 according to General Method 4.1. 29 H 51 Calculated value for N3O7: m / z = 553.37 Found: [M+Na] + =576.81. 1 H NMR (400 MHz, chloroform-d) δ 5.64 (d, J = 8.8 Hz, 1H), 5.37 (d, J = 10.1 Hz, 1H), 5.05 (s, 1H), 4.42 (d, J = 10.1 Hz, 1H), 4.23-4.17 (m, 1H), 4.02 (dd, J = 8.8, 2.5 Hz, 1H), 3.53-3.46 (m, 1H), 3.45 (s, 3H), 3.39- 3.27(m, 1H), 2.93(s, 3H), 2.51-2.36(m, 1H), 2.08-1.77(m, 4H), 1.90(s, 3H), 1.73-1.60(m, 1H) , 1.40 (s, 9H), 1.25 (d, J = 7.1Hz, 3H), 0.95 (s, 9H), 0.91 (d, J = 6.5Hz, 3H), 0.82 (d, J = 6.5Hz, 3H).

[1227] Example 1.98: Tert-butyl ((S)-1-(((S,E)-6-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-((4-(2,2,2-trifluoroacetamido)phenyl)sulfonamido)propyl)pyrrolidin-1-yl)-2,5-dimethyl-6-oxohex-4-en-3-yl)(methyl)amino)-3,3-dimethyl-1-oxobutan-2-yl)carbamate.

[1228]

[1229] The title compound was prepared from the product of Example 1.97 and the product of Example 1.39 according to General Method 2. 37 H 56 Calculated value for F3N5O9S: m / z = 803.38 Found: [M+Na] + =826.69. 1 H NMR (400MHz, chloroform-d) δ9.66 (s, 1H), 8.03 (d, J = 8.8Hz, 2H), 7.82 (d, J = 8.8Hz, 2H), 5.62 (d, J = 8.6Hz, 1H), 5.54 (d, J =10.0Hz, 1H), 5.10-4.98 (m, 1H), 4.45 (d, J = 10.1Hz, 1H), 4.01 (dd, J = 7.2, 2.4Hz, 1H)...

Claims

1. A method for preparing a conjugate of formula II: (T)-(L)-(D) II wherein (T) is an antibody, (L) is a linker, and (D) is a compound of formula Ig: Where R 2 is selected from the group consisting of 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-aminophenyl, 4-(aminomethyl)phenyl, 4-(1-aminocyclopropyl)benzyl and 4-(1-aminocyclopropyl)phenyl, The method comprises: a) preparing a drug-linker (D)-(L) comprising a compound of formula Ig and a linker (L), and b) conjugating the drug-linker (D)-(L) to the antibody (T), and Wherein (L) is MT-VC-OH having the following structure: (L) is MT-OH having the following structure:

2. The method according to claim 1, wherein R 2 Selected from: 4-aminobenzyl, 4-aminophenyl and 4-(1-aminocyclopropyl)phenyl.

3. The method according to claim 1, wherein the linker (L) is MT-VC-OH having the following structure:

4. The method of claim 3, wherein preparing the drug-linker (D)-(L) comprises reacting the compound of formula Ig with MT-VC-OH.

5. The method of claim 3, wherein preparing the drug-linker (D)-(L) comprises: i) reacting a compound of formula Ig with Boc-VC-OH having the following structure: To provide a drug-linker intermediate, and ii) reacting the drug-linker intermediate with MT-NHS having the following structure:

6. The method according to claim 3, wherein R 2 Selected from: 4-aminobenzyl, 4-aminophenyl and 4-(1-aminocyclopropyl)phenyl.

7. The method according to claim 3, wherein R 2 It is 4-aminophenyl.

8. The method of claim 1, wherein the drug-linker (D)-(L) is selected from:

9. The method of claim 1, wherein the drug-linker (D)-(L) is:

10. The method according to any one of claims 1 to 9, wherein conjugating the drug-linker (D)-(L) to the antibody (T) comprises conjugating 1 to 8 drug-linkers (D)-(L) to the antibody (T).

11. The method according to any one of claims 1 to 9, wherein the antibody is a bispecific antibody.

12. The method of any one of claims 1 to 9, wherein the antibody specifically binds to a cancer cell antigen.

13. The method of claim 12, wherein the cancer cell antigen is HER2.

14. A method for preparing an antibody-drug conjugate, the method comprising conjugating a drug-linker to an antibody, wherein the drug-linker is selected from:

15. The method of claim 14, wherein the drug-linker is:

16. The method of claim 14 or 15, wherein conjugating the drug-linker to the antibody comprises conjugating 1 to 8 drug-linkers to the antibody.

17. The method of claim 14 or 15, wherein the antibody is a bispecific antibody.

18. The method of claim 14 or 15, wherein the antibody specifically binds to a cancer cell antigen.

19. The method of claim 18, wherein the cancer cell antigen is HER2.

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