RU2815714C2 - 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and use thereof in treating diseases associated with zinc finger protein 2 of ikaros (ikzf2) family - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds based on 3-(5-amino-1-oxoisoindolin-2-yl) piperidine-2,6-dione, specifically to a compound of formula (I'), where each of X₁ and X₂ is independently H or halogen; R_x is H; each of R_a and R_b is independently H, or R_a and R_b together with the atom to which they are attached form =(O); R₁ is or ; R₂ is H or (C₁-C₆) alkyl; or R₅ is -OR₆ or -NR₇R_7'; R₆ is H, (C₁-C₆) alkyl, wherein alkyl is optionally substituted with one substituent independently selected from phenyl; each of R₇ and R_7' independently represents H, (C₁-C₆) alkyl, wherein alkyl is optionally substituted with one to three R₈; or R₇ and R_7' together with the nitrogen atom to which they are attached form 5-member heterocycloalkyl ring; each R₈ is -C(O)OH, (C₃-C₇) cycloalkyl, phenyl or 6-member heteroaryl containing 1 heteroatom selected from N, wherein cycloalkyl is optionally substituted with one to four R₁₀; each R₁₀ independently in each occurrence is (C₁-C₆) alkyl; n1 equals 1, 2 or 3; each of n2 and n3 independently equals 1; or its pharmaceutically acceptable salts. Invention also relates to a compound selected from a group of individual compounds, a pharmaceutical composition, a method for breaking down IKZF2, a method of treating a disease or disorder, a method of modulating IKZF2 protein levels, a method of reducing IKZF2 protein levels, use of the compound of formula (I') in the manufacture of a drug preparation for treating a disease or disorder, use of the compound of formula (I') in treating the disease or disorder.

EFFECT: obtaining novel compounds which can be used in treating diseases or disorders associated with zinc finger protein 2 of the IKAROS (IKZF2) family.

25 cl, 21 tbl, 34 ex

Description

Related applications

This application claims the benefit and priority of U.S. Provisional Patent Application No. 62/695922, filed July 10, 2018, the entire contents of which are incorporated herein by reference in their entirety.

Field of technology to which the invention relates

The present invention relates to 3-(5-amino-1-oxoisoindolin-2-yl)piperidin-2,6-dione-based compounds and compositions thereof, and their use in the treatment of diseases or disorders associated with zinc-containing protein. fingers" 2 of the IKAROS family (IKZF2) or in which reduction of IKZF2 or IKZF4 protein levels may reduce the severity of the disease or disorder.

BACKGROUND OF THE INVENTION

IKAROS family zinc finger protein 2 (IKZF2) (also called Helios) is one of five members of the Ikaros family of transcription factors found in mammals. IKZF2 contains four N-terminal zinc finger domains that are involved in DNA binding and two C-terminal zinc finger domains that are involved in protein dimerization. IKZF2 is approximately 50% identical to the IKAROS family members Ikaros (IKZF1), Aiolos (IKZF3) and Eos (IKZF4) with the highest homology in the zinc finger regions (80%+ identity). These four Ikaros family transcription factors bind to the same DNA consensus site and can heterodimerize with each other when coexpressed in cells. The fifth Ikaros family protein, Pegasus (IKZF5), is only 25% identical to IKZF2, binds a different DNA site than other IKAROS family members, and does not readily heterodimerize with other IKAROS family proteins. IKZF2, IKZF1 and IKZF3 are expressed primarily in hematopoietic cells, whereas IKZF4 and IKZF5 are expressed in a wide variety of tissues. (John, L.B., et al., (2011), Mol. Immunol. 48:1272-1278; Perdomo, J., et al., (2000), J. Biol. Chem. 275:38347-38354.)

IKZF2 is thought to play an important role in the function and stability of regulatory T cells (Tregs). IKZF2 are expressed at high levels at the mRNA and protein levels in regulatory T cell populations. Knockdown of IKZF2 by siRNA has been shown to result in down-regulation of FoxP3 and attenuation of the ability of isolated human CD4+ CD25+ Tregs to block T cell activation in vitro . In addition, overexpression of IKZF2 in isolated mouse Tregs has been shown to increase the expression of Treg-associated markers such as CD103 and GITR, and cells overexpressing IKZF2 exhibit increased suppression of responder T cells. IKZF2 was also found to bind the T cell lineage regulatory transcription factor-determining transcription factor FoxP3 promoter and influence FoxP3 expression.

Knockout of IKZF2 in FoxP3-expressing Tregs in mice has been shown to cause activated Tregs to lose their inhibitory properties, express T-effector cytokines, and assume T-effector functions. IKZF2 knockout mutant mice develop an autoimmune disease at 6–8 months of age with increased numbers of activated CD4 and CD8 T cells, follicular helper T cells, and germinal center B cells. This observed effect is believed to be cell-specific because Rag2−/− mice that receive bone marrow from IKZF2 knockout mice, but not bone marrow from IKZF2+/+ mice, develop an autoimmune disease. Direct evidence that IKZF2 affects regulatory T cell function came from a study in mice in which IKZF2 was deleted only in FoxP3-expressing cells (FoxP3-YFP-Cre Heliosfl/fl). The results showed that these mice also developed an autoimmune disease with similar features to those observed in IKZF2 knockouts throughout the animal's body. Moreover, CHIP-SEQ signaling pathway analysis also suggested that IKZF2 influences gene expression in the STAT5/IL-2Rα signaling pathway in regulatory T cells. This effect of IKZF2 loss was shown to become more apparent after immunization (viral infection or sheep blood injection), and it was noted that after immunostimulation, IKZF2 negative regulatory T cells began to acquire the properties of effector T cells. (Getnet, D., et al., Mol. Immunol. (2010), 47:1595-1600; Bin Dhuban, K., et al., (2015), J. Immunol. 194:3687-96; Kim, H-J., et al., (2015), Science 350:334-339; Nakawaga, H., et al., (2016) PNAS, 113: 6248-6253).

Overexpression of Ikaros isoforms lacking DNA binding regions has been shown to be associated with many human hematological malignancies. Recently, mutations in the IKZF2 gene that lead to abnormal splicing variants have been identified in adult T-cell leukemias and low hypodiploid acute lymphoblastic leukemias. It has been suggested that these dimerization-competent isoforms have a dominant negative effect on Ikaros family transcription factors that drive the primary development of lymphomas. IKZF2 knockout mutants that survive into adulthood do not develop lymphomas, supporting this hypothesis (Asanuma, S., et al., (2013), Cancer Sci. 104:1097-1106; Zhang, Z., et al. , (2007), Blood 109:2190-2197; Kataoka, D., et al., (2015), Nature Genetics 47:1304-1315.).

Currently, anti-CTLA4 antibodies are used in clinical practice to target Tregs in tumors. However, targeting CTLA4 often causes systemic activation of T effector cells, leading to excessive toxicity and limiting therapeutic benefit. No more than 3/4 of patients receiving the combination of anti-PD1 and anti-CTLA4 antibodies reported grade 3 or worse adverse events (National Cancer Institute, Division of Cancer Treatment and Diagnosis, Common Terminology for Adverse Events (CTCAE), https://ctep .cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). Thus, there is an urgent need to create compounds that target Tregs in tumors and do not cause systemic activation of T effector cells.

The IKZF2-specific disruptor has the ability to focus an enhanced immune response to areas within or near tumors, providing a potentially more tolerable and less toxic cancer therapeutic.

Brief description of the invention

The compounds of the present invention find use as therapeutic agents, in particular for the treatment of cancers and diseases associated with them. In one aspect, the compounds of the present invention have IKZF2 degrading activity, preferably they have such activity at levels of 50 μM or lower, and more preferably they have such activity at levels of 10 μM or lower. In another aspect, the compounds of the present invention have IKZF2 degrading activity, which activity is selective for one or more of IKZF1, IKZF3, IKZF4 and/or IKZF5. In another aspect, the compounds of the present invention have disruptor activity against both IKZF2 and IKZF4. The compounds of the present invention are useful in the treatment of cancer and other diseases in which such disruptive activity provides benefits to the patient. For example, without being bound by any theory, the authors believe that reducing IKZF2 levels in Tregs in a tumor may allow the patient's immune system to more effectively attack the disease. Thus, the present invention provides new means of destroying IKZF2 useful for the treatment of cancer and other diseases.

The first aspect of the present invention relates to compounds of formula (I')

Where:

each of X ₁ and X ₂ independently represents H, (C ₁ -C ₄ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₄ )haloalkyl,

(C ₁ -C ₆ )haloalkoxy, (C ₃ -C ₇ )cycloalkyl, halogen, CN, -OH or -NH ₂ ;

R _x represents H or D;

R _a and R _b are each independently H or D, or R _a and R _b together with the atom to which they are attached form =(O);

R ₁ represents

R ₂ represents H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl or (C ₃ -C ₆ )cycloalkyl; or

R ₂ and R ₇ together with the nitrogen atoms to which they are attached form a 6- or 7-membered heterocycloalkyl ring;

each R ₃ independently in each case represents (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy,

(C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )haloalkoxy, halogen, CN, -OH or -NH ₂ ; or

two R ₃ together with the carbon atoms to which they are attached form a (C ₃ -C ₇ )cycloalkyl or 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S; or two R ₃ when located at adjacent carbon atoms, together form a phenyl or 5- or 6-membered heteroaryl ring containing 1-3 heteroatoms selected from O, N and S; or

R ₃ and R ₇ together with the nitrogen and carbon atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, optionally substituted with one to four substituents, each of which is independently selected from (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, halogen, -OH, CN and -NH ₂ ;

each R ₄ is (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )haloalkoxy, halogen, -OH or

_-NH2 ;

R ₅ is -OR ₆ or -NR ₇ R _7' ;

R ₆ is H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, -C(O)(C ₁ -C ₆ )alkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three substituents, each of which is independently selected from (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S;

each of R ₇ and R _7' independently represents H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1 -3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one - three R ₈ , and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one to four R ₁₁ ; or

R ₇ and R _7', together with the nitrogen atom to which they are attached, form a 4-7 membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, optionally substituted by one to four R ₉ ; or

R ₂ and R ₇ together with the nitrogen atoms to which they are attached form a 6- or 7-membered heterocycloalkyl ring; or

R ₃ and R ₇ together with the nitrogen and carbon atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, optionally substituted with one to four substituents, each of which is independently selected from (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, halogen, -OH, CN and -NH ₂ ;

each R ₈ is -C(O)OH, (C ₃ -C ₇ )cycloalkyl, a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ ) aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, with cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally substituted by one to four R ₁₀ ;

each R ₉ is independently in each case a (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )haloalkoxy, halogen, -OH, CN, -NR ₁₂ R ₁₃ or -NH ₂ , wherein the alkoxy is optionally substituted with one to three substituents independently selected from (C ₃ -C ₇ )cycloalkyl, a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S; or

two R ₉ together with the atoms to which they are attached form a (C ₅ -C ₇ )cycloalkyl or 5-7-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N and S;

each R ₁₀ independently in each case represents (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )alkoxy,

(C ₁ -C ₆ )haloalkoxy, halogen, -OH, CN or -NH ₂ ; or

two R ₁₀ together with the atoms to which they are attached form a (C ₄ -C ₇ )cycloalkyl or 5-7-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N and S, optionally substituted with one to four substituents , each independently selected from (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, halogen, -OH, CN or -NH ₂ ;

each R ₁₁ independently in each case represents (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )alkoxy,

(C ₁ -C ₆ )haloalkoxy, halogen, -OH, CN or -NH ₂ ;

each of R ₁₂ and R ₁₃ is independently selected from (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₃ -C ₇ )cycloalkyl, 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms , selected from O, N and S, (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S;

each of m and m1 is independently equal to 0, 1 or 2;

n1 is 0, 1, 2 or 3;

each of n2 and n3 is independently equal to 1 or 2; And

each of s and n is independently equal to 1, 2 or 3, where s+n ≤ 4;

or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs based thereon, stereoisomers and tautomers thereof.

In one embodiment, the present invention relates to compounds of formula (I') characterized by the structure of formula (I):

Where:

R _x represents H or D;

R ₁ represents or ;

R ₂ represents H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl or (C ₃ -C ₆ )cycloalkyl; or

R ₂ and R ₇ together with the nitrogen atoms to which they are attached form a 6- or 7-membered heterocycloalkyl ring;

each R ₃ independently in each case represents (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy,

(C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )haloalkoxy, halogen, CN, -OH or -NH ₂ ; or

two R ₃ together with the carbon atoms to which they are attached form a (C ₃ -C ₇ )cycloalkyl or 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S; or two R ₃ , when present at adjacent carbon atoms, together form a phenyl or 5- or 6-membered heteroaryl ring containing 1-3 heteroatoms selected from O, N and S; or

R ₃ and R ₇ together with the nitrogen and carbon atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, optionally substituted with one to four substituents, each of which is independently selected from (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, halogen, -OH, CN and -NH ₂ ;

each R ₄ is (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )haloalkoxy, halogen, -OH or

_-NH2 ;

R ₅ is -OR ₆ or -NR ₇ R _7' ;

R ₆ is H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, -C(O)(C ₁ -C ₆ )alkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three substituents, each of which is independently selected from (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S;

each of R ₇ and R _7' independently represents H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1 -3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one - three R ₈ ; or

R ₇ and R _7', together with the nitrogen atom to which they are attached, form a 4-7 membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, optionally substituted by one to four R ₉ ; or

R ₂ and R ₇ together with the nitrogen atoms to which they are attached form a 6- or 7-membered heterocycloalkyl ring; or

R ₃ and R ₇ together with the nitrogen and carbon atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, optionally substituted with one to four substituents, each of which is independently selected from (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, halogen, -OH, CN and -NH ₂ ;

each R ₈ is (C ₃ -C ₇ )cycloalkyl, a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6- member heteroaryl containing 1-3 heteroatoms selected from O, N and S, with cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally substituted by one to four R ₁₀ ;

each R ₉ is independently in each case a (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, halogen, -OH, CN or

_-NH2 ; or

two R ₉ together with the atoms to which they are attached form a (C ₅ -C ₇ )cycloalkyl or 5-7-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N and S;

each R ₁₀ is independently in each case a (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, halogen, -OH, CN or -NH ₂ ; or

two R ₁₀ together with the atoms to which they are attached form a (C ₅ -C ₇ )cycloalkyl or 5-7-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N and S, optionally substituted with one to four substituents , each independently selected from (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, halogen, -OH, CN or -NH ₂ ;

each of m and m1 is independently equal to 0, 1 or 2;

n1 is 0, 1, 2 or 3; And

each of s and n is independently equal to 1, 2 or 3, where s+n ≤ 4;

or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs based thereon, stereoisomers and tautomers thereof.

In one aspect of the present invention, the hydrogen atoms in a compound of formula (I') or formula (I) are present in their normal isotopic composition. In a preferred aspect of the present invention, the hydrogen atoms are isotopically enriched in deuterium (D), and in a particularly preferred aspect of the present invention, the hydrogen at the R _x position is enriched in D, as discussed in more detail below with respect to isotopes and isotopic enrichment.

Another aspect of the present invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier or excipient . The pharmaceutical composition is useful in the treatment of IKZF2-related diseases or disorders. The pharmaceutical composition may further comprise at least one additional pharmaceutical agent.

In another aspect, the present invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier or auxiliary a substance for use in treating an IKZF2-related disease or disorder by reducing levels of IKZF2 protein, wherein reducing levels of IKZF2 protein provides treatment for an IKZF2-related disease or disorder. The pharmaceutical composition is useful in the treatment of IKZF2-related diseases or disorders. The pharmaceutical composition may further comprise at least one additional pharmaceutical agent.

Another aspect of the present invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier or excipient . The pharmaceutical composition is useful in the treatment of diseases or disorders that are affected by a decrease in IKZF2 protein levels. The pharmaceutical composition may further comprise at least one additional pharmaceutical agent.

In another aspect, the present invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier or auxiliary a substance for use in the treatment of a disease or disorder that is affected by reduction in levels of IKZF2 protein, wherein reduction in levels of IKZF2 protein provides treatment for the disease or disorder. The pharmaceutical composition may further comprise at least one additional pharmaceutical agent.

In another aspect, the present invention relates to a method for destroying IKZF2. The method involves administering to a patient in need thereof a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof.

Another aspect of the present invention relates to a method for modulating IKZF2 protein levels. The method involves administering to a patient in need thereof a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof.

In another aspect, the present invention provides a method for reducing IKZF2 protein levels. The method involves administering to a patient in need thereof a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof.

In another aspect, the present invention provides a method for reducing IKZF2 protein levels. The method involves administering to a patient in need thereof a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof.

Another aspect of the present invention relates to a method for reducing the level of cell proliferation. The method includes administering to a patient in need thereof a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof and causing a reduction in IKZF2 protein levels.

In another aspect, the present invention provides a method for reducing IKZF2 protein levels. The method involves administering to a patient in need thereof a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof.

In another aspect, the present invention relates to a method for treating cancer. The method involves administering to a patient in need thereof a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof. In one embodiment, the cancer is selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer , glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid types cancer and Ewing's sarcoma. In another embodiment, the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and stromal tumor gastrointestinal tract (GIST). In yet another embodiment, the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (mssCRC). In another embodiment, the cancer is a cancer to which the immune response is insufficient, or a cancer with immunogenic properties.

Another aspect of the present invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier or excipient , for use in the treatment of an IKZF2-related disease or disorder.

In another aspect, the present invention relates to the use of a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier or an excipient in the manufacture of a medicinal product for the treatment of an IKZF2-related disease or disorder.

Another aspect of the present invention relates to a method of treating an IKZF2-related disease or disorder, comprising the step of administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrugs based thereon, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.

In another aspect, the present invention provides a method of treating an IKZF2-related disease or disorder, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof based on it, its stereoisomer or tautomer.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof for use in the treatment of an IKZF2-related disease or disorder.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the manufacture of a medicament for the treatment of an IKZF2-related disease or disorder .

Another aspect of the present invention relates to a method of treating a disease or disorder affected by modulating levels of IKZF2 protein, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug based on it, stereoisomer or tautomer thereof.

In another aspect, the present invention provides a method of treating a disease or disorder affected by reduction of IKZF2 protein levels, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt thereof , hydrate, solvate, prodrug based on it, its stereoisomer or tautomer.

Another aspect of the present invention relates to a method of treating a disease or disorder affected by providing reduction in levels of IKZF2 protein, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt thereof , hydrate, solvate, prodrug based on it, its stereoisomer or tautomer.

In another aspect, the present invention provides a compound of formula (I') or formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of a disease or disorder affected by modulation of levels IKZF2 protein content.

Another aspect of the present invention relates to a compound of formula (I') or formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of a disease or disorder affected by reduced levels of IKZF2 protein.

In another aspect, the present invention relates to a compound of formula (I') or formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of a disease or disorder affected by decreased levels of IKZF2 protein content.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the manufacture of a medicament for the treatment of a disease or disorder to which influences modulation of IKZF2 protein levels.

Another aspect of the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the manufacture of a medicament for the treatment of a disease or disorder affected by decrease in IKZF2 protein levels.

Another aspect of the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the manufacture of a medicament for the treatment of a disease or disorder affected by decreased IKZF2 protein levels.

In another aspect, the present invention relates to a method of treating cancer, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, or stereoisomer or tautomer, where the cancer is a cancer to which the immune response is insufficient, or a cancer with immunogenic properties.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof for use in the manufacture of a medicament for the treatment of a disease or disorder associated with modulating IKZF2 protein levels. In one embodiment, the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, types of rhabdoid cancer and Ewing's sarcoma. In one embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (mssCRC).

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the treatment of a disease or disorder associated with modulation of protein levels IKZF2. In one embodiment, the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, types of rhabdoid cancer and Ewing's sarcoma. In one embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (mssCRC).

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof for use in the manufacture of a medicament for the treatment of a disease or disorder associated with a decrease in IKZF2 protein levels. In one embodiment, the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, types of rhabdoid cancer and Ewing's sarcoma. In one embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (mssCRC).

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the treatment of a disease or disorder associated with decreased protein levels IKZF2. In one embodiment, the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, types of rhabdoid cancer and Ewing's sarcoma. In one embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (mssCRC).

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof for use in the manufacture of a medicament for the treatment of a disease or disorder associated with decreased IKZF2 protein levels. In one embodiment, the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, types of rhabdoid cancer and Ewing's sarcoma. In one embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (mssCRC).

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the treatment of a disease or disorder associated with decreased protein levels IKZF2. In one embodiment, the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, types of rhabdoid cancer and Ewing's sarcoma. In one embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (mssCRC).

Another aspect of the present invention relates to a method of treating cancer, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer thereof or a tautomer, wherein the cancer is selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, skin melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, cancer kidney, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, types rhabdoid cancer and Ewing's sarcoma. In one embodiment, the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and stromal tumor gastrointestinal tract (GIST). In another embodiment, the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (mssCRC).

In another aspect, the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof for use in the treatment of cancer, wherein the cancer is selected from prostate cancer gland, breast carcinoma, lymphoma, leukemia, myeloma, bladder carcinoma, colon cancer, skin melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer , parathyroid tumors, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers and Ewing's sarcoma. In one embodiment, the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and stromal tumor gastrointestinal tract (GIST). In another embodiment, the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (mssCRC).

Another aspect of the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the manufacture of a medicament for the treatment of cancer, wherein cancer is selected from prostate cancer, breast carcinoma, lymphoma, leukemia, myeloma, bladder carcinoma, colon cancer, skin melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, glioblastoma multiforme, glioma, cancer thyroid, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers and Ewing's sarcoma. In one embodiment, the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and stromal tumor gastrointestinal tract (GIST). In another embodiment, the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (mssCRC).

In another aspect, the present invention provides a method of treating a disease or disorder affected by modulating IKZF2 protein levels, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt thereof , hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, wherein the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer and soft tissue sarcomas , selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers and Ewing's sarcoma. In one embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (mssCRC).

Another aspect of the present invention relates to a method of treating a disease or disorder that is affected by reducing levels of IKZF2 protein, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, wherein the disease or disorder is selected from prostate cancer, breast carcinoma, lymphoma, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, cancer endometrial cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, stomach cancer and soft tissue sarcomas, selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers and Ewing's sarcoma. In one embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (mssCRC).

In another aspect, the present invention provides a method of treating a disease or disorder affected by reduction of IKZF2 protein levels, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt thereof , hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, wherein the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer and soft tissue sarcomas , selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers and Ewing's sarcoma. In one embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (mssCRC).

In another aspect, the present invention provides a compound of formula (I') or formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of a disease or disorder affected by modulation of levels IKZF2 protein content, wherein the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, cancer lung, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, types of rhabdoid cancer and Ewing's sarcoma. In one embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (mssCRC).

Another aspect of the present invention relates to a compound of formula (I') or formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of a disease or disorder affected by reduced levels of IKZF2 protein, wherein the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer , kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma , types of rhabdoid cancer and Ewing's sarcoma. In one embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (mssCRC).

In another aspect, the present invention relates to a compound of formula (I') or formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of a disease or disorder affected by decreased levels of IKZF2 protein content, wherein the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, cancer lung, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, types of rhabdoid cancer and Ewing's sarcoma. In one embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (mssCRC).

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the manufacture of a medicament for the treatment of a disease or disorder to which modulation of IKZF2 levels, the disease or disorder selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer , lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, types of rhabdoid cancer and Ewing's sarcoma. In one embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (mssCRC).

Another aspect of the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the manufacture of a medicament for the treatment of a disease or disorder affected by reduction in IKZF2 protein levels, wherein the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer , lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, types of rhabdoid cancer and Ewing's sarcoma. In one embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (mssCRC).

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the manufacture of a medicament for the treatment of a disease or disorder to which affected by a decrease in IKZF2 protein levels, the disease or disorder selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer uterine, lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, types of rhabdoid cancer and Ewing's sarcoma. In one embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (mssCRC).

In another aspect, the present invention provides a method of treating a disease or disorder affected by modulating IKZF2 protein levels, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt thereof , hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, wherein the disease or disorder is a cancer to which the immune response is insufficient, or a cancer with immunogenic properties.

Another aspect of the present invention relates to a method of treating a disease or disorder that is affected by reducing levels of IKZF2 protein, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt thereof, a hydrate, solvate, prodrug thereof, a stereoisomer or tautomer thereof, wherein the disease or disorder is a cancer to which the immune response is insufficient, or a cancer with immunogenic properties.

In another aspect, the present invention provides a method of treating a disease or disorder affected by reduction of IKZF2 protein levels, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt thereof , hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, wherein the disease or disorder is a cancer to which the immune response is insufficient, or a cancer with immunogenic properties.

In another aspect, the present invention provides a compound of formula (I') or formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of a disease or disorder affected by modulation of levels IKZF2 protein content, where the disease or disorder is a cancer to which the immune response is insufficient, or a cancer with immunogenic properties.

Another aspect of the present invention relates to a compound of formula (I') or formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of a disease or disorder affected by reduced levels of IKZF2 protein, where the disease or disorder is a cancer to which the immune response is insufficient, or a cancer with immunogenic properties.

In another aspect, the present invention relates to a compound of formula (I') or formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of a disease or disorder affected by decreased levels of IKZF2 protein content, where the disease or disorder is a cancer to which the immune response is insufficient, or a cancer with immunogenic properties.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the manufacture of a medicament for the treatment of a disease or disorder to which influence modulation of IKZF2 protein levels, where the disease or disorder is a cancer to which the immune response is insufficient, or a cancer with immunogenic properties.

Another aspect of the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the manufacture of a medicament for the treatment of a disease or disorder affected by reducing IKZF2 protein levels, where the disease or disorder is a cancer to which the immune response is insufficient, or a cancer with immunogenic properties.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the manufacture of a medicament for the treatment of a disease or disorder to which affected by a decrease in IKZF2 protein levels, where the disease or disorder is a cancer to which the immune response is insufficient, or a cancer with immunogenic properties.

In another aspect, the present invention relates to a method of treating cancer, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, or stereoisomer or tautomer, where the cancer is a cancer to which the immune response is insufficient, or a cancer with immunogenic properties.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof for use in the treatment of cancer to which the immune response is insufficient, or cancer with immunogenic properties.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the manufacture of a medicament for the treatment of cancer, the immune response to which insufficient, or cancer with immunogenic properties.

Another aspect of the present invention relates to a method of treating an IKZF2-related disease or disorder by modulating IKZF2 protein levels, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, wherein modulating IKZF2 protein levels provides treatment for an IKZF2-related disease or disorder.

In another aspect, the present invention provides a method of treating an IKZF2-related disease or disorder by reducing IKZF2 protein levels, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt thereof , hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, wherein reducing the levels of IKZF2 protein provides treatment for an IKZF2-related disease or disorder.

Another aspect of the present invention relates to a method of treating an IKZF2-related disease or disorder by reducing IKZF2 protein levels, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, wherein reducing IKZF2 protein levels provides treatment for an IKZF2-related disease or disorder.

Another aspect of the present invention relates to a method of treating an IKZF2-related disease or disorder by modulating IKZF2 protein levels, comprising the step of administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, wherein modulating IKZF2 protein levels provides treatment for an IKZF2-related disease or disorder.

In another aspect, the present invention provides a method of treating an IKZF2-related disease or disorder by reducing IKZF2 protein levels, comprising the step of administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, wherein reducing IKZF2 protein levels provides treatment for an IKZF2-related disease or disorder.

Another aspect of the present invention relates to a method of treating an IKZF2-related disease or disorder by reducing IKZF2 protein levels, comprising the step of administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, wherein reducing IKZF2 protein levels provides treatment for an IKZF2-related disease or disorder.

In another aspect, the present invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of associated with an IKZF2 disease or disorder by reducing the levels of the IKZF2 protein, wherein reducing the levels of the IKZF2 protein provides treatment for the IKZF2-related disease or disorder.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof for use in the treatment of an IKZF2-related disease or disorder by reducing levels of IKZF2 protein, wherein reducing the levels of IKZF2 protein provides treatment for an IKZF2-related disease or disorder.

In another aspect, the present invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of associated with an IKZF2 disease or disorder by modulating IKZF2 protein levels, wherein modulating IKZF2 protein levels provides treatment for an IKZF2-related disease or disorder.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof for use in the treatment of an IKZF2-related disease or disorder by modulating levels of IKZF2 protein, wherein modulating IKZF2 protein levels provides treatment for an IKZF2-related disease or disorder.

In another aspect, the present invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of associated with an IKZF2 disease or disorder by reducing the levels of the IKZF2 protein, wherein the reduction in the levels of the IKZF2 protein provides treatment for the IKZF2-related disease or disorder.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof for use in the treatment of an IKZF2-related disease or disorder by reducing levels of IKZF2 protein, wherein reducing the levels of IKZF2 protein provides treatment for an IKZF2-related disease or disorder.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the treatment of an IKZF2-related disease or disorder by reducing levels of IKZF2 protein, wherein reducing the levels of IKZF2 protein provides treatment for an IKZF2-related disease or disorder.

Another aspect of the present invention relates to the use of a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the treatment of IKZF2-related disease or disorder by reducing IKZF2 protein levels, wherein reducing IKZF2 protein levels provides treatment for an IKZF2-related disease or disorder.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the treatment of an IKZF2-related disease or disorder by modulating levels of IKZF2 protein, wherein modulating IKZF2 protein levels provides treatment for an IKZF2-related disease or disorder.

Another aspect of the present invention relates to the use of a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the treatment of IKZF2-related disease or disorder by modulating IKZF2 protein levels, wherein modulating IKZF2 protein levels provides treatment for an IKZF2-related disease or disorder.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the treatment of an IKZF2-related disease or disorder by reducing levels of IKZF2 protein, wherein reducing the levels of IKZF2 protein provides treatment for an IKZF2-related disease or disorder.

Another aspect of the present invention relates to the use of a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the treatment of IKZF2-related disease or disorder by reducing IKZF2 protein levels, wherein reducing IKZF2 protein levels provides treatment for an IKZF2-related disease or disorder.

Another aspect of the present invention relates to a method of treating a disease or disorder by reducing levels of IKZF2 protein, comprising the step of administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt thereof , hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, wherein reducing the levels of IKZF2 protein provides treatment for the disease or disorder.

In another aspect, the present invention provides a method of treating a disease or disorder by reducing levels of IKZF2 protein, comprising the step of administering to a subject in need thereof a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof based on it, a stereoisomer or tautomer thereof, wherein reducing the levels of the IKZF2 protein provides treatment for the disease or disorder.

Another aspect of the present invention relates to a method of treating a disease or disorder by modulating levels of IKZF2 protein, comprising the step of administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt thereof , hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, wherein modulating IKZF2 protein levels provides treatment for the disease or disorder.

In another aspect, the present invention provides a method of treating a disease or disorder by modulating IKZF2 protein levels, comprising the step of administering to a subject in need thereof a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof based on it, a stereoisomer or tautomer thereof, wherein modulating the levels of IKZF2 protein provides treatment for the disease or disorder.

Another aspect of the present invention relates to a method of treating a disease or disorder by reducing levels of IKZF2 protein, comprising the step of administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt thereof , hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, wherein reducing the levels of IKZF2 protein provides treatment for the disease or disorder.

In another aspect, the present invention relates to a method of treating a disease or disorder by reducing levels of IKZF2 protein, comprising the step of administering to a subject in need thereof a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof based on it, a stereoisomer or tautomer thereof, wherein reducing the levels of IKZF2 protein provides treatment for the disease or disorder.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof for use in the treatment of an IKZF2-related disease or disorder by reducing levels of IKZF2 protein, wherein reducing the levels of IKZF2 protein provides treatment for an IKZF2-related disease or disorder.

In another aspect, the present invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of associated with an IKZF2 disease or disorder by reducing the levels of the IKZF2 protein, wherein reducing the levels of the IKZF2 protein provides treatment for the IKZF2-related disease or disorder.

Another aspect of the present invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of IKZF2 disease or disorder by modulating IKZF2 protein levels, wherein modulating IKZF2 protein levels provides treatment for an IKZF2-related disease or disorder.

In another aspect, the present invention provides a compound of formula (I') or formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of an IKZF2-related disease or disorder by modulating levels of IKZF2 protein levels, wherein modulating IKZF2 protein levels provides treatment for an IKZF2-related disease or disorder.

Another aspect of the present invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of IKZF2 disease or disorder by reducing IKZF2 protein levels, wherein reducing IKZF2 protein levels provides treatment for an IKZF2-related disease or disorder.

In another aspect, the present invention provides a compound of formula (I') or formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of an IKZF2-related disease or disorder by reducing levels of IKZF2 protein levels, wherein reducing IKZF2 protein levels provides treatment for an IKZF2-related disease or disorder.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof for use in the treatment of a disease or disorder by reducing levels of IKZF2 protein, wherein reducing the levels of IKZF2 protein provides treatment for the disease or disorder.

In another aspect, the present invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of a disease or disorder by reducing the levels of IKZF2 protein, wherein reducing the levels of IKZF2 protein provides treatment for the disease or disorder.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof for use in the treatment of a disease or disorder by modulating levels of IKZF2 protein, wherein modulating IKZF2 protein levels provides treatment for the disease or disorder.

In another aspect, the present invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of a disease or disorder by modulating IKZF2 protein levels, wherein modulating IKZF2 protein levels provides treatment for the disease or disorder.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof for use in the treatment of a disease or disorder by reducing levels of IKZF2 protein, wherein reducing the levels of IKZF2 protein provides treatment for the disease or disorder.

In another aspect, the present invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of a disease or disorder by reducing IKZF2 protein levels, wherein reducing IKZF2 protein levels provides treatment for the disease or disorder.

Another aspect of the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the manufacture of a medicament for the treatment of an IKZF2-related disease or disorder by reducing IKZF2 protein levels, wherein reducing IKZF2 protein levels provides treatment for an IKZF2-related disease or disorder.

In another aspect, the present invention relates to the use of a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the manufacture of a medicinal product for treating an IKZF2-related disease or disorder by reducing the levels of the IKZF2 protein, wherein reducing the levels of the IKZF2 protein provides treatment for the IKZF2-related disease or disorder.

Another aspect of the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the manufacture of a medicament for the treatment of an IKZF2-related disease or disorder by modulating IKZF2 protein levels, wherein modulating IKZF2 protein levels provides treatment for an IKZF2-related disease or disorder.

In another aspect, the present invention relates to the use of a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the manufacture of a medicinal product for treating an IKZF2-related disease or disorder by modulating IKZF2 protein levels, wherein modulating IKZF2 protein levels provides treatment for an IKZF2-related disease or disorder.

Another aspect of the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the manufacture of a medicament for the treatment of an IKZF2-related disease or disorder by reducing IKZF2 protein levels, wherein reducing IKZF2 protein levels provides treatment for an IKZF2-related disease or disorder.

In another aspect, the present invention relates to the use of a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the manufacture of a medicinal product for treating an IKZF2-related disease or disorder by reducing levels of IKZF2 protein, wherein reducing the levels of IKZF2 protein provides treatment for an IKZF2-related disease or disorder.

Another aspect of the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the manufacture of a medicament for the treatment of a disease or disorder by reducing levels of IKZF2 protein, wherein reducing the levels of IKZF2 protein provides treatment for the disease or disorder.

In another aspect, the present invention relates to the use of a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the manufacture of a medicinal product for treating a disease or disorder by reducing levels of IKZF2 protein, wherein reducing levels of IKZF2 protein treats the disease or disorder.

Another aspect of the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the manufacture of a medicament for the treatment of a disease or disorder by modulating levels of IKZF2 protein, wherein modulating the levels of IKZF2 protein provides treatment for the disease or disorder.

In another aspect, the present invention relates to the use of a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the manufacture of a medicinal product for treating a disease or disorder by modulating levels of IKZF2 protein, wherein modulating levels of IKZF2 protein provides treatment for the disease or disorder.

Another aspect of the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the manufacture of a medicament for the treatment of a disease or disorder by reducing levels of IKZF2 protein, wherein reducing the levels of IKZF2 protein provides treatment for the disease or disorder.

In another aspect, the present invention relates to the use of a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the manufacture of a medicinal product for treating a disease or disorder by reducing levels of IKZF2 protein, wherein reducing levels of IKZF2 protein treats the disease or disorder.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof for use in the treatment of a disease or disorder by reducing levels of IKZF2 protein, wherein reducing the levels of IKZF2 protein provides treatment for the disease or disorder.

In another aspect, the present invention provides a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof for use in the treatment of a disease or disorder by modulating levels of IKZF2 protein wherein modulating IKZF2 protein levels provides treatment for the disease or disorder.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof for use in the treatment of a disease or disorder by reducing levels of IKZF2 protein, wherein reducing the levels of IKZF2 protein provides treatment for the disease or disorder.

Another aspect of the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the treatment of a disease or disorder by reducing levels of IKZF2 protein, wherein reducing IKZF2 protein levels provides treatment for a disease or disorder.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the treatment of a disease or disorder by modulating the levels of IKZF2 protein, wherein modulating IKZF2 protein levels provides treatment for the disease or disorder.

Another aspect of the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the treatment of a disease or disorder by reducing levels of IKZF2 protein, wherein reducing IKZF2 protein levels provides treatment for a disease or disorder.

In another aspect of the present invention, the compounds of the invention are formulated into pharmaceutical compositions containing an effective amount, preferably a pharmaceutically effective amount, of a compound of the invention or a salt, hydrate, solvate thereof, a prodrug thereof, a stereoisomer or tautomer thereof, and a pharmaceutically acceptable excipient or carrier.

Another aspect of the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the manufacture of a medicament for the treatment of an IKZF2-related disease or disorder.

In another aspect, the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof for use in the manufacture of a medicament for the treatment of a disease associated with modulation IKZF2 protein levels.

Another aspect of the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the treatment of a disease associated with modulation of IKZF2 protein levels.

In some embodiments of the methods disclosed herein, administration of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof is administered orally, parenterally, subcutaneously, by injections or infusions.

The present invention provides IKZF2 degrading agents that are therapeutic agents in the treatment of diseases such as cancer and metastasis, for the treatment of diseases affected by modulation of IKZF2 protein levels, and for the treatment of IKZF2-related diseases or disorders.

In one embodiment, the disease or disorder that can be treated with the compounds of the present invention is selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer , ovarian cancer, cervical cancer, lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers and Ewing's sarcoma. In another embodiment, the disease or disorder that can be treated with the compounds of the present invention is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer ( mssCRC), thymoma, carcinoid, acute myelogenous leukemia and gastrointestinal stromal tumor (GIST). In another embodiment, the disease or disorder that can be treated with the compounds of the present invention is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC) and microsatellite stable colorectal cancer ( mssCRC). In another embodiment, the IKZF2-related disease or disorder is a cancer to which the immune response is deficient, or a cancer with immunogenic properties.

The present invention provides agents with novel mechanisms of action against IKZF2 proteins for the treatment of various types of diseases, including cancer and metastasis, for the treatment of diseases affected by modulation of IKZF2 protein levels, and for the treatment of IKZF2-related diseases or disorders. In summary, the present invention provides the medical community with a new pharmacological strategy for the treatment of diseases and disorders associated with IKZF2 proteins.

Detailed Description of the Invention

The present invention relates to compounds and compositions capable of modulating IKZF2 protein levels. The present invention discloses methods of treating, preventing, or reducing the severity of a disease or disorder affected by IKZF2 by administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I') or formula (I), or a pharmaceutically acceptable salt, hydrate thereof, solvate, prodrug based on it, stereoisomer or tautomer thereof. The methods of the present invention can be used in the treatment of various IKZF2-related diseases or disorders by modulating IKZF2 protein levels. Modulating IKZF2 protein levels through disruption provides a new approach to treating, preventing or reducing the severity of diseases, including but not limited to cancer and metastasis, and other IKZF2-related diseases or disorders.

In one aspect, the compounds of the present invention find use as therapeutic agents, in particular for the treatment of cancers and diseases associated therewith. In one aspect, the compounds of the present invention have IKZF2 degrading activity, preferably having such activity at a level of 50 μM or less, and more preferably having such activity at a level of 10 μM or less. In another aspect, the compounds of the present invention have IKZF2 degrading activity, which activity is selective for one or more of IKZF1, IKZF3, IKZF4 and/or IKZF5. In another aspect, the compounds of the present invention have disruptor activity against both IKZF2 and IKZF4. The compounds of the present invention are useful in the treatment of cancer and other diseases in which such destruction activity provides benefits to the patient. For example, without being bound by any theory, the authors believe that reducing IKZF2 levels in Tregs in a tumor may allow the patient's immune system to more effectively attack the disease. Thus, the present invention provides new means of destroying IKZF2 useful for the treatment of cancer and other diseases.

The first aspect of the present invention describes compounds of formula (I'):

or pharmaceutically acceptable salts, hydrates, solvates, prodrugs thereof, stereoisomers and tautomers thereof, wherein R _a , R _b , R _x , R ₁ , R ₂ , X ₁ and X ₂ are described herein.

Details of the present invention are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein may be used in practicing or testing the present invention, the methods and materials are described below by way of illustration. Other features, objects and advantages of the present invention will be apparent from the description and claims. In the specification and the accompanying claims, the singular form also includes the plural unless the context clearly requires otherwise. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as would be commonly understood by one of ordinary skill in the art to which this invention relates. All patents and publications cited herein are incorporated herein by reference in their entirety.

Definition of terms and conventions used

Terms that are not defined herein are to be interpreted in a manner that would be understood by one skilled in the art based on the disclosure and context. However, in the following description and the accompanying claims, the following terms will be used, generally accepted, unless otherwise indicated, the definitions and conventions of which are set out below.

A. Chemical nomenclature, terms and concepts

In groups, radicals or fragments defined below, the number of carbon atoms is often indicated before the group, for example, (C₁-C₁₀)alkyl means an alkyl group or radical containing from 1 to 10 carbon atoms. Typically, for groups containing two or more subgroups, the last group named is the point of addition of the radical, for example, "alkylaryl" means a monovalent radical of the formula alkylaryl-, while "arylalkyl" means a monovalent radical of the formula arylalkyl-. In addition, the use of a term designating a monovalent radical where a divalent radical is appropriate should be construed to mean the corresponding divalent radical and vice versa. Unless otherwise stated, generally accepted definitions of terms prevail and the generally accepted valences of stable atoms in all resulting formulas and groups are implied. The singular form refers to one or more (i.e. at least one) grammatical objects of form. For example, "element" means one element or several elements.

The term "and/or" means either "and" or "or" unless otherwise noted.

The term "optionally substituted" means that the chemical moiety (for example, an alkyl group) may (but not necessarily) be associated with other substituents (for example, heteroatoms). For example, an alkyl group, which optionally substituted, may be a fully saturated alkyl chain (for example, exclusively hydrocarbon). Alternatively the same is optional a substituted alkyl group may have substituents other than hydrogen. For example, it can be connected at any point in the chain with a halogen atom, hydroxyl group or any other described herein deputy Thus, the term "optionally substituted" means that a given chemical fragment may contain other functional groups, but does not necessarily contain any additional functional groups. Suitable Substituents Used with optional substitution of the described groups, include without limitation halogen, oxo-, -OH, -CN, -COOH, -CH₂CN, -O-(C₁-C₆)alkyl, (C₁-C₆)alkyl, (C₁-C₆)alkoxy group, (C₁-C₆)haloalkyl, (C₁-C₆)haloalkoxy group, -O-(C₂-C₆)alkenyl, -O-(C₂-C₆)alkynyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, -OH, -OP(O)(OH)₂, -OC(O)(C)₁-C₆)alkyl, -C(O)(C₁-C₆)alkyl, -OC(O)O(C₁-C₆)alkyl, -NH₂, -NH((C₁-C₆)alkyl), -N((C₁-C₆)alkyl)₂, -NHC(O)(C)₁-C₆)alkyl, -C(O)NH(C₁-C₆)alkyl, -S(O)₂(C₁-C₆)alkyl, -S(O)NH(C₁-C₆)alkyl and S(O)N((C₁-C₆)alkyl)₂. The substituents themselves may not necessarily be substituted. As used herein, "optionally substituted" also means substituted or unsubstituted, the meanings of which are described below.

The term "substituted" means that the specified group or fragment has one or more suitable substituents, and the substituents may be connected to the specified group or fragment in one or more positions. For example, aryl substituted with cycloalkyl may indicate that the cycloalkyl is attached to one atom in the aryl by bonding or by condensation with aryl when they have two or more atoms in common.

The term "unsubstituted" means that the specified group has no substituents.

Unless specifically stated otherwise, "aryl" means a cyclic aromatic hydrocarbon group containing 1-3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. If it contains two aromatic rings (bicyclic group, etc.), then the aromatic rings of the aryl group are optionally joined at one point (for example, biphenyl) or fused (for example, naphthyl). The aryl group is optionally substituted with one or more substituents, for example 1-5 substituents, at any point of attachment. Typical substituents include, but are not limited to -H, -halogen, -CN, -O-(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl, -O-(C ₂ -C ₆ )alkenyl, -O- (C ₂ -C ₆ )alkynyl, (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ )alkynyl, -OH, -OP(O)(OH) ₂ , -OC(O)(C ₁ -C ₆ )alkyl, -C(O)(C ₁ -C ₆ )alkyl, -OC(O)O(C ₁ -C ₆ )alkyl, -NH ₂ , -NH((C ₁ -C ₆ )alkyl), -N((C ₁ -C ₆ )alkyl) ₂ , -S(O) ₂ -(C ₁ -C ₆ )alkyl, -S(O)NH(C ₁ -C ₆ )alkyl and S(O)N ((C ₁ -C ₆ )alkyl) ₂ . The substituents are themselves not necessarily substituted. In addition, when they contain two fused rings, aryl groups optionally have an unsaturated or partially saturated ring fused to a fully saturated ring. Representative ring systems of such aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.

Unless specifically stated otherwise, "heteroaryl" means a monovalent monocyclic aromatic radical with 5 to 24 ring atoms or a polycyclic aromatic radical containing one or more heteroatoms on the ring selected from N, O or S, the remaining atoms on the ring being C. As used herein, heteroaryl also means a bicyclic heteroaromatic group in which the heteroatom is selected from N, O or S. The aromatic radical is optionally independently substituted with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[ 3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3- c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3- b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanil, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinoline silt, pyrido[4,3- b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazole[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1δ ² -pyrrolo[2,1-b]pyrimidine, dibenzo[b, d]thiophene, pyridin-2-one, furo[3,2 -c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1, 5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[l,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl , [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, 1,3-dihydro- 2H-benz[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a ]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl and their derivatives. Additionally, when they contain two fused rings, aryl groups as defined herein contain an unsaturated or partially saturated ring fused to a fully saturated ring. Examples of ring systems of these heteroaryl groups include indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl and dihydrobenzoxanyl.

Halogen or "halogeno" means fluorine, chlorine, bromine or iodine.

"Alkyl" means a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms. Examples of the (C ₁ -C ₆ )alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec- butyl, tert- butyl, isopentyl, neopentyl, and isohexyl.

"Alkoxy" means a straight or branched chain saturated hydrocarbon of 1-12 carbon atoms containing a terminal "O" in the chain, such as -O(alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, tert-butoxy or pentoxy groups.

"Alkenyl" means an unsaturated straight or branched chain hydrocarbon containing 2-12 carbon atoms. An "alkenyl" group contains at least one double bond in the chain. The double bond in an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n -butenyl, isobutenyl, pentenyl or hexenyl. The alkenyl group may be unsubstituted or substituted and may be straight or branched.

"Alkynyl" means an unsaturated straight or branched chain hydrocarbon containing 2-12 carbon atoms. An "alkynyl" group contains at least one triple bond in the chain. Examples of alkenyl groups include ethynyl, propargyl, butynyl, n- isobutynyl, pentynyl or hexynyl. The alkynyl group may be unsubstituted or substituted.

"Cycloalkyl" or "carbocyclyl" means a monocyclic or polycyclic saturated carbon ring containing 3-18 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl or bicyclo[2.2.2]octenyl and derivatives thereof. (C ₃ -C ₈ )cycloalkyl is a cycloalkyl group containing from 3 to 8 carbon atoms. The cycloalkyl group may be fused (eg, decalin) or bridged (eg, norbornane).

"Heterocyclyl" or "heterocycloalkyl" means a saturated or partially saturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from oxygen, nitrogen or sulfur (O, N or S), and does not have delocalized n electrons (aromaticity) common to the carbon atoms or heteroatoms in the ring. The heterocycloalkyl ring structure may be substituted with one or more substituents. The substituents themselves may optionally be substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperedenyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S -oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinil, oxepinil, diazepinil, tropanil, oxazolidinonyl, 1,4-dioxanyl, dihydrofuranyl, 1,3-dioxolanil, imidazolidinyl, imidazolinil, dithiolanil and homotropanil.

"Haloalkyl" means an alkyl group substituted with one or more halogen atoms. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

"Haloalkoxy group" means an alkoxy group substituted with one or more halogen atoms. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

"Cyano group" means a substituent containing a carbon atom linked to a nitrogen atom by a triple bond, for example, C≡N.

"Amino" means a substituent containing at least one nitrogen atom (eg, -NH ₂ ).

B. Salt, prodrug, derivative and solvate - terms and concepts

“Prodrug” or “prodrug derivative” means a covalently linked derivative or carrier of a parent compound or active drug substance that undergoes at least some biotransformation before exerting its pharmacological effect(s). Typically, such prodrugs have metabolic leaving groups and are rapidly converted in vivo to the parent compound, for example by hydrolysis in the blood, and typically include esters and amide analogues of the parent compounds. A prodrug is designed to improve chemical stability, improve patient tolerability and compliance, improve bioavailability, increase duration of action, improve organ selectivity, improve formulation (e.g., increased aqueous solubility), and/or reduce side effects (e.g., toxicity) . Typically, the prodrugs themselves have little or no biological activity and are stable under normal conditions. Prodrugs can be readily prepared from the parent compounds using methods known in the art, such as those described in A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991, especially Chapter 5: "Design and Applications of Prodrugs"; Design of Products, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs: Topical and Ocular Drug Delivery, K.B. Sloan (ed.), Marcel Dekker, 1998; Methods in Enzymology, K. Widder et al. (eds.), Vol. 42, Academic Press, 1985, especially pp. 309-396; Burger's Medicinal Chemistry and Drug Discovery, 5th Ed., M. Wolff (ed.), John Wiley & Sons, 1995, especially volume 1 and pp. 172-178 and pp. 949-982; Pro-Drugs as Novel Delivery Systems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975; Bioreversible Carriers in Drug Design, E.B. Roche (ed.), Elsevier, 1987, each of these sources is incorporated herein by reference in its entirety.

As used herein, "pharmaceutically acceptable prodrug" means a prodrug of a compound of the present invention that is medically suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic response, or the like. , is commensurate with a reasonable benefit/risk ratio and is effective for its intended use, and zwitterionic forms are included where possible.

"Salt" means the ionic form of the parent compound or the reaction product of the parent compound with a suitable acid or base to produce an acid salt or a basic salt of the parent compound. Salts of the compounds of the present invention can be synthesized from starting compounds that contain a basic or acidic moiety by conventional chemical methods. Typically, salts are prepared by reacting the free base or acid of the parent compound with stoichiometric amounts or an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.

"Pharmaceutically acceptable salt" means a salt of a compound of the present invention that is medically suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit/risk ratio, usually soluble or dispersible in water or oil, and effective for the intended use. The term includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. Since the compounds of the present invention are useful in both free base and salt form, in practice the use of the salt form is equivalent to the use of the base form. Lists of suitable salts can be found, for example, in the publication S.M. Birge et al., J. Pharm. Sci., 1977, 66, pp. 1-19, which is incorporated herein by reference in its entirety.

"Pharmaceutically acceptable acid addition salt" means those salts which retain the biological effectiveness and properties of the free base and which are not biologically or otherwise undesirable formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid , nitric acid, phosphoric acid, etc., and organic acids such as acetic acid, trichloroacetic acid, trifluoroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 2-acetoxybenzoic acid, butyric acid acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphoric acid, hemisulfonic acid, heptanoic acid, hexanoic acid, formic acid, fumaric acid, 2-hydroxyethanesulfonic acid (isethionic acid), lactic acid, maleic acid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid, mesitylenesulfonic acid, methanesulfonic acid, naphthalene sulfonic acid, nicotinic acid, 2-naphthalene sulfonic acid, oxalic acid, pamoic acid, pectic acid, phenylacetic acid, 3-phenylpropy onic acid, picric acid , pivalic acid, propionic acid, pyruvic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid, etc.

"Pharmaceutically acceptable base addition salt" means those salts which retain the biological effectiveness and properties of free acids and are not biologically or otherwise undesirable, they are formed with inorganic bases such as ammonia or hydroxide, carbonate or bicarbonate of ammonium or a metal cation such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc. Particularly preferred are ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, quaternary ammonium compounds, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, pi perazine, piperidine, N-ethylpiperidine, tetramethylammonium compounds, tetraethylammonium compounds, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, dibenzylamine, N, N-dibenzylphenethylamine, 1-ephenamine, N, N-dibenzylethylenediamine, polyamine resins etc. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

"Solvate" means a complex of variable stoichiometry formed by a solute, for example a compound of formula (I') or formula (I), and a solvent, for example water, ethanol or acetic acid. This physical interaction may involve varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases, the solvate can be isolated, for example, in cases where one or more solvent molecules are included in the crystal lattice of the crystalline solid. Typically, such solvents selected for the purposes of the present invention do not affect the biological activity of the solute. Solvates cover solvates both in the dissolved phase and those amenable to isolation. Typical solvates include hydrates, ethanolates, methanolates, etc.

"Hydrate" means a solvate in which the solvent molecule(s) is water.

The compounds of the present invention discussed below include their free base or acid, their salts, solvates and prodrugs thereof, and may include oxidized sulfur atoms or quaternary nitrogen atoms in their structure, although this is not explicitly stated or indicated, especially pharmaceutically. acceptable forms. Such forms, in particular pharmaceutically acceptable forms, are intended to fall within the scope of the appended claims.

C. Isomer - terms and concepts

"Isomers" means compounds having the same number and nature of atoms and therefore the same molecular weight, but differing in the arrangement or configuration of the atoms in space. The term includes stereoisomers and geometric isomers.

"Stereoisomer" or "optical isomer" means a stable isomer that contains at least one chiral atom or whose rotation is limited, resulting in perpendicular planes of asymmetry (for example, some biphenyls, allenes and spiro compounds), and is capable of rotating the plane of plane-polarized light . Since asymmetric centers and different chemical structures exist in the compounds of the present invention, which may lead to stereoisomerism, stereoisomers and mixtures thereof are contemplated herein. The compounds of the present invention and their salts contain asymmetric carbon atoms and, therefore, can exist as individual stereoisomers, racemates and as mixtures of enantiomers and diastereomers. Typically, such compounds are prepared as a racemic mixture. However, if necessary, such compounds can be prepared or isolated in the form of pure stereoisomers, i.e. e. in the form of individual enantiomers or diastereomers, or in the form of mixtures enriched in one stereoisomer. As discussed in more detail below, individual stereoisomers of compounds are prepared by synthesis from optically active starting materials containing the desired chiral centers, or by preparing mixtures of enantiomeric products followed by separation or isolation, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic methods, the use of chiral separating agents or direct separation of enantiomers on chiral chromatography columns. Starting compounds with defined stereochemistry are either commercially available or prepared by the methods described below and separated by methods well known in the art.

"Enantiomers" means a pair of stereoisomers that are non-matching mirror images of each other.

"Diastereoisomers" or "diastereomers" mean optical isomers that are not mirror images of each other.

"Racemic mixture" or "racemate" means a mixture containing equal parts of the individual enantiomers.

"Non-racemic mixture" means a mixture containing unequal parts of the individual enantiomers.

"Geometric isomer" means a stable isomer that results from limited freedom of rotation around double bonds (e.g., cis-2-butene and trans-2-butene) or in a cyclic structure (e.g., cis-1,3-dichlorocyclobutane and trans- 1,3-dichlorocyclobutane). Since carbon-carbon double bonds, C=N double bonds, cyclic structures, and the like may be present in the compounds of the present invention, the present invention contemplates each of the various stable geometric isomers and mixtures thereof resulting from specific positions of substituents around these double bonds and in these cyclic structures. Substituents and isomers are designated using cis/trans notation or using the E- or Z-system, where the term "E" denotes higher order substituents on opposite sides of the double bond and the term "Z" denotes higher order substituents on the same side of the double bond. A detailed discussion of E- and Z-isomerism is given in J. March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th ed., John Wiley & Sons, 1992, which is incorporated herein by reference in its entirety. Some of the following examples represent single E-isomers, single Z-isomers, and mixtures of E/Z-isomers. Determination of E- and Z-isomers can be performed by analytical methods such as X-ray crystallography, ¹ H NMR and ¹³ C NMR.

Some of the compounds of the present invention may exist in more than one tautomeric form. As mentioned above, the compounds of the present invention include all such tautomers.

It is well known in the art that the biological and pharmacological activity of a compound is influenced by the stereochemical structure of the compound. Thus, for example, enantiomers often exhibit very different biological activities, including differences in pharmacokinetic properties, such as metabolism, protein binding, and the like, and pharmacological properties, including the type of action exhibited, the degree of activity, toxicity, and the like. Thus, one skilled in the art will appreciate that one enantiomer may be more active or may exhibit a beneficial effect when enriched with it over the other enantiomer or when separated from the other enantiomer. In addition, one skilled in the art will know how to separate, enrich, or selectively obtain enantiomers of the compounds of the present invention based on this disclosure and knowledge from the prior art.

Thus, although the racemic form of a drug can be used, it is often less effective than administering the same amount of enantiomerically pure drug; indeed, in some cases one enantiomer may be pharmacologically inactive and merely act as a diluent. For example, although ibuprofen was previously administered as a racemate, only the S-isomer of ibuprofen has been shown to be effective as an anti-inflammatory agent (however, in the case of ibuprofen, although the R-isomer is inactive, it is converted to the S-isomer in vivo, thus the rate of action of the racemic form of the drug is lower than that of the pure S-isomer). In addition, the pharmacological action of enantiomers may have certain biological activity. For example, S-penicillamine is a therapeutic agent for chronic arthritis, while R-penicillamine is toxic. Indeed, some purified enantiomers have advantages over racemates, as purified individual isomers have been reported to have higher skin penetration rates compared to the racemic mixture. See US Patent Nos. 5,114,946 and 4,818,541.

Thus, if one enantiomer is pharmacologically more active, less toxic, or has a preferential effect in the body compared to another enantiomer, then from a therapeutic point of view it will be preferable to administer that enantiomer. Thus, the patient undergoing treatment will be exposed to a lower total dose of drug and a lower dose of the enantiomer that may be toxic, or an inhibitor of another enantiomer.

Preparation of pure enantiomers or mixtures with the desired enantiomeric excess(ee) or enantiomeric purity is accomplished by one or more of a variety of (a) separation or separation of enantiomers or (b) enantioselective synthesis methods known to those skilled in the art, or a combination thereof. These resolution methods are typically based on chiral recognition and include, for example, chromatography using chiral stationary phases, enantioselective host-guest complexation, resolution or synthesis using chiral auxiliaries, enantioselective synthesis, enzymatic and non-enzymatic kinetic resolution, or spontaneous enantioselective crystallization. Such methods are generally described in Chiral Separation Techniques: A Practical Approach (2nd Ed.), G. Subramanian (ed.), Wiley-VCH, 2000; T.E. Beesley and R.P.W. Scott, Chiral Chromatography, John Wiley & Sons, 1999 and Satinder Ahuja, Chiral Separations by Chromatography, Am. Chem. Soc., 2000. In addition, there are equally well known methods for quantifying enantiomeric excess or purity, for example, GC, HPLC, CE or NMR, and for determining absolute configuration and conformation, for example, CD ORD, X-ray crystallography or NMR.

In general, all tautomeric forms and isomeric forms and mixtures, whether individual geometric isomers or stereoisomers or racemic or non-racemic mixtures, of a chemical structure or compound are meant, unless the particular stereochemistry or isomeric form is specifically indicated in the name or structure of the compound.

D. Pharmaceutical Administration and Treatment Terms and Concepts

A “patient” or “subject” is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate such as a monkey, chimpanzee, baboon, or rhesus. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

"Effective amount" or "therapeutically effective amount" when used in combination with a compound means an amount of a compound of the present invention that (i) provides treatment or prevention of a particular disease, condition or disorder, (ii) attenuates, reduces the severity of, or eliminates one or more symptoms of a specific disease, condition or disorder or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition or disorder described herein.

The terms “pharmaceutically effective amount” or “therapeutically effective amount” mean an amount of a compound of the present invention that, when administered to a patient in need thereof, is sufficient to provide treatment for diseases, conditions or disorders that benefit from the use of the compounds. Such an amount will be sufficient to produce the biological or medical response of the tissue, system, or patient that the researcher or physician expects. The amount of a compound of the present invention that constitutes a therapeutically effective amount will vary depending on factors such as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of elimination of the compound, the duration of treatment, the type of disease state, or the disorder being treated and its severity, drugs used in combination with or concurrently with the compounds of the present invention, and the age, weight, general health, sex, and diet of the patient. Such a therapeutically effective amount can generally be determined by one of ordinary skill in the art in light of his/her own knowledge, the prior art, and this disclosure.

As used herein, the term “pharmaceutical composition” refers to a compound of this invention or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof together with at least one pharmaceutically acceptable carrier in a form suitable for oral or parenteral administration.

"Carrier" includes carriers, excipients and diluents and means a material, composition or carrier medium, such as a liquid or solid excipient, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ or part of the body , into another organ or part of the subject's body.

A subject "needs" treatment if such treatment would benefit the subject (preferably a person) biologically, medically, or improve their quality of life.

As used herein, the terms “suppress,” “suppress,” or “suppress” mean a reduction or attenuation of a given condition, symptom, or disorder, or disease, or a significant reduction in the original level of activity of a biological activity or process.

As used herein, the term “treat,” “treat,” or “cure” any disease or disorder refers to alleviating or reducing the severity of the disease or disorder (i.e., slowing or stopping the progression of the disease or at least one of its clinical symptoms) ; or alleviation or reduction of at least one physical parameter or biomarker associated with a disease or disorder, including those that may not be obvious to the patient.

As used herein, the term “prevent,” “prevent,” or “prevent” any disease or disorder refers to prophylactically treating a disease or disorder or delaying the onset or progression of a disease or disorder.

"Pharmaceutically acceptable" means that the substance or composition must be compatible chemically and/or toxicologically with the other ingredients contained in the composition and/or with the mammal being treated therewith.

“Disorder” means and is used interchangeably with the terms disease, condition or disease unless otherwise noted.

“Administering,” “administering,” or “administration” means either the direct administration of a disclosed compound or a pharmaceutically acceptable salt of a disclosed compound or composition to a subject, or the administration of a derivative of a prodrug or analogue of a compound or a pharmaceutically acceptable salt of a compound or composition to a subject that can form an equivalent amount of the active compound in the subject's body.

"Prodrug" means a compound that is converted in vivo by metabolic means (eg, hydrolysis) into the disclosed compound.

"Compounds of the present invention", "compounds of formula (I')", "compounds of this invention" and equivalent expressions (unless specifically stated otherwise) refer to compounds of formula (I'), (I), (Ia), ( Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im) (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Ia-1), (Ib-1), (Ic-1), (Id-1), (Ie -1), (If-1), (Ig-1), (Ih-1), (Ii-1), (Ij-1), (Ik-1), (Il-1), (Im-1 ), (In-1), (Io-1), (Ip-1), (Iq-1), (Ir-1), (Is-1), (It-1), (Ia-2), (Ia-3), (Ib-2), and/or (Ib-3) described herein, including tautomers thereof, prodrugs thereof, salts thereof, in particular pharmaceutically acceptable salts, and solvates and hydrates, wherein this is permitted by the context, as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers and isotopically labeled compounds (including deuterium substitutions), as well as naturally occurring species (e.g. polymorphs, solvates and/or hydrates). For purposes of the present invention, solvates and hydrates generally refer to compositions. In general and preferably, the compounds of the present invention and the formulas denoting the compounds of the present invention are intended to include only their stable compounds and exclude unstable compounds, even though the unstable compound may be considered to be formally covered by the formula of the compound. Likewise, reference to intermediates, whether they themselves are claimed or not, is intended to cover their salts and solvates where the context allows. For clarity, specific cases where the context permits are sometimes indicated in the text, but these examples are illustrative only and are not intended to exclude other cases where the context permits.

"Stable compound" or "stable structure" means a compound that is sufficiently stable to withstand isolation from the reaction mixture to the required degree of purity and formulation into an effective therapeutic or diagnostic agent. For example, a compound that would have a "free valency" or is a carbanion is not a compound contemplated by the present invention.

In a particular embodiment, the term "about" or "approximately" means an amount within 20%, preferably within 10%, and more preferably within 5% of a given value or range.

The yield of each of the reactions described herein is expressed as a percentage of theoretical yield. “Cancer” means any cancer caused by the proliferation of malignant tumor cells such as tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas, etc. For example, cancers include, but are not limited to, mesothelioma, leukemias and lymphomas such as cutaneous T -cell lymphomas (CTCL), noncutaneous peripheral T-cell lymphomas, human T-cell lymphotrophic virus (HTLV)-associated lymphomas such as adult T-cell leukemia/lymphoma (ATLL), B-cell lymphoma, types of acute nonlymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, lymphomas and multiple myeloma, non-Hodgkin's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, Burkitt's lymphoma, T-cell leukemia/lymphoma in adults, acute myeloid leukemia (AML), chronic myeloid leukemia (CML) or hepatocellular carcinoma. Additional examples include myelodysplastic syndrome, solid tumors in children such as brain tumors, neuroblastoma, retinoblastoma, Wilms tumor, bone tumors and soft tissue sarcomas, common solid tumors in adults such as head and neck cancers (eg, oral cancer , larynx, nasopharynx, esophagus), genitourinary cancer (eg, prostate, bladder, kidney, uterus, ovary, testis), lung cancer (eg, small cell and non-small cell), breast cancer (triple negative breast cancer (TNBC) )), pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, tumors associated with Gorlin syndrome (eg medulloblastoma, meningioma, etc.) and liver cancer. Additional examples of forms of cancer that can be treated with subject compounds include, but are not limited to, skeletal or smooth muscle cancer, gastric cancer, small bowel cancer, rectal carcinoma, salivary gland cancer, endometrial cancer, adrenal cancer, anal cancer, rectal cancer , parathyroid cancer and pituitary cancer.

Additional cancers that the compounds described herein may be useful in preventing, treating, and studying include, for example, colon carcinoma, familial adenomatous polyposis carcinoma, and hereditary nonpolyposis colorectal cancer or melanoma. In addition, cancers include, but are not limited to, labial carcinoma, laryngeal carcinoma, subpharyngeal carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, thyroid cancer (medullary and papillary thyroid carcinoma), renal carcinoma, renal parenchymal carcinoma, cervical carcinoma uterus, uterine body carcinoma, endometrial carcinoma, choriocarcinoma, testicular carcinoma, urinary tract carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, gallbladder carcinoma, bronchial carcinoma, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngeoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, plasmacytoma, non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC) ), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia and gastrointestinal stromal tumor (GIST).

The term "simultaneously" or "simultaneous" with respect to a method of treatment or therapeutic use regarding a combination of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof and one or more other agents means administration of the compound and one or more other means in the same way and at the same time.

The term "alone" or "separate" in relation to a method of treatment or therapeutic use regarding a combination of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate thereof, a prodrug thereof, a stereoisomer or tautomer thereof and one or more other agents means the administration compounds and one or more other means in different ways and at approximately the same time.

Therapeutic administration is intended to be "over a period of time" with respect to a method of treatment or therapeutic use of a combination of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate thereof, a prodrug thereof, a stereoisomer or tautomer thereof, and one or more others agents means administering a compound and one or more other agents by the same or different routes and at different times. In some embodiments, administration of the compound or one or more other agents occurs before administration of the other. Thus, one of the active ingredients (i.e., a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate thereof, a prodrug thereof, a stereoisomer or tautomer thereof, or one or more second agents) can be administered for several months before administration of another active ingredient or ingredients. In this case, simultaneous administration does not occur. Another type of therapeutic administration over a period of time is the administration over a period of time of two or more active ingredients of the combination using different frequencies of administration for each of the active ingredients, whereby at certain points in time there is simultaneous administration of all active ingredients, whereas at other times, only a portion of the active ingredients of the combination may be administered (for example, for a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate thereof, a prodrug thereof, a stereoisomer or tautomer thereof, and one or more other agents, therapeutic administration during period of time may be such that a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof is administered once daily and one or more other agents are administered once every four weeks) .

The compounds may be administered simultaneously (as a single drug or separate drugs), sequentially, separately, or over a period of time with another drug therapy or treatment. Typically, combination therapy involves the administration of two or more drugs during one cycle or course of therapy.

“IKZF2-related disease or disorder” means any disease or disorder that is directly or indirectly affected by modulation of IKZF2 protein levels.

“IKZF4-related disease or disorder” means any disease or disorder that is directly or indirectly affected by modulation of IKZF4 protein levels.

D. Specific Embodiments and Methods for Testing Compounds of Formula (I') or Formula (I)

The present invention relates to compounds or pharmaceutically acceptable salts, hydrates, solvates, prodrugs thereof, stereoisomers or tautomers thereof, capable of modulating IKZF2 protein levels, which are useful for the treatment of diseases and disorders associated with modulating IKZF2 protein levels. The present invention further relates to compounds or pharmaceutically acceptable salts, hydrates, solvates, prodrugs thereof, stereoisomers or tautomers thereof, which are useful for reducing or reducing IKZF2 protein levels.

In one embodiment, compounds of formula (I') or formula (I) are characterized by the structure of formula (Ia) or formula (Ia-1):

or

or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs based thereon, stereoisomers and tautomers thereof.

In another embodiment, compounds of formula (I') or formula (I) are characterized by the structure of formula (Ib) or formula (Ib-1):

or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs based thereon, stereoisomers and tautomers thereof.

In one embodiment, compounds of formula (I') are characterized by a structure of formula (Ia-2) or formula (Ia-3):

or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs based thereon, stereoisomers and tautomers thereof.

In another embodiment, compounds of formula (I') are characterized by the structure of formula (Ib-2) or formula (Ib-3):

or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs based thereon, stereoisomers and tautomers thereof.

In yet another embodiment, compounds of formula (I') or formula (I) are characterized by the structure of formula (lc) or formula (lc-1):

or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs based thereon, stereoisomers and tautomers thereof.

In another embodiment, compounds of formula (I') or formula (I) are characterized by the structure of formula (Id) or formula (Id-1):

or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs based thereon, stereoisomers and tautomers thereof.

In another embodiment, compounds of formula (I') or formula (I) are characterized by the structure of formula (Ie) or formula (Ie-1):

or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs based thereon, stereoisomers and tautomers thereof.

In another embodiment, compounds of formula (I') or formula (I) are characterized by the structure of formula (If) or formula (If-1):

or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs based thereon, stereoisomers and tautomers thereof.

In another embodiment, compounds of formula (I') or formula (I) are characterized by the structure of formula (Ig) or formula (Ig-1):

or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs based thereon, stereoisomers and tautomers thereof.

In another embodiment, compounds of formula (I') or formula (I) are characterized by the structure of formula (Ih) or formula (Ih-1):

or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs based thereon, stereoisomers and tautomers thereof.

In another embodiment, compounds of formula (I') or formula (I) are characterized by the structure of formula (Ii) or formula (Ii-1):

or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs based thereon, stereoisomers and tautomers thereof.

In another embodiment, compounds of formula (I') or formula (I) are characterized by the structure of formula (Ij) or formula (Ij-1):

or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs based thereon, stereoisomers and tautomers thereof.

In another embodiment, compounds of formula (I') or formula (I) are characterized by the structure of formula (Ik) or formula (Ik-1):

or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs based thereon, stereoisomers and tautomers thereof.

In another embodiment, compounds of formula (I') or formula (I) are characterized by the structure of formula (Il) or formula (Il-1):

or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs based thereon, stereoisomers and tautomers thereof.

In another embodiment, compounds of formula (I') or formula (I) are characterized by the structure of formula (Im) or formula (Im-1):

or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs based thereon, stereoisomers and tautomers thereof.

In another embodiment, compounds of formula (I') or formula (I) are characterized by the structure of formula (In) or formula (In-1):

or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs based thereon, stereoisomers and tautomers thereof.

In another embodiment, compounds of formula (I') or formula (I) are characterized by the structure of formula (Io) or formula (Io-1):

or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs based thereon, stereoisomers and tautomers thereof.

In another embodiment, compounds of formula (I') or formula (I) are characterized by the structure of formula (Ip) or formula (Ip-1):

or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs based thereon, stereoisomers and tautomers thereof.

In another embodiment, compounds of formula (I') or formula (I) are characterized by the structure of formula (Iq) or formula (Iq-1):

or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs based thereon, stereoisomers and tautomers thereof.

In another embodiment, compounds of formula (I') or formula (I) are characterized by the structure of formula (Ir) or formula (Ir-1):

or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs based thereon, stereoisomers and tautomers thereof.

In another embodiment, compounds of formula (I') or formula (I) are characterized by the structure of formula (Is) or formula (Is-1):

or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs based thereon, stereoisomers and tautomers thereof.

In another embodiment, compounds of formula (I') or formula (I) are characterized by the structure of formula (It) or formula (It-1):

or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs based thereon, stereoisomers and tautomers thereof.

In some embodiments of the above formulas (e.g., formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih ), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Ia-1), (Ib-1), (Ic-1), (Id-1), (Ie-1), (If-1), (Ig-1), (Ih-1), (Ii -1), (Ij-1), (Ik-1), (Il-1), (Im-1), (In-1), (Io-1), (Ip-1), (Iq-1 ), (Ir-1), (Is-1), (It-1), (Ia-2), (Ia-3), (Ib-2), and/or (Ib-3),

), R ₁ represents or . In another embodiment, R ₁ is or . In yet another embodiment, R ₁ is or .

In another embodiment, R ₁ is . In yet another embodiment, R ₁ is . In another embodiment, R ₁ is .

In some embodiments of the above formulas, R _a and R _b are each independently H or D. In another embodiment, R _a and R _b are each independently H, or R _a and R _b together with the atom to which they are attached, form =(O). In yet another embodiment, R _a and R _b are each independently H. In another embodiment, R _a and R _b together with the atom to which they are attached form =(O).

In some embodiments of the above formulas, X ₁ is H, (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₃ )haloalkyl, (C ₁ -C ₆ )haloalkoxy, ( C ₃ -C ₇ )cycloalkyl, halogen, CN, -OH or -NH ₂ . In another embodiment, X ₁ is H, (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₃ )haloalkyl, (C ₁ -C ₃ )haloalkoxy, halogen, CN, -OH or -NH ₂ . In yet another embodiment, X ₁ is H, (C ₁ -C ₄ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C ₄ )haloalkoxy, (C ₃ -C ₇ )cycloalkyl or halogen. In another embodiment, X ₁ is H, (C ₁ -C ₄ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C ₄ )haloalkoxy or halogen. In yet another embodiment, X ₁ represents H, halogen, CN, -OH or -NH ₂ . In another embodiment, X ₁ is H, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl, halogen, CN, -OH or -NH ₂ . In yet another embodiment, X ₁ represents H, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl, halogen, -OH or -NH ₂ . In another embodiment, X ₁ represents H, (C ₁ -C ₄ )alkyl, halogen, -OH or -NH ₂ . In yet another embodiment, X ₁ represents H, halogen, -OH or -NH ₂ . In another embodiment, X ₁ is H.

In some embodiments of the above formulas, X ₂ is H, (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₃ )haloalkyl, (C ₁ -C ₆ )haloalkoxy, ( C ₃ -C ₇ )cycloalkyl, halogen, CN, -OH or -NH ₂ . In another embodiment, X ₂ is H, (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₃ )haloalkyl, (C ₁ -C ₃ )haloalkoxy, halogen, CN, -OH or -NH ₂ . In yet another embodiment, X ₂ is H, (C ₁ -C ₄ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C ₄ )haloalkoxy, (C ₃ -C ₇ )cycloalkyl or halogen. In another embodiment, X ₂ is H, (C ₁ -C ₄ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C ₄ )haloalkoxy or halogen. In yet another embodiment, X ₂ represents H, halogen, CN, -OH or -NH ₂ . In another embodiment, X ₂ is H, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl, halogen, CN, -OH or -NH ₂ . In yet another embodiment, X ₂ represents H, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl, halogen, -OH or -NH ₂ . In another embodiment, X ₂ represents H, (C ₁ -C ₄ )alkyl, halogen, -OH or -NH ₂ . In yet another embodiment, X ₂ represents H, halogen, -OH or -NH ₂ . In another embodiment, X ₂ is H.

In some embodiments of the above formulas, X ₁ is H, and X ₂ is (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₃ )haloalkyl, (C ₁ -C ₆ ) haloalkoxy, (C ₃ -C ₇ ) cycloalkyl, halogen, CN, -OH or -NH ₂ . In another embodiment, X ₁ is (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₃ )haloalkyl, (C ₁ -C ₆ )haloalkoxy, (C ₃ -C ₇ )cycloalkyl, halogen, CN, -OH, or _-NH2 , and _X2 is H. In yet another embodiment, _X1 is H and _X2 is H.

In some embodiments of the above formulas, R _x is D. In another embodiment, R _x is H.

In some embodiments of the above formulas, R ₂ is H, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )haloalkyl, or (C ₃ -C ₆ )cycloalkyl. In another embodiment, R ₂ is (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )haloalkyl or (C ₃ -C ₆ )cycloalkyl. In yet another embodiment, R ₂ represents H, (C ₁ -C ₃ )alkyl or (C ₃ -C ₆ )cycloalkyl. In another embodiment, R ₂ represents H, (C ₁ -C ₃ )alkyl or (C ₁ -C ₃ )haloalkyl. In yet another embodiment, R ₂ represents H or (C ₁ -C ₃ )alkyl. In another embodiment, R ₂ is H, methyl, ethyl, n-propyl or isopropyl. In yet another embodiment, R ₂ represents H, methyl or ethyl. In another embodiment, R ₂ represents H or methyl.

In some embodiments of the above formulas, R ₂ and R ₇ together with the nitrogen atoms to which they are attached form a 7-membered heterocycloalkyl ring. In another embodiment, R ₂ and R ₇ together with the nitrogen atoms to which they are attached form a 6-membered heterocycloalkyl ring.

In some embodiments of the above formulas, each R ₃ is independently in each case a (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkoxy, (C ₁ -C ₃ )haloalkyl, (C ₁ -C ₃ ) haloalkoxy, halogen, CN, -OH or -NH ₂ . In another embodiment, R ₃ is independently in each instance (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkoxy, (C ₁ -C ₃ )haloalkyl, (C ₁ -C ₃ )haloalkoxy or halogen. In yet another embodiment, R ₃ is independently in each instance halogen, CN, -OH or -NH ₂ . In another embodiment, R ₃ is independently in each instance (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkoxy, (C ₁ -C ₃ )haloalkyl or (C ₁ -C ₃ )haloalkoxy. In yet another embodiment, R ₃ is independently in each instance (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )haloalkyl, halogen, CN, -OH or -NH ₂ . In another embodiment, R ₃ is independently in each instance (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )haloalkyl, halogen or CN. In yet another embodiment, R ₃ is independently in each instance (C ₁ -C ₃ )alkyl, halogen or CN. In another embodiment, R ₃ is independently in each case a (C ₁ -C ₃ )alkyl or a (C ₁ -C ₃ )haloalkyl. In yet another embodiment, R ₃ is independently in each instance (C ₁ -C ₃ )alkyl or CN. In another embodiment, R ₃ is independently in each instance (C ₁ -C ₃ )alkyl. In yet another embodiment, R ₃ is independently in each instance methyl, ethyl, n-propyl or isopropyl.

In some embodiments of the above formulas, two R ₃ together with the carbon atoms to which they are attached form a (C ₃ -C ₇ )cycloalkyl or 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S; or two R ₃ when at adjacent carbon atoms, together form a phenyl or 5- or 6-membered heteroaryl ring containing 1-3 heteroatoms selected from O, N and S. In another embodiment, the two R ₃ together with the atoms carbons to which they are attached form a (C ₃ -C ₇ )cycloalkyl or 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S. In yet another embodiment, two R ₃ together with the atoms carbons to which they are attached form a (C ₃ -C ₇ )cycloalkyl or 5-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S. In another embodiment, two R ₃ together with carbon atoms to which they are attached form a (C ₃ -C ₇ )cycloalkyl or 5- or 6-membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S. In yet another embodiment, two R ₃ together with the atoms carbons to which they are attached form a (C ₄ -C ₇ )cycloalkyl or 5- or 6-membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S. In another embodiment, two R ₃ together with the atoms carbons to which they are attached form a (C ₅ -C ₇ )cycloalkyl or 5- or 6-membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S.

In another embodiment, two R ₃ together with the carbon atoms to which they are attached form a (C ₃ -C ₇ )cycloalkyl. In another embodiment, two R ₃ together with the carbon atoms to which they are attached form a (C ₄ -C ₇ )cycloalkyl. In yet another embodiment, two R ₃ together with the carbon atoms to which they are attached form a (C ₅ -C ₇ )cycloalkyl. In another embodiment, the two R ₃ together with the carbon atoms to which they are attached form a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S. In another embodiment, the two R ₃ together with the atoms carbons to which they are attached form a 5-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S. In another embodiment, two R ₃ together with the carbon atoms to which they are attached form a 5- or a 6-membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S.

In another embodiment, the two R ₃ , when at adjacent carbon atoms, together form a phenyl or 5- or 6-membered heteroaryl ring containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, the two R ₃ , when at adjacent carbon atoms, together form a phenyl or 5-membered heteroaryl ring containing 1-3 heteroatoms selected from O, N and S. In yet another embodiment, two R ₃ when at adjacent carbon atoms, together form a phenyl or a 6-membered heteroaryl ring containing 1-3 heteroatoms selected from O, N and S. In another embodiment, two R ₃ when at adjacent carbon atoms together form phenyl. In yet another embodiment, the two _R3s , when at adjacent carbon atoms, together form a 5- or 6-membered heteroaryl ring containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, the two _R3s , when they are at adjacent carbon atoms, together form a 5-membered heteroaryl ring containing 1-3 heteroatoms selected from O, N and S. In yet another embodiment, two R ₃ when they are at adjacent carbon atoms, together form 6 -membered heteroaryl ring containing 1-3 heteroatoms selected from O, N and S.

In another embodiment, two R ₃ together with the carbon atoms to which they are attached form a (C ₃ -C ₇ )cycloalkyl, or two R ₃ when on adjacent carbon atoms together form a phenyl or 5- or 6-membered heteroaryl a ring containing 1-3 heteroatoms selected from O, N and S. In yet another embodiment, two R ₃ together with the carbon atoms to which they are attached form a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected of O, N and S, or two R ₃ when they are at adjacent carbon atoms, together form a phenyl or 5- or 6-membered heteroaryl ring containing 1-3 heteroatoms selected from O, N and S. In another embodiment implementation, two R ₃ together with the carbon atoms to which they are attached form a (C ₃ -C ₇ )cycloalkyl or 4-7-membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, or two R ₃ , when they are on adjacent carbon atoms, together they form phenyl. In yet another embodiment, two R ₃ together with the carbon atoms to which they are attached form a (C ₃ -C ₇ )cycloalkyl or 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, or two R ₃ , when on adjacent carbon atoms, together form a 5- or 6-membered heteroaryl ring containing 1-3 heteroatoms selected from O, N and S.

In another embodiment, two R ₃ together with the carbon atoms to which they are attached form a (C ₃ -C ₇ )cycloalkyl, or two R ₃ when on adjacent carbon atoms together form phenyl. In another embodiment, two R ₃ together with the carbon atoms to which they are attached form a (C ₄ -C ₇ )cycloalkyl, or two R ₃ when on adjacent carbon atoms together form phenyl. In another embodiment, two R ₃ together with the carbon atoms to which they are attached form a (C ₅ -C ₇ )cycloalkyl, or two R ₃ when on adjacent carbon atoms together form phenyl.

In another embodiment, two R ₃ together with the carbon atoms to which they are attached form a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, or two R ₃ when they are adjacent carbon atoms, together form a 5- or 6-membered heteroaryl ring containing 1-3 heteroatoms selected from O, N and S. In yet another embodiment, two R ₃ together with the carbon atoms to which they are attached form 5-7 -membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, or two R ₃ when they are at adjacent carbon atoms, together form a 5- or 6-membered heteroaryl ring containing 1-3 heteroatoms selected of O, N and S. In another embodiment, two R ₃ together with the carbon atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, or two _R3 , when present at adjacent carbon atoms, together form a 5- or 6-membered heteroaryl ring containing 1-3 heteroatoms selected from O, N and S.

In another embodiment, two R ₃ , when attached to the same carbon atom, together form a (C ₃ -C ₇ )spirocycloalkyl or 4-7 membered spiroheterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S. In another embodiment, two R ₃ , when present at adjacent carbon atoms, form a (C ₃ -C ₇ )cycloalkyl or 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S. In another embodiment, two R ₃ together with the carbon atoms to which they are attached form a bridged (C ₃ -C ₇ )cycloalkyl or 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S.

In some embodiments of the above formulas, _R3 and _R7 , together with the nitrogen and carbon atoms to which they are attached, form a 5- or 6-membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, optionally substituted with one to four substituents, each independently selected from (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl and halogen. In another embodiment, R ₃ and R ₇ together with the nitrogen and carbon atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, substituted by one - four substituents, each independently selected from (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl and halogen. In another embodiment, _R3 and _R7 , together with the nitrogen and carbon atoms to which they are attached, form a 5- or 6-membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S.

In some embodiments of the above formulas, each R ₄ is (C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkoxy, (C ₁ -C ₃ )haloalkyl, (C ₁ -C ₃ )haloalkoxy, halogen, -OH or -NH ₂ . In another embodiment, R ₄ is (C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkoxy, (C ₁ -C ₃ )haloalkyl, (C ₁ -C ₃ )haloalkoxy or halogen. In another embodiment, R ₄ is (C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkoxy, (C ₁ -C ₃ )haloalkyl or (C ₁ -C ₃ )haloalkoxy. In another embodiment, R ₄ is (C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )haloalkyl or halogen. In another embodiment, R ₄ is halogen, -OH or -NH ₂ . In another embodiment, R ₄ is (C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )haloalkyl, halogen, -OH or -NH ₂ . In another embodiment, R ₄ is (C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )haloalkyl, halogen or -OH. In another embodiment, R ₄ is (C ₁ -C ₆ )alkyl or (C ₁ -C ₃ )haloalkyl. In another embodiment, R ₄ represents (C ₁ -C ₆ )alkyl.

In some embodiments of the above formulas, R ₅ is -OR ₆ . In another embodiment, R ₅ is -NR ₇ R _7' .

In some embodiments of the above formulas, R ₆ is H, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )haloalkyl, -C(O)(C ₁ -C ₃ )alkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three substituents, each of which is independently selected from (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S. In another embodiment, R ₆ is (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )haloalkyl, -C(O)(C ₁ -C ₃ )alkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three substituents, each of which is independently selected from (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S.

In another embodiment, R ₆ is H, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )haloalkyl, -C(O)(C ₁ -C ₃ )alkyl, (C ₃ -C ₇ )cycloalkyl , 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is substituted with one to three substituents, each of which is independently selected from (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S. In yet another embodiment, R ₆ is (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )haloalkyl, -C(O)(C ₁ -C ₃ )alkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is substituted with one to three substituents, each of which is independently selected from (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S.

In another embodiment, R ₆ is H, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )haloalkyl, or -C(O)(C ₁ -C ₃ )alkyl, wherein the alkyl is optionally substituted with one to three substituents each independently selected from (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S. In yet another embodiment, R ₆ is (C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )haloalkyl or -C(O)(C ₁ -C ₃ )alkyl, wherein the alkyl is optionally substituted with one to three substituents, each independently selected from (C ₆ - C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S. In another embodiment, R ₆ is (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S.

In another embodiment, R ₆ is H, (C ₁ -C ₃ )alkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three substituents, each of which is independently selected from (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S. In yet another embodiment, R ₆ represents H, (C ₁ -C ₃ )alkyl, (C ₃ -C ₇ )cycloalkyl or 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three substituents, each of which is independently selected from (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S.

In another embodiment, R ₆ is H, (C ₁ -C ₃ )alkyl, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three substituents, each of which is independently selected from (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S. In yet another In an embodiment, R ₆ is H, (C ₁ -C ₃ )alkyl, (C ₃ -C ₇ )cycloalkyl or (C ₆ -C ₁₀ )aryl, wherein the alkyl is optionally substituted with one to three substituents, each independently selected from (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S.

In another embodiment, R ₆ is H, (C ₁ -C ₃ )alkyl, (C ₃ -C ₇ )cycloalkyl or (C ₆ -C ₁₀ )aryl, wherein the alkyl is optionally substituted with one to three (C ₆ -C ₁₀ )aryls. In yet another embodiment, R ₆ is H, (C ₁ -C ₃ )alkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, or 5- or 6-membered heteroaryl , containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three substituents, each of which is independently selected from (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1 -3 heteroatoms selected from O, N and S. In another embodiment, R ₆ is H, (C ₁ -C ₃ )alkyl, (C ₃ -C ₇ )cycloalkyl or (C ₆ -C ₁₀ )aryl, where this alkyl is optionally substituted with one to three (C ₆ -C ₁₀ )aryls.

In some embodiments of the above formulas, R ₇ is H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1 -3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one - three R ₈ , and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one to four R ₁₁ . In another embodiment, R ₇ is H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )haloalkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three R ₈ and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one to four R ₁₁ . In yet another embodiment, R ₇ is (C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )haloalkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms, selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three R ₈ , and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one to four R ₁₁ . In another embodiment, R ₇ is H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )haloalkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms , selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, with the alkyl substituted by one to three R ₈ , and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one to four R ₁₁ .

In another embodiment, R ₇ is H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three R ₈ . In another embodiment, R ₇ is H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )haloalkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three R ₈ . In another embodiment, R ₇ is (C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )haloalkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three R ₈ . In another embodiment, R ₇ is H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )haloalkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms , selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, with the alkyl substituted by one to three R ₈ .

In another embodiment, R ₇ is (C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )haloalkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected of O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three R ₈ , and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one to four R ₁₁ . In yet another embodiment, R ₇ is H, (C ₁ -C ₆ )alkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S , (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three R ₈ , and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one to four R ₁₁ . In another embodiment, R ₇ is H, (C ₁ -C ₆ )alkyl, (C ₃ -C ₇ )cycloalkyl, or 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, wherein alkyl is optionally substituted with one to three R ₈ , and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one to four R ₁₁ . In yet another embodiment, R ₇ is H, (C ₁ -C ₆ )alkyl, (C ₆ -C ₁₀ )aryl, or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S wherein alkyl is optionally substituted with one to three R ₈ , and wherein aryl and heteroaryl are optionally substituted with one to four R ₁₁ .

In another embodiment, R ₇ is (C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )haloalkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three R ₈ . In yet another embodiment, R ₇ is H, (C ₁ -C ₆ )alkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S , (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three R ₈ . In another embodiment, R ₇ is H, (C ₁ -C ₆ )alkyl, (C ₃ -C ₇ )cycloalkyl, or 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three R ₈ . In yet another embodiment, R ₇ is H, (C ₁ -C ₆ )alkyl, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S wherein the alkyl is optionally substituted with one to three R ₈ .

In another embodiment, R ₇ is H, (C ₁ -C ₆ )alkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, or 5- or 6-membered heteroaryl, containing 1-3 heteroatoms selected from O, N and S, wherein alkyl is optionally substituted with one to three R ₈ , and wherein heterocycloalkyl and heteroaryl are optionally substituted with one to four R ₁₁ . In yet another embodiment, R ₇ is H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )haloalkyl, (C ₃ -C ₇ )cycloalkyl or (C ₆ -C ₁₀ )aryl, wherein alkyl optionally substituted with one to three R ₈ . In another embodiment, R ₇ is H, (C ₁ -C ₆ )alkyl, (C ₃ -C ₇ )cycloalkyl or (C ₆ -C ₁₀ )aryl, wherein the alkyl is optionally substituted with one to three R ₈ , and where In this case, cycloalkyl and aryl are optionally substituted with one to four R ₁₁ .

In another embodiment, R ₇ is H, (C ₁ -C ₆ )alkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, or 5- or 6-membered heteroaryl, containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three R ₈ . In yet another embodiment, R ₇ is H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )haloalkyl, (C ₃ -C ₇ )cycloalkyl or (C ₆ -C ₁₀ )aryl, wherein alkyl optionally substituted with one to three R ₈ . In another embodiment, R ₇ is H, (C ₁ -C ₆ )alkyl, (C ₃ -C ₇ )cycloalkyl, or (C ₆ -C ₁₀ )aryl, wherein the alkyl is optionally substituted with one to three R ₈ .

In some embodiments of the above formulas, R _7' is H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one - three R ₈ , and cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one to four R ₁₁ . In another embodiment, R _7' is H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )haloalkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatom selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three R ₈ , and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one to four R ₁₁ . In another embodiment, R _7' is (C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )haloalkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms, selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three R ₈ , and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one to four R ₁₁ . In another embodiment, R _7' is H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )haloalkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatom selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, with the alkyl substituted by one to three R ₈ and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one to four R ₁₁ .

In another embodiment, R _7' is H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatom selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three R ₈ . In another embodiment, R _7' is H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )haloalkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatom selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three R ₈ . In yet another embodiment, R _7' is (C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )haloalkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three R ₈ . In another embodiment, R _7' is H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )haloalkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatom selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, with the alkyl substituted by one to three R ₈ .

In another embodiment, R _7' is (C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )haloalkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms, selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is substituted with one to three R ₈ , and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one to four R ₁₁ . In yet another embodiment, R _7' is H, (C ₁ -C ₆ )alkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three R ₈ , and wherein cycloalkyl, heterocycloalkyl , aryl and heteroaryl are optionally substituted with one to four R ₁₁ . In another embodiment, R _7' is H, (C ₁ -C ₆ )alkyl, (C ₃ -C ₇ )cycloalkyl, or 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S wherein alkyl is optionally substituted with one to three R ₈ , and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one to four R ₁₁ . In yet another embodiment, R _7' is H, (C ₁ -C ₆ )alkyl, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein alkyl is optionally substituted with one to three R ₈ , and wherein aryl and heteroaryl are optionally substituted with one to four R ₁₁ .

In another embodiment, R _7' is (C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )haloalkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms, selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three R ₈ . In yet another embodiment, R _7' is H, (C ₁ -C ₆ )alkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three R ₈ . In another embodiment, R _7' is H, (C ₁ -C ₆ )alkyl, (C ₃ -C ₇ )cycloalkyl, or 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S wherein the alkyl is optionally substituted with one to three R ₈ . In yet another embodiment, R _7' is H, (C ₁ -C ₆ )alkyl, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three R ₈ .

In another embodiment, R _7' is H, (C ₁ -C ₆ )alkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein alkyl is optionally substituted with one to three R ₈ , and wherein heterocycloalkyl and heteroaryl are optionally substituted with one to four R ₁₁ . In yet another embodiment, R _7' is H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )haloalkyl, (C ₃ -C ₇ )cycloalkyl, or (C ₆ -C ₁₀ )aryl, wherein the alkyl is optionally substituted with one to three R ₈ . In another embodiment, R _7' is H, (C ₁ -C ₆ )alkyl, (C ₃ -C ₇ )cycloalkyl, or (C ₆ -C ₁₀ )aryl, wherein alkyl is optionally substituted with one to three R ₈ , and wherein cycloalkyl and aryl are optionally substituted with one to four R ₁₁ .

In another embodiment, R _7' is H, (C ₁ -C ₆ )alkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three R ₈ . In yet another embodiment, R _7' is H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )haloalkyl, (C ₃ -C ₇ )cycloalkyl, or (C ₆ -C ₁₀ )aryl, wherein the alkyl is optionally substituted with one to three R ₈ . In another embodiment, R _7' is H, (C ₁ -C ₆ )alkyl, (C ₃ -C ₇ )cycloalkyl, or (C ₆ -C ₁₀ )aryl, wherein the alkyl is optionally substituted with one to three R ₈ . In yet another embodiment, R _7' is H or (C ₁ -C ₆ )alkyl, wherein the alkyl is optionally substituted with one to three R ₈ . In another embodiment, R _7' is H or (C ₁ -C ₆ )alkyl, wherein the alkyl is substituted with one to three R ₈ . In yet another embodiment, R _7' represents H or (C ₁ -C ₆ )alkyl.

In some embodiments of the above formulas, R ₇ and R _7' , together with the nitrogen atom to which they are attached, form a 4-7 membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, optionally substituted one to four R ₉ . In another embodiment, R ₇ and R _7' , together with the nitrogen atom to which they are attached, form a 4-7 membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, optionally substituted with one to three _R9 . In yet another embodiment, R ₇ and R _7' , together with the nitrogen atom to which they are attached, form a 5-7 membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, optionally substituted with one - three R ₉ . In yet another embodiment, R ₇ and R _7' , together with the nitrogen atom to which they are attached, form a 4- or 5-membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, optionally substituted with one - three R ₉ . In yet another embodiment, R ₇ and R _7' , together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, optionally substituted with one - three R ₉ .

In yet another embodiment, R ₇ and R _7' , together with the nitrogen atom to which they are attached, form a 6- or 7-membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, optionally substituted with one - three R ₉ . In yet another embodiment, R ₇ and R _7' , together with the nitrogen atom to which they are attached, form a 4-membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, optionally substituted with one to three R ₉ . In another embodiment, R ₇ and R _7' , together with the nitrogen atom to which they are attached, form a 5-membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, optionally substituted with one to three R ₉ . In yet another embodiment, R ₇ and R _7' , together with the nitrogen atom to which they are attached, form a 6-membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, optionally substituted with one to three R ₉ . In another embodiment, R ₇ and R _7' , together with the nitrogen atom to which they are attached, form a 7-membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, optionally substituted with one to three R ₉ .

In some embodiments of the above formulas, _R3 and _R7 , together with the nitrogen and carbon atoms to which they are attached, form a 5- or 6-membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, optionally substituted with one to four substituents, each independently selected from (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl and halogen. In another embodiment, R ₃ and R ₇ together with the nitrogen and carbon atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, substituted by one - four substituents, each independently selected from (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl and halogen. In yet another embodiment, _R3 and _R7 , together with the nitrogen and carbon atoms to which they are attached, form a 5- or 6-membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S.

In another embodiment, R ₃ and R ₇ together with the nitrogen and carbon atoms to which they are attached form a 5-membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, optionally substituted with one to four substituents , each independently selected from (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl and halogen. In yet another embodiment, R ₃ and R ₇ together with the nitrogen and carbon atoms to which they are attached form a 5-membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, substituted with one to four substituents , each independently selected from (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl and halogen. In another embodiment, _R3 and _R7 , together with the nitrogen and carbon atoms to which they are attached, form a 5-membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S.

In another embodiment, R ₃ and R ₇ together with the nitrogen and carbon atoms to which they are attached form a 6-membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, optionally substituted with one to four substituents , each independently selected from (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl and halogen. In yet another embodiment, R ₃ and R ₇ together with the nitrogen and carbon atoms to which they are attached form a 6-membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, substituted with one to four substituents , each independently selected from (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl and halogen. In another embodiment, _R3 and _R7 , together with the nitrogen and carbon atoms to which they are attached, form a 6-membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S.

In some embodiments of the above formulas, each R ₈ is -C(O)OH, (C ₃ -C ₇ )cycloalkyl, a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, with cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally substituted by one to three R ₁₀ . In another embodiment, each R ₈ is -C(O)OH, (C ₃ -C ₇ )cycloalkyl or a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, wherein cycloalkyl and heterocycloalkyl are optionally substituted with one to three R ₁₀ . In yet another embodiment, each R ₈ is -C(O)OH, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein aryl and heteroaryl are optionally substituted with one to three R ₁₀ .

In another embodiment, each R ₈ is (C ₃ -C ₇ )cycloalkyl, a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5 - or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, with cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally substituted by one to three R ₁₀ . In another embodiment, each R ₈ is a (C ₃ -C ₇ )cycloalkyl or a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, wherein cycloalkyl and heterocycloalkyl are optionally substituted with one to three R ₁₀ . In yet another embodiment, each R ₈ is (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the aryl and heteroaryl are optionally substituted with one - three R ₁₀ .

In another embodiment, each R ₈ is -C(O)OH, (C ₃ -C ₇ )cycloalkyl, or (C ₆ -C ₁₀ )aryl, wherein the cycloalkyl and aryl are optionally substituted with one to three R ₁₀ . In yet another embodiment, each R ₈ is a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O , N and S, wherein heterocycloalkyl and heteroaryl are optionally substituted with one to three R ₁₀ . In another embodiment, each R ₈ is -C(O)OH, (C ₃ -C ₇ )cycloalkyl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein cycloalkyl and heteroaryl are optionally substituted with one to three R ₁₀ . In yet another embodiment, each R ₈ is -C(O)OH, a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, or (C ₆ -C ₁₀ )aryl, with in this case, heterocycloalkyl and aryl are optionally substituted with one to three R ₁₀ .

In another embodiment, each R ₈ is (C ₃ -C ₇ )cycloalkyl or (C ₆ -C ₁₀ )aryl, wherein the cycloalkyl and aryl are optionally substituted with one to three R ₁₀ . In yet another embodiment, each R ₈ is a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O , N and S, wherein heterocycloalkyl and heteroaryl are optionally substituted with one to three R ₁₀ . In another embodiment, each R ₈ is a (C ₃ -C ₇ )cycloalkyl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the cycloalkyl and heteroaryl are optionally substituted with one to three R ₁₀ . In yet another embodiment, each R ₈ is a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, or (C ₆ -C ₁₀ )aryl, wherein heterocycloalkyl and aryl are optionally substituted with one - three R ₁₀ .

In another embodiment, each R ₈ is -C(O)OH or (C ₃ -C ₇ )cycloalkyl, optionally substituted with one to three R ₁₀ . In yet another embodiment, each R ₈ is (C ₃ -C ₇ )cycloalkyl substituted with one to three R ₁₀ . In another embodiment, each R ₈ represents -C(O)OH or (C ₃ -C ₇ )cycloalkyl. In yet another embodiment, each R ₈ is (C ₆ -C ₁₀ )aryl, optionally substituted with one to three R ₁₀ . In another embodiment, each R ₈ is -C(O)OH or (C ₆ -C ₁₀ )aryl, substituted with one to three R ₁₀ . In yet another embodiment, each R ₈ is -C(O)OH or (C ₆ -C ₁₀ )aryl. In another embodiment, each R ₈ represents -C(O)OH.

In another embodiment, each R ₈ is (C ₃ -C ₇ )cycloalkyl, optionally substituted with one to three R ₁₀ . In yet another embodiment, each R ₈ is (C ₃ -C ₇ )cycloalkyl substituted with one to three R ₁₀ . In another embodiment, each R ₈ is (C ₃ -C ₇ )cycloalkyl. In yet another embodiment, each R ₈ is (C ₆ -C ₁₀ )aryl, optionally substituted with one to three R ₁₀ . In another embodiment, each R ₈ is (C ₆ -C ₁₀ )aryl substituted with one to three R ₁₀ . In yet another embodiment, each R ₈ is (C ₆ -C ₁₀ )aryl.

In another embodiment, each R ₈ is -C(O)OH or a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, optionally substituted with one to three R ₁₀ . In yet another embodiment, each R ₈ is -C(O)OH or a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, substituted with one to three R ₁₀ . In another embodiment, each R ₈ is -C(O)OH or a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S. In yet another embodiment, each R ₈ is -C (O)OH or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, optionally substituted with one to three R ₁₀ . In another embodiment, each R ₈ is -C(O)OH or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, substituted with one to three R ₁₀ . In yet another embodiment, each R ₈ is -C(O)OH or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S.

In another embodiment, each R ₈ is a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, optionally substituted with one to three R ₁₀ . In yet another embodiment, each R ₈ is a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, substituted with one to three R ₁₀ . In another embodiment, each R ₈ is a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S. In yet another embodiment, each R ₈ is a 5 or 6 membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, optionally substituted with one to three R ₁₀ . In another embodiment, each R ₈ is a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, substituted with one to three R ₁₀ . In yet another embodiment, each R ₈ is a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S.

In some embodiments of the above formulas, each R ₉ is independently in each case halogen, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C ₄ )haloalkoxy, -OH, CN, -NR ₁₂ R ₁₃ or -NH ₂ , wherein the alkoxy is optionally substituted with one to three substituents independently selected from (C ₃ -C ₇ )cycloalkyl, a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S. In another embodiment, each R ₉ is independently in each case halogen, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C ₄ )haloalkoxy, CN, -OH or -NH ₂ , wherein alkoxy is optionally substituted with one to three substituents independently selected from (C ₃ -C ₇ )cycloalkyl, a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S. In another embodiment, each R ₉ is independently in each case a halogen, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C ₄ )haloalkoxy, CN, -NR ₁₂ R ₁₃ or -OH, wherein the alkoxy is optionally substituted with one to three substituents , independently selected from (C ₃ -C ₇ )cycloalkyl, a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl and 5 or 6 membered heteroaryl containing 1-3 heteroatoms selected from O, N and S.

In another embodiment, each R ₉ is independently in each instance halogen, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C ₄ )haloalkoxy , CN or -OH, wherein the alkoxy is optionally substituted with one to three substituents independently selected from (C ₃ -C ₇ )cycloalkyl, a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S. In yet another embodiment, each R ₉ is independently in each case a halogen, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C ₄ )haloalkoxy, halogen, CN, -NR ₁₂ R ₁₃ or -OH, where alkoxy is optional substituted with (C ₃ -C ₇ )cycloalkyl, a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, and (C ₆ -C ₁₀ )aryl. In another embodiment, each R ₉ is independently in each instance halogen, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C ₄ )haloalkoxy , halogen, CN or -OH, wherein the alkoxy is optionally substituted with (C ₃ -C ₇ )cycloalkyl, a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, and (C ₆ -C ₁₀ )aryl.

In another embodiment, each R ₉ is independently in each instance halogen, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C ₄ )haloalkoxy , halogen, CN or -OH, wherein the alkoxy is optionally substituted with one to three substituents independently selected from (C ₃ -C ₇ )cycloalkyl, a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, and a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S. In another embodiment, each R ₉ is independently in each instance halogen, (C ₁ -C ₄ )alkyl, ( C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C ₄ )haloalkoxy, halogen, CN or -OH, wherein the alkoxy is optionally substituted with one to three substituents independently selected from (C ₃ - C ₇ cycloalkyl, (C ₆ -C ₁₀ ) aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S. In another embodiment, each R ₉ independently in each case is a halogen , (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C ₄ )haloalkoxy, halogen, CN or -OH, wherein the alkoxy is optionally substituted with one - three substituents independently selected from a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl and a 5- or 6-membered heteroaryl containing 1-3 heteroatom selected from O, N and S.

In another embodiment, each R ₉ is independently in each instance halogen, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C ₄ )haloalkoxy , halogen, CN or -OH, wherein the alkoxy is optionally substituted with one to three substituents independently selected from (C ₃ -C ₇ )cycloalkyl and a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S. In another embodiment, each R ₉ is independently in each instance halogen, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C ₄ )haloalkoxy, halogen, CN or -OH, wherein the alkoxy is optionally substituted with one to three substituents independently selected from (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S.

In another embodiment, each R ₉ is independently in each instance halogen, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C ₄ )haloalkoxy , halogen, CN or -OH, wherein the alkoxy is optionally substituted with one to three substituents independently selected from a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, and a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S. In another embodiment, each R ₉ is independently in each instance halogen, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy, ( C ₁ -C ₄ )haloalkyl, (C ₁ -C ₄ )haloalkoxy, halogen, CN or -OH, wherein alkoxy is optionally substituted with one to three substituents independently selected from (C ₃ -C ₇ )cycloalkyl and (C ₆ - C ₁₀ )aryl.

In another embodiment, each R ₉ is independently in each case a (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )haloalkyl, halogen, CN, -OH or -NH ₂ . In another embodiment, each R ₉ is independently in each case a (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, halogen, -OH or -NH ₂ . In yet another embodiment, each R ₉ is independently in each case a (C ₁ -C ₆ )alkyl, a (C ₁ -C ₆ )haloalkyl, or a halogen. In another embodiment, each R ₉ is independently in each case a (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, halogen or -OH. In yet another embodiment, each R ₉ is independently in each case a (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, halogen or -NH ₂ . In another embodiment, each R ₉ is independently in each case a halogen, -OH or -NH ₂ . In yet another embodiment, each R ₉ is independently in each case a (C ₁ -C ₃ )alkyl, a (C ₁ -C ₃ )haloalkyl, or a halogen. In another embodiment, each R ₉ is independently in each case a (C ₁ -C ₆ )alkyl or halogen. In yet another embodiment, each R ₉ is independently in each case a halogen.

In some embodiments of the above formulas, two R ₉ together with the atoms to which they are attached form a (C ₅ -C ₇ )cycloalkyl or 5-7 membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N and S In another embodiment, two R ₉ together with the atoms to which they are attached form a (C ₅ -C ₇ )cycloalkyl. In yet another embodiment, two R ₉ together with the atoms to which they are attached form a (C ₅ -C ₆ )cycloalkyl. In another embodiment, two R ₉ together with the atoms to which they are attached form a (C ₆ -C ₇ )cycloalkyl. In yet another embodiment, two R ₉ together with the atoms to which they are attached form a (C ₅ )cycloalkyl. In another embodiment, two R ₉ together with the atoms to which they are attached form a (C ₆ )cycloalkyl. In yet another embodiment, two R ₉ together with the atoms to which they are attached form a (C ₇ )cycloalkyl.

In another embodiment, the two R ₉ together with the atoms to which they are attached form a 5-7 membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N and S. In yet another embodiment, the two R ₉ together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N and S. In another embodiment, two R ₉ together with the atoms to which they are attached form a 6- or A 7-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N and S. In yet another embodiment, two R ₉ together with the atoms to which they are attached form a 5-membered heterocycloalkyl ring containing 1-2 heteroatoms, selected from O, N and S. In another embodiment, the two R ₉ together with the atoms to which they are attached form a 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N and S. In yet another embodiment two R ₉ together with the atoms to which they are attached form a 7-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N and S.

In another embodiment, two R ₉ when attached to the same carbon atom together form a (C ₅ -C ₇ )spirocycloalkyl or 5-7 membered spiroheterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S. In another embodiment, two R ₉ when present at adjacent atoms form a (C ₅ -C ₇ )cycloalkyl or 5-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S. B In another embodiment, two R ₉ together with the carbon atoms to which they are attached form a bridged (C ₅ -C ₇ )cycloalkyl or 5-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S.

In some embodiments of the above formulas, each R ₁₀ is independently in each case (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ ) haloalkoxy, halogen, -OH, CN or -NH ₂ . In another embodiment, each R ₁₀ is independently in each case a (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )haloalkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkoxy, halogen or CN. In another embodiment, each R ₁₀ is independently in each case a (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )haloalkyl, (C ₁ -C ₆ )alkoxy, halogen or CN. In yet another embodiment, each R ₁₀ is independently in each case a halogen, -OH, CN or -NH ₂ . In another embodiment, each R ₁₀ is independently in each case a (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )haloalkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkoxy or halogen . In another embodiment, each R ₁₀ is independently in each case a (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )haloalkyl, (C ₁ -C ₆ )alkoxy or halogen. In another embodiment, each R ₁₀ is independently in each case a (C ₁ -C ₃ )alkyl, a (C ₁ -C ₃ )haloalkyl, or a halogen. In yet another embodiment, each R ₁₀ is independently in each case a (C ₁ -C ₃ )alkyl, a (C ₁ -C ₃ )haloalkyl, or CN. In another embodiment, each R ₁₀ is independently in each case a (C ₁ -C ₃ )alkyl or a (C ₁ -C ₃ )haloalkyl. In yet another embodiment, each R ₁₀ is independently in each case halogen or CN. In another embodiment, each R ₁₀ is independently in each case a (C ₁ -C ₃ )alkyl or halogen. In yet another embodiment, each R ₁₀ is independently in each case a (C ₁ -C ₃ )haloalkyl.

In another embodiment, each R ₁₀ is independently in each case a (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, halogen, -OH, CN or -NH ₂ . In another embodiment, each R ₁₀ is independently in each case a (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )haloalkyl, halogen or CN. In yet another embodiment, each R ₁₀ is independently in each case a halogen, -OH, CN or -NH ₂ . In another embodiment, each R ₁₀ is independently in each case a (C ₁ -C ₃ )alkyl, a (C ₁ -C ₃ )haloalkyl, or a halogen. In yet another embodiment, each R ₁₀ is independently in each case a (C ₁ -C ₃ )alkyl, a (C ₁ -C ₃ )haloalkyl, or CN. In another embodiment, each R ₁₀ is independently in each case a (C ₁ -C ₃ )alkyl or a (C ₁ -C ₃ )haloalkyl. In yet another embodiment, each R ₁₀ is independently in each case halogen or CN. In another embodiment, each R ₁₀ is independently in each case a (C ₁ -C ₃ )alkyl or halogen. In yet another embodiment, each R ₁₀ is independently in each case a (C ₁ -C ₃ )haloalkyl.

In some embodiments of the above formulas, two R ₁₀ together with the atoms to which they are attached form a (C ₅ -C ₇ )cycloalkyl or 5-7 membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N and S , optionally substituted with one to three substituents, each independently selected from (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, halogen, -OH, CN or -NH ₂ . In another embodiment, two R ₁₀ together with the atoms to which they are attached form a (C ₅ -C ₇ )cycloalkyl or 5-7 membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N and S. In another In an embodiment, two R ₁₀ together with the atoms to which they are attached form a (C ₅ -C ₇ )cycloalkyl. In another embodiment, two R ₁₀ together with the atoms to which they are attached form a (C ₅ -C ₆ )cycloalkyl. In yet another embodiment, two R ₁₀ together with the atoms to which they are attached form a (C ₆ -C ₇ )cycloalkyl. In another embodiment, two R ₁₀ together with the atoms to which they are attached form a (C ₅ )cycloalkyl. In yet another embodiment, two R ₁₀ together with the atoms to which they are attached form a (C ₆ )cycloalkyl. In another embodiment, two R ₁₀ together with the atoms to which they are attached form a (C ₇ )cycloalkyl.

In another embodiment, the two R _10s , together with the atoms to which they are attached, form a 5-7 membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N and S. In another embodiment, the two R _10s , together with the atoms, to which they are attached form a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N and S. In another embodiment, two R ₁₀ together with the atoms to which they are attached form a 6- or 7 -membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N and S. In another embodiment, two R ₁₀ together with the atoms to which they are attached form a 5-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N and S. In another embodiment, the two R ₁₀ together with the atoms to which they are attached form a 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N and S. In another embodiment, the two R ₁₀ together with the atoms to which they are attached, form a 7-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N and S.

In another embodiment, two R ₁₀ when attached to the same carbon atom together form a (C ₅ -C ₇ )spirocycloalkyl or 5-7 membered spiroheterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, optionally substituted with one to three substituents, each independently selected from (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, halogen, -OH, CN or -NH ₂ . In another embodiment, two R ₁₀ when present at adjacent atoms form a (C ₅ -C ₇ )cycloalkyl or 5-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, optionally substituted with one - three substituents, each independently selected from (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, halogen, -OH, CN or -NH ₂ . In another embodiment, two R ₁₀ together with the carbon atoms to which they are attached form a bridged (C ₅ -C ₇ )cycloalkyl or 5-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, optionally substituted with one to three substituents, each independently selected from (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, halogen, -OH, CN or -NH ₂ .

In some embodiments of the above formulas, each R ₁₁ is independently in each case a (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl, halogen, -OH, CN or -NH ₂ . In another embodiment, each R ₁₁ is independently in each case a (C ₁ -C ₄ )alkyl, a (C ₁ -C ₄ )haloalkyl, or a halogen. In another embodiment, each R ₁₁ is independently in each case a halogen, -OH, CN or -NH ₂ . In another embodiment, each R ₁₁ is independently in each case a (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl, halogen, -OH or -NH ₂ . In another embodiment, each R ₁₁ is independently in each case (C ₁ -C ₄ )alkyl, halogen, -OH, CN or -NH ₂ . In another embodiment, each R ₁₁ is independently in each case a (C ₁ -C ₄ )alkyl or halogen. In another embodiment, each R ₁₁ is independently in each case a (C ₁ -C ₄ )haloalkyl or halogen. In another embodiment, each R ₁₁ is independently in each case a halogen.

In another embodiment, each R ₁₁ is independently in each case a (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkoxy, halogen , -OH, CN or -NH ₂ . Each of R ₁₁ is independently in each case a (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )haloalkoxy, halogen, -OH , CN or -NH ₂ . In another embodiment, each R ₁₁ is independently in each case a (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )haloalkoxy or halogen . In another embodiment, each R ₁₁ is independently in each case a (C ₁ -C ₄ )alkyl, a (C ₁ -C ₄ )haloalkyl, or a halogen. In another embodiment, each R ₁₁ is independently in each case a halogen, -OH, CN or -NH ₂ . In another embodiment, each R ₁₁ is independently in each case a (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl, halogen, -OH or -NH ₂ . In another embodiment, each R ₁₁ is independently in each case (C ₁ -C ₄ )alkyl, halogen, -OH, CN or -NH ₂ . In another embodiment, each R ₁₁ is independently in each case a (C ₁ -C ₄ )alkyl or halogen. In another embodiment, each R ₁₁ is independently in each case a (C ₁ -C ₄ )haloalkyl or halogen. In another embodiment, each R ₁₁ is independently in each case a halogen.

In some embodiments of the above formulas, R ₁₂ is selected from (C ₁ -C ₆ )alkyl and (C ₁ -C ₆ )haloalkyl. In another embodiment, R ₁₂ is selected from (C ₃ -C ₇ )cycloalkyl, a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, and (C ₆ -C ₁₀ )aryl. In another embodiment, R ₁₂ is selected from (C ₃ -C ₇ )cycloalkyl, a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, and a 5- or 6-membered heteroaryl containing 1 -3 heteroatoms selected from O, N and S. In another embodiment, R ₁₂ is selected from (C ₃ -C ₇ )cycloalkyl, (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatom selected from O, N and S. In another embodiment, R ₁₂ is selected from a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl and 5 - or a 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S.

In another embodiment, R ₁₂ is selected from (C ₃ -C ₇ )cycloalkyl and a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S. In yet another embodiment, R ₁₂ is selected from (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S. In another embodiment, R ₁₂ is selected from (C ₃ -C ₇ )cycloalkyl and (C ₆ - C ₁₀ )aryl. In yet another embodiment, R ₁₂ is selected from a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, and a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S. In another embodiment, R ₁₂ is selected from (C ₃ -C ₇ )cycloalkyl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S. In yet another embodiment, R ₁₂ selected from a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, and (C ₆ -C ₁₀ )aryl. In another embodiment, R ₁₂ is (C ₃ -C ₇ )cycloalkyl. In yet another embodiment, R ₁₂ is a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S. In another embodiment, R ₁₂ is (C ₆ -C ₁₀ )aryl. In yet another embodiment, R ₁₂ is a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S.

In some embodiments of the above formulas, R ₁₃ is selected from (C ₁ -C ₆ )alkyl and (C ₁ -C ₆ )haloalkyl. In another embodiment, R ₁₃ is selected from (C ₃ -C ₇ )cycloalkyl, a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, and (C ₆ -C ₁₀ )aryl. In another embodiment, R ₁₃ is selected from (C ₃ -C ₇ )cycloalkyl, a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, and a 5- or 6-membered heteroaryl containing 1 -3 heteroatoms selected from O, N and S. In another embodiment, R ₁₃ is selected from (C ₃ -C ₇ )cycloalkyl, (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatom selected from O, N and S. In another embodiment, R ₁₃ is selected from a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl and 5 - or a 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S.

In another embodiment, R ₁₃ is selected from (C ₃ -C ₇ )cycloalkyl and a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S. In yet another embodiment, R ₁₃ is selected from (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S. In another embodiment, R ₁₃ is selected from (C ₃ -C ₇ )cycloalkyl and (C ₆ - C ₁₀ )aryl. In yet another embodiment, R ₁₃ is selected from a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, and a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S. In another embodiment, R ₁₃ is selected from (C ₃ -C ₇ )cycloalkyl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S. In yet another embodiment, R ₁₃ selected from a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, and (C ₆ -C ₁₀ )aryl. In another embodiment, R ₁₃ is (C ₃ -C ₇ )cycloalkyl. In yet another embodiment, R ₁₃ is a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S. In another embodiment, R ₁₃ is (C ₆ -C ₁₀ )aryl. In yet another embodiment, R ₁₃ is a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S.

In some embodiments of the above formulas, m is 0, 1, or 2. In another embodiment, m is 0 or 1. In yet another embodiment, m is 1 or 2. In another embodiment, m is 0. In yet another embodiment, m equals 1. In another embodiment, m equals 2.

In some embodiments of the above formulas, m1 is 0, 1, or 2. In another embodiment, m1 is 0 or 1. In yet another embodiment, m1 is 1 or 2. In another embodiment, m1 is 0. In yet another embodiment, m1 is equals 1. In another embodiment, m1 equals 2.

In some embodiments of the above formulas, n1 is 0, 1, or 2. In another embodiment, n1 is 1, 2, or 3. In another embodiment, n1 is 0 or 1. In another embodiment, n1 is 1 or 2. In another embodiment n1 is 2 or 3. In another embodiment, n1 is 0. In another embodiment, n1 is 1. In another embodiment, n1 is 2. In another embodiment, n1 is 3.

In some embodiments of the above formulas, n2 is equal to 1. In another embodiment, n2 is equal to 2.

In some embodiments of the above formulas, n3 is equal to 1. In another embodiment, n3 is equal to 2.

In some embodiments of the above formulas, n2 is 1 and n3 is 1. In another embodiment, n2 is 2 and n3 is 1. In yet another embodiment, n2 is 1 and n3 is 2. In another embodiment, n2 is 1 or 2, and n3 is 1. In yet another embodiment, n2 is 1 or 2, and n3 is 2. In another embodiment, n2 is 1, and n3 is 1 or 2. In yet another embodiment, n2 is 2, and n3 equals 1 or 2.

In some embodiments of the above formulas, s and n are each independently equal to 1, 2, or 3, where s+n ≤ 4. In another embodiment, s and n are each independently equal to 1 or 2, where s+n ≤ 4. In In another embodiment, s and n are each independently equal to 2 or 3, where s+n ≤ 4. In another embodiment, s is 1 and n is 1. In another embodiment, s is 2 and n is 2. In another embodiment implementation, s is 1 and n is 2. In another embodiment, s is 2 and n is 1. In another embodiment, s is 3 and n is 1. In another embodiment, s is 1 and n is 3.

In some embodiments of the above formulas, R ₁ is and R ₂ is H or methyl.

In some embodiments of the above formulas, R ₁ is and R ₅ is -OR ₆ .

In some embodiments of the above formulas, R ₁ is and R ₅ is -NR ₇ R _7' .

In some embodiments of the above formulas, R ₁ is _R2 is H or methyl, and _R5 is _-OR6 .

In some embodiments of the above formulas, R ₁ is _R2 is H or methyl, and _R5 is _{-NR7R7 '} .

In some embodiments of the above formulas, R ₁ is , and n1 equals 1 or 2.

In some embodiments of the above formulas, R ₁ is , n1 is 1 or 2, and _R2 is H or methyl.

In some embodiments of the above formulas, R ₁ is n1 is 1 or 2, _R2 is H or methyl, and _R5 is _-OR6 .

In some embodiments of the above formulas, R ₁ is , n1 is 1 or 2, _R2 is H or methyl, _R5 is _-OR6 , _X1 is H, and _X2 is H.

In some embodiments of the above formulas, R ₁ is , n1 is 1 or 2, _R2 is H or methyl, _R5 is _-OR6 , and _X1 is H.

In some embodiments of the above formulas, R ₁ is , n1 is 1 or 2, _R2 is H or methyl, _R5 is _-OR6 , and _X2 is H.

In some embodiments of the above formulas, R ₁ is n1 is 1 or 2, _R2 is H or methyl, and _R5 is _{-NR7R7 '} .

In some embodiments of the above formulas, R ₁ is , n1 is 1 or 2, R ₂ is H or methyl, R ₅ is -NR ₇ R _7' , X ₁ is H, and X ₂ is H.

In some embodiments of the above formulas, R ₁ is , n1 is 1 or 2, _R2 is H or methyl, _R5 is _{-NR7R7 '} , and _X1 is H.

In some embodiments of the above formulas, R ₁ is , n1 is 1 or 2, _R2 is H or methyl, _R5 is _{-NR7R7 '} , and _X2 is H.

In some embodiments of the above formulas, n1 is 1 or 2, and _R2 is H or methyl.

In some embodiments of the above formulas, n1 is 1 or 2, _R2 is H or methyl, and _R5 is _-OR6 .

In some embodiments of the above formulas, n1 is 1 or 2, _R2 is H or methyl, and _R5 is _{-NR7R7 '} .

In some embodiments of the above formulas, n1 is 1 or 2, and _R5 is _-OR6 .

In some embodiments of the above formulas, n1 is 1 or 2, and _R5 is _{-NR7R7 '} .

In some embodiments of the above formulas, R ₁ is , n1 is 1 or 2, and m1 is 0.

In some embodiments of the above formulas, R ₁ is , n1 is 1 or 2, m1 is 0, and R ₅ is -OR ₆ .

In some embodiments of the above formulas, R ₁ is , n1 is 1 or 2, m1 is 0, and R ₅ is -NR ₇ R _7' .

In some embodiments of the above formulas, R ₂ is H or methyl, and R ₅ is -NR ₇ R _7' .

In some embodiments of the above formulas, R ₂ is H or methyl, and R ₅ is -OR ₆ .

In some embodiments of the above formulas, m1 is 0 and _R5 is _{-NR7R7 '} .

In some embodiments of the above formulas, m1 is 0 and _R5 is _-OR6 .

In some embodiments of the above formulas, R ₁ is , n1 is 1 or 2, m1 is 0, and _R2 is H or methyl.

In some embodiments of the above formulas, R ₁ is , n1 is 1 or 2, m1 is 0, R ₂ is H or methyl, and R ₅ is -OR ₆ .

In some embodiments of the above formulas, R ₁ is , n1 is 1 or 2, m1 is 0, R ₂ is H or methyl, and R ₅ is -NR ₇ R _7' .

In some embodiments of the above formulas, R ₁ is , and m1 equals 0.

In some embodiments of the above formulas, R ₁ is , m1 is 0, and R ₅ is -OR ₆ .

In some embodiments of the above formulas, R ₁ is , m1 is 0, and R ₅ is -NR ₇ R _7' .

In some embodiments of the above formulas, R ₁ is , m1 is 0, and R ₂ is H or methyl.

In some embodiments of the above formulas, R ₁ is , m1 is 0, R ₂ is H or methyl, and R ₅ is -OR ₆ .

In some embodiments of the above formulas, R ₁ is , m1 is 0, R ₂ is H or methyl, and R ₅ is -NR ₇ R _7' .

In some embodiments of the above formulas, n1 is 1 or 2, and m1 is 0.

In some embodiments of the above formulas, n1 is 1 or 2, m1 is 0, and _R5 is _-OR6 .

In some embodiments of the above formulas, n1 is 1 or 2, m1 is 0, and _R5 is _{-NR7R7 '} .

In some embodiments of the above formulas, n1 is 1 or 2, m1 is 0, and _R2 is H or methyl.

In some embodiments of the above formulas, n1 is 1 or 2, m1 is 0, _R2 is H or methyl, and _R5 is _-OR6 .

In some embodiments of the above formulas, n1 is 1 or 2, m1 is 0, _R2 is H or methyl, and _R5 is _{-NR7R7 '} .

In some embodiments of the above formulas, m1 is 0 and _R2 is H or methyl.

In some embodiments of the above formulas, m1 is 0, _R2 is H or methyl, and _R5 is _-OR6 .

In some embodiments of the above formulas, m1 is 0, _R2 is H or methyl, and _R5 is _{-NR7R7 '} .

In some embodiments of the above formulas, R ₁ is , n1 is 1 or 2, and m1 is 2.

In some embodiments of the above formulas, R ₁ is , n1 is 1 or 2, m1 is 2, and R ₅ is -OR ₆ .

In some embodiments of the above formulas, R ₁ is , n1 is 1 or 2, m1 is 2, and R ₅ is -NR ₇ R _7' .

In some embodiments of the above formulas, R ₁ is , and m1 equals 2.

In some embodiments of the above formulas, R ₁ is , m1 is 2, and R ₅ is -OR ₆ .

In some embodiments of the above formulas, R ₁ is , m1 is 2, and R ₅ is -NR ₇ R _7' .

In some embodiments of the above formulas, n1 is 1 or 2, and m1 is 2.

In some embodiments of the above formulas, n1 is 1 or 2, m1 is 2, and _R5 is _-OR6 .

In some embodiments of the above formulas, n1 is 1 or 2, m1 is 2, and _R5 is _{-NR7R7 '} .

In some embodiments of the above formulas, m1 is 2 and _R5 is _-OR6 .

In some embodiments of the above formulas, m1 is equal to 2, and R ₅ is -NR ₇ R _7' .

In some embodiments of the above formulas, R ₁ is , n is 2, and s is 1 or 2.

In some embodiments of the above formulas, R ₁ is and R ₂ is H or methyl.

In some embodiments of the above formulas, R ₁ is and R ₅ is -OR ₆ .

In some embodiments of the above formulas, R ₁ is and R ₅ is -NR ₇ R _7' .

In some embodiments of the above formulas, R ₁ is , n equals 2, s equals 1 or 2, and m equals 0 or 1.

In some embodiments of the above formulas, R ₁ is , n is 2, s is 1 or 2, m is 0 or 1, and R ₂ is H or methyl.

In some embodiments of the above formulas, R ₁ is , n is 2, s is 1 or 2, m is 0 or 1, R ₂ is H or methyl, and R ₅ is -OR ₆ .

In some embodiments of the above formulas, R ₁ is , n is 2, s is 1 or 2, m is 0 or 1, R ₂ is H or methyl, and R ₅ is -NR ₇ R _7' .

In some embodiments of the above formulas, R ₁ is , n is 2, s is 1 or 2, m is 0 or 1, and R ₅ is -OR ₆ .

In some embodiments of the above formulas, R ₁ is , n is 2, s is 1 or 2, m is 0 or 1, and R ₅ is -NR ₇ R _7' .

In some embodiments of the above formulas, R ₁ is , and m is 0 or 1.

In some embodiments of the above formulas, R ₁ is , m is 0 or 1, and R ₂ is H or methyl.

In some embodiments of the above formulas, R ₁ is , m is 0 or 1, R ₂ is H or methyl, and R ₅ is -OR ₆ .

In some embodiments of the above formulas, R ₁ is , m is 0 or 1, R ₂ is H or methyl, and R ₅ is -NR ₇ R _7' .

In some embodiments of the above formulas, R ₁ is , m is 0 or 1, and R ₅ is -OR ₆ .

In some embodiments of the above formulas, R ₁ is , m is 0 or 1, and R ₅ is -NR ₇ R _7' .

In some embodiments of the above formulas, n is 2, s is 1 or 2, and m is 0 or 1.

In some embodiments of the above formulas, n is 2, s is 1 or 2, m is 0 or 1, and R ₂ is H or methyl.

In some embodiments of the above formulas, n is 2, s is 1 or 2, m is 0 or 1, and R ₅ is -OR ₆ .

In some embodiments of the above formulas, n is 2, s is 1 or 2, m is 0 or 1, and R ₅ is -NR ₇ R _7' .

In some embodiments of the above formulas, n is 2, s is 1 or 2, m is 0 or 1, R ₂ is H or methyl, and R ₅ is -OR ₆ .

In some embodiments of the above formulas, n is 2, s is 1 or 2, m is 0 or 1, R ₂ is H or methyl, and R ₅ is -NR ₇ R _7' .

In some embodiments of the above formulas, n is 2, s is 1 or 2, and R ₂ is H or methyl.

In some embodiments of the above formulas, n is 2, s is 1 or 2, and R ₅ is -OR ₆ .

In some embodiments of the above formulas, n is 2, s is 1 or 2, and R ₅ is -NR ₇ R _7' .

In some embodiments of the above formulas, n is 2, s is 1 or 2, R ₂ is H or methyl, and R ₅ is -OR ₆ .

In some embodiments of the above formulas, n is 2, s is 1 or 2, R ₂ is H or methyl, and R ₅ is -NR ₇ R _7' .

In some embodiments of the above formulas, m is 0 or 1, and R ₂ is H or methyl.

In some embodiments of the above formulas, m is 0 or 1, R ₂ is H or methyl, and R ₅ is -OR ₆ .

In some embodiments of the above formulas, m is 0 or 1, R ₂ is H or methyl, and R ₅ is -NR ₇ R _7' .

In some embodiments of the above formulas, m is 0 or 1, and R ₅ is -OR ₆ .

In some embodiments of the above formulas, m is 0 or 1, and R ₅ is -NR ₇ R _7' .

In some embodiments of the above formulas, R ₁ is , and R ₂ represents H. In another embodiment, R ₁ represents , R ₂ is H, and m1 is 0. In another embodiment, R ₁ is , R ₂ is H, m1 is 0, and R ₅ is -OR ₆ . In another embodiment, R ₁ is , R ₂ is H, m1 is 0, R ₅ is -OR ₆ , and R ₆ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three substituents, each independently selected from (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S. In another embodiment, R ₁ is _R2 is H, m1 is 0, _R5 is _-OR6 , and _R6 is H or ( _C1 - _C6 )alkyl, optionally substituted with one to three ( _C6 - _C10 )aryls. In another embodiment, R ₁ is , R ₂ is H, m1 is 0, R ₅ is -OR ₆ , R ₆ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three substituents, each independently selected from (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, and n1 is 1 or 2. In another embodiment, R ₁ is , R ₂ is H, m1 is 0, R ₅ is -OR ₆ , R ₆ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three (C ₆ -C ₁₀ )aryls, and n1 equals 1 or 2. In another embodiment, R ₁ is , R ₂ is H, m1 is 0, R ₅ is -OR ₆ , R ₆ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three (C ₆ -C ₁₀ )aryls, and n1 equals 1. In another embodiment, R ₁ is , R ₂ is H, m1 is 0, R ₅ is -OR ₆ , R ₆ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three (C ₆ -C ₁₀ )aryls, and n1 equals 2.

In another embodiment, R ₁ is , R ₂ represents H, m1 is 0, and R ₅ represents -NR ₇ R _7' . In another embodiment, R ₁ is R ₂ is H, m1 is 0, R ₅ is -NR ₇ R _7' , and R ₇ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ . In another embodiment, R ₁ is , R ₂ is H, m1 is 0, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , and R _7' is is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ . In another embodiment, R ₁ is , R ₂ is H, m1 is 0, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R _7' is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , and R ₈ is (C ₆ -C ₁₀ )aryl, optionally substituted with one or two R ₁₀ .

In another embodiment, R ₁ is , R ₂ is H, m1 is 0, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R _7' is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R ₈ is (C ₆ -C ₁₀ )aryl, optionally substituted with one or two R ₁₀ , and n1 is 1 or 2. In another embodiment implementation R ₁ represents , R ₂ is H, m1 is 0, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R _7' is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R ₈ is (C ₆ -C ₁₀ )aryl, optionally substituted with one or two R ₁₀ , and n1 is 1. In another embodiment, R ₁ represents , R ₂ is H, m1 is 0, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R _7' is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R ₈ is (C ₆ -C ₁₀ )aryl, optionally substituted with one or two R ₁₀ , and n1 is 2.

In another embodiment, R ₁ is , R ₂ is H, m1 is 0, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R _7' is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , and R ₈ is (C ₆ -C ₁₀ )aryl. In another embodiment, R ₁ is , R ₂ is H, m1 is 0, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R _7' is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R ₈ is (C ₆ -C ₁₀ )aryl, and n1 is 1 or 2. In another embodiment, R ₁ is , R ₂ is H, m1 is 0, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R _7' is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R ₈ is (C ₆ -C ₁₀ )aryl, and n1 is 1. In another embodiment, R ₁ is , R ₂ is H, m1 is 0, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R _7' is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R ₈ is (C ₆ -C ₁₀ )aryl, and n1 is 2.

In some embodiments of the above formulas, R ₁ is , and R ₂ represents methyl. In another embodiment, R ₁ is , R ₂ is methyl, and m1 is 0. In another embodiment, R ₁ is _R2 is methyl, m1 is 0, and _R5 is _-OR6 . In another embodiment, R ₁ is _R2 is methyl, m1 is 0, _R5 is _-OR6 , and _R6 is H or ( _C1 - _C6 )alkyl, optionally substituted with one to three substituents, each independently selected from (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S. In another embodiment, R ₁ is , _R2 is methyl, m1 is 0, _R5 is _-OR6 , _R6 is H or ( _C1 - _C6 )alkyl, optionally substituted with one to three substituents, each independently selected from ( _C6 -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, and n1 is 1 or 2. In another embodiment, R ₁ is , _R2 is methyl, m1 is 0, _R5 is _-OR6 , _R6 is H or ( _C1 - _C6 )alkyl, optionally substituted with one to three substituents, each independently selected from ( _C6 -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, and n1 is 1. In another embodiment, R ₁ is , _R2 is methyl, m1 is 0, _R5 is _-OR6 , _R6 is H or ( _C1 - _C6 )alkyl, optionally substituted with one to three substituents, each independently selected from ( _C6 -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, and n1 is 2.

In another embodiment, R ₁ is _R2 is methyl, m1 is 0, _R5 is _-OR6 , and _R6 is H or ( _C1 - _C6 )alkyl, optionally substituted with one to three ( _C6 - _C10 )aryls. In another embodiment, R ₁ is _R2 is methyl, m1 is 0, _R5 is _-OR6 , _R6 is H or ( _C1 - _C6 )alkyl, optionally substituted with one to three ( _C6 - _C10 )aryls, and n1 equals 1 or 2. In another embodiment, R ₁ is _R2 is methyl, m1 is 0, _R5 is _-OR6 , _R6 is H or ( _C1 - _C6 )alkyl, optionally substituted with one to three ( _C6 - _C10 )aryls, and n1 equals 1. In another embodiment, R ₁ is _R2 is methyl, m1 is 0, _R5 is _-OR6 , _R6 is H or ( _C1 - _C6 )alkyl, optionally substituted with one to three ( _C6 - _C10 )aryls, and n1 equals 2.

In another embodiment, R ₁ is _R2 is methyl, m1 is 0, and _R5 is _{-NR7R7 '} . In another embodiment, R ₁ is _R2 is methyl, m1 is 0, _R5 is _{-NR7R7 '} , and _R7 is H or ( _C1 - _C6 )alkyl, optionally substituted with one to three _R8 . In another embodiment, R ₁ is R ₂ is methyl, m1 is 0, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , and R _7' is is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ . In another embodiment, R ₁ is , R ₂ is methyl, m1 is 0, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R _7' is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , and R ₈ is (C ₆ -C ₁₀ )aryl, optionally substituted with one or two R ₁₀ . In another embodiment, R ₁ is , R ₂ is methyl, m1 is 0, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R _7' is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R ₈ is (C ₆ -C ₁₀ )aryl, optionally substituted with one or two R ₁₀ , and n1 is 1 or 2. In another embodiment implementation R ₁ represents , R ₂ is methyl, m1 is 0, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R _7' is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R ₈ is (C ₆ -C ₁₀ )aryl, optionally substituted with one or two R ₁₀ , and n1 is 1. In another embodiment, R ₁ represents , R ₂ is methyl, m1 is 0, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R _7' is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R ₈ is (C ₆ -C ₁₀ )aryl, optionally substituted with one or two R ₁₀ , and n1 is 2.

In another embodiment, R ₁ is , R ₂ is methyl, m1 is 0, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R _7' is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , and R ₈ is (C ₆ -C ₁₀ )aryl. In another embodiment, R ₁ is , R ₂ is methyl, m1 is 0, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R _7' is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R ₈ is (C ₆ -C ₁₀ )aryl, and n1 is 1 or 2. In another embodiment, R ₁ is , R ₂ is methyl, m1 is 0, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R _7' is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R ₈ is (C ₆ -C ₁₀ )aryl, and n1 is 1. In another embodiment, R ₁ is , R ₂ is methyl, m1 is 0, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R _7' is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R ₈ is (C ₆ -C ₁₀ )aryl, and n1 is 2.

In some embodiments of the above formulas, R ₁ is , R ₂ is H or methyl, and m1 is 0. In another embodiment, R ₁ is _R2 is H or methyl, m1 is 0, and _R5 is _-OR6 . In another embodiment, R ₁ is _R2 is H or methyl, m1 is 0, _R5 is _-OR6 , and _R6 is H or ( _C1 - _C6 )alkyl, optionally substituted with one to three substituents, each independently selected from (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S. In another embodiment, R ₁ is _R2 is H or methyl, m1 is 0, _R5 is _-OR6 , and _R6 is H or ( _C1 - _C6 )alkyl, optionally substituted with one to three ( _C6 - _C10 )aryls . In another embodiment, R ₁ is _R2 is H or methyl, m1 is 0, _R5 is _-OR6 , _R6 is H or ( _C1 - _C6 )alkyl, optionally substituted with one to three ( _C6 - _C10 )aryls, and n1 is 1 or 2. In another embodiment, R ₁ is _R2 is H or methyl, m1 is 0, _R5 is _-OR6 , _R6 is H or ( _C1 - _C6 )alkyl, optionally substituted with one to three ( _C6 - _C10 )aryls, and n1 is 1. In another embodiment, R ₁ is _R2 is H or methyl, m1 is 0, _R5 is _-OR6 , _R6 is H or ( _C1 - _C6 )alkyl, optionally substituted with one to three ( _C6 - _C10 )aryls, and n1 equals 2.

In some embodiments of the above formulas, R ₁ is _R2 is H or methyl, m1 is 0, and _R5 is _{-NR7R7 '} . In another embodiment, R ₁ is _R2 is H or methyl, m1 is 0, _R5 is _{-NR7R7 '} , and _R7 is H or ( _C1 - _C6 )alkyl, optionally substituted with one to three _R8 . In another embodiment, R ₁ is , R ₂ is H or methyl, m1 is 0, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , and R _{7 '} represents H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ . In another embodiment, R ₁ is , R ₂ is H or methyl, m1 is 0, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , and R ₈ is (C ₆ -C ₁₀ )aryl, optionally substituted with one or two R ₁₀ .

In another embodiment, R ₁ is , R ₂ represents H or methyl, m1 is 0, R ₅ represents -NR ₇ R _7' , R ₇ represents H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R ₈ represents is (C ₆ -C ₁₀ )aryl, optionally substituted with one or two R ₁₀ , and n1 is 1 or 2. In another embodiment, R ₁ is , R ₂ represents H or methyl, m1 is 0, R ₅ represents -NR ₇ R _7' , R ₇ represents H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R ₈ represents is (C ₆ -C ₁₀ )aryl, optionally substituted with one or two R ₁₀ , and n1 is 1. In another embodiment, R ₁ is , R ₂ represents H or methyl, m1 is 0, R ₅ represents -NR ₇ R _7' , R ₇ represents H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R ₈ represents is (C ₆ -C ₁₀ )aryl, optionally substituted with one or two R ₁₀ , and n1 is 2.

In another embodiment, R ₁ is , R ₂ is H or methyl, m1 is 0, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R _7' is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , and R ₈ is (C ₆ -C ₁₀ )aryl.

In another embodiment, R ₁ is , R ₂ represents H or methyl, m1 is 0, R ₅ represents -NR ₇ R _7' , R ₇ represents H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R _7' is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R ₈ is (C ₆ -C ₁₀ )aryl, and n1 is 1 or 2. In another embodiment, R ₁ is , R ₂ represents H or methyl, m1 is 0, R ₅ represents -NR ₇ R _7' , R ₇ represents H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R _7' is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R ₈ is (C ₆ -C ₁₀ )aryl, and n1 is 1. In another embodiment, R ₁ is , R ₂ represents H or methyl, m1 is 0, R ₅ represents -NR ₇ R _7' , R ₇ represents H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R _7' is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , R ₈ is (C ₆ -C ₁₀ )aryl, and n1 is 2.

In some embodiments of the above formulas, R ₁ is R ₂ is H or methyl, m is 0, n is 1, and s is 1. In another embodiment, R ₁ is _R2 is H or methyl, m is 0, n is 1, s is 1, and _R5 is _-OR6 . In another embodiment, R ₁ is _R2 is H or methyl, m is 0, n is 1, s is 1, _R5 is _-OR6 , and _R6 is H or ( _C1 - _C6 )alkyl, optionally substituted with one to three (C ₆ -C ₁₀ )aryls.

In some embodiments of the above formulas, R ₁ is _R2 is H or methyl, m is 0, n is 1, s is 1, and _R5 is _{-NR7R7 '} . In another embodiment, R ₁ is _R2 is H or methyl, m is 0, n is 1, s is 1, _R5 is _{-NR7R7 '} , and _R7 is H or ( _C1 - _C6 )alkyl, optionally substituted one to three R ₈ . In another embodiment, R ₁ is , R ₂ is H or methyl, m is 0, n is 1, s is 1, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one - three R ₈ , and R _7' is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ . In another embodiment, R ₁ is , R ₂ is H or methyl, m is 0, n is 1, s is 1, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one - three R ₈ , R _7' represents H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , and R ₈ represents (C ₆ -C ₁₀ )aryl.

In some embodiments of the above formulas, R ₁ is R ₂ is H or methyl, m is 0, n is 2, and s is 1. In another embodiment, R ₁ is _R2 is H or methyl, m is 0, n is 2, s is 1, and _R5 is _-OR6 . In another embodiment, R ₁ is _R2 is H or methyl, m is 0, n is 2, s is 1, _R5 is _-OR6 , and _R6 is H or ( _C1 - _C6 )alkyl, optionally substituted with one to three (C ₆ -C ₁₀ )aryls.

In some embodiments of the above formulas, R ₁ is _R2 is H or methyl, m is 0, n is 2, s is 1, and _R5 is _{-NR7R7 '} . In another embodiment, R ₁ is _R2 is H or methyl, m is 0, n is 2, s is 1, _R5 is _{-NR7R7 '} , and _R7 is H or ( _C1 - _C6 )alkyl, optionally substituted one to three R ₈ . In another embodiment, R ₁ is , R ₂ is H or methyl, m is 0, n is 2, s is 1, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one - three R ₈ , and R _7' is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ . In another embodiment, R ₁ is , R ₂ is H or methyl, m is 0, n is 2, s is 1, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one - three R ₈ , R _7' represents H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , and R ₈ represents (C ₆ -C ₁₀ )aryl.

In some embodiments of the above formulas, R ₁ is , R ₂ is H or methyl, m is 0, n is 2, and s is 2. In another embodiment, R ₁ is _R2 is H or methyl, m is 0, n is 2, s is 2, and _R5 is _-OR6 . In another embodiment, R ₁ is _R2 is H or methyl, m is 0, n is 2, s is 2, _R5 is _-OR6 , and _R6 is H or ( _C1 - _C6 )alkyl, optionally substituted with one to three (C ₆ -C ₁₀ )aryls.

In some embodiments of the above formulas, R ₁ is _R2 is H or methyl, m is 0, n is 2, s is 2, and _R5 is _{-NR7R7 '} . In another embodiment, R ₁ is _R2 is H or methyl, m is 0, n is 2, s is 2, _R5 is _{-NR7R7 '} , and _R7 is H or ( _C1 - _C6 )alkyl, optionally substituted one to three R ₈ . In another embodiment, R ₁ is , R ₂ is H or methyl, m is 0, n is 2, s is 2, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one - three R ₈ , and R _7' is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ . In another embodiment, R ₁ is , R ₂ is H or methyl, m is 0, n is 2, s is 2, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optionally substituted with one - three R ₈ , R _7' represents H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , and R ₈ represents (C ₆ -C ₁₀ )aryl.

In some embodiments of the above formulas, R ₁ is _R2 is H or methyl, m is 0, n is 2, s is 1 or 2, and _R5 is _-OR6 . In another embodiment, R ₁ is _R2 is H or methyl, m is 0, n is 2, s is 1 or 2, _R5 is _-OR6 , and _R6 is H or ( _C1 - _C6 )alkyl, optionally substituted with one - three (C ₆ -C ₁₀ )aryls.

In some embodiments of the above formulas, R ₁ is _R2 is H or methyl, m is 0, n is 2, s is 1 or 2, and _R5 is _{-NR7R7 '} . In another embodiment, R ₁ is _R2 is H or methyl, m is 0, n is 2, s is 1 or 2, _R5 is _{-NR7R7 '} , and _R7 is H or ( _C1 - _C6 )alkyl, optionally substituted with one to three R ₈ . In another embodiment, R ₁ is , R ₂ is H or methyl, m is 0, n is 2, s is 1 or 2, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optional substituted with one to three R ₈ , and R _7' is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ . In another embodiment, R ₁ is , R ₂ is H or methyl, m is 0, n is 2, s is 1 or 2, R ₅ is -NR ₇ R _7' , R ₇ is H or (C ₁ -C ₆ )alkyl, optional substituted with one to three R ₈ , R _7' is H or (C ₁ -C ₆ )alkyl, optionally substituted with one to three R ₈ , and R ₈ is (C ₆ -C ₁₀ )aryl.

In some embodiments of the above formulas, R ₁ is , and R ₂ represents H or (C ₁ -C ₃ )alkyl. In another embodiment, R ₁ is , R ₂ is H or (C ₁ -C ₃ )alkyl, and m1 is 0. In another embodiment, R ₁ is , R ₂ represents H or (C ₁ -C ₃ )alkyl, m1 is 0, and R ₅ represents -NR ₇ R _7' . In another embodiment, R ₁ is _R2 is H or ( _C1 - _C3 )alkyl, m1 is 0, and _R5 is _-OR6 .

In some embodiments of the above formulas, R ₁ is , and R ₂ represents H or (C ₁ -C ₃ )alkyl. In another embodiment, R ₁ is , R ₂ is H or (C ₁ -C ₃ )alkyl, and m1 is 0. In another embodiment, R ₁ is , R ₂ represents H or (C ₁ -C ₃ )alkyl, m1 is 0, and R ₅ represents -NR ₇ R _7' . In another embodiment, R ₁ is _R2 is H or ( _C1 - _C3 )alkyl, m1 is 0, and _R5 is _-OR6 .

In another embodiment, R ₁ is , R ₂ is H, m1 is 0, R ₅ is -NR ₇ R _7' , R ₇ and R _7', together with the nitrogen atom to which they are attached, form a 4-7 membered heterocycloalkyl ring, optionally containing 1 -2 additional heteroatoms selected from O, N and S, optionally substituted with one to four _R9 , and n1 is 1 or 2. In another embodiment, _R1 is , R ₂ is H, m1 is 0, R ₅ is -NR ₇ R _7' , R ₇ and R _7', together with the nitrogen atom to which they are attached, form a 4-7 membered heterocycloalkyl ring, optionally containing 1 -2 additional heteroatoms selected from O, N and S, optionally substituted by one to four _R9 , and n1 is 1. In another embodiment, _R1 is , R ₂ is H, m1 is 0, R ₅ is -NR ₇ R _7' , R ₇ and R _7', together with the nitrogen atom to which they are attached, form a 4-7 membered heterocycloalkyl ring, optionally containing 1 -2 additional heteroatoms selected from O, N and S, optionally substituted by one to four _R9 , and n1 equals 2.

Embodiment 1. A compound of formula (I'), wherein

each of X ₁ and X ₂ independently represents H, (C ₁ -C ₄ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₄ )haloalkyl,

(C ₁ -C ₆ )haloalkoxy, (C ₃ -C ₇ )cycloalkyl, halogen, CN, -OH or -NH ₂ ;

R _x represents H or D;

R _a and R _b are each independently H or D, or R _a and R _b together with the atom to which they are attached form =(O);

R ₁ represents , or ;

R ₂ represents H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl or (C ₃ -C ₆ )cycloalkyl; or

R ₂ and R ₇ together with the nitrogen atoms to which they are attached form a 6- or 7-membered heterocycloalkyl ring;

each R ₃ independently in each case represents (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy,

(C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )haloalkoxy, halogen, CN, -OH or -NH ₂ ; or

two R ₃ together with the carbon atoms to which they are attached form a (C ₃ -C ₇ )cycloalkyl or 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S; or two R ₃ when located at adjacent carbon atoms, together form a phenyl or 5- or 6-membered heteroaryl ring containing 1-3 heteroatoms selected from O, N and S; or

R ₃ and R ₇ together with the nitrogen and carbon atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, optionally substituted with one to four substituents, each of which is independently selected from (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, halogen, -OH, CN and -NH ₂ ;

each R ₄ is (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )haloalkoxy, halogen, -OH or

_-NH2 ;

R ₅ is -OR ₆ or -NR ₇ R _7' ;

R ₆ is H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, -C(O)(C ₁ -C ₆ )alkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three substituents, each of which is independently selected from (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S;

each of R ₇ and R _7' independently represents H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1 -3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one - three R ₈ , and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one to four R ₁₁ ; or

R ₇ and R _7', together with the nitrogen atom to which they are attached, form a 4-7 membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, optionally substituted by one to four R ₉ ; or

R ₂ and R ₇ together with the nitrogen atoms to which they are attached form a 6- or 7-membered heterocycloalkyl ring; or

R ₃ and R ₇ together with the nitrogen and carbon atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, optionally substituted with one to four substituents, each of which is independently selected from (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, halogen, -OH, CN and -NH ₂ ;

each R ₈ is -C(O)OH, (C ₃ -C ₇ )cycloalkyl, a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ ) aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, with cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally substituted by one to four R ₁₀ ;

each R ₉ is independently in each case a (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )haloalkoxy, halogen, -OH, CN, -NR ₁₂ R ₁₃ or -NH ₂ , wherein the alkoxy is optionally substituted with one to three substituents independently selected from (C ₃ -C ₇ )cycloalkyl, a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S; or

two R ₉ together with the atoms to which they are attached form a (C ₅ -C ₇ )cycloalkyl or 5-7-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N and S;

each R ₁₀ independently in each case represents (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )alkoxy,

(C ₁ -C ₆ )haloalkoxy, halogen, -OH, CN or -NH ₂ ; or

two R ₁₀ together with the atoms to which they are attached form a (C ₄ -C ₇ )cycloalkyl or 5-7-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N and S, optionally substituted with one to four substituents , each independently selected from (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, halogen, -OH, CN or -NH ₂ ;

each R ₁₁ independently in each case represents (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )alkoxy,

(C ₁ -C ₆ )haloalkoxy, halogen, -OH, CN or -NH ₂ ;

each of R ₁₂ and R ₁₃ is independently selected from (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₃ -C ₇ )cycloalkyl, 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms , selected from O, N and S, (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S;

each of m and m1 is independently equal to 0, 1 or 2;

n1 is 0, 1, 2 or 3;

each of n2 and n3 is independently equal to 1 or 2; And

each of s and n is independently equal to 1, 2 or 3, where s+n ≤ 4;

or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs thereof, stereoisomers and tautomers thereof.

Embodiment 2. The compound according to Embodiment 1, characterized by formula (I), wherein:

R _x represents H or D;

R ₁ represents or ;

R ₂ represents H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl or (C ₃ -C ₆ )cycloalkyl; or

R ₂ and R ₇ together with the nitrogen atoms to which they are attached form a 6- or 7-membered heterocycloalkyl ring;

each R ₃ independently in each case represents (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkyl,

(C ₁ -C ₆ )haloalkoxy, halogen, CN, -OH or -NH ₂ ; or

two R ₃ together with the carbon atoms to which they are attached form a (C ₃ -C ₇ )cycloalkyl or 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S; or two R ₃ when located at adjacent carbon atoms, together form a phenyl or 5- or 6-membered heteroaryl ring containing 1-3 heteroatoms selected from O, N and S; or

R ₃ and R ₇ together with the nitrogen and carbon atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, optionally substituted with one to four substituents, each of which is independently selected from (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, halogen, -OH, CN and -NH ₂ ;

each R ₄ is (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )haloalkoxy, halogen, -OH or

_-NH2 ;

R ₅ is -OR ₆ or -NR ₇ R _7' ;

R ₆ is H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, -C(O)(C ₁ -C ₆ )alkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three substituents, each of which is independently selected from (C ₆ -C ₁₀ )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S;

each of R ₇ and R _7' independently represents H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₃ -C ₇ )cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1 -3 heteroatoms selected from O, N and S,

(C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, wherein the alkyl is optionally substituted with one to three R ₈ ; or

R ₇ and R _7', together with the nitrogen atom to which they are attached, form a 4-7 membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, optionally substituted by one to four R ₉ ; or

R ₂ and R ₇ together with the nitrogen atoms to which they are attached form a 6- or 7-membered heterocycloalkyl ring; or

R ₃ and R ₇ together with the nitrogen and carbon atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally containing 1-2 additional heteroatoms selected from O, N and S, optionally substituted with one to four substituents, each of which is independently selected from (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, halogen, -OH, CN and -NH ₂ ;

each R ₈ is (C ₃ -C ₇ )cycloalkyl, a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, (C ₆ -C ₁₀ )aryl or 5- or 6- member heteroaryl containing 1-3 heteroatoms selected from O, N and S, with cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally substituted by one to four R ₁₀ ;

each R ₉ is independently in each case a (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, halogen, -OH, CN or

_-NH2 ; or

two R ₉ together with the atoms to which they are attached form a (C ₅ -C ₇ )cycloalkyl or 5-7-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N and S;

each R ₁₀ is independently in each case a (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, halogen, -OH, CN or -NH ₂ ; or

two R ₁₀ together with the atoms to which they are attached form a (C ₅ -C ₇ )cycloalkyl or 5-7-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N and S, optionally substituted with one to four substituents , each independently selected from (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, halogen, -OH, CN or -NH ₂ ;

each of m and m1 is independently equal to 0, 1 or 2;

n1 is 0, 1, 2 or 3; And

each of s and n is independently equal to 1, 2 or 3, where s+n ≤ 4;

or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs based thereon, stereoisomers and tautomers thereof.

Embodiment 3. The connection according to embodiment 1 or 2, where R ₁ is .

Embodiment 4: The connection according to any one of Embodiments 1 to 3, where n1 is 1 or 2.

Embodiment 5: A connection according to any one of Embodiments 1 to 4, where m1 is 0.

Embodiment 6: The connection according to any one of Embodiments 1 to 5, where m1 is 2.

Embodiment 7: The connection according to Embodiment 1, wherein R ₁ is .

Embodiment 8: The connection according to Embodiment 7, where n is 2 and s is 1 or 2.

Embodiment 9: Connection according to Embodiment 7 or 8, where m is 0 or 1.

Embodiment 10. The compound according to Embodiment 1 or 2, characterized by formula (Ia), formula (Ib), formula (Ia-1) or formula (Ib-1); or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs thereof, stereoisomers and tautomers thereof.

Embodiment 11. The compound of Embodiment 1 or 2, characterized by Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), Formula (Ii), Formula ( Ij), formula (Ic-1), formula (Id-1), formula (Ie-1), formula (If-1), formula (Ig-1), formula (Ih-1), formula (Ii-1 ) or formula (Ij-1); or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs thereof, stereoisomers and tautomers thereof.

Embodiment 12. The compound according to Embodiment 1 or 2, characterized by Formula (Ik), Formula (Il), Formula (Im), Formula (In), Formula (Io), Formula (Ip), Formula (Ik-1), formula (Il-1), formula (Im-1), formula (In-1), formula (Io-1) or formula (Ip-1), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs thereof, its stereoisomers and tautomers.

Embodiment 13. The compound according to any one of embodiments 1 to 12, wherein R ₅ is -OR ₆ .

Embodiment 14. The compound according to any one of embodiments 1 to 12, wherein R ₅ is -NR ₇ R _7' .

Embodiment 15. The compound of Embodiment 1 or 2, characterized by Formula (Iq), Formula (Ir), Formula (Is), Formula (It), Formula (Iq-1), Formula (Ir-1), Formula (Is -1) or formula (It-1); or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs thereof, stereoisomers and tautomers thereof.

Embodiment 16. The compound according to any one of embodiments 1-15, wherein R ₂ represents H or methyl.

Embodiment 17. The connection according to Embodiment 1 selected from the following connections:

Connection no. Connection structure Connection name I-1 3-(5-(((1S,2S)-2-hydroxycyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-5 3-(5-(((1R,2S)-2-hydroxycyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-18 3-(5-(((1S,2R)-2-hydroxycyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-19 3-(5-(((1R,2R)-2-hydroxycyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-20 3-(5-((2-hydroxycyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-2 3-(5-(methyl((1R,2R)-2-(methylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-21 3-(5-(methyl((1S,2R)-2-(methylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-22 3-(5-(methyl((1R,2S)-2-(methylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-8 3-(5-(methyl((1S,2S)-2-(methylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-23 3-(5-(methyl(2-(methylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-3 3-(5-(((1S,2S)-2-(benzylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-24 3-(5-(((1R,2S)-2-(benzylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-25 3-(5-(((1S,2R)-2-(benzylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-26 3-(5-(((1R,2R)-2-(benzylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-27 3-(5-((2-(benzylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-4 3-(5-(((1S,2S)-2-(benzyloxy)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-28 3-(5-(((1R,2S)-2-(benzyloxy)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-29 3-(5-(((1S,2R)-2-(benzyloxy)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-30 3-(5-(((1R,2R)-2-(benzyloxy)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-31 3-(5-((2-(benzyloxy)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-6 3-(5-(((1S,2S)-2-(benzyl(methyl)amino)cyclohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-32 3-(5-(((1R,2S)-2-(benzyl(methyl)amino)cyclohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-33 3-(5-(((1S,2R)-2-(benzyl(methyl)amino)cyclohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-34 3-(5-(((1R,2R)-2-(benzyl(methyl)amino)cyclohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-35 3-(5-((2-(benzyl(methyl)amino)cyclohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-7 3-(5-(((1S,2S)-2-aminocyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-36 3-(5-(((1R,2S)-2-aminocyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-37 3-(5-(((1S,2R)-2-aminocyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-38 3-(5-(((1R,2R)-2-aminocyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-39 3-(5-((2-aminocyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-40 3-(5-(((1S,2S)-2-(ethylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-41 3-(5-(((1S,2R)-2-(ethylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-42 3-(5-(((1R,2R)-2-(ethylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-43 3-(5-(((1R,2S)-2-(ethylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-44 3-(5-((2-(ethylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-45 3-(5-(((1S,2S)-2-(isopropylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-46 3-(5-(((1S,2R)-2-(isopropylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-47 3-(5-(((1R,2R)-2-(isopropylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-48 3-(5-(((1R,2S)-2-(isopropylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-49 3-(5-((2-(isopropylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-50 3-(5-((4aS,8aS)-octahydroquinoxalin-1(2H)-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-51 3-(5-((4aR,8aS)-octahydroquinoxalin-1(2H)-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-52 3-(5-((4aR,8aR)-octahydroquinoxalin-1(2H)-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-53 3-(5-((4aS,8aR)-octahydroquinoxalin-1(2H)-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-54 3-(5-(octahydroquinoxalin-1(2H)-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-55 3-(5-(ethyl((1S,2S)-2-(ethylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-56 3-(5-(ethyl((1S,2R)-2-(ethylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-57 3-(5-(ethyl((1R,2R)-2-(ethylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-58 3-(5-(ethyl((1R,2S)-2-(ethylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-59 3-(5-(ethyl(2-(ethylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-60 3-(5-(((1S,2S)-2-(ethylamino)cyclopentyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-61 3-(5-(((1S,2R)-2-(ethylamino)cyclopentyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-62 3-(5-(((1R,2R)-2-(ethylamino)cyclopentyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-63 3-(5-(((1R,2S)-2-(ethylamino)cyclopentyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-64 3-(5-((2-(ethylamino)cyclopentyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-65 3-(5-(methyl((1S,2S)-2-(methylamino)cyclopentyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-66 3-(5-(methyl((1S,2R)-2-(methylamino)cyclopentyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-67 3-(5-(methyl((1R,2R)-2-(methylamino)cyclopentyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-68 3-(5-(methyl((1R,2S)-2-(methylamino)cyclopentyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-69 3-(5-(methyl(2-(methylamino)cyclopentyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-70 3-(5-(ethyl((1S,2S)-2-(ethylamino)cyclopentyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-71 3-(5-(ethyl((1S,2R)-2-(ethylamino)cyclopentyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-72 3-(5-(ethyl((1R,2R)-2-(ethylamino)cyclopentyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-73 3-(5-(ethyl((1R,2S)-2-(ethylamino)cyclopentyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-74 3-(5-(ethyl(2-(ethylamino)cyclopentyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-11 3-(5-(((1S,2S)-2-(benzyl(methyl)amino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-10 3-(5-(((1S,2S)-2-(methylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-75 3-(5-(((1S,2R)-2-(methylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-76 3-(5-(((1R,2R)-2-(methylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-77 3-(5-(((1R,2S)-2-(methylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-78 3-(5-((2-(methylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-12 3-(5-(((1S,2S)-2-((cyclohexylmethyl)amino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-79 3-(5-(((1S,2R)-2-((cyclohexylmethyl)amino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-80 3-(5-((((1R,2R)-2-((cyclohexylmethyl)amino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-81 3-(5-(((1R,2S)-2-((cyclohexylmethyl)amino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-82 3-(5-((2-((cyclohexylmethyl)amino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-14 3-(1-oxo-5-(((1S,2S)-2-(piperidin-1-yl)cyclopentyl)amino)isoindolin-2-yl)piperidin-2,6-dione; I-83 3-(1-oxo-5-(((1S,2R)-2-(piperidin-1-yl)cyclopentyl)amino)isoindolin-2-yl)piperidin-2,6-dione; I-84 3-(1-oxo-5-(((1R,2R)-2-(piperidin-1-yl)cyclopentyl)amino)isoindolin-2-yl)piperidin-2,6-dione; I-85 3-(1-oxo-5-(((1R,2S)-2-(piperidin-1-yl)cyclopentyl)amino)isoindolin-2-yl)piperidin-2,6-dione; I-86 3-(1-oxo-5-((2-(piperidin-1-yl)cyclopentyl)amino)isoindolin-2-yl)piperidin-2,6-dione; I-15 3-(5-(((1S,2S)-2-(isobutylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-87 3-(5-(((1S,2R)-2-(isobutylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-88 3-(5-(((1R,2R)-2-(isobutylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-89 3-(5-(((1R,2S)-2-(isobutylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-90 3-(5-((2-(isobutylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-16 3-(5-(methyl((1S,6S)-6-(methylamino)cyclohex-3-en-1-yl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-91 3-(5-(methyl((1S,6R)-6-(methylamino)cyclohex-3-en-1-yl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-17 3-(5-(methyl((1R,6R)-6-(methylamino)cyclohex-3-en-1-yl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-92 3-(5-(methyl((1R,6S)-6-(methylamino)cyclohex-3-en-1-yl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-93 3-(5-(methyl(6-(methylamino)cyclohex-3-en-1-yl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-94 5-(((1R,2R)-2-(dimethylamino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; I-95 5-(((1R,2S)-2-(dimethylamino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione; I-96 5-(((1S,2S)-2-(dimethylamino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione; I-97 5-(((1S,2R)-2-(dimethylamino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione; I-98 5-((2-(dimethylamino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; I-99 5-(((1S,2S)-2-aminocyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione; I-100 5-(((1S,2R)-2-aminocyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione; I-101 5-(((1R,2R)-2-aminocyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione; I-102 5-(((1R,2S)-2-aminocyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione; I-103 5-((2-aminocyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; I-104 2-(2,6-dioxopiperidin-3-yl)-5-(((1S,2S)-2-(ethylamino)cyclohexyl)(methyl)amino)isoindoline-1,3-dione; I-105 2-(2,6-dioxopiperidin-3-yl)-5-(((1S,2R)-2-(ethylamino)cyclohexyl)(methyl)amino)isoindoline-1,3-dione; I-106 2-(2,6-dioxopiperidin-3-yl)-5-(((1R,2R)-2-(ethylamino)cyclohexyl)(methyl)amino)isoindoline-1,3-dione; I-107 2-(2,6-dioxopiperidin-3-yl)-5-(((1R,2S)-2-(ethylamino)cyclohexyl)(methyl)amino)isoindoline-1,3-dione; I-108 2-(2,6-dioxopiperidin-3-yl)-5-((2-(ethylamino)cyclohexyl)(methyl)amino)isoindoline-1,3-dione; I-109 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1S,2S)-2-(methylamino)cycloheptyl)amino)isoindoline-1,3-dione; I-110 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1S,2R)-2-(methylamino)cycloheptyl)amino)isoindoline-1,3-dione; I-111 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1R,2R)-2-(methylamino)cycloheptyl)amino)isoindoline-1,3-dione; I-112 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1R,2S)-2-(methylamino)cycloheptyl)amino)isoindoline-1,3-dione; I-113 2-(2,6-dioxopiperidin-3-yl)-5-(methyl(2-(methylamino)cycloheptyl)amino)isoindoline-1,3-dione; I-114 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1S,2S)-2-(methylamino)cyclohexyl)amino)isoindoline-1,3-dione; I-115 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1S,2R)-2-(methylamino)cyclohexyl)amino)isoindoline-1,3-dione; I-116 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1R,2R)-2-(methylamino)cyclohexyl)amino)isoindoline-1,3-dione; I-117 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1R,2S)-2-(methylamino)cyclohexyl)amino)isoindoline-1,3-dione; I-118 2-(2,6-dioxopiperidin-3-yl)-5-(methyl(2-(methylamino)cyclohexyl)amino)isoindoline-1,3-dione; I-119 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1S,6S)-6-(methylamino)cyclohex-3-en-1-yl)amino)isoindolin-1,3-dione; I-120 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1S,6R)-6-(methylamino)cyclohex-3-en-1-yl)amino)isoindoline-1,3-dione; I-121 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1R,6R)-6-(methylamino)cyclohex-3-en-1-yl)amino)isoindolin-1,3-dione; I-122 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1R,6S)-6-(methylamino)cyclohex-3-en-1-yl)amino)isoindolin-1,3-dione; I-123 2-(2,6-dioxopiperidin-3-yl)-5-(methyl(6-(methylamino)cyclohex-3-en-1-yl)amino)isoindolin-1,3-dione; I-13 3-(5-(((1S,2S)-2-aminocyclopentyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-124 3-(5-(((1S,2R)-2-aminocyclopentyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-125 3-(5-(((1R,2R)-2-aminocyclopentyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-126 3-(5-(((1R,2S)-2-aminocyclopentyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-127 3-(5-((2-aminocyclopentyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-128 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1S,2S)-2-(methylamino)cyclopentyl)amino)isoindoline-1,3-dione; I-129 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1S,2R)-2-(methylamino)cyclopentyl)amino)isoindoline-1,3-dione; I-130 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1R,2R)-2-(methylamino)cyclopentyl)amino)isoindoline-1,3-dione; I-131 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1R,2S)-2-(methylamino)cyclopentyl)amino)isoindoline-1,3-dione; I-132 2-(2,6-dioxopiperidin-3-yl)-5-(methyl(2-(methylamino)cyclopentyl)amino)isoindoline-1,3-dione; I-133 5-(((1S,2S)-2-(benzylamino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; I-134 5-(((1S,2R)-2-(benzylamino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; I-135 5-(((1R,2R)-2-(benzylamino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; I-136 5-(((1R,2S)-2-(benzylamino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; I-137 5-((2-(benzylamino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; I-138 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1S,2S)-2-(((1-(trifluoromethyl)cyclopropyl)methyl)amino)cyclohexyl)amino)isoindoline-1,3 -dion; I-139 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1S,2R)-2-(((1-(trifluoromethyl)cyclopropyl)methyl)amino)cyclohexyl)amino)isoindoline-1,3 -dion; I-140 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1R,2R)-2-(((1-(trifluoromethyl)cyclopropyl)methyl)amino)cyclohexyl)amino)isoindoline-1,3 -dion; I-141 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1R,2S)-2-(((1-(trifluoromethyl)cyclopropyl)methyl)amino)cyclohexyl)amino)isoindoline-1,3 -dion; I-142 2-(2,6-dioxopiperidin-3-yl)-5-(methyl(2-(((1-(trifluoromethyl)cyclopropyl)methyl)amino)cyclohexyl)amino)isoindoline-1,3-dione; I-143 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1S,2S)-2-((pyridin-3-ylmethyl)amino)cyclohexyl)amino)isoindoline-1,3-dione; I-144 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1S,2R)-2-((pyridin-3-ylmethyl)amino)cyclohexyl)amino)isoindoline-1,3-dione; I-145 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1R,2R)-2-((pyridin-3-ylmethyl)amino)cyclohexyl)amino)isoindoline-1,3-dione; I-146 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1R,2S)-2-((pyridin-3-ylmethyl)amino)cyclohexyl)amino)isoindoline-1,3-dione; I-147 2-(2,6-dioxopiperidin-3-yl)-5-(methyl(2-((pyridin-3-ylmethyl)amino)cyclohexyl)amino)isoindoline-1,3-dione; I-148 ((1S,2S)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)(methyl)amino)cyclohexyl)glycine; I-149 ((1R,2S)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)(methyl)amino)cyclohexyl)glycine; I-150 ((1R,2R)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)(methyl)amino)cyclohexyl)glycine; I-151 ((1S,2R)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)(methyl)amino)cyclohexyl)glycine; I-152 (2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)(methyl)amino)cyclohexyl)glycine; I-153 5-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione; I-154 5-(((1S,2R)-2-(dimethylamino)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione; I-155 5-(((1R,2R)-2-(dimethylamino)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione; I-156 5-(((1R,2S)-2-(dimethylamino)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione; I-157 5-((2-(dimethylamino)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; I-158 2-(2,6-dioxopiperidin-3-yl)-5-(methyl(3-(methylamino)bicyclo[2.2.1]hept-5-en-2-yl)amino)isoindolin-1,3-dione; I-159 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((2S,3S)-3-(methylamino)bicyclo[2.2.1]hept-5-en-2-yl)amino)isoindolin- 1,3-dione; I-160 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((2S,3R)-3-(methylamino)bicyclo[2.2.1]hept-5-en-2-yl)amino)isoindolin- 1,3-dione; I-161 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((2R,3R)-3-(methylamino)bicyclo[2.2.1]hept-5-en-2-yl)amino)isoindolin- 1,3-dione; I-162 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((2R,3S)-3-(methylamino)bicyclo[2.2.1]hept-5-en-2-yl)amino)isoindolin- 1,3-dione; I-163 3-(4-fluoro-5-(methyl((1S,2S)-2-(methylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-164 3-(4-fluoro-5-(methyl((1S,2R)-2-(methylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-165 3-(4-fluoro-5-(methyl((1R,2R)-2-(methylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-166 3-(4-fluoro-5-(methyl((1R,2S)-2-(methylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-167 3-(4-fluoro-5-(methyl(2-(methylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-168 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(methyl((1S,2S)-2-(methylamino)cyclohexyl)amino)isoindoline-1,3-dione; I-169 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(methyl((1S,2R)-2-(methylamino)cyclohexyl)amino)isoindoline-1,3-dione; I-170 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(methyl((1R,2R)-2-(methylamino)cyclohexyl)amino)isoindoline-1,3-dione; I-171 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(methyl((1R,2S)-2-(methylamino)cyclohexyl)amino)isoindoline-1,3-dione; I-172 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(methyl(2-(methylamino)cyclohexyl)amino)isoindoline-1,3-dione; I-173 3-(5-(((1S,2S)-2-(3-ethoxyazetidin-1-yl)cyclohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-174 3-(5-(((1S,2R)-2-(3-ethoxyazetidin-1-yl)cyclohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-175 3-(5-(((1R,2R)-2-(3-ethoxyazetidin-1-yl)cyclohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-176 3-(5-(((1R,2S)-2-(3-ethoxyazetidin-1-yl)cyclohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-177 3-(5-((2-(3-ethoxyazetidin-1-yl)cyclohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-178 2-(2,6-dioxopiperidin-3-yl)-5-(((1S,2S)-2-(3-ethoxyazetidin-1-yl)cyclohexyl)(methyl)amino)isoindoline-1,3-dione; I-179 2-(2,6-dioxopiperidin-3-yl)-5-(((1S,2R)-2-(3-ethoxyazetidin-1-yl)cyclohexyl)(methyl)amino)isoindoline-1,3-dione; I-180 2-(2,6-dioxopiperidin-3-yl)-5-(((1R,2R)-2-(3-ethoxyazetidin-1-yl)cyclohexyl)(methyl)amino)isoindoline-1,3-dione; I-181 2-(2,6-dioxopiperidin-3-yl)-5-(((1R,2S)-2-(3-ethoxyazetidin-1-yl)cyclohexyl)(methyl)amino)isoindoline-1,3-dione; I-182 2-(2,6-dioxopiperidin-3-yl)-5-((2-(3-ethoxyazetidin-1-yl)cyclohexyl)(methyl)amino)isoindoline-1,3-dione; I-183 3-(5-(((1S,2S)-2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-184 3-(5-(((1S,2R)-2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-185 3-(5-(((1R,2R)-2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-186 3-(5-(((1R,2S)-2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-187 3-(5-((2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-188 5-(((1S,2S)-2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione ; I-189 5-(((1S,2R)-2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione ; I-190 5-(((1R,2R)-2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione ; I-191 5-(((1R,2S)-2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione ; I-192 5-((2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione; I-193 3-(5-(((1S,2S)-2-(((3,3-difluorocyclobutyl)methyl)amino)cyclohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6- dione; I-194 3-(5-(((1S,2R)-2-(((3,3-difluorocyclobutyl)methyl)amino)cyclohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6- dione; I-195 3-(5-(((1R,2R)-2-(((3,3-difluorocyclobutyl)methyl)amino)cyclohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6- dione; I-196 3-(5-(((1R,2S)-2-(((3,3-difluorocyclobutyl)methyl)amino)cyclohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6- dione; I-197 3-(5-((2-(((3,3-difluorocyclobutyl)methyl)amino)cyclohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-198 5-(((1S,2S)-2-(((3,3-difluorocyclobutyl)methyl)amino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1, 3-dione; I-199 5-(((1S,2R)-2-(((3,3-difluorocyclobutyl)methyl)amino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1, 3-dione; I-200 5-(((1R,2R)-2-(((3,3-difluorocyclobutyl)methyl)amino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1, 3-dione; I-201 5-(((1R,2S)-2-(((3,3-difluorocyclobutyl)methyl)amino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1, 3-dione; I-202 5-((2-(((3,3-difluorocyclobutyl)methyl)amino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione; I-203 3-(5-(methyl((1S,2S)-2-(piperidin-1-yl)cyclopentyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-204 3-(5-(methyl((1S,2R)-2-(piperidin-1-yl)cyclopentyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-205 3-(5-(methyl((1R,2R)-2-(piperidin-1-yl)cyclopentyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-206 3-(5-(methyl((1R,2S)-2-(piperidin-1-yl)cyclopentyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-207 3-(5-(methyl(2-(piperidin-1-yl)cyclopentyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-208 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1S,2S)-2-(piperidin-1-yl)cyclopentyl)amino)isoindoline-1,3-dione; I-209 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1S,2R)-2-(piperidin-1-yl)cyclopentyl)amino)isoindoline-1,3-dione; I-210 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1R,2R)-2-(piperidin-1-yl)cyclopentyl)amino)isoindoline-1,3-dione; I-211 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1R,2S)-2-(piperidin-1-yl)cyclopentyl)amino)isoindoline-1,3-dione; I-212 2-(2,6-dioxopiperidin-3-yl)-5-(methyl(2-(piperidin-1-yl)cyclopentyl)amino)isoindoline-1,3-dione; I-213 5-(((1S,2S)-2-(diethylamino)cyclopentyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione; I-214 5-(((1S,2R)-2-(diethylamino)cyclopentyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; I-215 5-(((1R,2R)-2-(diethylamino)cyclopentyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione; I-216 5-(((1R,2S)-2-(diethylamino)cyclopentyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; I-217 5-((2-(diethylamino)cyclopentyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione; I-218 2-(2,6-dioxopiperidin-3-yl)-5-(((1S,2S)-2-(3-ethoxyazetidin-1-yl)cyclopentyl)(methyl)amino)isoindoline-1,3-dione; I-219 2-(2,6-dioxopiperidin-3-yl)-5-(((1S,2R)-2-(3-ethoxyazetidin-1-yl)cyclopentyl)(methyl)amino)isoindoline-1,3-dione; I-220 2-(2,6-dioxopiperidin-3-yl)-5-(((1R,2R)-2-(3-ethoxyazetidin-1-yl)cyclopentyl)(methyl)amino)isoindoline-1,3-dione; I-221 2-(2,6-dioxopiperidin-3-yl)-5-(((1R,2S)-2-(3-ethoxyazetidin-1-yl)cyclopentyl)(methyl)amino)isoindoline-1,3-dione; I-222 2-(2,6-dioxopiperidin-3-yl)-5-((2-(3-ethoxyazetidin-1-yl)cyclopentyl)(methyl)amino)isoindoline-1,3-dione; I-223 5-(((1S,2S)-1-amino-2,3-dihydro-1H-inden-2-yl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1 ,3-dione; I-224 5-(((1R,2S)-1-amino-2,3-dihydro-1H-inden-2-yl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1 ,3-dione; I-225 5-(((1R,2R)-1-amino-2,3-dihydro-1H-inden-2-yl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1 ,3-dione; I-226 5-(((1S,2R)-1-amino-2,3-dihydro-1H-inden-2-yl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1 ,3-dione; I-227 5-((1-amino-2,3-dihydro-1H-inden-2-yl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione; I-228 2-(2,6-dioxopiperidin-3-yl)-5-(((1S,2S)-1-(ethylamino)-2,3-dihydro-1H-inden-2-yl)(methyl)amino)isoindoline -1,3-dione; I-229 2-(2,6-dioxopiperidin-3-yl)-5-(((1R,2S)-1-(ethylamino)-2,3-dihydro-1H-inden-2-yl)(methyl)amino)isoindoline -1,3-dione; I-230 2-(2,6-dioxopiperidin-3-yl)-5-(((1R,2R)-1-(ethylamino)-2,3-dihydro-1H-inden-2-yl)(methyl)amino)isoindoline -1,3-dione; I-231 2-(2,6-dioxopiperidin-3-yl)-5-(((1S,2R)-1-(ethylamino)-2,3-dihydro-1H-inden-2-yl)(methyl)amino)isoindoline -1,3-dione; I-232 2-(2,6-dioxopiperidin-3-yl)-5-((1-(ethylamino)-2,3-dihydro-1H-inden-2-yl)(methyl)amino)isoindoline-1,3-dione ; I-233 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1S,2S)-1-(methylamino)-2,3-dihydro-1H-inden-2-yl)amino)isoindoline-1 ,3-dione; I-234 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1R,2S)-1-(methylamino)-2,3-dihydro-1H-inden-2-yl)amino)isoindoline-1 ,3-dione; I-235 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1R,2R)-1-(methylamino)-2,3-dihydro-1H-inden-2-yl)amino)isoindoline-1 ,3-dione; I-236 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1S,2R)-1-(methylamino)-2,3-dihydro-1H-inden-2-yl)amino)isoindoline-1 ,3-dione; I-237 2-(2,6-dioxopiperidin-3-yl)-5-(methyl(1-(methylamino)-2,3-dihydro-1H-inden-2-yl)amino)isoindoline-1,3-dione; I-238 5-(((1S,2S)-2-amino-2,3-dihydro-1H-inden-1-yl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1 ,3-dione; I-239 5-(((1S,2R)-2-amino-2,3-dihydro-1H-inden-1-yl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1 ,3-dione; I-240 5-(((1R,2R)-2-amino-2,3-dihydro-1H-inden-1-yl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1 ,3-dione; I-241 5-(((1R,2S)-2-amino-2,3-dihydro-1H-inden-1-yl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1 ,3-dione; I-242 5-((2-amino-2,3-dihydro-1H-inden-1-yl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione; I-243 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1S,2S)-2-(methylamino)-2,3-dihydro-1H-inden-1-yl)amino)isoindoline-1 ,3-dione; I-244 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1S,2R)-2-(methylamino)-2,3-dihydro-1H-inden-1-yl)amino)isoindoline-1 ,3-dione; I-245 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1R,2R)-2-(methylamino)-2,3-dihydro-1H-inden-1-yl)amino)isoindoline-1 ,3-dione; I-246 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1R,2S)-2-(methylamino)-2,3-dihydro-1H-inden-1-yl)amino)isoindoline-1 ,3-dione; I-247 2-(2,6-dioxopiperidin-3-yl)-5-(methyl(2-(methylamino)-2,3-dihydro-1H-inden-1-yl)amino)isoindoline-1,3-dione; I-248 2-(2,6-dioxopiperidin-3-yl)-5-(((1S,2S)-2-(ethylamino)-2,3-dihydro-1H-inden-1-yl)(methyl)amino)isoindoline -1,3-dione; I-249 2-(2,6-dioxopiperidin-3-yl)-5-(((1S,2R)-2-(ethylamino)-2,3-dihydro-1H-inden-1-yl)(methyl)amino)isoindoline -1,3-dione; I-250 2-(2,6-dioxopiperidin-3-yl)-5-(((1R,2R)-2-(ethylamino)-2,3-dihydro-1H-inden-1-yl)(methyl)amino)isoindoline -1,3-dione; I-251 2-(2,6-dioxopiperidin-3-yl)-5-(((1R,2S)-2-(ethylamino)-2,3-dihydro-1H-inden-1-yl)(methyl)amino)isoindoline -1,3-dione; I-252 2-(2,6-dioxopiperidin-3-yl)-5-((2-(ethylamino)-2,3-dihydro-1H-inden-1-yl)(methyl)amino)isoindoline-1,3-dione ; I-253 3-(4-amino-5-(((1S,2S)-2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6 -dion; I-254 3-(4-amino-5-(((1S,2R)-2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6 -dion; I-255 3-(4-amino-5-(((1R,2R)-2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6 -dion; I-256 3-(4-amino-5-(((1R,2S)-2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6 -dion; I-257 3-(4-amino-5-((2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-258 3-(5-(((1S,2S)-2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-4-hydroxy-1-oxoisoindolin-2-yl)piperidin-2,6 -dion; I-259 3-(5-(((1S,2R)-2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-4-hydroxy-1-oxoisoindolin-2-yl)piperidin-2,6 -dion; I-260 3-(5-(((1R,2R)-2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-4-hydroxy-1-oxoisoindolin-2-yl)piperidin-2,6 -dion; I-261 3-(5-(((1R,2S)-2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-4-hydroxy-1-oxoisoindolin-2-yl)piperidin-2,6 -dion; I-262 3-(5-((2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-4-hydroxy-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-263 4-amino-5-(((1S,2S)-2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1 ,3-dione; I-264 4-amino-5-(((1S,2R)-2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1 ,3-dione; I-265 4-amino-5-(((1R,2R)-2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1 ,3-dione; I-266 4-amino-5-(((1R,2S)-2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1 ,3-dione; I-267 4-amino-5-((2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione; I-268 5-(((1S,2S)-2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1, 3-dione; I-269 5-(((1S,2R)-2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1, 3-dione; I-270 5-(((1R,2R)-2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1, 3-dione; I-271 5-(((1R,2S)-2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1, 3-dione; I-271 5-((2-((4,4-difluorocyclohexyl)amino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione; I-272 3-(5-(((1S,2S)-2-(3-ethoxyazetidin-1-yl)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-273 3-(5-(((1S,2R)-2-(3-ethoxyazetidin-1-yl)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-274 3-(5-(((1R,2R)-2-(3-ethoxyazetidin-1-yl)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-275 3-(5-(((1R,2S)-2-(3-ethoxyazetidin-1-yl)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-276 3-(5-((2-(3-ethoxyazetidin-1-yl)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-277 3-(5-(((1S,2S)-2-((4,4-difluorocyclohexyl)amino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-278 3-(5-(((1S,2R)-2-((4,4-difluorocyclohexyl)amino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-279 3-(5-(((1R,2R)-2-((4,4-difluorocyclohexyl)amino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-280 3-(5-(((1R,2S)-2-((4,4-difluorocyclohexyl)amino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; And I-281 3-(5-((2-((4,4-difluorocyclohexyl)amino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; I-282 rac - trans -2-(2,6-dioxopiperidin-3-yl)-5-(octahydroquinoxalin-1(2H)-yl)isoindolin-1,3-dione and I-9 trans-3-(5-(methyl(-2-(methylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione.

Embodiment 18. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any of embodiments 1-17 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

Embodiment 19. The pharmaceutical composition according to embodiment 18, further comprising at least one additional pharmaceutical agent.

Embodiment 20. The pharmaceutical composition of Embodiment 18 or Embodiment 19 for use in treating a disease or disorder affected by providing a reduction in IKZF2 protein levels.

Embodiment 21. A method of disrupting IKZF2, comprising administering to a patient in need thereof a compound according to any of embodiments 1-17 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof.

Embodiment 22. A method of treating a disease or disorder affected by modulating IKZF2 protein levels, comprising administering to a patient in need thereof a compound of any one of Embodiments 1-17 or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof. , its stereoisomer or tautomer.

Embodiment 23. A method of modulating IKZF2 protein levels, comprising administering to a patient in need thereof a compound according to any of Embodiments 1-17 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof.

Embodiment 24. A method for reducing the level of proliferation of a cell, the method comprising contacting the cell with a compound according to any of Embodiments 1-17 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, and causing the reduction IKZF2 protein levels.

Embodiment 25. A method of treating cancer, comprising administering to a patient in need thereof a compound according to any of Embodiments 1 to 17 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof.

Embodiment 26. The method of Embodiment 25, wherein the cancer is selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, skin melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer uterine, lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, types of rhabdoid cancer and Ewing's sarcoma.

Embodiment 27. The method of Embodiment 25, wherein the cancer is a cancer to which the immune response is insufficient or a cancer with immunogenic properties.

Embodiment 28. A method of reducing IKZF2 protein levels in a subject, comprising the step of administering to the subject in need thereof a therapeutically effective amount of a compound according to any of Embodiments 1-17 or a pharmaceutically acceptable salt thereof.

Embodiment 29. The method according to any one of embodiments 21-28, wherein administration is oral, parenteral, subcutaneous, by injection or infusion.

Embodiment 30. The compound of any one of Embodiments 1-17, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer, or tautomer thereof, for use in treating a disease or disorder affected by decreased levels of IKZF2 protein.

Embodiment 31. Use of a compound of any one of Embodiments 1 to 17 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the manufacture of a medicament for the treatment of a disease or disorder affected by reduction in protein levels IKZF2.

Embodiment 32. The compound of any one of Embodiments 1-17, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for the treatment of a disease or disorder associated with decreased protein levels IKZF2.

Embodiment 33. The compound of Embodiment 32, wherein the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, skin melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer and soft tissue sarcomas selected from rhabdomyosarcoma (RMS ), synovial sarcoma, osteosarcoma, types of rhabdoid cancer and Ewing's sarcoma.

Embodiment 34. Use of a compound of any one of Embodiments 1 to 17, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer, or tautomer thereof, in the treatment of a disease or disorder associated with decreased levels of IKZF2 protein.

Embodiment 35. The compound of Embodiment 34, wherein the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, skin melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer and soft tissue sarcomas selected from rhabdomyosarcoma (RMS ), synovial sarcoma, osteosarcoma, types of rhabdoid cancer and Ewing's sarcoma.

Embodiment 36. The method of Embodiment 25, wherein the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid , acute myelogenous leukemia and gastrointestinal stromal tumor (GIST).

Embodiment 37. The compound of Embodiment 32, wherein the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma , carcinoid, acute myelogenous leukemia and gastrointestinal stromal tumor (GIST).

Embodiment 38. Use as in embodiment 34, wherein the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma , carcinoid, acute myelogenous leukemia and gastrointestinal stromal tumor (GIST).

In another embodiment, the compounds of the present invention are enantiomers. In some embodiments, the compounds are the (S)-enantiomer. In other embodiments, the compounds are the (R)-enantiomer. In yet other embodiments, the compounds of the present invention may be (+) or (-) enantiomers.

It should be understood that the present invention includes all isomeric forms, including mixtures thereof. If the compound contains a double bond, the substituent may be in the E- or Z-configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. It is also assumed that all tautomeric forms are covered.

The compounds of the present invention and their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers and prodrugs thereof may exist in their tautomeric form (eg, amide or imino ester). All such tautomeric forms are contemplated herein as part of the present invention.

The compounds of the present invention may contain asymmetric or chiral centers and, therefore, exist in various stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, as well as mixtures thereof, including racemic mixtures, are intended to form part of the present invention. Moreover, the present invention covers all geometric and positional isomers. For example, if a compound of the present invention includes a double bond or a fused ring, both cis and trans forms, as well as mixtures, are included within the scope of the present invention. Each compound disclosed herein includes all enantiomers that correspond to the general structure of the compound. From a stereochemical point of view, compounds may be in racemic or enantiomerically pure form or in any other form. The analytical results may reflect data obtained for the racemic form, the enantiomerically pure form, or any other form in terms of stereochemistry.

Diastereomeric mixtures can be separated into their individual diastereoisomers based on their physicochemical differences using methods well known to those skilled in the art, such as, for example, chromatography and/or fractional crystallization. Enantiomers can be separated by converting an enantiomeric mixture into a diastereomeric mixture by reacting with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher acid chloride), separating the diastereoisomers, and converting (e.g., by hydrolysis) the individual diastereoisomers to the corresponding pure enantiomers. In addition, some of the compounds of the present invention may be atropisomers (eg, substituted biaryls) and are contemplated as part of the present invention. Enantiomers can also be separated by using a chiral HPLC column.

It is also possible that the compounds of the present invention may exist in various tautomeric forms, and all such forms are included within the scope of the present invention, as well as chemical structures and names. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the present invention.

All stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the compounds of the present invention (including those for salts, solvates, esters of the compounds and prodrugs thereof, and salts, solvates and esters of prodrugs), such as those that can exist due to asymmetric carbon atoms on various substituents, including enantiomeric forms (which can exist even in the absence of asymmetric carbon atoms), rotameric forms, atropoisomers, and diastereomeric forms are also contemplated within the scope of this disclosure, as are positional isomers ( such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of formula (I') or formula (I) contains a double bond or a fused ring, then both cis and trans forms, as well as mixtures, are included within the scope of the present invention. Also, for example, all keto-enol and imine α-enamine forms of the compounds are included in the present invention.) The individual stereoisomers of the compounds of the present invention may, for example, be substantially free of other isomers or present in a mixture, eg, as racemates, or present in a mixture with all other stereoisomers or other selected stereoisomers.

The chiral centers of the compounds of the present invention may be characterized by an S or R configuration, as defined by the IUPAC 1974 Recommendations. In certain embodiments, each asymmetric atom is characterized by at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess or at least 99% enantiomeric excess in the (R) or (S) configuration. Substituents on atoms with unsaturated double bonds may, if possible, be in cis (Z) or trans (E) form.

The use of the terms "salt", "solvate", "ester", "prodrug" etc. applies equally to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs compounds of the present invention.

The compounds of the present invention can form salts, which are also included within the scope of this invention. A reference to a compound of formula herein generally should be construed as a reference to its salts unless otherwise indicated.

Compounds and intermediates can be isolated and used as a compound as such. Any formula given herein is intended to represent the unlabeled forms as well as the isotopically labeled forms of the compounds. Isotopically labeled compounds are characterized by the structures depicted by the formulas given herein, except that one or more atoms are replaced by an atom having the selected atomic mass or mass number. Examples of isotopes that may be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and such as²H,³H,^elevenC,¹³C,¹⁴C,¹⁵N,¹⁸F,³¹P,³²P, respectively. Included in the present invention are various isotopically labeled compounds as defined herein, for example compounds that contain radioactive isotopes such as³H,¹³C and¹⁴C. Such isotopically labeled compounds are useful in metabolic studies (using¹⁴C), reaction kinetics studies (e.g. using²H or³H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radiotherapy of patients. In particular,¹⁸F,^elevenC or labeled compound may be particularly useful for PET or SPECT studies.

Additionally, substitution with heavier isotopes, particularly deuterium (i.e., ^2H or D), may provide certain therapeutic benefits due to greater metabolic stability, e.g., increased in vivo half-life, reduced dosage requirement, decreased CYP450 inhibition (competitive or time-dependent) or improvement of the therapeutic index. For example, substitution with deuterium may modify the undesirable side effects of the non-deuterated compound, such as competitive inhibition of CYP450, time-dependent inactivation of CYP450, etc. It is understood that deuterium in this context is considered as a substitute in the compounds of the present invention. The concentration of such a heavier isotope, specifically deuterium, can be determined by means of an isotope enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio of the abundance of an isotope to the natural occurrence of that isotope. Where the substituent in a compound of the present invention is specified deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (incorporation of 52.5% deuterium for each designated deuterium atom), at least 4000 ( injection of 60% deuterium), at least 4500 (injection of 67.5% deuterium), at least 5000 (injection of 75% deuterium), at least 5500 (injection of 82.5% deuterium), at least 6000 (injection of 90 % deuterium), at least 6333.3 (injection of 95% deuterium), at least 6466.7 (injection of 97% deuterium), at least 6600 (injection of 99% deuterium) or at least 6633.3 (injection of 99 .5% deuterium).

The isotopically labeled compounds of the present invention can generally be prepared by conventional methods known to those skilled in the art, or by the procedures described in the Schemes, or in the Examples and Procedures described below, using a suitable isotopically labeled reagent in place of the unlabeled reagent. isotopes of the reagent.

Pharmaceutically acceptable solvates in accordance with the present invention include those where the crystallization solvent can be replaced by an isotope, for example, D ₂ O, d ₆ -acetone, d ₆ -DMSO.

The present invention relates to compounds that are modulators of IKZF2 protein levels. In one embodiment, the compounds of the present invention reduce IKZF2 protein levels. In yet another embodiment, the compounds of the present invention reduce IKZF2 protein levels. In another embodiment, the compounds of the present invention are IKZF2 disruptors.

The present invention relates to compounds that are modulators of the levels of IKZF2 and IKZF4 proteins. In one embodiment, the compounds of the present invention reduce the levels of IKZF2 and IKZF4 proteins. In one embodiment, the compounds of the present invention reduce the levels of IKZF2 and IKZF4 proteins. In another embodiment, the compounds of the present invention are IKZF2 disruptors.

In some embodiments, the compounds of the present invention are selective for other proteins. As used herein, the term "selective modulator", "selective disruptor" or "selective compound" means, for example, a compound of the present invention that effectively modulates, reduces or reduces the levels of a particular protein or degrades a particular protein to a greater extent than any another protein. A "selective modulator", "selective disruptor" or "selective compound" can be identified, for example, by comparing the compound's ability to modulate, reduce or reduce the levels of a particular protein or disrupt a particular protein with its ability to modulate, reduce or reduce the levels of other proteins or destroy other proteins. In some embodiments, selectivity can be determined by measuring the EC ₅₀ or IC ₅₀ of compounds.

In some embodiments, the compounds of the present invention are selective IKZF2 modulators. As used herein, the term “IKZF2 selective modulator”, “IKZF2 selective degrader” or “IKZF2 selective compound” refers to a compound of the present invention, for example, that effectively modulates, reduces or reduces IKZF2 protein levels or degrades IKZF2 protein more than any other protein, especially any protein (transcription factor) from the Ikaros family of proteins (e.g. IKZF1, IKZF3, IKZF4 and IKZF5).

“IKZF2 selective modulator”, “IKZF2 selective degrader” or “IKZF2 selective compound” can be identified, for example, by comparing the compound's ability to modulate IKZF2 protein levels with its ability to modulate levels of other members of the Ikaros family of proteins or other proteins. For example, a substance can be analyzed for its ability to modulate levels of the IKZF2 protein, as well as IKZF1, IKZF3, IKZF4, IKZF5 and other proteins. In some embodiments, selectivity can be determined by measuring the EC ₅₀ of compounds. In some embodiments, a selective IKZF2 disruptor is identified by comparing the compound's ability to disrupt IKZF2 with its ability to disrupt other members of the Ikaros protein family or other proteins.

In certain embodiments, the compounds of the present invention are IKZF2 degraders that have a selectivity for IKZF2 degradation that is at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater than that of others proteins (eg IKZF1, IKZF3, IKZF4 and IKZF5). In various embodiments, the compounds of the present invention have selectivity for degradation of IKZF2 that is no more than 1000 times greater than that of other proteins.

In certain embodiments, the compounds of the present invention have selectivity for degradation of IKZF2 that is at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater than that of other members of the Ikaros family of proteins (e.g. , IKZF1, IKZF3, IKZF4 and IKZF5). In various embodiments, the compounds of the present invention have selectivity for degradation of IKZF2 that is no more than 1000 times greater than that of other members of the Ikaros protein family (eg, IKZF1, IKZF3, IKZF4 and IKZF5).

In certain embodiments, the compounds of the present invention have selectivity for degradation of IKZF2 that is at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater than that of IKZF1. In various embodiments, the compounds of the present invention have selectivity for degradation of IKZF2 that is no more than 1000 times greater than that of IKZF1.

In certain embodiments, the compounds of the present invention have selectivity for degradation of IKZF2 that is at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater than that of IKZF3. In various embodiments, the compounds of the present invention have selectivity for degradation of IKZF2 that is no more than 1000 times greater than that of IKZF3.

In certain embodiments, the compounds of the present invention have selectivity for degradation of IKZF2 that is at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater than that of IKZF4. In various embodiments, the compounds of the present invention have selectivity for degradation of IKZF2 that is no more than 1000 times greater than that of IKZF4.

In certain embodiments, the compounds of the present invention have selectivity for degradation of IKZF2 that is at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater than that of IKZF5. In various embodiments, the compounds of the present invention have selectivity for degradation of IKZF2 that is no more than 1000 times greater than that of IKZF5.

In certain embodiments, the compounds of the present invention have selectivity for degradation of IKZF2 and IKZF4 that is at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater than that of other members of the protein family Ikaros (eg IKZF1, IKZF3 and IKZF5). In various embodiments, the compounds of the present invention have selectivity for degradation of IKZF2 and IKZF4 that is no more than 1000 times greater than that of other members of the Ikaros protein family (eg, IKZF1, IKZF3, and IKZF5).

In certain embodiments, the compounds of the present invention have a selectivity for degradation of IKZF2 and IKZF4 that is at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater than that of IKZF1. In various embodiments, the compounds of the present invention have selectivity for degradation of IKZF2 and IKZF4 that is no more than 1000 times greater than that of IKZF1.

In certain embodiments, the compounds of the present invention have a selectivity for degradation of IKZF2 and IKZF4 that is at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater than that of IKZF3. In various embodiments, the compounds of the present invention have selectivity for degradation of IKZF2 and IKZF4 that is no more than 1000 times greater than that of IKZF3.

In certain embodiments, the compounds of the present invention have a selectivity for degradation of IKZF2 and IKZF4 that is at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater than that of IKZF5. In various embodiments, the compounds of the present invention have selectivity for degradation of IKZF2 and IKZF4 that is no more than 1000 times greater than that of IKZF5.

In various embodiments, IKZF2 degradation is measured using EC ₅₀ .

Efficiency can be determined by the EC ₅₀ value. A compound with a lower EC ₅₀ value, determined under substantially similar conditions, is more effective at breaking than a compound with a higher EC ₅₀ value. In some embodiments, substantially similar conditions include detecting a decrease in protein levels in cells expressing a particular protein or a fragment of any thereof.

The present invention is directed to the compounds described herein and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs thereof, stereoisomers or tautomers thereof, and pharmaceutical compositions containing one or more of the compounds described herein or pharmaceutically acceptable salts thereof. , hydrates, solvates, prodrugs based on them, their stereoisomers or tautomers.

E. Methods for the synthesis of compounds of formula (I') or formula (I)

The compounds of the present invention can be prepared by various methods, including standard chemical methods. Suitable synthesis routes are indicated in the schemes below.

The compounds of the present invention can be prepared by methods known in the field of organic synthesis, as set forth in the following synthetic schemes. In the schemes described below, it is understood that protecting groups for unstable or reactive groups are used, if necessary, in accordance with general principles or chemistry. Protecting groups are handled according to standard organic synthesis procedures (T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a suitable stage in the synthesis of the compound using methods obvious to those skilled in the art. The selection methods, as well as the reaction conditions and the order of their implementation, must correspond to the preparation of compounds of formula (I') or formula (I).

Those skilled in the art will be able to determine the presence of a stereocenter in the compounds of the present invention. Accordingly, the present invention includes all possible stereoisomers (unless specified in the synthesis), and also includes not only racemic compounds, but also individual enantiomers and/or diastereoisomers. If the compound is desired as a separate enantiomer or diastereoisomer, it can be obtained by stereospecific synthesis or resolution of the final product or any suitable intermediate. Separation of the final product, intermediate, or starting material can be accomplished by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E.L. Eliel, S.H. Wilen, and L.N. Mander (Wiley-Interscience, 1994).

The compounds described herein can be obtained from commercially available starting materials or synthesized using known organic, inorganic and/or enzymatic methods.

Receiving connections

The compounds of the present invention can be prepared by a variety of methods well known to those skilled in the art of organic synthesis. By way of example, the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the field of organic synthesis chemistry, or variations thereof, as understood by one skilled in the art. Preferred methods include, but are not limited to, those described below.

The compounds of the present invention can be synthesized using the steps summarized in General Schemes I , II , III , IV and V , which contain different sequences for the synthesis of intermediates Ia , Ib , Ic , Id , II-b , IIIa , IV-a . IV-b , IV-c , IV-d , Va , Vb , Vc and Vd . The starting materials are either commercially available or prepared using known procedures in the literature mentioned or illustrated herein.

General scheme I

where R _a , R _b , R _x , R ₂ , R ₃ , R ₇ , R ₈ , X ₁ , X ₂ , m1 and n1 are as defined for formula (I').

General method for preparing compounds of formula (I'), where R₁ represents , and R_7'represents H or optionally substituted alkyl (optionally substituted with one or more R₈), using intermediate compoundsIa,Ib,Ic AndID shown in general diagram I. If R_a and R_b represent H, then the coupling reaction of the compoundIa with 1,2-diamineIb using a catalyst (e.g. CuI or RuPhos Palladacycle), base (e.g. cesium carbonate (Cs₂CO₃) orrubs-sodium butoxide (t-BuONa)) in a solvent (eg N,N-dimethylformamide (DMF) or 1,4-dioxane), optionally at elevated temperature, provides the desired compounds of formula (I'), where R_7' represents H. If R_a and R_b together with the atom to which they are attached form =(O), then the combination reaction of the compound can be carried outIa with 1,2-diamineIb using a base (for example,i-Pr₂Net) in a solvent (eg N-methyl-2-pyrrolidone (NMP)), optionally at elevated temperature, to give the desired compounds of formula (I'), where R_7' represents H. Reductive amination of compound (I'), where R_7' represents H, using an aldehydeIDprovides the required compounds of formula (I), where R_7' represents alkyl, optionally substituted with R₈. Alternatively, compounds of formula (I') wherein R_7' represents alkyl, optionally substituted with R₈, can be obtained by alkylation of compound (I'), where R_7' is H, alkyl halide, tosylate or mesylateIc in the presence of a base (for example, Et₃N,i-Pr₂NEt, Cs₂CO₃ etc.) in a solvent (eg MeCN, N, N-dimethylformamide (DMF), etc.) and optionally at elevated temperature.

General scheme II

where R _a , R _b , R _x , R ₂ , R ₄ , R ₇ , R ₈ , X ₁ , X ₂ , m, s and n are as defined for formula (I').

General method for preparing compounds of formula (I'), where R₁ represents , and R_7'represents H or optionally substituted alkyl (optionally substituted with one or more R₈), using intermediate compoundsIa,Ic,ID AndII-b shown in general diagram II. If R_a and R_b represents H, then the coupling reaction of the compoundIa with 1,2-diamineII-b using a catalyst (e.g. CuI or RuPhos Palladacycle), base (e.g. cesium carbonate (Cs₂CO₃) orrubs-sodium butoxide (t-BuONa)) in a solvent (e.g. N,N-dimethylformamide (DMF) or 1,4-dioxane), optionally at elevated temperature, provides the desired compounds of formula(I'), where R_7' represents H. If R_a and R_b together with the atom to which they are attached form =(O), then the combination reaction of the compound can be carried outIa with 1,2-diamineII-b using a base (for example,i-Pr₂NEt) in a solvent (eg N-methyl-2-pyrrolidone (NMP)), optionally at elevated temperature, to give the desired compounds of formula (I'), where R_7' represents H. Reductive amination of the compound(I), where R_7' represents H, an aldehydeIDprovides the required compounds of formula (I'), where R_7' represents alkyl, optionally substituted with R₈. Alternatively, compounds of formula (I') wherein R_7' represents alkyl, optionally substituted with R₈, can be obtained by alkylation of compound (I'), where R_7' is H, alkyl halide, tosylate or mesylateIc in the presence of a base (for example, Et₃N,i-Pr₂NEt, Cs₂CO₃ etc.) in a solvent (eg MeCN, N, N-dimethylformamide (DMF), etc.) and optionally at elevated temperature.

General scheme III

where R _a , R _b , R _x , R ₂ , R ₃ , R ₆ , X ₁ , X ₂ , m1 and n1 are as defined for formula (I').

General method for preparing compounds of formula (I') wherein R ₁ is , and R ₅ is -OR ₆ , using intermediates Ia and III-a is shown in General Scheme III. Coupling compound Ia with 1,2-amino ester III-a , where R ₆ is benzyl, using a catalyst (eg RuPhos Palladacycle), base (eg cesium carbonate (Cs ₂ CO ₃ ) or sodium tert -butoxide ( t -BuONa)) in a solvent (e.g. N,N-dimethylformamide (DMF) or 1,4-dioxane), optionally at elevated temperature, provides the desired compounds of formula (I') wherein R ₅ is -OR ₆ . and R ₆ is benzyl. Compounds of formula (I') wherein R ₆ is H can be prepared by hydrogenating compound (I') wherein R ₆ is benzyl in the presence of a suitable catalyst (eg Pd/C or PtO ₂ ) in a solvent (eg DMF or EtOH) and in an atmosphere of hydrogen gas.

General scheme IV

where R _x , R ₂ , R ₃ , R ₇ , R ₈ , X ₁ , X ₂ , m 1 and n 1 are as defined for formula (I').

Alternatively, compounds of formula (I') wherein R₁ represents , R_a and R_b represent H, and R_7'represents H or optionally substituted alkyl (optionally substituted with one or more R₈), can be obtained using intermediate compoundsIb,Ic,ID,IV-a,IV-b,IV-c AndIV-d, which is shown in the general diagram IV. Alkylation of a compoundIV-a dimethylformamide (DMF) in the presence of a base (e.g. LiTMP, LDA, TMPMgCl•LiCl, etc.) in a solvent (e.g. tetrahydrofuran (THF), etc.) and optionally at low temperature providesIV-b. Carrying out the compound reactionIV-b and connectionsIV-cin the presence of a reducing agent (for example, sodium triacetoxyborohydride (NaB(OAc)₃H), sodium cyanoborohydride (NaBH₃CN), etc.) and in a solvent (e.g. DMF, THF, etc.) providesIV-d. Carrying out a compound coupling reactionIV-d with 1,2-diamineIb using a catalyst (e.g. CuI or RuPhos Palladacycle), base (e.g. cesium carbonate (Cs₂CO₃) orrubs-sodium butoxide (t-BuONa)) in a solvent (e.g. N,N-dimethylformamide (DMF) or 1,4-dioxane), optionally at elevated temperature, provides the desired compounds of formula(I'), where R_7' represents H. Reductive amination of compound (I'), where R_7' represents H, an aldehydeIDprovides the required compounds of formula (I'), where R_7' represents alkyl, optionally substituted with R₈. Alternatively, compounds of formula (I') wherein R_7' represents alkyl, optionally substituted with R₈, can be obtained by alkylation of compound (I'), where R_7' is H, alkyl halide, tosylate or mesylateIc in the presence of a base (for example, Et₃N,i-Pr₂NEt, Cs₂CO₃ etc.) in a solvent (eg MeCN, N, N-dimethylformamide (DMF), etc.) and optionally at elevated temperature.

General scheme V

where R _x , R ₂ , R ₃ , R ₇ , R ₈ , X ₁ , X ₂ , m 1 and n 1 are as defined for formula (I').

General method for preparing compounds of formula (I'), where R₁ represents , R_a and R_b together with the atom to which they are attached form =(O), and R_7' represents H or optionally substituted alkyl (optionally substituted with one or more R₈), using intermediate compoundsIV-c,Va,Vb,Vc AndVd shown in General Scheme V. Carrying out the compound reactionVa with connectionIV-c in the presence of a weak base (eg KOAc) in a solvent (eg HOAc), optionally at elevated temperature, provides an intermediateVb. Carrying out a compound coupling reactionVb with 1,2-diamineVc, optionally protected with a suitable amine protecting group (e.g. Boc, Cbz, etc.), can be provided using a base (e.g.i-Pr₂NEt) in a solvent (e.g. N-methyl-2-pyrrolidone (NMP), isopropanol (i-PrOH), optionally at elevated temperature, to obtainVd, where R_7' is H. Alternatively, such a coupling reaction can be carried out using a catalyst (for example, CuI or RuPhos Palladacycle), a base (for example, cesium carbonate (Cs₂CO₃) orrubs-sodium butoxide (t-BuONa)) in a solvent (eg N,N-dimethylformamide (DMF) or 1,4-dioxane) optionally at elevated temperature. If the amine protecting group is onVd is a Boc group, deprotection can be accomplished using a strong acid (eg, HCl or trifluoroacetic acid (TFA)) in a solvent (eg, tetrahydrofuran (THF), 1,4-dioxane, etc.) to obtain compounds (I'), where R_7' represents H. Reductive amination of compound (I'), where R_7' represents H, an aldehydeIDprovides the required compounds of formula (I'), where R_7' represents alkyl, optionally substituted with R₈. Alternatively, compounds of formula (I') wherein R_7' represents alkyl, optionally substituted with R₈, can be obtained by alkylation of compound (I'), where R_7' is H, alkyl halide, tosylate or mesylateIc in the presence of a base (for example, Et₃N,i-Pr₂NEt, Cs₂CO₃ etc.) in a solvent (eg MeCN, N, N-dimethylformamide (DMF), etc.) and optionally at elevated temperature.

The mixture of enantiomers, diastereoisomers and cis/trans isomers obtained from the above process can be separated into their individual components by a chiral salt method, normal phase, reverse phase or chiral column chromatography, depending on the nature of the separation.

Any resulting racemates of the compounds of the present invention or intermediates can be resolved into optical antipodes by known methods, for example, by separating their diastereomeric salts derived from the optically active acid or base and isolating the optically active acid or base compound. In particular, it is thus possible to use the basic moiety to separate the compounds of the present invention into their optical antipodes, for example by fractional crystallization of a salt formed with an optically active acid, for example tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O, O'-p-toluoyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic compounds of the present invention or racemic intermediates can also be separated by chiral chromatography, for example high pressure liquid chromatography (HPLC) using a chiral adsorbent.

Any resulting mixtures of stereoisomers can be separated based on the physicochemical differences of the constituents into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.

It should be understood that in the above description and formula, the various groups R _x , R ₂ , R ₃ , R ₄ , R ₆ , R ₇ , R ₈ , X ₁ , X ₂ , m, m1, n, n1 and s and other variables are as defined above unless otherwise noted. In addition, for synthetic purposes, compounds prepared according to the general schemes I , II , III , IV and V are presented with selected radicals only to illustrate the general procedure for the synthesis of compounds of formula (I') as defined herein.

F. Methods of using compounds of formula (I') or formula (I)

Another aspect of the present invention relates to a method of treating, preventing, suppressing symptoms or eliminating a disease or disorder associated with modulating IKZF2 protein levels in a patient. The method includes administering to a patient in need of treatment of diseases or disorders associated with modulation of IKZF2 protein levels an effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, or a stereoisomer thereof. or a tautomer or composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof.

In another aspect, the present invention provides a method for treating, preventing, suppressing symptoms, or eliminating a disease or disorder that is affected by modulating IKZF2 protein levels. The method includes administering to a patient in need of treatment of diseases or disorders affected by modulation of IKZF2 protein levels an effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, or a stereoisomer or tautomer or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof.

In another aspect, the present invention relates to a method of treating, preventing, suppressing symptoms or eliminating a disease or disorder that is affected by reduction in IKZF2 protein levels. The method includes administering to a patient in need of treatment of diseases or disorders affected by decreased levels of IKZF2 protein, an effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, or a stereoisomer or tautomer or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof.

Another aspect of the present invention relates to a method of treating, preventing, suppressing symptoms or eliminating a disease or disorder that is affected by reduction in IKZF2 protein levels. The method includes administering to a patient in need of treatment of diseases or disorders affected by reduction or decrease in levels of IKZF2 protein, an effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof , a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, a stereoisomer or tautomer thereof.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the manufacture of a medicament for the treatment, prevention, suppression of symptoms or elimination of a disease or disorder affected by modulation of IKZF2 protein levels.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the manufacture of a medicament for the treatment, prevention, suppression of symptoms or cure of a disease or disorder affected by reduction in levels of IKZF2 protein.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for the treatment, prevention, suppression of symptoms or elimination of a disease or disorder affected by modulation of IKZF2 protein levels.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for the treatment, prevention, suppression of symptoms or elimination of a disease or disorder affected by reduction or reduction in levels of IKZF2 protein .

In another aspect, the present invention is directed to a method of modulating IKZF2 protein levels. The method involves administering to a patient in need thereof an effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I' ) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof. In some embodiments, modulation of IKZF2 protein levels is achieved through disruption of the IKZF2 protein. In other embodiments, modulation of IKZF2 protein levels is achieved through E3 ligase-mediated degradation of the IKZF2 protein.

Another aspect of the invention relates to a method of treating, preventing, suppressing symptoms or eliminating a disease or disorder associated with decreased or reduced levels of IKZF2 protein in a patient, the method comprising administering to the patient in need thereof an effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof its basis, its stereoisomer or tautomer.

The present invention also relates to the use of an IKZF2 degrading agent to produce a medicinal product useful in the treatment, prevention, suppression of symptoms or elimination of an IKZF2-related disease or disorder, wherein the medicinal product contains a compound of formula (I') or formula (I) or pharmaceutically acceptable thereof a salt, hydrate, solvate, a prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, a prodrug thereof, a stereoisomer or tautomer thereof.

In another aspect, the present invention relates to a method of treating, preventing, suppressing symptoms or eliminating an IKZF2-associated disease or disorder, wherein the medicinal preparation contains a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof based thereon, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, a stereoisomer or tautomer thereof.

In another aspect, the present invention relates to a method of making a medicament for the treatment, prevention, suppression of symptoms or elimination of an IKZF2-associated disease or disorder, wherein the medicament contains a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, a solvate, a prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, a prodrug thereof, a stereoisomer or tautomer thereof.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for the treatment of a disease or disorder associated with modulating IKZF2 protein levels. In some embodiments, modulation of IKZF2 levels is achieved through disruption of the IKZF2 protein. In some embodiments, modulation of IKZF2 protein levels is achieved through E3 ligase-mediated degradation of the IKZF2 protein.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of a disease associated with modulation of IKZF2 protein levels. In some embodiments, modulation of IKZF2 levels is achieved through disruption of the IKZF2 protein. In some embodiments, modulation of IKZF2 protein levels is achieved through E3 ligase-mediated degradation of the IKZF2 protein.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the treatment of a disease associated with modulation of IKZF2 protein levels. In some embodiments, modulation of IKZF2 protein levels is achieved through disruption of the IKZF2 protein. In some embodiments, modulation of IKZF2 protein levels is achieved through E3 ligase-mediated degradation of the IKZF2 protein.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for the treatment of a disease or disorder associated with decreased levels of IKZF2 protein. In some embodiments, the reduction in IKZF2 levels is achieved by disrupting the IKZF2 protein. In some embodiments, the reduction in IKZF2 levels is achieved through E3 ligase-mediated degradation of the IKZF2 protein.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of a disease associated with decreased levels of IKZF2 protein. In some embodiments, the reduction in IKZF2 levels is achieved by disrupting the IKZF2 protein. In some embodiments, the reduction in IKZF2 levels is achieved through E3 ligase-mediated degradation of the IKZF2 protein.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the treatment of a disease associated with decreased levels of IKZF2 protein. In some embodiments, the reduction in IKZF2 protein levels is achieved by disrupting the IKZF2 protein. In some embodiments, the reduction in IKZF2 levels is achieved through E3 ligase-mediated degradation of the IKZF2 protein.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for the treatment of a disease or disorder associated with decreased levels of IKZF2 protein. In some embodiments, the reduction in IKZF2 levels is achieved through disruption of the IKZF2 protein. In some embodiments, the reduction in IKZF2 protein levels is achieved through E3 ligase-mediated degradation of the IKZF2 protein.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of a disease associated with decreased levels of IKZF2 protein. In some embodiments, the reduction in IKZF2 levels is achieved through disruption of the IKZF2 protein. In some embodiments, the reduction in IKZF2 protein levels is achieved through E3 ligase-mediated degradation of the IKZF2 protein.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the treatment of a disease associated with decreased levels of IKZF2 protein. In some embodiments, the reduction in IKZF2 protein levels is achieved by disrupting the IKZF2 protein. In some embodiments, the reduction in IKZF2 protein levels is achieved through E3 ligase-mediated degradation of the IKZF2 protein.

In another aspect, the present invention provides a method of inhibiting IKZF2 activity by disrupting IKZF2. In some embodiments, degradation of the IKZF2 and IKZF4 proteins is mediated by an E3 ligase.

Another aspect of the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for inhibiting the activity of IKZF2 by degrading IKZF2. In some embodiments, degradation of the IKZF2 protein is mediated by an E3 ligase.

In another aspect, the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in inhibiting IKZF2 activity by degrading IKZF2. In some embodiments, degradation of the IKZF2 protein is mediated by an E3 ligase.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for inhibiting IKZF2 activity by disrupting IKZF2. In some embodiments, degradation of the IKZF2 protein is mediated by an E3 ligase.

In another aspect, the present invention provides a method for inhibiting the activity of IKZF2 and IKZF4 by disrupting IKZF2 and IKZF4. In some embodiments, degradation of the IKZF2 and IKZF4 proteins is mediated by an E3 ligase.

Another aspect of the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for inhibiting the activity of IKZF2 and IKZF4 by destroying IKZF2 and IKZF4. In some embodiments, degradation of the IKZF2 and IKZF4 proteins is mediated by an E3 ligase.

In another aspect, the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in inhibiting the activity of IKZF2 and IKZF4 by disrupting IKZF2 and IKZF4. In some embodiments, degradation of the IKZF2 and IKZF4 proteins is mediated by an E3 ligase.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for inhibiting the activity of IKZF2 and IKZF4 by degrading IKZF2 and IKZF4. In some embodiments, degradation of the IKZF2 and IKZF4 proteins is mediated by an E3 ligase.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for inhibiting the activity of IKZF2 and IKZF4 by degrading IKZF2 and IKZF4. In some embodiments, degradation of the IKZF2 and IKZF4 proteins is mediated by an E3 ligase.

Another aspect of the present invention relates to a method of treating, preventing, suppressing symptoms or eliminating a disease or disorder associated with modulating the levels of IKZF2 and IKZF4 proteins. The method involves administering to a patient in need of treatment of diseases or disorders associated with modulating the levels of IKZF2 and IKZF4 proteins, an effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, a stereoisomer or tautomer thereof or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof.

In another aspect, the present invention is directed to a method for modulating the levels of IKZF2 and IKZF4 proteins. The method involves administering to a patient in need thereof an effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I' ) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof. In some embodiments, modulation of IKZF2 and IKZF4 protein levels is achieved through disruption of the IKZF2 and IKZF4 proteins. In other embodiments, modulation of IKZF2 and IKZF4 protein levels is achieved through E3 ligase-mediated degradation of the IKZF2 and IKZF4 proteins.

Another aspect of the present invention relates to a method of treating, preventing, suppressing symptoms or eliminating a disease or disorder associated with modulating, reducing or reducing IKZF4 protein levels. The method includes administering to a patient in need of treatment of diseases or disorders associated with modulating, reducing or lowering the levels of IKZF4 protein, an effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof base, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, a stereoisomer or tautomer thereof. In some embodiments, modulation, reduction, or reduction of IKZF4 protein levels is achieved through disruption of the IKZF4 protein. In some embodiments, modulation, reduction, or reduction of IKZF4 protein levels is achieved through E3 ligase-mediated degradation of the IKZF4 protein.

In another aspect, the present invention is directed to a method of modulating, reducing or reducing IKZF4 protein levels. The method involves administering to a patient in need thereof an effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I' ) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof. In some embodiments, modulation, reduction, or reduction of IKZF4 protein levels is achieved through disruption of the IKZF4 protein. In other embodiments, modulation, reduction, or reduction of IKZF4 protein levels is achieved through E3 ligase-mediated degradation of the IKZF4 protein.

Another aspect of the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for the treatment, prevention, suppression of symptoms or elimination of a disease or disorder associated with modulating, reducing or decreasing levels of IKZF4 protein. In some embodiments, modulation, reduction, or reduction of IKZF4 protein levels is achieved through disruption of the IKZF4 protein. In some embodiments, modulation, reduction, or reduction of IKZF4 protein levels is achieved through E3 ligase-mediated degradation of the IKZF4 protein.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment, prevention, suppression of symptoms or elimination of a disease or disorder associated with modulating, reducing or decreasing levels of IKZF4 protein. In some embodiments, modulation, reduction, or reduction of IKZF4 protein levels is achieved through disruption of the IKZF4 protein. In some embodiments, modulation, reduction, or reduction of IKZF4 protein levels is achieved through E3 ligase-mediated degradation of the IKZF4 protein.

In another aspect, the present invention is directed to a compound of formula (I') or formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicinal product for the treatment, prevention, suppression of symptoms or elimination of a disease or disorder associated with the modulation, reduction or reduction of levels of IKZF4 protein. In some embodiments, modulation, reduction, or reduction of IKZF4 protein levels is achieved through disruption of the IKZF4 protein. In some embodiments, modulation, reduction, or reduction of IKZF4 protein levels is achieved through E3 ligase-mediated degradation of the IKZF4 protein.

Another aspect of the present invention relates to a method of treating, preventing, suppressing symptoms or eliminating a disease or disorder associated with a decrease in the levels of IKZF2 and IKZF4 proteins. The method includes administering to a patient in need of treatment of diseases or disorders associated with a decrease in the levels of IKZF2 and IKZF4 proteins, an effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, a stereoisomer or tautomer thereof or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof.

In another aspect, the present invention is directed to a method for reducing the levels of IKZF2 and IKZF4 proteins. The method involves administering to a patient in need thereof an effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I' ) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof. In some embodiments, the reduction in IKZF2 and IKZF4 protein levels is achieved by disrupting the IKZF2 and IKZF4 proteins. In other embodiments, the reduction in IKZF2 and IKZF4 protein levels is achieved through E3 ligase-mediated degradation of the IKZF2 and IKZF4 proteins.

Another aspect of the present invention relates to a method of treating, preventing, suppressing symptoms or eliminating a disease or disorder associated with a decrease in the levels of IKZF2 and IKZF4 proteins. The method includes administering to a patient in need of treatment of diseases or disorders associated with a decrease in the levels of IKZF2 and IKZF4 proteins, an effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, a stereoisomer or tautomer thereof or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof.

In another aspect, the present invention is directed to a method for reducing the levels of IKZF2 and IKZF4 proteins. The method involves administering to a patient in need thereof an effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I' ) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof. In some embodiments, the reduction in IKZF2 and IKZF4 protein levels is achieved by disrupting the IKZF2 and IKZF4 proteins. In other embodiments, the reduction in IKZF2 and IKZF4 protein levels is achieved through E3 ligase-mediated degradation of the IKZF2 and IKZF4 proteins.

Another aspect of the present invention relates to a method of treating, preventing, suppressing symptoms or eliminating a disease or disorder associated with modulating the levels of IKZF2 and IKZF4 proteins in a patient, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof its basis, its stereoisomer or tautomer. In one embodiment, the disease or disorder is selected from the group consisting of cancer and metastasis.

In another aspect, the present invention provides a method of treating, preventing, suppressing symptoms or eliminating a disease or disorder associated with decreased levels of IKZF2 and IKZF4 proteins in a patient, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof based on it, its stereoisomer or tautomer. In one embodiment, the disease or disorder is selected from the group consisting of cancer and metastasis.

Another aspect of the present invention relates to a method of treating, preventing, suppressing symptoms or eliminating a disease or disorder associated with decreased levels of IKZF2 and IKZF4 proteins in a patient, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof its basis, its stereoisomer or tautomer. In one embodiment, the disease or disorder is selected from the group consisting of cancer and metastasis.

The present invention also relates to the use of a modulator of IKZF2 and IKZF4 protein levels to produce a medicinal product useful in the treatment, prevention, suppression of symptoms or elimination of an IKZF2 and IKZF4-related disease or disorder, wherein the medicinal product contains a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof , its stereoisomer or tautomer. In another aspect, the present invention relates to a method of making a medicament for the treatment, prevention, suppression of symptoms or elimination of an IKZF2 and IKZF4 associated disease or disorder, wherein the medicament contains a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt thereof, a hydrate, solvate, a prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, a prodrug thereof, a stereoisomer or tautomer thereof.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicinal product for the treatment of a disease associated with modulating the levels of IKZF2 and IKZF4 proteins. In some embodiments, modulation of IKZF2 and IKZF4 protein levels is achieved through disruption of the IKZF2 and IKZF4 proteins. In other embodiments, modulation of IKZF2 and IKZF4 protein levels is achieved through E3 ligase-mediated degradation of the IKZF2 and IKZF4 proteins.

In another aspect, the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of a disease associated with modulating the levels of IKZF2 and IKZF4 proteins. In some embodiments, modulation of IKZF2 and IKZF4 protein levels is achieved through disruption of the IKZF2 and IKZF4 proteins. In other embodiments, modulation of IKZF2 and IKZF4 protein levels is achieved through E3 ligase-mediated degradation of the IKZF2 and IKZF4 proteins.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for the treatment of a disease associated with a decrease in the levels of IKZF2 and IKZF4 proteins. In some embodiments, the reduction in IKZF2 and IKZF4 protein levels is achieved by disrupting the IKZF2 and IKZF4 proteins. In other embodiments, the reduction in IKZF2 and IKZF4 protein levels is achieved through E3 ligase-mediated degradation of the IKZF2 and IKZF4 proteins.

In another aspect, the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of a disease associated with a decrease in the levels of IKZF2 and IKZF4 proteins. In some embodiments, the reduction of IKZF2 and IKZF4 is achieved through disruption of the IKZF2 and IKZF4 proteins. In other embodiments, the reduction in IKZF2 and IKZF4 protein levels is achieved through E3 ligase-mediated degradation of the IKZF2 and IKZF4 proteins.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicinal product for the treatment of a disease associated with a decrease in the levels of IKZF2 and IKZF4 proteins. In some embodiments, the reduction in IKZF2 and IKZF4 protein levels is achieved by disrupting the IKZF2 and IKZF4 proteins. In other embodiments, the reduction in IKZF2 and IKZF4 protein levels is achieved through E3 ligase-mediated degradation of the IKZF2 and IKZF4 proteins.

In another aspect, the present invention provides a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of a disease associated with a decrease in the levels of IKZF2 and IKZF4 proteins. In some embodiments, the reduction in IKZF2 and IKZF4 levels is achieved by degrading the IKZF2 and IKZF4 proteins. In other embodiments, the reduction in IKZF2 and IKZF4 protein levels is achieved through E3 ligase-mediated degradation of the IKZF2 and IKZF4 proteins.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the treatment of a disease associated with modulation of the levels of IKZF2 and IKZF4 proteins. In some embodiments, modulation of IKZF2 and IKZF4 protein levels is achieved through disruption of the IKZF2 and IKZF4 proteins. In other embodiments, modulation of IKZF2 and IKZF4 protein levels is achieved through E3 ligase-mediated degradation of the IKZF2 and IKZF4 proteins.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of an IKZF2-related disease or disorder by reducing or lowering levels of IKZF2 protein, wherein reducing or lowering levels of IKZF2 protein provides the treatment IKZF2-related diseases or disorders.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the treatment of an IKZF2-related disease or disorder by reducing or lowering levels of IKZF2 protein, wherein reducing or lowering levels of IKZF2 protein provides the treatment IKZF2-related diseases or disorders.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the manufacture of a medicament for the treatment of an IKZF2-related disease or disorder by reducing or reducing levels of IKZF2 protein, wherein reducing or reducing levels of IKZF2 protein provides treatment for an IKZF2-related disease or disorder.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of an IKZF2 and IKZF4 associated disease or disorder by reducing or reducing the levels of the IKZF2 and IKZF4 proteins, wherein the reduction or decrease in the levels of IKZF2 and IKZF4 proteins provide treatment for a disease or disorder associated with IKZF2 and IKZF4.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the treatment of an IKZF2 and IKZF4-related disease or disorder by reducing or reducing the levels of the IKZF2 and IKZF4 proteins, wherein the reduction or decrease in the levels of IKZF2 and IKZF4 proteins provide treatment for a disease or disorder associated with IKZF2 and IKZF4.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the manufacture of a medicament for the treatment of an IKZF2 and IKZF4 related disease or disorder by reducing or lowering the levels of the IKZF2 and IKZF4 proteins, wherein the reduction or reducing the levels of IKZF2 and IKZF4 proteins provides treatment for an IKZF2 and IKZF4 associated disease or disorder.

Another aspect of the present invention relates to a method of treating cancer. The method involves administering to a patient in need thereof an effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I' ) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the treatment of cancer.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for the treatment of cancer.

In another aspect, the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of cancer.

Another aspect of the present invention relates to a method of treating IKZF2-related cancer. The method involves administering to a patient in need thereof an effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I' ) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the treatment of IKZF2-associated cancer.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for the treatment of IKZF2-related cancer.

In another aspect, the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of IKZF2-related cancer.

Another aspect of the present invention relates to a method of treating IKZF2-related and IKZF4-related cancer. The method involves administering to a patient in need thereof an effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I' ) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the treatment of IKZF2-related and IKZF4-related cancer.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for the treatment of IKZF2-related and IKZF4-related cancer.

In another aspect, the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of IKZF2-related and IKZF4-related cancer.

Another aspect of the present invention relates to a method of treating cancer that is affected by modulating, reducing or reducing IKZF2 protein levels. The method involves administering to a patient in need thereof an effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I' ) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the treatment of cancer affected by modulation, reduction or reduction of IKZF2 protein levels.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for the treatment of cancer affected by modulation, reduction or reduction of IKZF2 protein levels.

In another aspect, the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of cancer affected by modulation, reduction or reduction of IKZF2 protein levels.

Another aspect of the present invention relates to a method of treating cancer that is affected by modulating, decreasing or lowering the levels of IKZF2 and IKZF4 proteins. The method involves administering to a patient in need thereof an effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I' ) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the treatment of cancer affected by modulation, reduction or reduction in the levels of IKZF2 and IKZF4 proteins.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for the treatment of cancer, which is affected by modulating, reducing or reducing the levels of IKZF2 and IKZF4 proteins.

In another aspect, the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of cancer affected by modulation, reduction or reduction in the levels of IKZF2 and IKZF4 proteins.

Another aspect of the present invention relates to a method for destroying IKZF2. The method involves administering to a patient in need thereof an effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I' ) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof. In some embodiments, degradation of the IKZF2 protein is mediated by an E3 ligase.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for the purpose of destroying IKZF2. In some embodiments, degradation of the IKZF2 protein is mediated by an E3 ligase.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in degrading IKZF2. In some embodiments, degradation of the IKZF2 protein is mediated by an E3 ligase.

In another aspect, the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for degrading IKZF2. In some embodiments, degradation of the IKZF2 protein is mediated by an E3 ligase.

In another aspect, the present invention provides a method for modulating IKZF2 protein levels by disrupting IKZF2. In some embodiments, degradation of the IKZF2 protein is mediated by an E3 ligase.

Another aspect of the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for the purpose of modulating IKZF2 protein levels by disrupting IKZF2. In some embodiments, degradation of the IKZF2 protein is mediated by an E3 ligase.

In another aspect, the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in modulating IKZF2 protein levels by disrupting IKZF2. In some embodiments, degradation of the IKZF2 protein is mediated by an E3 ligase.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for modulating IKZF2 protein levels by disrupting IKZF2. In some embodiments, degradation of the IKZF2 protein is mediated by an E3 ligase.

Another aspect of the present invention relates to a method of treating an IKZF2-related disease or disorder in a patient in need thereof by modulating IKZF2 protein levels through disruption of IKZF2. In some embodiments, degradation of the IKZF2 protein is mediated by an E3 ligase.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for treating an IKZF2-related disease or disorder in a patient in need thereof by modulating IKZF2 protein levels through disruption of IKZF2. In some embodiments, degradation of the IKZF2 protein is mediated by an E3 ligase.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of an IKZF2-related disease or disorder in a patient in need thereof by modulating the levels of IKZF2 protein through the destruction of IKZF2. In some embodiments, degradation of the IKZF2 protein is mediated by an E3 ligase.

In another aspect, the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for the treatment of an IKZF2-related disease or disorder in a patient in need thereof by modulating the levels of IKZF2 protein by destruction of IKZF2. In some embodiments, degradation of the IKZF2 protein is mediated by an E3 ligase.

In another aspect, the present invention relates to a method for destroying IKZF2. The method involves administering to a patient in need thereof an effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I' ) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof. In some embodiments, degradation of the IKZF2 protein is mediated by an E3 ligase.

Another aspect of the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof for the purpose of degrading IKZF2. In some embodiments, degradation of the IKZF2 protein is mediated by an E3 ligase.

In another aspect, the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in degrading IKZF2. In some embodiments, degradation of the IKZF2 protein is mediated by an E3 ligase.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for degrading IKZF2. In some embodiments, degradation of the IKZF2 protein is mediated by an E3 ligase.

Another aspect of the present invention relates to a method of reducing the level of proliferation of a cell, the method comprising contacting the cell with a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, which provides a reduction in IKZF2 protein levels. In some embodiments, the reduction in IKZF2 protein levels is achieved by disrupting the IKZF2 protein. In some embodiments, the reduction in IKZF2 protein levels is achieved through E3 ligase-mediated degradation of the IKZF2 protein.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for reducing the level of cell proliferation by reducing the levels of IKZF2 protein. In some embodiments, the reduction in IKZF2 protein levels is achieved by disrupting the IKZF2 protein. In some embodiments, the reduction in IKZF2 protein levels is achieved through E3 ligase-mediated degradation of the IKZF2 protein.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in reducing cell proliferation levels via IKZF 2 protein levels. In some embodiments, reduction in IKZF 2 protein levels is achieved through protein degradation IKZF2. In some embodiments, the reduction in IKZF2 protein levels is achieved through E3 ligase-mediated degradation of the IKZF2 protein.

In another aspect, the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for reducing the level of cell proliferation by reducing the levels of IKZF2 protein. In some embodiments, the reduction in IKZF2 protein levels is achieved by disrupting the IKZF2 protein. In some embodiments, the reduction in IKZF2 protein levels is achieved through E3 ligase-mediated degradation of the IKZF2 protein.

In another aspect, the present invention provides a method for treating, preventing, suppressing symptoms, or eliminating a disease or disorder that is affected by modulating the levels of IKZF2 and IKZF4 proteins. The method involves administering to a patient in need of treatment of diseases or disorders affected by modulation of the levels of IKZF2 and IKZF4 proteins, an effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof. , a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, a stereoisomer or tautomer thereof.

Another aspect of the present invention relates to a method of treating, preventing, suppressing symptoms or eliminating a disease or disorder that is affected by a reduction or decrease in the levels of IKZF2 and IKZF4 proteins. The method includes administering to a patient in need of treatment of diseases or disorders affected by a decrease or reduction in the levels of IKZF2 and IKZF4 proteins, an effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, based thereon, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the manufacture of a medicament for the treatment, prevention, suppression of symptoms or cure of a disease or disorder affected by modulation of the levels of IKZF2 and IKZF4 proteins .

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for the treatment, prevention, suppression of symptoms or elimination of a disease or disorder affected by modulation of the levels of the IKZF2 and IKZF4 proteins .

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the manufacture of a medicament for the treatment, prevention, suppression of symptoms or cure of a disease or disorder affected by a decrease in the levels of IKZF2 and IKZF4 proteins .

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for the treatment, prevention, suppression of symptoms or cure of a disease or disorder affected by a decrease in the levels of the IKZF2 and IKZF4 proteins .

Another aspect of the present invention relates to a method for destroying IKZF2 and IKZF4. The method involves administering to a patient in need thereof an effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I' ) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof. In some embodiments, degradation of the IKZF2 and IKZF4 proteins is mediated by an E3 ligase.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for the purpose of destroying IKZF2 and IKZF4. In some embodiments, degradation of the IKZF2 and IKZF4 proteins is mediated by an E3 ligase.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in disrupting IKZF2 and IKZF4. In some embodiments, degradation of the IKZF2 and IKZF4 proteins is mediated by an E3 ligase.

In another aspect, the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for the destruction of IKZF2 and IKZF4. In some embodiments, degradation of the IKZF2 and IKZF4 proteins is mediated by an E3 ligase.

In another aspect, the present invention provides a method for modulating the levels of IKZF2 and IKZF4 proteins by disrupting IKZF2 and IKZF4. In some embodiments, degradation of the IKZF2 and IKZF4 proteins is mediated by an E3 ligase.

Another aspect of the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for the purpose of modulating the levels of IKZF2 and IKZF4 proteins by destroying IKZF2 and IKZF4. In some embodiments, degradation of the IKZF2 and IKZF4 proteins is mediated by an E3 ligase.

In another aspect, the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in modulating the levels of IKZF2 and IKZF4 proteins by disrupting IKZF2 and IKZF4. In some embodiments, degradation of the IKZF2 and IKZF4 proteins is mediated by an E3 ligase.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for modulating the levels of IKZF2 and IKZF4 proteins by degrading IKZF2 and IKZF4. In some embodiments, degradation of the IKZF2 and IKZF4 proteins is mediated by an E3 ligase.

Another aspect of the present invention relates to a method of treating an IKZF2-related and IKZF4-related disease or disorder in a patient in need thereof by modulating the levels of IKZF2 and IKZF4 proteins by destroying IKZF2 and IKZF4. In some embodiments, degradation of the IKZF2 and IKZF4 proteins is mediated by an E3 ligase.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for the treatment of IKZF2-related and IKZF4-related disease or disorder in a patient in need thereof by modulating the levels of IKZF2 and IKZF4 proteins through destruction of IKZF2 and IKZF4. In some embodiments, degradation of the IKZF2 and IKZF4 proteins is mediated by an E3 ligase.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of IKZF2-related and IKZF4-related disease or disorder in a patient in need thereof by modulating the levels of IKZF2 and IKZF4 proteins through destruction of IKZF2 and IKZF4. In some embodiments, degradation of the IKZF2 and IKZF4 proteins is mediated by an E3 ligase.

In another aspect, the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for the treatment of an IKZF2-related or IKZF4-related disease or disorder in a patient in need thereof by modulating levels maintenance of IKZF2 and IKZF4 proteins through destruction of IKZF2 and IKZF4. In some embodiments, degradation of the IKZF2 and IKZF4 proteins is mediated by an E3 ligase.

In another aspect, the present invention relates to a method for destroying IKZF2 and IKZF4. The method involves administering to a patient in need thereof an effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I' ) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof. In some embodiments, degradation of the IKZF2 and IKZF4 proteins is mediated by an E3 ligase.

Another aspect of the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for the purpose of destroying IKZF2 and IKZF4. In some embodiments, degradation of the IKZF2 and IKZF4 proteins is mediated by an E3 ligase.

In another aspect, the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in destroying IKZF2 and IKZF4. In some embodiments, degradation of the IKZF2 and IKZF4 proteins is mediated by an E3 ligase.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for the destruction of IKZF2 and IKZF4. In some embodiments, degradation of the IKZF2 and IKZF4 proteins is mediated by an E3 ligase.

Another aspect of the present invention relates to a method of reducing the level of proliferation of a cell, the method comprising contacting the cell with a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, and causing a reduction in the levels of IKZF2 and IKZF4 proteins. In some embodiments, the reduction in IKZF2 and IKZF4 protein levels is achieved by disrupting the IKZF2 and IKZF4 proteins. In other embodiments, the reduction in IKZF2 and IKZF4 protein levels is achieved through E3 ligase-mediated degradation of the IKZF2 and IKZF4 proteins.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, to reduce the level of cell proliferation by reducing the levels of IKZF2 and IKZF4 proteins. In some embodiments, the reduction in IKZF2 and IKZF4 protein levels is achieved by disrupting the IKZF2 and IKZF4 proteins. In other embodiments, the reduction in IKZF2 and IKZF4 protein levels is achieved through E3 ligase-mediated degradation of the IKZF2 and IKZF4 proteins.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in reducing the level of cell proliferation by reducing the levels of IKZF2 and IKZF4 proteins. In some embodiments, the reduction in IKZF2 and IKZF4 protein levels is achieved by disrupting the IKZF2 and IKZF4 proteins. In other embodiments, the reduction in IKZF2 and IKZF4 protein levels is achieved through E3 ligase-mediated degradation of the IKZF2 and IKZF4 proteins.

In another aspect, the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for reducing the level of cell proliferation by reducing the levels of IKZF2 and IKZF4 proteins. In some embodiments, the reduction in IKZF2 and IKZF4 protein levels is achieved by disrupting the IKZF2 and IKZF4 proteins. In other embodiments, the reduction in IKZF2 and IKZF4 protein levels is achieved through E3 ligase-mediated degradation of the IKZF2 and IKZF4 proteins.

In another aspect, the present invention provides a method for treating an IKZF2-related disease or disorder. The method includes the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula ( I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of an IKZF2-related disease or disorder.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof in the manufacture of a medicament for the treatment of an IKZF2-related disease or disorder .

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for the treatment of an IKZF2-related disease or disorder.

In another aspect, the present invention provides a method for treating IKZF2-related and IKZF4-related diseases or disorders. The method includes the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula ( I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of IKZF2-related and IKZF4-related diseases or disorders.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the manufacture of a medicament for the treatment of an IKZF2-related and an IKZF4-related disease or disorder.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for the treatment of an IKZF2-related and an IKZF4-related disease or disorder.

In another aspect, the present invention provides a method for reducing IKZF2 protein levels. The method involves administering to a patient in need thereof a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate thereof, a prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof.

Another aspect of the present invention relates to a method for reducing the levels of IKZF2 and IKZF4 proteins. The method involves administering to a patient in need thereof a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate thereof, a prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof.

In another aspect, the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in reducing IKZF2 protein levels.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in reducing the levels of IKZF2 and IKZF4 proteins.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof or composition in the manufacture of a medicament for reducing levels of IKZF2 protein .

Another aspect of the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the manufacture of a medicament for reducing the levels of IKZF2 and IKZF4 proteins.

In another aspect, the present invention provides a method for reducing IKZF2 protein levels, wherein reducing IKZF2 protein levels treats or reduces the severity of a disease or disorder. The method involves administering to a patient in need thereof a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate thereof, a prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof.

Another aspect of the present invention relates to a method of reducing the levels of IKZF2 and IKZF4 proteins, wherein reducing the levels of IKZF2 and IKZF4 proteins provides treatment or reduction in the severity of a disease or disorder. The method involves administering to a patient in need thereof a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate thereof, a prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof.

In another aspect, the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in reducing IKZF2 protein levels, wherein reducing IKZF2 protein levels treats or reduces the severity of a disease or disorder.

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in reducing the levels of IKZF2 and IKZF4 proteins, wherein reducing the levels of IKZF2 and IKZF4 proteins provides treatment or reduction in the severity of a disease or disorder.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof or composition in the manufacture of a medicament for reducing levels of IKZF2 protein , wherein reducing the levels of IKZF2 protein provides treatment or reduction in the severity of the disease or disorder.

Another aspect of the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the manufacture of a medicament for reducing the levels of IKZF2 and IKZF4 proteins, wherein reducing the levels of IKZF2 and IKZF4 proteins provides treatment or reduction in the severity of the disease or violations.

In another aspect, the present invention provides a method of treating a disease or disorder by reducing IKZF2 protein levels, wherein reducing IKZF2 protein levels treats or reduces the severity of the disease or disorder. The method involves administering to a patient in need thereof a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate thereof, a prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof.

Another aspect of the present invention relates to a method of treating a disease or disorder by reducing the levels of IKZF2 and IKZF4 proteins, wherein reducing the levels of IKZF2 and IKZF4 proteins treats or reduces the severity of the disease or disorder. The method involves administering to a patient in need thereof a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate thereof, a prodrug thereof, a stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof.

In another aspect, the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in treating a disease or disorder by reducing levels of IKZF2 protein, wherein reducing levels of IKZF2 protein provides treatment or reduction in severity of the disease or disorder .

Another aspect of the present invention relates to a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula (I ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for use in the treatment of a disease or disorder by reducing the levels of the IKZF2 and IKZF4 proteins, wherein the reduction of the levels of the IKZF2 and IKZF4 proteins provides treatment or reduction in severity diseases or disorders.

In another aspect, the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof or composition in the manufacture of a medicament for treating a disease or disorder by reducing the levels of IKZF2 protein, wherein reducing the levels of IKZF2 protein provides treatment or reduction in the severity of the disease or disorder.

Another aspect of the present invention relates to the use of a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, or a composition containing a compound of formula (I') or formula ( I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder by reducing the levels of IKZF2 and IKZF4 proteins, wherein reducing the levels of IKZF2 and IKZF4 proteins provides the treatment or reducing the severity of a disease or disorder.

The compounds of the present invention can be used to treat cancers including, but not limited to, liposarcoma, neuroblastoma, glioblastoma, bladder cancer, adrenal cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, human papillomavirus-associated cervical cancer, oropharyngeal cancer, cancer penis, anal canal, thyroid or vagina or Epshetain-Barr virus-associated nasopharyngeal carcinoma, stomach cancer, rectal cancer, thyroid cancer, Hodgkin's lymphoma or diffuse large B-cell lymphoma, prostate cancer, breast carcinoma, lymphomas , leukemia, myeloma, bladder carcinoma, colon cancer, skin melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer , tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, types of rhabdoid cancer, cancer for which the immune response is insufficient, cancer with immunogenic properties, sarcoma Ewing, non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia and gastrointestinal stromal tumor (GIST) .

In some embodiments of the methods above, the IKZF2-related disease or disorder is a disease or disorder including, but not limited to, liposarcoma, neuroblastoma, glioblastoma, bladder cancer, adrenal cancer, multiple myeloma, colorectal cancer, virus-associated non-small cell lung cancer human papillomas cervical cancer, oropharyngeal cancer, penile, anal, thyroid or vaginal cancer or Epshetain-Barr virus-associated nasopharyngeal carcinoma, stomach cancer, rectal cancer, thyroid cancer, Hodgkin's lymphoma or diffuse large B-cell lymphoma , prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, skin melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer and soft tissue sarcoma selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, types of rhabdoid cancer, cancer, immune response deficient, immunogenic cancer, Ewing's sarcoma, non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia and gastrointestinal stromal tumor (GIST).

In some embodiments of the methods set forth above, the disease or disorder affected by the modulation, reduction, or reduction of IKZF2 and/or IKZF4 protein levels is a disease or disorder, including, but not limited to, liposarcoma, neuroblastoma, glioblastoma, bladder cancer, cancer adrenal gland, multiple myeloma, colorectal cancer, non-small cell lung cancer, human papillomavirus-associated cervical cancer, oropharyngeal cancer, penile, anal, thyroid or vaginal cancer or Epshetain-Barr virus-associated nasopharyngeal carcinoma, stomach cancer, rectal cancer colon, thyroid cancer, Hodgkin's lymphoma or diffuse large B-cell lymphoma, prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer and soft tissue sarcoma selected from rhabdomyosarcoma (RMS ), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancers for which the immune response is insufficient, cancers with immunogenic properties, Ewing's sarcoma, non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), colorectal microsatellite stable cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia and gastrointestinal stromal tumor (GIST).

In some embodiments of the methods above, the IKZF2-related cancer and the IKZF2-related and IKZF4-related cancer are cancers selected from liposarcoma, neuroblastoma, glioblastoma, bladder cancer, adrenal cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer , human papillomavirus-associated cervical cancer, oropharyngeal cancer, penile, anal, thyroid or vaginal cancer or Epshetain-Barr virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma or diffuse large cell B-cell lymphoma, prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, skin melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, multiforme glioblastoma, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer and soft tissue sarcoma selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, types of rhabdoid cancer, cancers for which the immune response is insufficient, cancers with immunogenic properties, Ewing's sarcoma, non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid , acute myelogenous leukemia and gastrointestinal stromal tumor (GIST).

In some embodiments of the above methods, IKZF2 protein levels are modulated by disrupting IKZF2. In some embodiments of the above methods, IKZF2 protein levels are reduced by disrupting IKZF2. In some embodiments of the above methods, IKZF2 protein levels are reduced by disrupting IKZF2.

In some embodiments of the above methods, the levels of IKZF2 and IKZF4 proteins are modulated by disrupting IKZF2 and IKZF4. In some embodiments of the above methods, the levels of IKZF2 and IKZF4 proteins are reduced by disrupting IKZF2 and IKZF4. In some embodiments of the above methods, IKZF2 protein levels are reduced by disrupting IKZF2 and IKZF4.

One therapeutic use of the compounds or compositions of the present invention that modulate IKZF2 and/or IKZF4 protein levels by degrading IKZF2 and/or IKZF4 is to provide treatment to patients or subjects suffering from cancer and metastasis.

The disclosed compounds of the present invention can be administered in effective amounts to treat or prevent a disorder and/or prevent its development in subjects.

The compounds of the present invention can be administered in therapeutically effective amounts in combination therapy with one or more therapeutic agents (pharmaceutical combinations) or treatments, for example, non-drug therapies. For example, synergistic effects may occur with other antiproliferative, anticancer, immunomodulatory, or anti-inflammatory agents. If the compounds of the present invention are administered in combination with other therapies, the dosages of the co-administered compounds will, of course, vary depending on the type of additional drug used, the specific drug used, the condition being treated, etc.

Combination therapy involves administering the subject compounds in additional combination with other biologically active ingredients (such as, without limitation, a second and other anticancer agent or a second agent that targets Helios or another oncologic target) and non-drug therapies (such as, without limitation, surgery or radiation therapy). For example, the compounds of the present invention can be used in combination with other pharmaceutically active compounds, preferably compounds that are capable of enhancing the effects of the compounds of the present invention. The compounds of the present invention may be administered simultaneously (as a single formulation or as a separate formulation) or sequentially with another drug therapy or treatment method. Typically, combination therapy involves the administration of two or more drugs during one cycle or course of therapy.

G. Routes of Administration, Pharmaceutical Compositions and Dosage of Compounds of Formula (I') or Formula (I)

Administration of the disclosed compounds can be accomplished by any route of administration of therapeutic agents. These methods include systemic or local administration, such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration.

Depending on the intended route of administration, the disclosed compositions may be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, sustained release capsules, elixirs, tinctures, emulsions, syrups. powders, liquids, suspensions or the like, sometimes in unit doses and in accordance with normal pharmaceutical practice. Likewise, they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular forms, and in all useful forms well known to those skilled in the pharmaceutical arts.

Exemplary pharmaceutical compositions are tablets and gelatin capsules containing a compound of this invention and a pharmaceutically acceptable carrier, such as a) a diluent, for example purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium saccharin, glucose and/or glycine; b) a lubricant, for example silicon dioxide, talc, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene glycol; for tablets also; c) a binder, for example magnesium aluminosilicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) disintegrant, for example starches, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt or effervescent mixtures; f) absorbent, colorant, flavoring and sweetener; f) an emulsifier or dispersant such as Tween 80, Labrasol, HPMC, DOSS, Caproyl 909, Labrafac, Labrafil, Peceol, Transcutol, Capmul MCM, Capmul PG-12, Captex 355, Gelucire, Vitamin E TGPS or other suitable emulsifier; and/or g) an agent that enhances the absorption of the compound, such as cyclodextrin, hydroxypropylcyclodextrin, PEG400, PEG200.

Liquid compositions, especially injection compositions, can, for example, be prepared by dissolving, dispersing, etc. For example, the disclosed compound is dissolved or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, etc., thereby forming an isotonic solution or suspension for injection. Proteins such as albumin, chylomicron particles or whey proteins can be used to solubilize the disclosed compounds.

The disclosed compounds can also be formulated as a suppository, which can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol as a carrier.

The disclosed compounds can also be administered in the form of liposomal delivery systems, such as small monolamellar vesicles, large monolamellar vesicles and multilamellar vesicles. Liposomes can be formed from various phospholipids containing cholesterol, stearylamine or phosphatidylcholines.

In some embodiments, the film of lipid components is hydrated with an aqueous solution of the drug to form a lipid layer encapsulating the drug, as described in US Pat. No. 5,262,564, which is incorporated herein by reference in its entirety.

The disclosed compounds can also be delivered using monoclonal antibodies as individual carriers to which the disclosed compounds are bound. The disclosed compounds can also be associated with soluble polymers as targeted drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide phenol, polyhydroxyethyl aspanamide phenol, or polyethylene oxide polylysine substituted with palmitoyl moieties. In addition, the disclosed compounds can be combined with biodegradable polymers that are used to achieve controlled drug release, such as polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymer hydrogels. In one embodiment, the disclosed compounds are not covalently bonded to a polymer, such as a polycarboxylic acid polymer or a polyacrylate.

Parenteral injection is typically used for subcutaneous, intramuscular, or intravenous injections and infusions. Injectable preparations can be prepared in conventional forms, either as liquid solutions or suspensions, or in solid forms suitable for dissolution in liquid before injection.

Another aspect of the present invention relates to pharmaceutical compositions containing a compound of formula (I') or formula (I) and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further include an excipient, diluent or surfactant.

The compositions can be prepared according to conventional mixing, granulating or coating methods, as appropriate, and the pharmaceutical compositions of the present invention can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compound by weight or volume.

In one embodiment, the present invention provides a kit containing two or more separate pharmaceutical compositions, at least one of which contains a compound of the present invention. In one embodiment, the kit contains means for separately containing the specified compositions, such as a container, a divided bottle or a divided foil pouch. An example of such a set is blister packaging, usually used for packaging tablets, capsules, etc.

The kit of the present invention can be used to administer different dosage forms, for example, for oral and parenteral use, to administer individual compositions at different dosage intervals, or to titrate individual compositions against each other. To promote compliance with a treatment regimen, the kit of the present invention typically contains instructions for administration.

The dosage regimen using the disclosed compound is selected according to various factors, including the type, species, age, weight, sex and health status of the patient; the severity of the condition being treated; route of administration; the renal or hepatic function of the patient and the specific disclosed compound used. The treating physician or veterinarian can easily determine and prescribe the effective amount of drug needed to prevent, counteract, or halt the progression of the condition.

Effective dosage amounts of the disclosed compounds, when used to obtain the indicated effects, range from about 0.5 mg to about 5000 mg of the disclosed compound as needed to treat the condition. Compositions for in vivo or in vitro use may contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500 or 5000 mg of the disclosed compound, or in the range of one quantities to another quantity in the list of doses. In one embodiment, the compositions are in the form of a tablet that can be divisible.

H. Combination therapy

The compounds of the present invention can be administered in therapeutically effective amounts in combination therapy with one or more therapeutic agents (pharmaceutical combinations) or methods, such as non-drug therapies. For example, synergistic effects may occur with other anticancer agents. If the compounds of the present invention are administered in combination with other therapies, the dosages of the co-administered compounds will, of course, vary depending on the type of additional drug used, the specific drug used, the condition being treated, etc.

The compounds can be administered simultaneously (as a single drug or separate drugs), sequentially, separately, or over a period of time with another drug therapy or treatment. Typically, combination therapy involves the administration of two or more drugs during one cycle or course of therapy. A therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment or nucleic acid that is therapeutically active or enhances therapeutic activity when administered to a patient in combination with a compound of the present invention.

In one aspect, a compound of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof of the present invention can be combined with other therapeutic agents, such as other anti-cancer agents, antiallergic agents, antinausea agents (or antiemetics), analgesics, cytoprotective agents and combinations thereof.

In some embodiments, compounds of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof of the present invention are administered in combination with one or more other agents selected from an inhibitor PD-1, PD-L1 inhibitor, LAG-3 inhibitor, cytokine, A2A antagonist, GITR agonist, TIM-3 inhibitor, STING agonist and TLR7 agonist, for treating a disease, such as cancer.

In another embodiment, one or more chemotherapeutic agents are used in combination with compounds of formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs thereof, stereoisomers or tautomers thereof, for the treatment of a disease, such as cancer, wherein said chemotherapeutic agents include, but are not limited to, anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl- 5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine -arabinoside (Cytosar-U®), liposomal cytarabine injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), liposomal daunorubicin citrate injection (DaunoXome®) , dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibin , gemcitabine (difluorodeoxycytidine), hydroxyurea (Hydrea®), idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol®), Phoenix (yttrium-90/MX-DTPA), pentostatin, polypheprozan 20 with carmustine for implantation (Gliadel®), citrate tamoxifen (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), vinorelbine (Navelbine®) , epirubicin (Ellence®), oxaliplatin (Eloxatin®), exemestane (Aromasin®), letrozole (Femara®), and fulvestrant (Faslodex®).

In other embodiments, the compounds of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof of the present invention are used in combination with one or more other anti-HER2 antibodies, e.g. , trastuzumab, pertuzumab, margetuximab or HT-19 described above, or other anti-HER2 antibody conjugates such as ado-trastuzumab-emtansine (also known as Kadcyla® or T-DM1).

In other embodiments, the compounds of formula (I') or formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer, or tautomer thereof, of the present invention are used in combination with one or more tyrosine kinase inhibitors, including but not limited to EGFR, Her3 inhibitors, IGFR inhibitors and Met inhibitors, for the treatment of a disease, such as cancer.

For example, tyrosine kinase inhibitors include, but are not limited to, erlotinib hydrochloride (Tarceva®); linifanib (N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea, also known as ABT 869, available from Genentech); sunitinib malate (Sutent®); bosutinib (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-3-carbonitrile, also known as SKI- 606 and described in US Pat. No. 6,780,996); dasatinib (Sprycel®); pazopanib (Votrient®); sorafenib (Nexavar®); zaktim (ZD6474) and imatinib or imatinib mesylate (Gilvec® and Gleevec®).

Epidermal growth factor receptor (EGFR) inhibitors include, but are not limited to, erlotinib hydrochloride (Tarceva®), gefitinib (Iressa®); N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3''S'')-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)- 2-butenamide, Tovok®); vandetanib (Caprelsa®); lapatinib (Tykerb®); (3R,4R)-4-amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-3 -ol (BMS690514); canertinib dihydrochloride (CI-1033); 6-[4-[(4-ethyl-1-piperazinyl)methyl]phenyl]-N-[(1R)-1-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (AEE788, CAS 497839-62-0); mubritinib (TAK165); pelitinib (EKB569); afatinib (Gilotrif®); neratinib (HKI-272); N-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6- yl]-carbamic acid, (3S)-3-morpholinyl methyl ester (BMS599626); N-(3,4-dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aα,5β,6aα)-octahydro-2-methylcyclopenta[c]pyrrol-5-yl]methoxy]-4-quinazolinamine (XL647, CAS 781613-23-8) and 4-[4-[[(1R)-1-phenylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol (PKI166, CAS 187724-61-4).

Antibodies to EGFR include, but are not limited to, cetuximab (Erbitux®); panitumumab (Vectibix®); matuzumab (EMD-72000); nimotuzumab (hR3); zalutumumab; TheraCIM h-R3; MDX0447 (CAS 339151-96-1) and ch806 (mAb-806, CAS 946414-09-1).

Other HER2 inhibitors include, but are not limited to, neratinib (HKI-272, (2E)-N-[4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7- ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide and described in PCT publication No. WO 05/028443); lapatinib or lapatinib ditosylate (Tykerb®); (3R,4R)-4-amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-3 -ol (BMS690514); (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)- 2-butenamide (BIBW-2992, CAS 850140-72-6); N-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6- yl]-carbamic acid, (3S)-3-morpholinyl methyl ester (BMS 599626, CAS 714971-09-2); canertinib dihydrochloride (PD183805 or CI-1033) and N-(3,4-dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aα,5β,6aα)-octahydro-2-methylcyclopenta[c]pyrrol- 5-yl]methoxy]-4-quinazolinamine (XL647, CAS 781613-23-8).

HER3 inhibitors include, but are not limited to, LJM716, MM-121, AMG-888, RG7116, REGN-1400, AV-203, MP-RM-1, MM-111, and MEHD-7945A.

MET inhibitors include, but are not limited to, cabozatinib (XL184, CAS 849217-68-1); foretinib (GSK1363089, formerly XL880, CAS 849217-64-7); tivantinib (ARQ197, CAS 1000873-98-2); 1-(2-hydroxy-2-methylpropyl) -N- (5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro -1 H -pyrazole-4-carboxamide (AMG 458); crizotinib (Xalkori®, PF-02341066); (3Z)-5-(2,3-dihydro-1H-indol-1-ylsulfonyl)-3-({3,5-dimethyl-4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrole -2-yl}methylene)-1,3-dihydro-2H-indol-2-one (SU11271); (3Z)-N-(3-chlorophenyl)-3-({3,5-dimethyl-4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrol-2-yl}methylene)-N- methyl 2-oxoindoline-5-sulfonamide (SU11274); (3Z)-N-(3-chlorophenyl)-3-{[3,5-dimethyl-4-(3-morpholin-4-ylpropyl)-1H-pyrrol-2-yl]methylene}-N-methyl-2 -oxoindoline-5-sulfonamide (SU11606); 6-[difluoro[6-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazolo[4,3-b]pyridazin-3-yl]methyl]-quinoline (JNJ38877605, CAS 943540 -75-8); 2-[4-[1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl]-1H-pyrazol-1-yl]ethanol ( PF04217903, CAS 956905-27-4); N-((2R)-1,4-dioxan-2-ylmethyl)-N-methyl-N'-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[ 4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide (MK2461, CAS 917879-39-1); 6-[[6-(1-Methyl- 1H -pyrazol-4-yl)-1,2,4-triazolo[4,3- b ]pyridazin-3-yl]thio]-quinoline (SGX523, CAS 1022150 -57-7) and (3 Z )-5-[[(2,6-dichlorophenyl)methyl]sulfonyl]-3-[[3,5-dimethyl-4-[[(2 R )-2-(1 -pyrrolidinylmethyl)-1-pyrrolidinyl]carbonyl] -1H- pyrrol-2-yl]methylene]-1,3-dihydro- 2H- indol-2-one (PHA665752, CAS 477575-56-7).

IGFR inhibitors include, but are not limited to, BMS-754807, XL-228, OSI-906, GSK0904529A, A-928605, AXL1717, KW-2450, MK0646, AMG479, IMCA12, MEDI-573, and BI836845. For an overview see e.g. in Yee, JNCI, 104; 975 (2012).

In another embodiment, the compounds of formula (I') or formula (I) of the present invention are used in combination with one or more inhibitors of the proliferation-related signal transduction pathway, including, without limitation, MEK inhibitors, BRAF inhibitors, PI3K/Akt inhibitors, SHP2 inhibitors , as well as mTOR inhibitors and CDK inhibitors for the treatment of a disease such as cancer.

For example, mitogen-activated protein kinase (MEK) inhibitors include, but are not limited to, XL-518 (also known as GDC-0973, CAS No. 1029872-29-4, available from ACC Corp.); 2-[(2-chloro-4-iodophenyl)amino]-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (also known as CI-1040 or PD184352 and described in PCT Publication No. WO2000035436); N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzamide (also known as PD0325901 and described in PCT Publication No. WO2002006213); 2,3-bis[amino[(2-aminophenyl)thio]methylene]butane dinitrile (also known as U0126 and described in US Pat. No. 2,779,780); N-[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl]-1-[(2R)-2,3-dihydroxypropyl]cyclopropanesulfonamide (also known as RDEA119 or BAY869766 and described in publication according to PCT No. WO2007014011); (3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine- 1,7(8H)-dione] (also known as E6201 and described in PCT Publication No. WO2003076424); 2'-amino-3'-methoxyflavone (also known as PD98059, available from Biaffin GmbH & Co., KG, Germany); vemurafenib (PLX-4032, CAS 918504-65-1); (R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H) -dione (TAK-733, CAS 1035555-63-5); pimasertib (AS-703026, CAS 1204531-26-9) and trametinib dimethyl sulfoxide (GSK-1120212, CAS 1204531-25-80).

BRAF inhibitors include, but are not limited to, vemurafenib (or Zelboraf®), GDC-0879, PLX-4720 (available from Symansis), dabrafenib (or GSK2118436), LGX 818, CEP-32496, UI-152, RAF 265, regorafenib (BAY 73- 4506), CCT239065 or sorafenib (or sorafenib tosylate, or Nexavar®), or ipilimumab (or MDX-010, MDX-101, or Yervoy).

Phosphoinositide 3-kinase (PI3K) inhibitors include, but are not limited to, 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2- d]pyrimidin-4-yl]morpholine (also known as GDC0941, RG7321, GNE0941, pictrelisib or pictilisib and described in PCT Publications Nos. WO 09/036082 and WO 09/055730); tosasertib (VX680 or MK-0457, CAS 639089-54-6); (5Z)-5-[[4-(4-pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidinedione (GSK1059615, CAS 958852-01-2); (1E,4S,4aR,5R,6aS,9aR)-5-(acetyloxy)-1-[(di-2-propenylamino)methylene]-4,4a,5,6,6a,8,9,9a-octahydro -11-hydroxy-4-(methoxymethyl)-4a,6a-dimethylcyclopenta[5,6]naphtho[1,2-c]pyran-2,7,10(1H)-trione (PX866, CAS 502632-66-8 ); 8-phenyl-2-(morpholin-4-yl)-chromen-4-one (LY294002, CAS 154447-36-6); (S)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidin-1,2 -dicarboxamide (also known as BYL719 or alpelisib); 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1 ,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide (also known as GDC0032, RG7604 or tazelisib).

mTOR inhibitors include, but are not limited to, temsirolimus (Torisel®); ridaforolimus (formerly known as deferolimus, (1 R ,2 R ,4 S )-4-[(2 R )-2 [(1 R ,9 S ,12 S ,15 R ,16 E ,18 R ,19 R , 21 R ,23 S ,24 E ,26 E ,28 Z ,30 S ,32 S ,35 R )-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl -2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2- methoxycyclohexyldimethylphosphinate, also known as AP23573 and MK8669 and described in PCT publication No. WO 03/064383); everolimus (Afinitor® or RAD001); rapamycin (AY22989, Sirolimus®); simapimod (CAS 164301-51-3); (5-{2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol (AZD8055); 2-amino-8-[ trans -4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxy-3-pyridinyl)-4-methylpyrido[2,3- d ]pyrimidin-7( 8H )-one (PF04691502, CAS 1013101-36-4) and N ² -[1,4-dioxo-4-[[4-(4-oxo-8-phenyl-4H- 1 -benzopyran-2-yl)morpholinium-4 -yl]methoxy]butyl]-L-arginylglycyl-L-α-aspartyl-L-serine-, internal salt (SF1126, CAS 936487-67-1).

CDK inhibitors include, but are not limited to, palbociclib (also known as PD-0332991, Ibrance®, 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(1-piperazinyl)-2-pyridinyl]amino}pyrido[2 ,3-d]pyrimidin-7( 8H )-one).

In yet another embodiment, the compounds of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof of the present invention are used in combination with one or more proapoptotic agents including: restrictions IAP inhibitors, BCL2 inhibitors, MCL1 inhibitors, TRAIL-based agents, CHK inhibitors, for the treatment of a disease such as cancer.

For example, IAP inhibitors include, but are not limited to, LCL161, GDC-0917, AEG-35156, AT406, and TL32711. Other examples of IAP inhibitors include, but are not limited to, those disclosed in WO04/005284, WO 04/007529, WO05/097791, WO 05/069894, WO 05/069888, WO 05/094818, US2006/0014700, US2006/0025347, WO 06/06 9063, WO 06/010118, WO 06/017295 and WO08/134679, all of which are incorporated herein by reference.

BCL-2 inhibitors include, but are not limited to, 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[[4- [[(1R)-3-(4-morpholinyl)-1-[(phenylthio)methyl]propyl]amino]-3-[(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide (also known as ABT-263 and described in publications according to PCT No. WO 09/155386); tetrocarcin A; antimycin; gossypol ((-)BL-193); obatoclax; ethyl 2-amino-6-cyclopentyl-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromone-3-carboxylate (HA14-1); oblimersen (G3139, Genasense®); Bak BH3 peptide; (-)-gossypoacetic acid (AT-101); 4-[4-[(4'-chloro[1,1'-biphenyl]-2-yl)methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(dimethylamino)- 1-[(phenylthio)methyl]propyl]amino]-3-nitrophenyl]sulfonyl]-benzamide (ABT-737, CAS 852808-04-9) and navitoclax (ABT-263, CAS 923564-51-6).

Proapoptotic receptor agonists (PARA), including DR4 (TRAILR1) and DR5 (TRAILR2), include, but are not limited to, dulanermine (AMG-951, RhApo2L/TRAIL); mapatumumab (HRS-ETR1, CAS 658052-09-6); lexatumumab (HGS-ETR2, CAS 845816-02-6); Apomab®; conatumumab (AMG655, CAS 896731-82-1) and tigatuzumab (CS1008, CAS 946415-34-5, available from Daiichi Sankyo).

Checkpoint kinase (CHK) inhibitors include, but are not limited to, 7-hydroxystaurosporine (UCN-01); 6-bromo-3-(1-methyl- 1H -pyrazol-4-yl)-5-( 3R )-3-piperidinylpyrazolo[1,5- a ]pyrimidin-7-amine (SCH900776, CAS 891494-63 -6); 5-(3-fluorophenyl)-3-ureidothiophen-2-carboxylic acid N-[(S)-piperidin-3-yl]amide (AZD7762, CAS 860352-01-8); 4-[((3S)-1-azabicyclo[2.2.2]oct-3-yl)amino]-3-(1H-benzimidazol-2-yl)-6-chloroquinolin-2(1H)-one (CHIR 124 , CAS 405168-58-3); 7-aminodactinomycin (7-AAD), isogranultimide, debromohymenialdizine; N-[5-bromo-4-methyl-2-[(2S)-2-morpholinylmethoxy]phenyl]-N'-(5-methyl-2-pyrazinyl)urea (LY2603618, CAS 911222-45-2); sulforaphane (CAS 4478-93-7, 4-methylsulfinylbutyl isothiocyanate); 9,10,11,12-tetrahydro-9,12-epoxy-1 H -diindolo[1,2,3- fg :3',2',1'- kl ]pyrrolo[3,4- i ][1 ,6]benzodiazocine-1,3( 2H )-dione (SB-218078, CAS 135897-06-2), and TAT-S216A (YGRKKRRQRRRLYRSPAMPENL (SEQ ID NO: 33)), and CBP501 ((d-Bpa) sws(d-Phe-F5)(d-Cha)rrrqrr).

In a further embodiment, the compounds of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof of the present invention are used in combination with one or more immunomodulators (e.g. one or more costimulatory molecule activators or immune checkpoint molecule inhibitor) for treating a disease, such as cancer.

In certain embodiments, the immunomodulator is an activator of a costimulatory molecule. In one embodiment, the costimulatory molecule agonist is selected from an agonist (e.g. agonist antibody or antigen binding fragment thereof, or soluble form of fusion protein) OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand.

GITR agonists

In some embodiments, a GITR agonist is used in combination with a compound of formula (I') or formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for the treatment of a disease, such as cancer. In some embodiments, the GITR agonist is GWN323 (Novartis), BMS-986156, MK-4166 or MK-1248 (Merck), TRX518 (Leap Therapeutics), INCAGN1876 (Incyte/Agenus), AMG 228 (Amgen), or INBRX-110 (Inhibrx).

Exemplary GITR agonists

In one embodiment, the GITR agonist is an anti-GITR antibody molecule. In one embodiment, the GITR agonist is an anti-GITR antibody molecule described in WO 2016/057846, published April 14, 2016 entitled "Compositions and Methods of Use for Augmented Immune Response and Cancer Therapy", incorporated by reference in its entirety .

In one embodiment, an anti-GITR antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all CDRs) of a heavy and light chain variable region comprising the amino acid sequence shown in Table 1 (e.g., from the MAB7 heavy and light chain variable region sequences disclosed in Table 1), or the encoded nucleotide sequence shown in Table 1. In some embodiments, the CDRs are as defined by Kabat (e.g., as set forth in Table 1 ). In some embodiments, the CDRs are specified as defined by Chothia (eg, as set forth in Table 1). In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, compared to the amino acid sequence , shown in Table 1 or encoded by the nucleotide sequence shown in Table 1.

In one embodiment, an anti-GITR antibody molecule comprises a heavy chain variable region (VH) comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 9, the amino acid sequence of VHCDR2 of SEQ ID NO: 11, and the amino acid sequence of VHCDR3 of SEQ ID NO: 13; and a light chain variable region (VL) comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 16, and the amino acid sequence of VLCDR3 of SEQ ID NO: 18, each of which is disclosed in Table 1.

In one embodiment, the anti-GITR antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence that is at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 1 In one embodiment, the anti-GITR antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence that is at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 2. In one embodiment, the anti-GITR antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 1 and a VL containing the amino acid sequence of SEQ ID NO: 2.

In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 5 or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 5. B In one embodiment, the antibody molecule comprises a VL encoded by a nucleotide sequence of SEQ ID NO: 6 or a nucleotide sequence that is at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 6. In one In an embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 5, and a VL encoded by the nucleotide sequence of SEQ ID NO: 6.

In one embodiment, the anti-GITR antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence that is at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 3. In one embodiment, the anti-GITR antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence that is at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 4. In one embodiment, the anti-GITR antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 3 and a light chain comprising the amino acid sequence of SEQ ID NO: 4.

In one embodiment, the antibody molecule contains a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 7 or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 7. In one embodiment, the antibody molecule contains a light chain encoded by the nucleotide sequence of SEQ ID NO: 8 or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 8. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 7 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 8.

The antibody molecules described herein can be produced using the vectors, host cells and methods described in WO 2016/057846, incorporated by reference in its entirety.

Table 1. Amino acid and nucleotide sequences of an exemplary anti-GITR antibody molecule MAB7 SEQ ID NO: 1 VH EVQLVESGGGLVQSGGSLRLSCAASGFSLSSYGVDWVRQAPGKGLEWVGVIWGGGGTYYASSLMGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHAYGHDGGFAMDYWGQGTLVTVSS SEQ ID NO: 2 VL EIVMTQSPATLSVSPGERATLLSCRASESVSSNVAWYQQRPGQAPRLLIYGASNRATGIPARFSGSGSGTDFTLTISRLEPEDFAVYYCGQSYSYPFTFGQGTKLEIK SEQ ID NO: 3 Heavy chain EVQLVESGGGLVQSGGSLRLSCAASGFSLSSYGVDWVRQAPGKGLEWVGVIWGGGGTYYASSLMGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHAYGHDGGFAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 4 Light chain EIVMTQSPATLSVSPGERATLSCRASESVSSNVAWYQQRPGQAPRLLIYGASNRATGIPARFSGSGSGTDFTLTISRLEPEDFAVYYCGQSYSYPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG LSSPVTKSFNRGEC SEQ ID NO: 5 DNA encoding VH GAGGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTGCAGTCCGGCGGCTCTCTGAGACTGTCTTGCGCTGCCTCCGGCTTCTCCCTGTCCTCTTACGGCGTGGACTGGGTGCGACAGGCCCCTGGCAAGGGCCTGGAATGGGTGGGAGTGATCTGGGGCGGAGGCGGCACCTACTACGCCTCTTCCCTGATGGGCCGGTTCACCATCTCCCGGGACAACTCCAAGAACACCCTGTACCTG CAGATGAACTCCCTGCGGGCCGAGGACACCGCCGTGTACTACTGCGCCAGACACGCCTACGGCCACGACGGCGGCTTCGCCATGGATTATTGGGGCCAGGGCACCCTGGTGACAGTGTCCTCC SEQ ID NO: 6 DNA encoding VL GAGATCGTGATGACCCAGTCCCCCGCCACCCTGTCTGTGTCTCCCGGCGAGAGCCACCCTGAGCTGCAGAGCCTCCGAGTCCGTGTCCTCCAACGTGGCCTGGTATCAGCAGAGACCTGGTCAGGCCCCTCGGCTGCTGATCTACGGCGCCTCTAACCGGGCCACCGGCATCCCTGCCAGATTCTCCGGCTCCGGCAGCGGCACCGACTTCACCCTGACCATCTCCCGGCTGGAACCCGAGGACT TCGCCGTGTACTACTGCGGCCAGTCCTACTCATACCCCTTCACCTTCGGCCAGGGCACAAGCTGGAAATCAAG SEQ ID NO: 7 DNA encoding the heavy chain GAGGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTGCAGTCCGGCGGCTCTCTGAGACTGTCTTGCGCTGCCTCCGGCTTCTCCCTGTCCTCTTACGGCGTGGACTGGGTGCGACAGGCCCCTGGCAAGGGCCTGGAATGGGTGGGAGTGATCTGGGGCGGAGGCGGCACCTACTACGCCTCTTCCCTGATGGGCCGGTTCACCATCTCCCGGGACAACTCCAAGAACACCCTGTACCTG CAGATGAACTCCCTGCGGGCCGAGGACACCGCCGTGTACTACTGCGCCAGACACGCCTACGGCCACGACGGCGGCTTCGCCATGGATTATTGGGGCCAGGGCACCCTGGTGACAGTGTCCTCCGCTAGCACCAAGGGCCCAAGTGTGTTTCCCCTGGCCCCCAGCAGCAAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAAGGACTACTTCCCCGAGCCCGTGACAGTGTCCTGGAACTCT GGGGCTCTGACTTCCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACCTATATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAGCTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTG TTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGTCCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAATACAAGTGCAAAG TCTCCAACAAGGCCCTGCCAGCCCCAATCGAAAAGACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCAGCGATATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTT CCTGTACAGCAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCGGCAAG SEQ ID NO: 8 DNA encoding the light chain GAGATCGTGATGACCCAGTCCCCCGCCACCCTGTCTGTGTCTCCCGGCGAGAGCCACCCTGAGCTGCAGAGCCTCCGAGTCCGTGTCCTCCAACGTGGCCTGGTATCAGCAGAGACCTGGTCAGGCCCCTCGGCTGCTGATCTACGGCGCCTCTAACCGGGCCACCGGCATCCCTGCCAGATTCTCCGGCTCCGGCAGCGGCACCGACTTCACCCTGACCATCTCCCGGCTGGAACCCGAGGACT TCGCCGTGTACTACTGCGGCCAGTCCTACTCATACCCCTTCACCTTCGGCCAGGGCACAAGCTGGAAATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCG AGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC SEQ ID NO: 9 (KABAT) HCDR1 SYGVD SEQ ID NO: 10 (CHOTHIA) HCDR1 GFSLSSY SEQ ID NO: 11 (KABAT) HCDR2 VIWGGGGTYYASSLMG SEQ ID NO: 12 (CHOTHIA) HCDR2 WGGGG SEQ ID NO: 13 (KABAT) HCDR3 HAYGHDGGFAMDY SEQ ID NO: 13 (CHOTHIA) HCDR3 HAYGHDGGFAMDY SEQ ID NO: 14 (KABAT) LCDR1 RASESVSSNVA SEQ ID NO: 15 (CHOTHIA) LCDR1 SESVSSN SEQ ID NO: 16 (KABAT) LCDR2 GASNRAT SEQ ID NO: 17 (CHOTHIA) LCDR2 G.A.S. SEQ ID NO: 18 (KABAT) LCDR3 GQSYSYPFT SEQ ID NO: 19 (CHOTHIA) LCDR3 SYSYPF

Other illustrative GITR agonists

In one embodiment, the anti-GITR antibody molecule is BMS-986156 (Bristol-Myers Squibb), also known as BMS 986156 or BMS986156. BMS-986156 and other anti-GITR antibodies are disclosed, e.g. in US 9228016 and WO 2016/196792, incorporated by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a BMS-986156 heavy chain or light chain sequence, e.g. disclosed in table 2.

In one embodiment, the anti-GITR antibody molecule is MK-4166 or MK-1248 (Merck). MK-4166, MK-1248 and other anti-GITR antibodies disclosed for example in US 8709424, WO 2011/028683, WO 2015/026684 and Mahneet al. Cancer Res. 2017; 77(5):1108-1118, incorporated by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a MK-4166 or MK-1248 heavy chain or light chain sequence.

In one embodiment, the anti-GITR antibody molecule is TRX518 (Leap Therapeutics). TRX518 and other anti-GITR antibodies have been disclosed, e.g. in US 7812135, US 8388967, US 9028823, WO 2006/105021 and Ponte Jet al. (2010)Clinical Immunology; 135:S96, incorporated by reference in its entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a TRX518 heavy chain or light chain sequence.

In one embodiment, the anti-GITR antibody molecule is INCAGN1876 (Incyte/Agenus). INCAGN1876 and other anti-GITR antibodies are disclosed, e.g. in US 2015/0368349 and WO 2015/184099, incorporated by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or an INCAGN1876 heavy chain or light chain sequence.

In one embodiment, the anti-GITR antibody molecule is AMG 228 (Amgen). AMG 228 and other anti-GITR antibodies are disclosed, e.g. in US 9464139 and WO 2015/031667, incorporated by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or an AMG 228 heavy chain or light chain sequence.

In one embodiment, the anti-GITR antibody molecule is INBRX-110 (Inhibrx). INBRX-110 and other anti-GITR antibodies are disclosed, e.g. in US 2017/0022284 and WO 2017/015623, incorporated by reference in their entirety. In one embodiment, the GITR agonist comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or an INBRX-110 heavy chain or light chain sequence.

In one embodiment, a GITR agonist (e.g. fusion protein) is MEDI 1873 (MedImmune), also known as MEDI1873. MEDI 1873 and other GITR agonists are disclosed, e.g. in US 2017/0073386, WO 2017/025610 and Rosset al. Cancer Res 2016; 76(14 Suppl): Abstract No. 561, incorporated by reference in its entirety. In one embodiment, the GITR agonist comprises one or more of an IgG Fc domain, a functional multimerization domain, and a glucocorticoid-inducible TNF receptor ligand (GITRL) receptor-binding domain in MEDI 1873.

Additional known GITR agonists (e.g. antibodies to GITR) include agonists described, for example, in WO 2016/054638, incorporated by reference in its entirety.

In one embodiment, an anti-GITR antibody is an antibody that competes for binding and/or binds to the same epitope in GITR as one of the anti-GITR antibodies described herein.

In one embodiment, the GITR agonist is a peptide that activates the GITR signaling pathway. In one embodiment, the GITR agonist is an immunoadhesin binding moiety (e.g. an immunoadhesin binding fragment containing the extracellular or GITR-binding portion of GITRL) fused to a constant region (e.g. Fc region of the immunoglobulin sequence).

Table 2. Amino acid sequence of other exemplary anti-GITR antibody molecules BMS-986156 SEQ ID NO: 20 VH QVQLVESGGGVVQPGRSLRLSCAASGFFSSYGMHWVRQAPGKGLEWVAVIWYEGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGGSMVRGDYYYGMDVWGQGTTVTVSS SEQ ID NO: 21 VL AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPYTFGQGTKLEIK

In certain embodiments, the immunomodulator is an immune checkpoint molecule inhibitor. In one embodiment, the immunomodulator is an inhibitor of PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and/or TGFRbeta. In one embodiment, the immune checkpoint molecule inhibitor inhibits PD-1, PD-L1, LAG-3, TIM-3, or CTLA4, or any combination thereof. The term "inhibition" or "inhibitor" implies a decrease in a certain parameter, e.g. activity of a given molecule, for example, immune checkpoint inhibitor. For example, the term implies inhibition of activity, e.g. PD-1 or PD-L1 activity by at least 5%, 10%, 20%, 30%, 40%, 50% or more. Thus, inhibition does not have to be 100%.

Inhibition of an inhibitory molecule can occur at the DNA, RNA or protein level. In some embodiments, an inhibitory nucleic acid (e.g., dsRNA, siRNA or shRNA). In other embodiments, the inhibitory signal inhibitor is a polypeptide, e.g. soluble form of the ligand (for example, PD-1 binding Ig or CTLA-4 binding Ig) or antibody or antigen binding fragment thereof that binds to an inhibitory molecule; For example, an antibody or fragment thereof (also referred to herein as an "antibody molecule") that binds PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and /or TGFR-beta or a combination thereof.

In one embodiment, the antibody molecule is a complete antibody or a fragment thereof (e.g. Fab, F(ab')2, Fv or single chain Fv fragment (scFv)). In yet other embodiments, the antibody molecule has a heavy chain constant region (Fc) selected, for example, from the heavy chain constant regions of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD and IgE; in particular, chosen, for example, of the heavy chain constant regions of IgG1, IgG2, IgG3 and IgG4, more particularly the heavy chain constant region of IgG1 or IgG4 (e.g. human IgG1 or IgG4). In one embodiment, the heavy chain constant region is derived from human IgG1 or human IgG4. In one embodiment, the constant region is changed, for example, subjected to mutation to modify the properties of the antibody molecule (for example, to increase or decrease one or more of Fc receptor binding, antibody glycosylation, number of cysteine residues, effector cell function, or complement function).

In certain embodiments, the antibody molecule is in the form of a bispecific or polyspecific antibody molecule. In one embodiment, the bispecific antibody molecule has a first binding specificity for PD-1 or PD-L1 and a second binding specificity, e.g. the second specificity is binding to TIM-3, LAG-3 or PD-L2. In one embodiment, the bispecific antibody molecule binds to PD-1 or PD-L1 and TIM-3. In another embodiment, the bispecific antibody molecule binds to PD-1 or PD-L1 and LAG-3. In another embodiment, the bispecific antibody molecule binds to PD-1 and PD-L1. In yet another embodiment, the bispecific antibody molecule binds to PD-1 and PD-L2. In another embodiment, the bispecific antibody molecule binds to TIM-3 and LAG-3. Any combination of the above molecules can be formulated into a multispecific antibody molecule, e.g. a trispecific antibody that has a first binding specificity for PD-1 or PD-1, and a second and third binding specificity for two or more of TIM-3, LAG-3 or PD-L2.

In certain embodiments, the immunomodulator is a PD-1 inhibitor, e.g. Human PD-1. In another embodiment, the immunomodulator is a PD-L1 inhibitor, e.g. Human PD-L1. In one embodiment, the PD-1 or PD-L1 inhibitor is an anti-PD-1 or PD-L1 antibody molecule. A PD-1 or PD-L1 inhibitor may be administered alone or in combination with other immunomodulators, e.g. in combination with a LAG-3, TIM-3 or CTLA4 inhibitor. In an illustrative embodiment, a PD-1 or PD-L1 inhibitor, e.g. anti-PD-1 or PD-L1 antibody molecule administered in combination with a LAG-3 inhibitor, e.g. an antibody molecule to LAG-3. In another embodiment, a PD-1 or PD-L1 inhibitor, e.g. anti-PD-1 or anti-PD-L1 antibody molecule administered in combination with a TIM-3 inhibitor, e.g. an antibody molecule to TIM-3. In yet other embodiments, a PD-1 or PD-L1 inhibitor, e.g. anti-PD-1 antibody molecule administered in combination with a LAG-3 inhibitor, e.g. an anti-LAG-3 antibody molecule, and a TIM-3 inhibitor, e.g. an antibody molecule to TIM-3.

Other combinations of immunomodulators with a PD-1 inhibitor (eg, with one or more of PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and/or TGFR) are also within the scope of the present invention. Any of the antibody molecules known in the art or disclosed herein can be used in the above checkpoint molecule inhibitor combinations.

PD-1 inhibitors

In some embodiments, compounds of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof of the present invention are used in combination with a PD-1 inhibitor to treat a disease, e.g. cancer. In some embodiments, the PD-1 inhibitor is selected from PDR001 (Novartis), nivolumab (Bristol-Myers Squibb), pembrolizumab (Merck & Co), pidilizumab (CureTech), MEDI0680 (Medimmune), REGN2810 (Regeneron), TSR-042 (Tesaro ), PF-06801591 (Pfizer), BGB-A317 (Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), or AMP-224 (Amplimmune).

Exemplary PD-1 inhibitors

In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule. In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule described in US 2015/0210769, published July 30, 2015 entitled "Antibody Molecules to PD-1 and Uses Thereof", incorporated by reference in its entirety completeness.

In one embodiment, the anti-PD-1 antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 3 (e.g. of the heavy and light chain variable region sequences of BAP049 clone E or BAP049 clone B disclosed in Table 3), or the encoded nucleotide sequence shown in Table 3. In some embodiments, the CDRs are as defined by Kabat (e.g. as outlined in Table 3). In some embodiments, the CDRs are as defined by Chothia (eg, as outlined in Table 3). In some embodiments, CDRs are specified according to a combination of both Kabat and Chothia definitions of CDR (e.g. as outlined in Table 3). In one embodiment, the VH CDR1, as defined by a combination of the Kabat and Chothia CDR definitions, contains the amino acid sequence GYTFTTYWMH (SEQ ID NO: 213). In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, e.g. amino acid substitutions (for example, conservative amino acid substitutions) or deletions, compared with the amino acid sequence shown in Table 3 or the encoded nucleotide sequence shown in Table 3.

In one embodiment, an anti-PD-1 antibody molecule comprises a heavy chain variable region (VH) comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 22, the amino acid sequence of VHCDR2 of SEQ ID NO: 23, and the amino acid sequence of VHCDR3 of SEQ ID NO: 24; and a light chain variable region (VL) comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 31, the amino acid sequence of VLCDR2 of SEQ ID NO: 32, and the amino acid sequence of VLCDR3 of SEQ ID NO: 286, each of which is disclosed in Table 3.

In one embodiment, the antibody molecule comprises a VH comprising VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 45, VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 46, and VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 47; and VL comprising VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 50, VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 51, and VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 52, each of which is disclosed in Table 3.

In one embodiment, the anti-PD-1 antibody molecule comprises a VH containing the amino acid sequence of SEQ ID NO: 27 or an amino acid sequence that is at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO : 27. In one embodiment, the anti-PD-1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 41 or an amino acid sequence that is at least 85%, 90%, 95% or 99% identical to SEQ ID NO: 41. In one embodiment, the anti-PD-1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 37 or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical with respect to SEQ ID NO: 37. In one embodiment, the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 27 and a VL comprising the amino acid sequence of SEQ ID NO: 41. In one embodiment, the molecule anti-PD-1 antibodies comprise a VH containing the amino acid sequence of SEQ ID NO: 27, and a VL containing the amino acid sequence of SEQ ID NO: 37.

In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 28 or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 28. B In one embodiment, the antibody molecule comprises a VL encoded by a nucleotide sequence of SEQ ID NO: 42 or 38 or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 42 or 38. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 28, and a VL encoded by the nucleotide sequence of SEQ ID NO: 42 or 38.

In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 29 or an amino acid sequence that is at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 29. In one embodiment, the anti-PD-1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 43 or an amino acid sequence that is at least 85%, 90%, 95%, or 99% identical in with respect to SEQ ID NO: 43. In one embodiment, the anti-PD-1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 39 or an amino acid sequence that is at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 39. In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 29 and a light chain comprising the amino acid sequence of SEQ ID NO: 43. In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 29 and a light chain comprising the amino acid sequence of SEQ ID NO: 39.

In one embodiment, the antibody molecule contains a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 30 or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 30. In one embodiment, the antibody molecule contains a light chain encoded by the nucleotide sequence of SEQ ID NO: 44 or 40 or a nucleotide sequence that is at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 44 or 40. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 30 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 44 or 40.

The antibody molecules described herein can be produced using the vectors, host cells and methods described in US 2015/0210769, incorporated by reference in its entirety.

Table 3. Amino acid and nucleotide sequences of exemplary anti-PD-1 antibody molecules HC BAP049 clone B SEQ ID NO: 22 (Kabat) HCDR1 TYWMH SEQ ID NO: 23 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 24 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 25 (Chothia) HCDR1 GYTFTY SEQ ID NO: 26 (Chothia) HCDR2 YPGTGG SEQ ID NO: 24 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 27 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 28 DNA encoding VH Gaggtgcagctggtgcagtcaggcgccgaagtgaagaagcccggcgagtcactgagaattagctgtaaaggttcaggctacaccttcactacctactggatgcactgggtccgccaggctaccggtcaaggcctcgagtggatgggtaatatctaccccggcaccggcggctctaacttcgacgagaagtttaagaatagagtgactatcaccgcc gataagtctactagcaccgcctatatggaactgtctagcctgagatcagaggacaccgccgtctactactgcactaggtggactaccggcacaggcgcctactggggtcaaggcactaccgtgaccgtgtctagc SEQ ID NO: 29 Heavy chain EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPS NTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 30 DNA encoding the heavy chain gaggtgcagctggtgcagtcaggcgccgaagtgaagaagcccggcgagtcactgagaattagctgtaaaggttcaggctacaccttcactacctactggatgcactgggtccgccaggctaccggtcaaggcctcgagtggatgggtaatatctaccccggcaccggcggctctaacttcgacgagaagtttaagaatagagtgactatcaccg ccgataagtctactagcaccgcctatatggaactgtctagcctgagatcagaggacaccgccgtctactactgcactaggtggactaccggcacaggcgcctactggggtcaaggcactaccgtgaccgtgtctagcgctagcactaagggcccgtccgtgttccccctggcaccttgtagccggagcactagcgaatccaccgctgccctcggctg cctggtcaaggattacttcccggagcccgtgaccgtgtcctggaacagcggagccctgacctccggagtgcacaccttccccgctgtgctgcagagctccgggctgtactcgctgtcgtcggtggtcacggtgccttcatctagcctgggtaccaagacctacacttgcaacgtggaccacaagccttccaacactaaggtgg acaagcgcgtcgaatcgaagtacggcccaccgtgcccgccttgtcccgcgccggagttcctcggcggtccctcggtctttctgttcccaccgaagcccaaggacactttgatgatttcccgcacccctgaagtgacatgcgtggtcgtggacgtgtcacaggaagatccggaggtgcagttcaattggt acgtggatggcgtcgaggtgcacaacgccaaaaccaagccgagggaggagcagttcaactccacttaccgcgtcgtgtccgtgctgacggtgctgcatcaggactggctgaacgggaaggagtacaagtgcaaagtgtccaacaagggacttcctagctcaatcgaaaagaccatctcgaaagccaagggacagccccggaaccccaagtgtat accctgccaccgagccaggaagaaatgactaagaaccaagtctcattgacttgccttgtgaagggcttctacccatcggatatcgccgtggaatgggagtccaacggccagccggaaaacaactacaagaccacccctccggtgctggactcagacggatccttcttcctctactcgcggctgaccgtggataagagcagatggcaggagggaaatgtg ttcagctgttctgtgatgcatgaagccctgcacaaccactacactcagaagtccctgtccctctccctggga LC BAP049 clone B SEQ ID NO: 31 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 32 (Kabat) LCDR2 WASTRES SEQ ID NO: 286 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 34 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 35 (Chothia) LCDR2 W.A.S. SEQ ID NO: 36 (Chothia) LCDR3 DYSYPY SEQ ID NO: 37 VL EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQNDYSYPYTFGQGTKVEIK SEQ ID NO: 38 DNA encoding VL Gagatcgtcctgactcagtcacccgctaccctgagcctgagccctggcgagcgggctacactgagctgtaaatctagtcagtcactgctggatagcggtaatcagaagaacttcctgacctggtatcagcagaagcccggtaaagcccctaagctgctgatctactgggcctctactagagaatcaggcgtgccctctaggtttagcggtagc ggtagtggcaccgacttcaccttcactatctctagcctgcagcccgaggatatcgctacctactactgtcagaacgactatagctacccctacaccttcggtcaaggcactaaggtcgagattaag SEQ ID NO: 39 Light chain EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH KVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 40 DNA encoding the light chain Gagatcgtcctgactcagtcacccgctaccctgagcctgagccctggcgagcgggctacactgagctgtaaatctagtcagtcactgctggatagcggtaatcagaagaacttcctgacctggtatcagcagaagcccggtaaagcccctaagctgctgatctactgggcctctactagagaatcaggcgtgccctctaggtttagcggtagc ggtagtggcaccgacttcaccttcactatctctagcctgcagcccgaggatatcgctacctactactgtcagaacgactatagctacccctacaccttcggtcaaggcactaaggtcgagattaagcgtacggtggccgctcccagcgtgttcatcttcccccccagcgacgagcagctgaagagcggcaccgccagcgtggtgtg cctgctgaacaacttctacccccgggaggccaaggtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggagagcgtcaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgaccctgagcaaggccgactacgagaagcataaggtgtacgcctgcgaggtgacccaccaggcctgtccagccccgt gaccaagagcttcaacaggggcgagtgc HC BAP049 clone E SEQ ID NO: 22 (Kabat) HCDR1 TYWMH SEQ ID NO: 23 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 24 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 25 (Chothia) HCDR1 GYTFTY SEQ ID NO: 26 (Chothia) HCDR2 YPGTGG SEQ ID NO: 24 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 27 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 28 DNA encoding VH Gaggtgcagctggtgcagtcaggcgccgaagtgaagaagcccggcgagtcactgagaattagctgtaaaggttcaggctacaccttcactacctactggatgcactgggtccgccaggctaccggtcaaggcctcgagtggatgggtaatatctaccccggcaccggcggctctaacttcgacgagaagtttaagaatagagtgactatcaccgcc gataagtctactagcaccgcctatatggaactgtctagcctgagatcagaggacaccgccgtctactactgcactaggtggactaccggcacaggcgcctactggggtcaaggcactaccgtgaccgtgtctagc SEQ ID NO: 29 Heavy chain EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPS NTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 30 DNA encoding the heavy chain gaggtgcagctggtgcagtcaggcgccgaagtgaagaagcccggcgagtcactgagaattagctgtaaaggttcaggctacaccttcactacctactggatgcactgggtccgccaggctaccggtcaaggcctcgagtggatgggtaatatctaccccggcaccggcggctctaacttcgacgagaagtttaagaatagagtgactatcaccg ccgataagtctactagcaccgcctatatggaactgtctagcctgagatcagaggacaccgccgtctactactgcactaggtggactaccggcacaggcgcctactggggtcaaggcactaccgtgaccgtgtctagcgctagcactaagggcccgtccgtgttccccctggcaccttgtagccggagcactagcgaatccaccgctgccctcggctg cctggtcaaggattacttcccggagcccgtgaccgtgtcctggaacagcggagccctgacctccggagtgcacaccttccccgcttgctgcagagctccgggctgtactcgctgtcgtcggtggtcacggtgccttcatctagcctgggtaccaagacctacacttgcaacgtggaccacaagccttccaacactaaggtgg acaagcgcgtcgaatcgaagtacggcccaccgtgcccgccttgtcccgcgccggagttcctcggcggtccctcggtctttctgttcccaccgaagcccaaggacactttgatgatttcccgcacccctgaagtgacatgcgtggtcgtggacgtgtcacaggaagatccggaggtgcagttcaattggt acgtggatggcgtcgaggtgcacaacgccaaaaccaagccgagggaggagcagttcaactccacttaccgcgtcgtgtccgtgctgacggtgctgcatcaggactggctgaacgggaaggagtacaagtgcaaagtgtccaacaagggacttcctagctcaatcgaaaagaccatctcgaaagccaagggacagccccggaaccccaagtgtat accctgccaccgagccaggaagaaatgactaagaaccaagtctcattgacttgccttgtgaagggcttctacccatcggatatcgccgtggaatgggagtccaacggccagccggaaaacaactacaagaccacccctccggtgctggactcagacggatccttcttcctctactcgcggctgaccgtggataagagcagatggcaggagggaaatgtg ttcagctgttctgtgatgcatgaagccctgcacaaccactacactcagaagtccctgtccctctccctggga LC BAP049 clone E SEQ ID NO: 31 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 32 (Kabat) LCDR2 WASTRES SEQ ID NO: 286 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 34 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 35 (Chothia) LCDR2 W.A.S. SEQ ID NO: 36 (Chothia) LCDR3 DYSYPY SEQ ID NO: 41 VL EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK SEQ ID NO: 42 DNA encoding VL Gagatcgtcctgactcagtcacccgctaccctgagcctgagccctggcgagcgggctacactgagctgtaaatctagtcagtcactgctggatagcggtaatcagaagaacttcctgacctggtatcagcagaagcccggtcaagcccctagactgctgatctactgggcctctactagagaatcaggcgtgccctctaggtttagcggtagcgg tagtggcaccgacttcaccttcactatctctagcctggaagccgaggacgccgctacctactactgtcagaacgactatagctacccctacaccttcggtcaaggcactaaggtcgagattaag SEQ ID NO: 43 Light chain EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 44 DNA encoding the light chain Gagatcgtcctgactcagtcacccgctaccctgagcctgagccctggcgagcgggctacactgagctgtaaatctagtcagtcactgctggatagcggtaatcagaagaacttcctgacctggtatcagcagaagcccggtcaagcccctagactgctgatctactgggcctctactagagaatcaggcgtgccctctaggtttagcggtagcgg tagtggcaccgacttcaccttcactatctctagcctggaagccgaggacgccgctacctactactgtcagaacgactatagctacccctacaccttcggtcaaggcactaaggtcgagattaagcgtacggtggccgctcccagcgtgttcatcttcccccccagcgacgagcagctgaagagcggcaccgccagcgtggtgtgcct gctgaacaacttctacccccgggaggccaaggtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggagagcgtcaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgaccctgagcaaggccgactacgagaagcataaggtgtacgcctgcgaggtgacccaccagggcctgtccagccccgtgacca agagcttcaacaggggcgagtgc HC BAP049 clone B SEQ ID NO: 45 (Kabat) HCDR1 ACCTACTGGATGCAC SEQ ID NO: 46 (Kabat) HCDR2 AATATCTACCCCGGCACCGGCGGCTCTAACTTCGACGAGAAGTTTAAGAAT SEQ ID NO: 47 (Kabat) HCDR3 TGGACTACCGGCACAGGCGCCTAC SEQ ID NO: 48 (Chothia) HCDR1 GGCTACACCTTCACTACCTAC SEQ ID NO: 49 (Chothia) HCDR2 TACCCCGGCACCGGCGGC SEQ ID NO: 47 (Chothia) HCDR3 TGGACTACCGGCACAGGCGCCTAC LC BAP049 clone B SEQ ID NO: 50 (Kabat) LCDR1 AAATCTAGTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTCCTGACC SEQ ID NO: 51 (Kabat) LCDR2 TGGGCCTCTACTAGAGAATCA SEQ ID NO: 52 (Kabat) LCDR3 CAGAACGACTATAGCTACCCCTACACC SEQ ID NO: 53 (Chothia) LCDR1 AGTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTC SEQ ID NO: 54 (Chothia) LCDR2 TGGGCCTCT SEQ ID NO: 55 (Chothia) LCDR3 GACTATAGCTACCCCTAC HC BAP049 clone E SEQ ID NO: 45 (Kabat) HCDR1 ACCTACTGGATGCAC SEQ ID NO: 46 (Kabat) HCDR2 AATATCTACCCCGGCACCGGCGGCTCTAACTTCGACGAGAAGTTTAAGAAT SEQ ID NO: 47 (Kabat) HCDR3 TGGACTACCGGCACAGGCGCCTAC SEQ ID NO: 48 (Chothia) HCDR1 GGCTACACCTTCACTACCTAC SEQ ID NO: 49 (Chothia) HCDR2 TACCCCGGCACCGGCGGC SEQ ID NO: 47 (Chothia) HCDR3 TGGACTACCGGCACAGGCGCCTAC LC BAP049 clone E SEQ ID NO: 50 (Kabat) LCDR1 AAATCTAGTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTCCTGACC SEQ ID NO: 51 (Kabat) LCDR2 TGGGCCTCTACTAGAGAATCA SEQ ID NO: 52 (Kabat) LCDR3 CAGAACGACTATAGCTACCCCTACACC SEQ ID NO: 53 (Chothia) LCDR1 AGTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTC SEQ ID NO: 54 (Chothia) LCDR2 TGGGCCTCT SEQ ID NO: 55 (Chothia) LCDR3 GACTATAGCTACCCCTAC

Other exemplary PD-1 inhibitors

In some embodiments, the anti-PD-1 antibody is nivolumab (CAS registration number: 946414-94-4). Alternative names for nivolumab include MDX-1106, MDX-1106-04, ONO-4538, BMS-936558, or OPDIVO®. Nivolumab is a fully human IgG4 monoclonal antibody that specifically blocks PD1. Nivolumab (clone 5C4) and other human monoclonal antibodies that specifically bind to PD1 are disclosed in US Pat. No. 8,008,449 and PCT Publication No. WO2006/121168, incorporated by reference in their entirety. In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a nivolumab heavy chain or light chain sequence, e.g. disclosed in table 4.

In other embodiments, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab (trade name KEYTRUDA, formerly lambrolizumab, also known as Merck 3745, MK-3475, or SCH-900475) is a humanized IgG4 monoclonal antibody that binds to PD1. Pembrolizumab is disclosed, e.g. in Hamid, O.et al. (2013)New England Journal of Medicine 369 (2): 134-44, publications according to PCT No. WO2009/114335 and US Patent No. 8354509, incorporated by reference in their entirety. In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a pembrolizumab heavy chain or light chain sequence, e.g. disclosed in table 4.

In some embodiments, the anti-PD-1 antibody is pidilizumab. Pidilizumab (CT-011; Cure Tech) is a humanized IgG1k monoclonal antibody that binds to PD1. Pidilizumab and other humanized anti-PD-1 monoclonal antibodies are disclosed in PCT Publication No. WO2009/101611, incorporated by reference in its entirety. In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a pidilizumab heavy chain or light chain sequence, e.g. disclosed in table 4.

Other anti-PD1 antibodies are disclosed in US Patent No. 8609089, US Patent Application Publication No. 2010028330 and/or US Patent Application Publication No. 20120114649, incorporated by reference in their entirety. Other anti-PD1 antibodies include AMP 514 (Amplimmune).

In one embodiment, the anti-PD-1 antibody molecule is MEDI0680 (Medimmune), also known as AMP-514. MEDI0680 and other anti-PD-1 antibodies are disclosed in US 9205148 and WO 2012/145493, incorporated by reference in their entirety. In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a MEDI0680 heavy chain or light chain sequence.

In one embodiment, the anti-PD-1 antibody molecule is REGN2810 (Regeneron). In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a REGN2810 heavy chain or light chain sequence.

In one embodiment, the anti-PD-1 antibody molecule is PF-06801591 (Pfizer). In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence PF-06801591.

In one embodiment, the anti-PD-1 antibody molecule is BGB-A317 or BGB-108 (Beigene). In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a BGB-A317 or BGB-108 heavy chain or light chain sequence.

In one embodiment, the anti-PD-1 antibody molecule is INCSHR1210 (Incyte), also known as INCSHR01210 or SHR-1210. In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or an INCSHR1210 heavy chain or light chain sequence.

In one embodiment, the anti-PD-1 antibody molecule is TSR-042 (Tesaro), also known as ANB011. In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a TSR-042 heavy chain or light chain sequence.

Additional known anti-PD-1 antibodies include those described, for example, in WO 2015/112800, WO 2016/092419, WO 2015/085847, WO 2014/179664, WO 2014/194302, WO 2014/209804, WO 2015/200119, US 8735553, US 748880 2, US 8927697, US 8993731 and US 9102727 , incorporated by reference in their entirety.

In one embodiment, an anti-PD-1 antibody is an antibody that competes for binding and/or binds to the same epitope on PD-1 as one of the anti-PD-1 antibodies described herein.

In one embodiment, a PD-1 inhibitor is a peptide that inhibits the PD-1 signaling pathway, for example, as described in US Pat. No. 8,907,053, incorporated by reference in its entirety. In some embodiments, the PD-1 inhibitor is an immunoadhesin (e.g. an immunoadhesin that contains the extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g. sequence of the Fc region of immunoglobulin)). In some embodiments, the PD-1 inhibitor is AMP-224 (B7-DCIg (Amplimmune), for example, disclosed in WO 2010/027827 and WO 2011/066342, incorporated by reference in their entirety).

Table 4. Amino acid sequences of other exemplary anti-PD-1 antibody molecules Nivolumab SEQ ID NO: 56 Heavy chain QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNT KVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 57 Light chain EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH QGLSSPVTKSFNRGEC Pembrolizumab SEQ ID NO: 58 Heavy chain QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTK TYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 59 Light chain EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPARFSGSGSGTDFTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC Pidilizumab SEQ ID NO: 60 Heavy chain QVQLVQSGSELKKPGASVKISCKASGYTFTNYGMNWVRQAPGQGLQWMGWINTDSGESTYAEEFKGRFVFSLDTSVNTAYLQITSLTAEDTGMYFCVRVGYDALDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 61 Light chain EIVLTQSPSSLSASVGDRVTITCSARSSVSYMHWFQQKPGKAPKLWIYRTSNLASGVPSRFSGSGSGTSYCLTINSLQPEDFATYYCQQRSSFPLTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV THQGLSSPVTKSFNRGEC

PD-L1 inhibitors

In some embodiments, compounds of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof of the present invention are used in combination with a PD-L1 inhibitor to treat a disease, e.g. cancer. In some embodiments, the PD-L1 inhibitor is selected from FAZ053 (Novartis), atezolizumab (Genentech/Roche), avelumab (Merck Serono and Pfizer), durvalumab (MedImmune/AstraZeneca), or BMS-936559 (Bristol-Myers Squibb).

Exemplary PD-L1 inhibitors

In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule. In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule disclosed in US 2016/0108123, published April 21, 2016 entitled "Antibody Molecules to PD-L1 and Uses Thereof", incorporated by reference in its entirety completeness.

In one embodiment, a PD-L1 antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all CDRs) of a heavy and light chain variable region comprising an amino acid sequence shown in Table 5 (for example, of the heavy and light chain variable region sequences of BAP058 clone O or BAP058 clone N disclosed in Table 5), or the encoded nucleotide sequence shown in Table 5. In some embodiments, the CDRs are as defined by Kabat (e.g. as outlined in Table 5). In some embodiments, the CDRs are as defined by Chothia (eg, as outlined in Table 5). In some embodiments, CDRs are specified according to a combination of both Kabat and Chothia definitions of CDR (e.g. as outlined in Table 5). In one embodiment, the VH CDR1, as defined by a combination of the Kabat and Chothia CDR definitions, contains the amino acid sequence GYTFTSYWMY (SEQ ID NO: 214). In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, e.g. amino acid substitutions (for example, conservative amino acid substitutions) or deletions, compared with the amino acid sequence shown in Table 5 or the encoded nucleotide sequence shown in Table 5.

In one embodiment, an anti-PD-L1 antibody molecule comprises a heavy chain variable region (VH) comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 62, the amino acid sequence of VHCDR2 of SEQ ID NO: 63, and the amino acid sequence of VHCDR3 of SEQ ID NO: 64; and a light chain variable region (VL) comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 70, the amino acid sequence of VLCDR2 of SEQ ID NO: 71, and the amino acid sequence of VLCDR3 of SEQ ID NO: 72, each of which is disclosed in Table 5.

In one embodiment, an anti-PD-L1 antibody molecule comprises a VH comprising VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 89, VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 90, and VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 91 ; and VL comprising VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 94, VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 95, and VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 96, each of which is disclosed in Table 5.

In one embodiment, the anti-PD-L1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 67 or an amino acid sequence that is at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: : 67. In one embodiment, the anti-PD-L1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 77 or an amino acid sequence that is at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 77. In one embodiment, the anti-PD-L1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 81 or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical with respect to SEQ ID NO: 81. In one embodiment, the anti-PD-L1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 85 or an amino acid sequence of at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 85. In one embodiment, the anti-PD-L1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 67 and a VL comprising the amino acid sequence of SEQ ID NO: 77. In one In an embodiment, the anti-PD-L1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 81 and a VL containing the amino acid sequence of SEQ ID NO: 85.

In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 68 or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 68. B In one embodiment, the antibody molecule comprises a VL encoded by a nucleotide sequence of SEQ ID NO: 78 or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 78. In one in an embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 82 or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 82. In one embodiment An antibody molecule comprises a VL encoded by a nucleotide sequence of SEQ ID NO: 86 or a nucleotide sequence that is at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 86. In one embodiment the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 68, and a VL encoded by the nucleotide sequence of SEQ ID NO: 78. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 82, and a VL, encoded by the nucleotide sequence under SEQ ID NO: 86.

In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 69 or an amino acid sequence that is at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 69. In one embodiment, the anti-PD-L1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 79 or an amino acid sequence that is at least 85%, 90%, 95% or 99% identical in with respect to SEQ ID NO: 79. In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 83 or an amino acid sequence of at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 83. In one embodiment, the anti-PD-L1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 87, or an amino acid sequence of at least 85%, 90%, 95 % or 99% or greater identical to SEQ ID NO: 87. In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 69 and a light chain comprising the amino acid sequence of SEQ ID NO: 79. In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 83 and a light chain comprising the amino acid sequence of SEQ ID NO: 87.

In one embodiment, the antibody molecule contains a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 76 or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 76. In one embodiment, the antibody molecule contains a light chain encoded by the nucleotide sequence of SEQ ID NO: 80 or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 80. In one embodiment, the antibody molecule contains a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 84 or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 84. In one embodiment, the antibody molecule contains a light chain encoded by the nucleotide sequence of SEQ ID NO: 88 or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 88. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 76 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 80. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 84, and the light chain encoded by the nucleotide sequence of SEQ ID NO: 88.

The antibody molecules described herein can be produced using the vectors, host cells and methods described in US 2016/0108123, incorporated by reference in its entirety.

Table 5. Amino acid and nucleotide sequences of exemplary anti-PD-L1 antibody molecules HC BAP058 clone O SEQ ID NO: 62 (Kabat) HCDR1 SYWMY SEQ ID NO: 63 (Kabat) HCDR2 RIDPNSGSTKYNEKFKN SEQ ID NO: 64 (Kabat) HCDR3 DYRKGLYAMDY SEQ ID NO: 65 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 66 (Chothia) HCDR2 DPNSGS SEQ ID NO: 64 (Chothia) HCDR3 DYRKGLYAMDY SEQ ID NO: 67 VH EVQLVQSGAEVKKPGATVKISCKVSGYTFTSYWMYWVRQARGQRLEWIGRIDPNSGSTKYNEKFKNRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDYRKGLYAMDYWGQGTTVTVSS SEQ ID NO: 68 DNA encoding VH GAAGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAACCCGGCGCTACCGTGAAGATTAGCTGTAAAGTCTCAGGCTACACCTTCACTAGCTACTGGATGTACTGGGTCCGACAGGCTAGAGGGCAAAGACTGGAGTGGATCGGTAGAATCGACCCTAATAGCGGCTCTACTAAGTATAACGAGAAGTTTAAGAATAGGTTCACTATTAGTAGGGATAACTCTAAGAACACCCTGTACC TGCAGATGAATAGCCTGAGAGCCGAGGACACCGCCGTCTACTACTGCGCTAGAGACTATAGAAAGGGCCTGTACGCTATGGACTACTGGGGTCAAGGCACTACCGTGACCGTGTCTTCA SEQ ID NO: 69 Heavy chain EVQLVQSGAEVKKPGATVKISCKVSGYTFTSYWMYWVRQARGQRLEWIGRIDPNSGSTKYNEKFKNRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDYRKGLYAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT KTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 76 DNA encoding the heavy chain GAAGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAACCCGGCGCTACCGTGAAGATTAGCTGTAAAGTCTCAGGCTACACCTTCACTAGCTACTGGATGTACTGGGTCCGACAGGCTAGAGGGCAAAGACTGGAGTGGATCGGTAGAATCGACCCTAATAGCGGCTCTACTAAGTATAACGAGAAGTTTAAGAATAGGTTCACTATTAGTAGGGATAACTCTAAGAACACCCTGTACC TGCAGATGAATAGCCTGAGAGCCGAGGACACCGCCGTCTACTACTGCGCTAGAGACTATAGAAAGGGCCTGTACGCTATGGACTACTGGGGTCAAGGCACTACCGTGACCGTGTCTTCAGCTAGCACTAAGGGCCCGTCCGTGTTCCCCCTGGCACCTTGTAGCCGGAGCACTAGCGAATCCACCGCTGCCCTCGGCTGCCTGGTCAAGGATTACTTCCCGGAGCCCGTGACCGTGTCCTGGAACAGCGGAG CCCTGACCTCCGGAGTGCACACCTTCCCCGCTGTGCTGCAGAGCTCCGGGCTGTACTCGCTGTCGTCGGTGGTCACGGTGCCTTCATCTAGCCTGGGTACCAAGACCTACACTTGCAACGTGGACCACAAGCCTTCCAACACTAAGGTGGACAAGCGCGTCGAATCGAAGTACGGCCCACCGTGCCCGCCTTGTCCCGCGCCGGAGTTCCTCGGCGGTCCCTCGGTCTTTCTGTTCCCACCGA AGCCCAAGGACACTTTGATGATTTCCCGCACCCCTGAAGTGACATGCGTGGTCGTGGACGTGTCACAGGAAGATCCGGAGGTGCAGTTCAATTGGTACGTGGATGGCGTCGAGGTGCACAACGCCAAAACCAAGCCGAGGGAGGAGCAGTTCAACTCCACTTACCGCGTCGTGTCCGTGCTGACGGTGCTGCATCAGGACTGGCTGAACGGGAAGGAGTACAAGTGCAAAGTGTCCAACA AGGGACTTCCTAGCTCAATCGAAAAGACCATCTCGAAAGCCAAGGGACAGCCCCGGGAACCCCAAGTGTATACCCTGCCACCGAGCCAGGAAGAAATGACTAAGAACCAAGTCTCATTGACTTGCCTTGTGAAGGGCTTCTACCCATCGGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCGGAAAACAACTACAAGACCACCCCTCCGGTGCTGGACTCAGACGGATCCTTCTTCCCTACTCGCGGCTGAC CGTGGATAAGAGCAGATGGCAGGAGGGAAATGTGTTCAGCTGTTCTGTGATGCATGAAGCCCTGCACAACCACTACACTCAGAAGTCCCTGTCCCTCTCCCTGGGA LC BAP058 clone O SEQ ID NO: 70 (Kabat) LCDR1 KASQDVGTAVA SEQ ID NO: 71 (Kabat) LCDR2 WASTRHT SEQ ID NO: 72 (Kabat) LCDR3 QQYNSYPLT SEQ ID NO: 73 (Chothia) LCDR1 SQDVGTA SEQ ID NO: 74 (Chothia) LCDR2 W.A.S. SEQ ID NO: 75 (Chothia) LCDR3 YNSYPL SEQ ID NO: 77 VL AIQLTQSPSSLSSASVGDRVTITCKASQDVGTAVAWYLQKPGQSPQLLIYWASTRHTGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQQYNSYPLTFGQGTKVEIK SEQ ID NO: 78 DNA encoding VL GCTATTCAGCTGACTCAGTCACCTAGTAGCCTGAGCGCTAGTGTGGGCGATAGAGTGACTATCACCTGTAAAGCCTCTCAGGACGTGGGCACCGCCGTGGCCTGGTATCTGCAGAAGCCTGGTCAATCACCTCAGCTGCTGATCTACTGGGCCTCTACTAGACACACCGGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCACCTTCACTATCTCTTCACTGGAAGCCGAGG ACGCCGCTACCTACTACTGTCAGCAGTATAATAGCTACCCCCTGACCTTTCGGTCAAGGCACTAAGGTCGAGATTAAG SEQ ID NO: 79 Light chain AIQLTQSPSSLSASVGDRVTITCKASQDVGTAVAWYLQKPGQSPQLLIYWASTRHTGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQQYNSYPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 80 DNA encoding the light chain GCTATTCAGCTGACTCAGTCACCTAGTAGCCTGAGCGCTAGTGTGGGCGATAGAGTGACTATCACCTGTAAAGCCTCTCAGGACGTGGGCACCGCCGTGGCCTGGTATCTGCAGAAGCCTGGTCAATCACCTCAGCTGCTGATCTACTGGGCCTCTACTAGACACACCGGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCACCTTCACTATCTCTTCACTGGAAGCCGAGG ACGCCGCTACCTACTACTGTCAGCAGTATAATAGCTACCCCCTGACCTTTCGGTCAAGGCACTAAGGTCGAGATTAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCG TCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC HC BAP058 clone N SEQ ID NO: 62 (Kabat) HCDR1 SYWMY SEQ ID NO: 63 (Kabat) HCDR2 RIDPNSGSTKYNEKFKN SEQ ID NO: 64 (Kabat) HCDR3 DYRKGLYAMDY SEQ ID NO: 65 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 66 (Chothia) HCDR2 DPNSGS SEQ ID NO: 64 (Chothia) HCDR3 DYRKGLYAMDY SEQ ID NO: 81 VH EVQLVQSGAEVKKPGATVKISCKVSGYTFTSYWMYWVRQATGQGLEWMGRIDPNSGSTKYNEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWGQGTTVTVSS SEQ ID NO: 82 DNA encoding VH GAAGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAACCCGGCGCTACCGTGAAGATTAGCTGTAAAGTCTCAGGCTACACCTTCACTAGCTACTGGATGTACTGGGTCCGACAGGCTACCGGTCAAGGCCTGGAGTGGATGGGTAGAATCGACCCTAATAGCGGCTCTACTAAGTATAACGAGAAGTTTAAGAATAGAGTGACTATCACCGCCGATAAGTCTACTAGCACCGCCTATA TGGAACTGTCTAGCCTGAGATCAGAGGACACCGCCGTCTACTACTGCGCTAGAGACTATAGAAAGGGCCTGTACGCTATGGACTACTGGGGTCAAGGCACTACCGTGACCGTGTCTTCA SEQ ID NO: 83 Heavy chain EVQLVQSGAEVKKPGATVKISCKVSGYTFTSYWMYWVRQATGQGLEWMGRIDPNSGSTKYNEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTK TYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 84 DNA encoding the heavy chain GAAGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAACCCGGCGCTACCGTGAAGATTAGCTGTAAAGTCTCAGGCTACACCTTCACTAGCTACTGGATGTACTGGGTCCGACAGGCTACCGGTCAAGGCCTGGAGTGGATGGGTAGAATCGACCCTAATAGCGGCTCTACTAAGTATAACGAGAAGTTTAAGAATAGAGTGACTATCACCGCCGATAAGTCTACTAGCACCGCCTATA TGGAACTGTCTAGCCTGAGATCAGAGGACACCGCCGTCTACTACTGCGCTAGAGACTATAGAAAGGGCCTGTACGCTATGGACTACTGGGGTCAAGGCACTACCGTGACCGTGTCTTCAGCTAGCACTAAGGGCCCGTCCGTGTTCCCCCTGGCACCTTGTAGCCGGAGCACTAGCGAATCCACCGCTGCCCTCGGCTGCCTGGTCAAGGATTACTTCCCGGAGCCCGTGACCGTGTCCTGGAACAGCAG CCCTGACCTCCGGAGTGCACACCTTCCCCGCTGTGCTGCAGAGCTCCGGGCTGTACTCGCTGTCGTCGGTGGTCACGGTGCCTTCATCTAGCCTGGGTACCAAGACCTACACTTGCAACGTGGACCACAAGCCTTCCAACACTAAGGTGGACAAGCGCGTCGAATCGAAGTACGGCCCACCGTGCCCGCCTTGTCCCGCGCCGGAGTTCCTCGGCGGTCCCTCGGTCTTTCTGTTCCCACCGA AGCCCAAGGACACTTTGATGATTTCCCGCACCCCTGAAGTGACATGCGTGGTCGTGGACGTGTCACAGGAAGATCCGGAGGTGCAGTTCAATTGGTACGTGGATGGCGTCGAGGTGCACAACGCCAAAACCAAGCCGAGGGAGGAGCAGTTCAACTCCACTTACCGCGTCGTGTCCGTGCTGACGGTGCTGCATCAGGACTGGCTGAACGGGAAGGAGTACAAGTGCAAAGTGTCCAACA AGGGACTTCCTAGCTCAATCGAAAAGACCATCTCGAAAGCCAAGGGACAGCCCCGGGAACCCCAAGTGTATACCCTGCCACCGAGCCAGGAAGAAATGACTAAGAACCAAGTCTCATTGACTTGCCTTGTGAAGGGCTTCTACCCATCGGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCGGAAAACAACTACAAGACCACCCCTCCGGTGCTGGACTCAGACGGATCCTTCTTCCCTACTCGCGGCTGAC CGTGGATAAGAGCAGATGGCAGGAGGGAAATGTGTTCAGCTGTTCTGTGATGCATGAAGCCCTGCACAACCACTACACTCAGAAGTCCCTGTCCCTCTCCCTGGGA LC BAP058 clone N SEQ ID NO: 70 (Kabat) LCDR1 KASQDVGTAVA SEQ ID NO: 71 (Kabat) LCDR2 WASTRHT SEQ ID NO: 72(Kabat) LCDR3 QQYNSYPLT SEQ ID NO: 73 (Chothia) LCDR1 SQDVGTA SEQ ID NO: 74 (Chothia) LCDR2 W.A.S. SEQ ID NO: 75 (Chothia) LCDR3 YNSYPL SEQ ID NO: 85 VL DVVMTQSPLSLPVTLGQPASISCKASQDVGTAVAWYQQKPGQAPRLLIYWASTRHTGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYPLTFGQGTKVEIK SEQ ID NO: 86 DNA encoding VL GACGTCGTGATGACTCAGTCACCCCTGAGCCTGCCCGTGACCCTGGGGCAGCCCGCCTCTATTAGCTGTAAAGCCTCTCAGGACGTGGGCACCGCCGTGGCCTGGTATCAGCAGAAGCCAGGGCAAGCCCCTAGACTGCTGATCTACTGGGCCTCTACTAGACACACCGGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGAGTTCACCCTGACTATCTCTTCACTGCAGCCC GACGACTTCGCTACCTACTACTGTCAGCAGTATAATAGCTACCCCCTGACCTTTCGGTCAAGGCACTAAGGTCGAGATTAAG SEQ ID NO: 87 Light chain DVVMTQSPLSLPVTLGQPASISCKASQDVGTAVAWYQQKPGQAPRLLIYWASTRHTGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 88 DNA encoding the light chain GACGTCGTGATGACTCAGTCACCCCTGAGCCTGCCCGTGACCCTGGGGCAGCCCGCCTCTATTAGCTGTAAAGCCTCTCAGGACGTGGGCACCGCCGTGGCCTGGTATCAGCAGAAGCCAGGGCAAGCCCCTAGACTGCTGATCTACTGGGCCTCTACTAGACACACCGGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGAGTTCACCCTGACTATCTCTTCACTGCAGCCC GACGACTTCGCTACCTACTACTGTCAGCAGTATAATAGCTACCCCCTGACCTTCGGTCAAGGCACTAAGGTCGAGATTAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGA GCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC HC BAP058 clone O SEQ ID NO: 89 (Kabat) HCDR1 agctactggatgtac SEQ ID NO: 90 (Kabat) HCDR2 agaatcgaccctaatagcggctctactaagtataacgagaagtttaagaat SEQ ID NO: 91 (Kabat) HCDR3 gactatagaaagggcctgtacgctatggactac SEQ ID NO: 92 (Chothia) HCDR1 ggctacaccttcactagctac SEQ ID NO: 93 (Chothia) HCDR2 gaccctaatagcggctct SEQ ID NO: 91 (Chothia) HCDR3 gactatagaaagggcctgtacgctatggactac LC BAP058 clone O SEQ ID NO: 94 (Kabat) LCDR1 aaagcctctcaggacgtgggcaccgccgtggcc SEQ ID NO: 95 (Kabat) LCDR2 tggggcctctactagacacacc SEQ ID NO: 96 (Kabat) LCDR3 cagcagtataatagctaccccctgacc SEQ ID NO: 97 (Chothia) LCDR1 tctcaggacgtgggcaccgcc SEQ ID NO: 98 (Chothia) LCDR2 tggggcctct SEQ ID NO: 99 (Chothia) LCDR3 tataatagctaccccctg HC BAP058 clone N SEQ ID NO: 89 (Kabat) HCDR1 agctactggatgtac SEQ ID NO: 90 (Kabat) HCDR2 agaatcgaccctaatagcggctctactaagtataacgagaagtttaagaat SEQ ID NO: 91 (Kabat) HCDR3 gactatagaaagggcctgtacgctatggactac SEQ ID NO: 92 (Chothia) HCDR1 ggctacaccttcactagctac SEQ ID NO: 93 (Chothia) HCDR2 gaccctaatagcggctct SEQ ID NO: 91 (Chothia) HCDR3 gactatagaaagggcctgtacgctatggactac LC BAP058 clone N SEQ ID NO: 94 (Kabat) LCDR1 aaagcctctcaggacgtgggcaccgccgtggcc SEQ ID NO: 95 (Kabat) LCDR2 tggggcctctactagacacacc SEQ ID NO: 96 (Kabat) LCDR3 cagcagtataatagctaccccctgacc SEQ ID NO: 97 (Chothia) LCDR1 tctcaggacgtgggcaccgcc SEQ ID NO: 98 (Chothia) LCDR2 tggggcctct SEQ ID NO: 99 (Chothia) LCDR3 tataatagctaccccctg

Other exemplary PD-L1 inhibitors

In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody inhibitor is selected from YW243.55.S70, MPDL3280A, MEDI-4736, or MDX-1105MSB-0010718C (also referred to as A09-246-2) disclosed, for example, in WO 2013/0179174, and has the sequence disclosed herein (or a sequence substantially identical or similar thereto, e.g. sequence that is at least 85%, 90%, 95% or more identical to the specified sequence).

In one embodiment, the PD-L1 inhibitor is MDX-1105. MDX-1105, also known as BMS-936559, is an anti-PD-L1 antibody described in PCT Publication No. WO 2007/005874.

In one embodiment, the PD-L1 inhibitor is YW243.55.S70. Antibody YW243.55.S70 is an anti-PD-L1 antibody described in PCT Publication No. WO 2010/077634.

In one embodiment, the PD-L1 inhibitor is MDPL3280A (Genentech/Roche), also known as atezolizumab, RG7446, RO5541267, YW243.55.S70, or TECENTRIQ™. MDPL3280A is an Fc optimized human IgG1 monoclonal antibody that binds to PD-L1. MDPL3280A and other human monoclonal antibodies to PD-L1 are disclosed in US Patent No. 7,943,743 and US Patent Application Publication No. 20120039906, incorporated by reference in their entirety. In one embodiment, the anti-PD-L1 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or an atezolizumab heavy chain or light chain sequence, such as those disclosed in Table 6.

In other embodiments, the PD-L2 inhibitor is AMP-224. AMP-224 is a soluble form of a PD-L2-Fc fusion protein receptor that blocks the interaction between PD1 and B7-H1 (B7-DCIg; Amplimmune; e.g. disclosed in publications according to PCT Nos. WO2010/027827 and WO2011/066342).

In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule. In one embodiment, the anti-PD-L1 antibody molecule is avelumab (Merck Serono and Pfizer), also known as MSB0010718C. Avelumab and other anti-PD-L1 antibodies are disclosed in WO 2013/079174, incorporated by reference in its entirety. In one embodiment, the anti-PD-L1 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or an avelumab heavy chain or light chain sequence, such as those disclosed in Table 6.

In one embodiment, the anti-PD-L1 antibody molecule is durvalumab (MedImmune/AstraZeneca), also known as MEDI4736. Durvalumab and other anti-PD-L1 antibodies are disclosed in US 8,779,108, incorporated by reference in its entirety. In one embodiment, the anti-PD-L1 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a durvalumab heavy chain or light chain sequence, such as those disclosed in Table 6.

In one embodiment, the anti-PD-L1 antibody molecule is BMS-936559 (Bristol-Myers Squibb), also known as MDX-1105 or 12A4. BMS-936559 and other anti-PD-L1 antibodies are disclosed in US 7943743 and WO 2015/081158, incorporated by reference in their entirety. In one embodiment, the anti-PD-L1 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a BMS-936559 heavy chain or light chain sequence, such as those disclosed in Table 6 .

Additional known anti-PD-L1 antibodies include those described, for example, in WO 2015/181342, WO 2014/100079, WO 2016/000619, WO 2014/022758, WO 2014/055897, WO 2015/061668, WO 2013/079174 , WO 2012/145493, WO 2015/112805, WO 2015/109124, WO 2015/195163, US 8168179, US 8552154, US 8460927 and US 9175082, incorporated by reference in their entirety.

In one embodiment, an anti-PD-L1 antibody is an antibody that competes for binding and/or binds to the same epitope on PD-L1 as one of the anti-PD-L1 antibodies described herein.

Table 6. Amino acid sequences of other exemplary anti-PD-L1 antibody molecules Atezolizumab SEQ ID NO: 100 Heavy chain EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK PSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 101 Light chain DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC Avelumab SEQ ID NO: 102 Heavy chain EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPSGGITFYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 103 Light chain QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTRVFGTGTKVTVLGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTH EGSTVEKTVAPTECS Durvalumab SEQ ID NO: 104 Heavy chain EVQLVESGGGLVQPGGSLRLSCAASGTFFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 105 Light chain EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC BMS-936559 SEQ ID NO: 106 VH QVQLVQSGAEVKKPGSSVKVSCKTSGDTFSTYAISWVRQAPGQGLEWMGGIIPIFGKAHYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYFCARKFHFVSSGSPFGMDVWGQGTTVTVSS SEQ ID NO: 107 VL EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPTFGQGTKVEIK

LAG-3 inhibitors

In some embodiments, compounds of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof of the present invention are used in combination with a LAG-3 inhibitor to treat a disease, e.g. cancer. In some embodiments, the LAG-3 inhibitor is selected from LAG525 (Novartis), BMS-986016 (Bristol-Myers Squibb), or TSR-033 (Tesaro).

Exemplary LAG-3 Inhibitors

In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule. In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule disclosed in US 2015/0259420, published September 17, 2015 entitled "Antibody Molecules to LAG-3 and Uses Thereof", incorporated by reference in its entirety completeness.

In one embodiment, an anti-LAG-3 antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 7 (e.g. of the heavy and light chain variable region sequences of BAP050 clone I or BAP050 clone J disclosed in Table 7), or the encoded nucleotide sequence shown in Table 7. In some embodiments, the CDRs are as defined by Kabat (e.g. as set out in Table 7). In some embodiments, the CDRs are as defined by Chothia (eg, as set out in Table 7). In some embodiments, CDRs are specified according to a combination of both Kabat and Chothia definitions of CDR (e.g. as set out in Table 7). In one embodiment, the VH CDR1, as defined by a combination of the Kabat and Chothia CDR definitions, contains the amino acid sequence GFTLTNYGMN (SEQ ID NO: 173). In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, e.g. amino acid substitutions (for example, conservative amino acid substitutions) or deletions, compared to the amino acid sequence shown in Table 7 or the encoded nucleotide sequence shown in Table 7.

In one embodiment, an anti-LAG-3 antibody molecule comprises a heavy chain variable region (VH) comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 108, the amino acid sequence of VHCDR2 of SEQ ID NO: 109, and the amino acid sequence of VHCDR3 of SEQ ID NO: 110; and a light chain variable region (VL) comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 117, the amino acid sequence of VLCDR2 of SEQ ID NO: 118, and the amino acid sequence of VLCDR3 of SEQ ID NO: 119, each of which is disclosed in Table 7.

In one embodiment, an anti-LAG-3 antibody molecule comprises a VH comprising VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 143 or 144, VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 145 or 146, and VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 147 or 148; and VL comprising VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 153 or 154, VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 155 or 156, and VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 157 or 158, each of which is disclosed in Table 7. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 165 or 144, VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 166 or 146, and VHCDR3, encoded by the nucleotide sequence of SEQ ID NO: 167 or 148; and VL comprising VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 153 or 154, VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 155 or 156, and VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 157 or 158, each of which is disclosed in Table 7.

In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 113 or an amino acid sequence that is at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO : 113. In one embodiment, the anti-LAG-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 125 or an amino acid sequence that is at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 125. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 131 or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical with respect to SEQ ID NO: 131. In one embodiment, the anti-LAG-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 137 or an amino acid sequence of at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 137. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 113 and a VL comprising the amino acid sequence of SEQ ID NO: 125. In one In an embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 131 and a VL containing the amino acid sequence of SEQ ID NO: 137.

In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 114 or 115 or a nucleotide sequence that is at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 114 or 115. In one embodiment, the antibody molecule comprises a VL encoded by a nucleotide sequence of SEQ ID NO: 126 or 127 or a nucleotide sequence that is at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 126 or 127. In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 132 or 133 or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to to SEQ ID NO: 132 or 133. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 138 or 139 or by the nucleotide sequence of at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 138 or 139. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 114 or 115, and a VL encoded by the nucleotide sequence of SEQ ID NO: 126 or 127. In one In an embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 132 or 133, and a VL encoded by the nucleotide sequence of SEQ ID NO: 138 or 139.

In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 116 or an amino acid sequence that is at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 116. In one embodiment, the anti-LAG-3 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 128 or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical in with respect to SEQ ID NO: 128. In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 134 or an amino acid sequence of at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 134. In one embodiment, the anti-LAG-3 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 140, or an amino acid sequence of at least 85%, 90%, 95 % or 99% or greater identical to SEQ ID NO: 140. In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 116 and a light chain comprising the amino acid sequence of SEQ ID NO: 128. In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 134 and a light chain comprising the amino acid sequence of SEQ ID NO: 140.

In one embodiment, the antibody molecule contains a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 123 or 124 or a nucleotide sequence that is at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 123 or 124. In one embodiment, the antibody molecule contains a light chain encoded by the nucleotide sequence of SEQ ID NO: 129 or 130 or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 129 or 130. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 135 or 136 or by a nucleotide sequence of at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 135 or 136. In one embodiment, the antibody molecule contains a light chain encoded by the nucleotide sequence of SEQ ID NO: 141 or 142 or nucleotide sequence, at least 85%, 90%, 95% or 99% or greater identical to SEQ ID NO: 141 or 142. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 123 or 124, and a light chain encoded by the nucleotide sequence of SEQ ID NO: 123 or 124. 129 or 130. In one embodiment, the antibody molecule contains a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 135 or 136, and a light chain encoded by the nucleotide sequence of SEQ ID NO: 141 or 142.

The antibody molecules described herein can be produced using the vectors, host cells and methods described in US 2015/0259420, incorporated by reference in its entirety.

Table 7. Amino acid and nucleotide sequences of exemplary anti-LAG-3 antibody molecules HC BAP050 clone I SEQ ID NO: 108 (Kabat) HCDR1 NYGMN SEQ ID NO: 109 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 110 (Kabat) HCDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 111 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 112 (Chothia) HCDR2 NTDTGE SEQ ID NO: 110 (Chothia) HCDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 113 VH QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 114 DNA encoding VH Caagtgcagctggtgcagtcgggagccgaagtgaagaagcctggagcctcggtgaaggtgtcgtgcaaggcatccggattcaccctcaccaattacgggatgaactgggtcagacaggcccggggtcaacggctggagtggatcggatggattaacaccgacaccggggagcctacctacgcggacgatttcaagggacggttcgtgttctcc ctcgacacctccgtgtccaccgcctacctccaaatctcctcactgaaagcggaggacaccgccgtgtactattgcgcgaggaacccgccctactactacggaaccaacaacgccgaagccatggactactggggccagggcaccactgtgactgtgtccagc SEQ ID NO: 115 DNA encoding VH CAGGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGAAACCTGGCGCCTCCGTGAAGGTGTCCTGCAAGGCCTCTGGCTTCACCCTGACCAACTACGGCATGAACTGGGTGCGACAGGCCAGGGGCCAGCGGCTGGAATGGATCGGCTGGATCAACACCGACACCGGCGAGCCTACCTACGCCGACGACTTCAAGGGCAGATTCGTGTTCTCCCTGGACACCTCCGTGTCCACCGCCTACCTGC AGATCTCCAGCCTGAAGGCCGAGGATACCGCCGTGTACTACTGCGCCCGGAACCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCT SEQ ID NO: 116 Heavy chain QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 123 DNA encoding the heavy chain caagtgcagctggtgcagtcgggagccgaagtgaagaagcctggagcctcggtgaaggtgtcgtgcaaggcatccggattcaccctcaccaattacgggatgaactgggtcagacaggcccggggtcaacggctggagtggatcggatggattaacaccgacaccggggagcctacctacgcggacgatttcaagggacggttcgtgttctcc ctcgacacctccgtgtccaccgcctacctccaaatctcctcactgaaagcggaggacaccgccgtgtactattgcgcgaggaacccgccctactactacggaaccaacaacgccgaagccatggactactggggccagggcaccactgtgactgtgtccagcgcgtccactaagggcccgtccgtgttccccctggcaccttgtagccggag cactagcgaatccaccgctgccctcggctgcctggtcaaggattacttcccggagcccgtgaccgtgtcctggaacagcggagccctgacctccggagtgcacaccttccccgctgtgctgcagagctccgggctgtactcgctgtcgtcggtggtcacggtgccttcatctagcctgggtaccaagacctacacttgcaacg tggaccacaagccttccaacactaaggtggacaagcgcgtcgaatcgaagtacggcccaccgtgcccgccttgtcccgcgccggagttcctcggcggtccctcggtctttctgttcccaccgaagcccaaggacactttgatgatttcccgcacccctgaagtgacatgcgtggtcgtggacgtgtcacagg aagatccggaggtgcagttcaattggtacgtggatggcgtcgaggtgcacaacgccaaaaccaagccgagggaggagcagttcaactccacttaccgcgtcgtgtccgtgctgacggtgctgcatcaggactggctgaacgggaaggagtacaagtgcaaagtgtccaacaagggacttcctagctcaatcgaaaagaccatctcgaa agccaagggacagccccgggaaccccaagtgtataccctgccaccgagccaggaagaaatgactaagaaccaagtctcattgacttgccttgtgaagggcttctacccatcggatatcgccgtggaatgggagtccaacggccagccggaaaacaactacaagaccacccctccggtgctggactcagacggatccttcttcctctactcgcggctgaccgtgg ataagagcagatggcaggagggaaatgtgttcagctgttctgtgatgcatgaagccctgcacaaccactacactcagaagtccctgtccctctccctggga SEQ ID NO: 124 DNA encoding the heavy chain CAGGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGAAACCTGGCGCCTCCGTGAAGGTGTCCTGCAAGGCCTCTGGCTTCACCCTGACCAACTACGGCATGAACTGGGTGCGACAGGCCAGGGGCCAGCGGCTGGAATGGATCGGCTGGATCAACACCGACACCGGCGAGCCTACCTACGCCGACGACTTCAAGGGCAGATTCGTGTTCTCCCTGGACACCTCCGTGTCCACCGCCTACCTGC AGATCTCCAGCCTGAAGGCCGAGGATACCGCCGTGTACTACTGCGCCCGGAACCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTATTGGGGCCAGGGCACCACGTGACCGTGTCCTCTGCTTCTACCAAGGGGCCCAGCGTGTTCCCCCTGGCCCCCTGCTCCAGAAGCACCAGCGAGAGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTACTTCCCCGAGCCGGTGACCGTGTCCTAA CAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCACCAAGACCTACACCTGTAACGTGGACCACAAGCCCAGCAACACCAAGGTGGACAAGAGGGTGGAGAGCAAGTACGGCCCACCCTGCCCCCCCTGCCCAGCCCCCGAGTTCCTGGGCGGACCCAGCGTGTTCCTGTT CCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGACGTGTCCCAGGAGGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTTTAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGTAAGG TCTCCAACAAGGGCCTGCCAAGCAGCATCGAAAAGACCATCAGCAAGGCCAAGGGCCAGCCTAGAGAGCCCCAGGTCTACACCCTGCCACCCAGCCAAGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCAAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTT CCTGTACAGCAGGCTGACCGTGGACAAGTCCAGATGGCAGGAGGGCAACGTCTTTAGCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCTGGGC LC BAP050 clone I SEQ ID NO: 117 (Kabat) LCDR1 SSSQDISNYLN SEQ ID NO: 118 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 119 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 120 (Chothia) LCDR1 SQDISNY SEQ ID NO: 121 (Chothia) LCDR2 YTS SEQ ID NO: 122 (Chothia) LCDR3 YYNLPW SEQ ID NO: 125 VL DIQMTQSPSSLSSASVGDRVTITCSSSQDISNYLNWYLQKPGQSPQLLIYYTSTLHLGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 126 DNA encoding VL Gatattcagatgactcagtcacctagtagcctgagcgctagtgtgggcgatagagtgactatcacctgtagctctagtcaggatatctctaactacctgaactggtatctgcagaagcccggtcaatcacctcagctgctgatctactacactagcaccctgcacctgggcgtgccctctaggtttagcggtagcggtagtggcaccgagttcaccct gactatctctagcctgcagcccgacgacttcgctacctactactgtcagcagtactataacctgccctggaccttcggtcaaggcactaaggtcgagattaag SEQ ID NO: 127 DNA encoding VL GACATCCAGATGACCCAGTCCCCCTCCAGCCTGTCTGCTTCCGTGGGCGACAGAGTGACCATCACCTGTTCCTCCAGCCAGGACATCTCCAACTACCTGAACTGGTATCTGCAGAAGCCCGGCCAGTCCCCTCAGCTGCTGATCTACTACACCTCCACCCTGCACCTGGGCGTGCCCTCCAGATTTTCCGGCTCTGGCTCTGGCACCGAGTTTACCCTGACCATCAGCTCCCTGCAGCCCGACGACT TCGCCACCTACTACTGCCAGCAGTACTACAACCTGCCCTGGACCTTCGGCCAGGGCACCAAGGTGGAAATCAAG SEQ ID NO: 128 Light chain DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYLQKPGQSPQLLIYYTSTLHLGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK HKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 129 DNA encoding the light chain Gatattcagatgactcagtcacctagtagcctgagcgctagtgtgggcgatagagtgactatcacctgtagctctagtcaggatatctctaactacctgaactggtatctgcagaagcccggtcaatcacctcagctgctgatctactacactagcaccctgcacctgggcgtgccctctaggtttagcggtagcggtagtggcaccgagttcaccct gactatctctagcctgcagcccgacgacttcgctacctactactgtcagcagtactataacctgccctggaccttcggtcaaggcactaaggtcgagattaagcgtacggtggccgctcccagcgtgttcatcttcccccccagcgacgagcagctgaagagcggcaccgccagcgtggtgtgcctgctgaacaacttctacc cccgggaggccaaggtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggagagcgtcaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgaccctgagcaaggccgactacgagaagcataaggtgtacgcctgcgaggtgacccaccagggcctgtccagccccgtgaccaagagcttcaacagggg cgagtgc SEQ ID NO: 130 DNA encoding the light chain GACATCCAGATGACCCAGTCCCCCTCCAGCCTGTCTGCTTCCGTGGGCGACAGAGTGACCATCACCTGTTCCTCCAGCCAGGACATCTCCAACTACCTGAACTGGTATCTGCAGAAGCCCGGCCAGTCCCCTCAGCTGCTGATCTACTACACCTCCACCCTGCACCTGGGCGTGCCCTCCAGATTTTCCGGCTCTGGCTCTGGCACCGAGTTTACCCTGACCATCAGCTCCCTGCAGCCCGACGACT TCGCCACCTACTACTGCCAGCAGTACTACAACCTGCCCTGGACCTTCGGCCAGGGCACCAAGGTGGAAATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCAAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCAGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCAC CGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC HC BAP050 clone J SEQ ID NO: 108 (Kabat) HCDR1 NYGMN SEQ ID NO: 109 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 110 (Kabat) HCDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 111 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 112 (Chothia) HCDR2 NTDTGE SEQ ID NO: 110 (Chothia) HCDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 131 VH QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 132 DNA encoding VH Caggtgcagctggtgcagtcaggcgccgaagtgaagaaacccggcgctagtgtgaaagtcagctgtaaagctagtggcttcaccctgactaactacgggatgaactgggtccgccaggccccaggtcaaggcctcgagtggatgggctggattaacaccgacaccggcgagcctacctacgccgacgactttaagggcagattcgtgt ttagcctggacactagtgtgtctaccgcctacctgcagatctctagcctgaaggccgaggacaccgccgtctactactgcgctagaaaccccccctactacggcactaacaacgccgaggctatggactactggggtcaaggcactaccgtgaccgtgtctagc SEQ ID NO: 133 DNA encoding VH CAGGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGAAACCTGGCGCCTCCGTGAAGGTGTCCTGCAAGGCCTCTGGCTTCACCCTGACCAACTACGGCATGAACTGGGTGCGACAGGCCCCTGGACAGGGCCTGGAATGGATGGGCTGGATCAACACCGACACCGGCGAGCCTACCTACGCCGACGACTTCAAGGGCAGATTCGTGTTCTCCCTGGACACCTCCGTGTCCACCGCCTACCTGC AGATCTCCAGCCTGAAGGCCGAGGATACCGCCGTGTACTACTGCGCCCGGAACCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCT SEQ ID NO: 134 Heavy chain QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 135 DNA encoding the heavy chain caggtgcagctggtgcagtcaggcgccgaagtgaagaaacccggcgctagtgtgaaagtcagctgtaaagctagtggcttcaccctgactaactacgggatgaactgggtccgccaggccccaggtcaaggcctcgagtggatgggctggattaacaccgacaccggcgagcctacctacgccgacgactttaagggcagattcgtgt ttagcctggacactagtgtgtctaccgcctacctgcagatctctagcctgaaggccgaggacaccgccgtctactactgcgctagaaaccccccctactacggcactaacaacgccgaggctatggactactggggtcaaggcactaccgtgaccgtgtctagcgctagcactaagggcccgtccgtgttccccctggcaccttgtagccggagc actagcgaatccaccgctgccctcggctgcctggtcaaggattacttcccggagcccgtgaccgtgtcctggaacagcggagccctgacctccggagtgcacaccttccccgctgtgctgcagagctccgggctgtactcgctgtcgtcggtggtcacggtgccttcatctagcctgggtaccaagacctacacttgcaacgt ggaccacaagccttccaacactaaggtggacaagcgcgtcgaatcgaagtacggcccaccgtgcccgccttgtcccgcgccggagttcctcggcggtccctcggtctttctgttcccaccgaagcccaaggacactttgatgatttcccgcacccctgaagtgacatgcgtggtcgtggacgtgtcacagga agatccggaggtgcagttcaattggtacgtggatggcgtcgaggtgcacaacgccaaaaccaagccgagggaggagcagttcaactccacttaccgcgtcgtgtccgtgctgacggtgctgcatcaggactggctgaacgggaaggagtacaagtgcaaagtgtccaacaagggacttcctagctcaatcgaaaagaccatctcgaaag ccaagggacagccccgggaaccccaagtgtataccctgccaccgagccaggaagaaatgactaagaaccaagtctcattgacttgccttgtgaagggcttctacccatcggatatcgccgtggaatgggagtccaacggccagccggaaaacaactacaagaccacccctccggtgctggactcagacggatccttcttcctctactcgcggctgaccgtggata agagcagatggcaggagggaaatgtgttcagctgttctgtgatgcatgaagccctgcacaaccactacactcagaagtccctgtccctctccctggga SEQ ID NO: 136 DNA encoding the heavy chain CAGGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGAAACCTGGCGCCTCCGTGAAGGTGTCCTGCAAGGCCTCTGGCTTCACCCTGACCAACTACGGCATGAACTGGGTGCGACAGGCCCCTGGACAGGGCCTGGAATGGATGGGCTGGATCAACACCGACACCGGCGAGCCTACCTACGCCGACGACTTCAAGGGCAGATTCGTGTTCTCCCTGGACACCTCCGTGTCCACCGCCTACCTGC AGATCTCCAGCCTGAAGGCCGAGGATACCGCCGTGTACTACTGCGCCCGGAACCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTATTGGGGCCAGGGCACCACGTGACCGTGTCCTCTGCTTCTACCAAGGGGCCCAGCGTGTTCCCCCTGGCCCCCTGCTCCAGAAGCACCAGCGAGAGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTACTTCCCCGAGCCGGTGACCGTGTCCTAA CAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCACCAAGACCTACACCTGTAACGTGGACCACAAGCCCAGCAACACCAAGGTGGACAAGAGGGTGGAGAGCAAGTACGGCCCACCCTGCCCCCCCTGCCCAGCCCCCGAGTTCCTGGGCGGACCCAGCGTGTTCCTGTT CCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGACGTGTCCCAGGAGGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTTTAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGTAAGG TCTCCAACAAGGGCCTGCCAAGCAGCATCGAAAAGACCATCAGCAAGGCCAAGGGCCAGCCTAGAGAGCCCCAGGTCTACACCCTGCCACCCAGCCAAGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCAAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTT CCTGTACAGCAGGCTGACCGTGGACAAGTCCAGATGGCAGGAGGGCAACGTCTTTAGCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCTGGGC LC BAP050 clone J SEQ ID NO: 117 (Kabat) LCDR1 SSSQDISNYLN SEQ ID NO: 118 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 119 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 120 (Chothia) LCDR1 SQDISNY SEQ ID NO: 121 (Chothia) LCDR2 YTS SEQ ID NO: 122 (Chothia) LCDR3 YYNLPW SEQ ID NO: 137 VL DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPPRFSGSGYGTDFTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 138 DNA encoding VL Gatattcagatgactcagtcacctagtagcctgagcgctagtgtgggcgatagagtgactatcacctgtagctctagtcaggatatctctaactacctgaactggtatcagcagaagcccggtaaagcccctaagctgctgatctactacactagcaccctgcacctgggaatcccccctaggtttagcggtagcggctacggcaccgacttcaccctgactattaa caatatcgagtcagaggacgccgcctactacttctgtcagcagtactataacctgccctggaccttcggtcaaggcactaaggtcgagattaag SEQ ID NO: 139 DNA encoding VL GACATCCAGATGACCCAGTCCCCCTCCAGCCTGTCTGCTTCCGTGGGCGACAGAGTGACCATCACCTGTTCCTCCAGCCAGGACATCTCCAACTACCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATCTACTACACCTCCACCCTGCACCTGGGCATCCCCCCTAGATTCTCCGGCTCTGGCTACGGCACCGACTTCACCCTGACCATCAACAACATCGAGTCCGAGGACGCCGC CTACTACTTCTGCCAGCAGTACTACAACCTGCCCTGGACCTTCGGCCAGGGCACCAAGGTGGAAATCAAG SEQ ID NO: 140 Light chain DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPPRFSGSGYGTDFTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH KVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 141 DNA encoding the light chain Gatattcagatgactcagtcacctagtagcctgagcgctagtgtgggcgatagagtgactatcacctgtagctctagtcaggatatctctaactacctgaactggtatcagcagaagcccggtaaagcccctaagctgctgatctactacactagcaccctgcacctgggaatcccccctaggtttagcggtagcggctacggcaccgacttcaccctgactattaa caatatcgagtcagaggacgccgcctactacttctgtcagcagtactataacctgccctggaccttcggtcaaggcactaaggtcgagattaagcgtacggtggccgctcccagcgtgttcatcttcccccccagcgacgagcagctgaagagcggcaccgccagcgtggtgtgcctgctgaacaacttctacccccgggagg ccaaggtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggagagcgtcaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgaccctgagcaaggccgactacgagaagcataaggtgtacgcctgcgaggtgacccaccagggcctgtccagccccgtgaccaagagcttcaacaggggcgagtg c SEQ ID NO: 142 DNA encoding the light chain GACATCCAGATGACCCAGTCCCCCTCCAGCCTGTCTGCTTCCGTGGGCGACAGAGTGACCATCACCTGTTCCTCCAGCCAGGACATCTCCAACTACCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATCTACTACACCTCCACCCTGCACCTGGGCATCCCCCCTAGATTCTCCGGCTCTGGCTACGGCACCGACTTCACCCTGACCATCAACAACATCGAGTCCGAGGACGCCGC CTACTACTTCTGCCAGCAGTACTACAACCTGCCCTGGACCTTCGGCCAGGGCACCAAGGTGGAAATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCAAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCAGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAG CAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC HC BAP050 clone I SEQ ID NO: 143 (Kabat) HCDR1 aattacgggatgaac SEQ ID NO: 144 (Kabat) HCDR1 AACTACGGCATGAAC SEQ ID NO: 145 (Kabat) HCDR2 tggattaacaccgacaccggggagcctacctacgcggacgatttcaaggga SEQ ID NO: 146 (Kabat) HCDR2 TGGATCAACACCGACACCGGCGAGCCTACCTACGCCGACGACTTCAAGGGC SEQ ID NO: 147 (Kabat) HCDR3 aacccgccctactacggaaccaacaacgccgaagccatggactac SEQ ID NO: 148 (Kabat) HCDR3 AACCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTAT SEQ ID NO: 149 (Chothia) HCDR1 ggattcaccctcaccaattac SEQ ID NO: 150 (Chothia) HCDR1 GGCTTCACCCTGACCAACTAC SEQ ID NO: 151 (Chothia) HCDR2 aacaccgacaccggggag SEQ ID NO: 152 (Chothia) HCDR2 AACACCGACACCGGCGAG SEQ ID NO: 147 (Chothia) HCDR3 aacccgccctactacggaaccaacaacgccgaagccatggactac SEQ ID NO: 148 (Chothia) HCDR3 AACCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTAT LC BAP050 clone I SEQ ID NO: 153 (Kabat) LCDR1 agctctagtcaggatatctctaactacctgaac SEQ ID NO: 154 (Kabat) LCDR1 TCCTCCAGCCAGGACATCTCCAACTACCTGAAC SEQ ID NO: 155 (Kabat) LCDR2 tacactagcaccctgcacctg SEQ ID NO: 156 (Kabat) LCDR2 TACACCTCCACCCTGCACCTG SEQ ID NO: 157 (Kabat) LCDR3 cagcagtactataacctgccctggacc SEQ ID NO: 158 (Kabat) LCDR3 CAGCAGTACTACAACCTGCCCTGGACC SEQ ID NO: 159 (Chothia) LCDR1 agtcaggatatctctaactac SEQ ID NO: 160 (Chothia) LCDR1 AGCCAGGACATCTCCAACTAC SEQ ID NO: 161 (Chothia) LCDR2 tacactagc SEQ ID NO: 162 (Chothia) LCDR2 TACACCTCC SEQ ID NO: 163 (Chothia) LCDR3 tactataacctgccctgg SEQ ID NO: 164 (Chothia) LCDR3 TACTACAACCTGCCCTGG HC BAP050 clone J SEQ ID NO: 165 (Kabat) HCDR1 aactacgggatgaac SEQ ID NO: 144 (Kabat) HCDR1 AACTACGGCATGAAC SEQ ID NO: 166 (Kabat) HCDR2 tggattaacaccgacaccggcgagcctacctacgccgacgactttaagggc SEQ ID NO: 146 (Kabat) HCDR2 TGGATCAACACCGACACCGGCGAGCCTACCTACGCCGACGACTTCAAGGGC SEQ ID NO: 167 (Kabat) HCDR3 aaccccccctactactacggcactaacaacgccgaggctatggactac SEQ ID NO: 148 (Kabat) HCDR3 AACCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTAT SEQ ID NO: 168 (Chothia) HCDR1 ggcttcaccctgactaactac SEQ ID NO: 150 (Chothia) HCDR1 GGCTTCACCCTGACCAACTAC SEQ ID NO: 151 (Chothia) HCDR2 aacaccgacaccggggag SEQ ID NO: 152 (Chothia) HCDR2 AACACCGACACCGGCGAG SEQ ID NO: 167 (Chothia) HCDR3 aaccccccctactactacggcactaacaacgccgaggctatggactac SEQ ID NO: 148 (Chothia) HCDR3 AACCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTAT LC BAP050 clone J SEQ ID NO: 153 (Kabat) LCDR1 agctctagtcaggatatctctaactacctgaac SEQ ID NO: 154 (Kabat) LCDR1 TCCTCCAGCCAGGACATCTCCAACTACCTGAAC SEQ ID NO: 155 (Kabat) LCDR2 TACACTAGCACCCTGCACCTG SEQ ID NO: 156 (Kabat) LCDR2 TACACCTCCACCCTGCACCTG SEQ ID NO: 157 (Kabat) LCDR3 cagcagtactataacctgccctggacc SEQ ID NO: 158 (Kabat) LCDR3 CAGCAGTACTACAACCTGCCCTGGACC SEQ ID NO: 159 (Chothia) LCDR1 agtcaggatatctctaactac SEQ ID NO: 160 (Chothia) LCDR1 AGCCAGGACATCTCCAACTAC SEQ ID NO: 161 (Chothia) LCDR2 TACACTAGC SEQ ID NO: 162 (Chothia) LCDR2 TACACCTCC SEQ ID NO: 163 (Chothia) LCDR3 tactataacctgccctgg SEQ ID NO: 164 (Chothia) LCDR3 TACTACAACCTGCCCTGG

Other exemplary LAG-3 inhibitors

In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule. In one embodiment, the LAG-3 inhibitor is BMS-986016 (Bristol-Myers Squibb), also known as BMS986016. BMS-986016 and other anti-LAG-3 antibodies are disclosed in WO 2015/116539 and US 9505839, incorporated by reference in their entirety. In one embodiment, the anti-LAG-3 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a BMS-986016 heavy chain or light chain sequence, e.g. disclosed in table 8.

In one embodiment, the anti-LAG-3 antibody molecule is TSR-033 (Tesaro). In one embodiment, the anti-LAG-3 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a TSR-033 heavy chain or light chain sequence.

In one embodiment, the anti-LAG-3 antibody molecule is IMP731 or GSK2831781 (GSK and Prima BioMed). IMP731 and other anti-LAG-3 antibodies are disclosed in WO 2008/132601 and US 9244059, incorporated by reference in their entirety. In one embodiment, the anti-LAG-3 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or an IMP731 heavy chain or light chain sequence, e.g. disclosed in Table 8. In one embodiment, the anti-LAG-3 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence GSK2831781.

In one embodiment, the anti-LAG-3 antibody molecule is IMP761 (Prima BioMed). In one embodiment, the anti-LAG-3 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or an IMP761 heavy chain or light chain sequence.

Additional known antibodies to LAG-3 include those described, for example, in WO 2008/132601, WO 2010/019570, WO 2014/140180, WO 2015/116539, WO 2015/200119, WO 2016/028672, US 9244059, US 9505839, incorporated by reference in their entirety.

In one embodiment, an anti-LAG-3 antibody is an antibody that competes for binding and/or binds to the same epitope on LAG-3 as one of the anti-LAG-3 antibodies described herein.

In one embodiment, the anti-LAG-3 antibody inhibitor is a soluble form of the LAG-3 protein, e.g. IMP321 (Prima BioMed), for example, disclosed in WO 2009/044273, incorporated by reference in its entirety.

Table 8. Amino acid sequences of other exemplary anti-LAG-3 antibody molecules BMS-986016 SEQ ID NO: 169 Heavy chain QVQLQQWGAGLLKPSETLSLTCAVYGGSFSDYYWNWIRQPPGKGLEWIGEINHRGSTNSNPSLKSRVTLSLDTSKNQFSLKLRSVTAADTAVYYCAFGYSDYEYNWFDPWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 170 Light chain EIVLTQSPATLSLSPGERATLSCRASQSISSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGQGTNLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG LSSPVTKSFNRGEC IMP731 SEQ ID NO: 171 Heavy chain QVQLKESGPGLVAPSQSLSITCTVSGFSLTAYGVNWVRQPPGKGLEWLGMIWDDGSTDYNSALKSRLSISKDNSKSQVFLKMNSLQTDDTARYYCAREGDVAFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN HKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 172 Light chain DIVMTQSPSSLAVSVGQKVTMSCKSSQSLLNGSNQKNYLAWYQQKPGQSPKLLVYFASTRDSGVPDRFIGSGSGTDFTLTISSVQAEDLADYFCLQHFGTPPTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK HKVYACEVTHQGLSSPVTKSFNRGEC

TIM-3 inhibitors

In certain embodiments, the immune checkpoint molecule inhibitor is a TIM-3 inhibitor. In some embodiments, compounds of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof of the present invention are used in combination with a TIM-3 inhibitor to treat a disease, e.g. cancer. In some embodiments, the TIM-3 inhibitor is MGB453 (Novartis) or TSR-022 (Tesaro).

Exemplary TIM-3 Inhibitors

In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule. In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule disclosed in US 2015/0218274, published August 6, 2015 entitled "Antibody Molecules to TIM-3 and Uses Thereof", incorporated by reference in its entirety completeness.

In one embodiment, the anti-TIM-3 antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 9 (e.g. from the heavy and light chain variable region sequences of ABTIM3-hum11 or ABTIM3-hum03 disclosed in Table 9), or the encoded nucleotide sequence shown in Table 9. In some embodiments, the CDRs are as defined by Kabat (e.g. as set out in Table 9). In some embodiments, the CDRs are as defined by Chothia (eg, as set out in Table 9). In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, e.g. amino acid substitutions (for example, conservative amino acid substitutions) or deletions, compared to the amino acid sequence shown in Table 9 or the encoded nucleotide sequence shown in Table 9.

In one embodiment, an anti-TIM-3 antibody molecule comprises a heavy chain variable region (VH) comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 174, the amino acid sequence of VHCDR2 of SEQ ID NO: 175, and the amino acid sequence of VHCDR3 of SEQ ID NO: 176; and a light chain variable region (VL) comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 183, the amino acid sequence of VLCDR2 of SEQ ID NO: 184, and the amino acid sequence of VLCDR3 of SEQ ID NO: 185, each of which is disclosed in Table 9. In one in an embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain variable region (VH) comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 174, the amino acid sequence of VHCDR2 of SEQ ID NO: 193, and the amino acid sequence of VHCDR3 of SEQ ID NO: 176; and a light chain variable region (VL) comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 183, the amino acid sequence of VLCDR2 of SEQ ID NO: 184, and the amino acid sequence of VLCDR3 of SEQ ID NO: 185, each of which is disclosed in Table 9.

In one embodiment, the anti-TIM-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 179 or an amino acid sequence that is at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO : 179. In one embodiment, the anti-TIM-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 189 or an amino acid sequence that is at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 189. In one embodiment, the anti-TIM-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 195 or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical with respect to SEQ ID NO: 195. In one embodiment, the anti-TIM-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 199 or an amino acid sequence of at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 199. In one embodiment, the anti-TIM-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 179 and a VL comprising the amino acid sequence of SEQ ID NO: 189. In one In an embodiment, the anti-TIM-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 195 and a VL containing the amino acid sequence of SEQ ID NO: 199.

In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 180 or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 180. B in one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 190 or a nucleotide sequence that is at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 190. In one in an embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 196 or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 196. In one embodiment An antibody molecule comprises a VL encoded by a nucleotide sequence of SEQ ID NO: 200 or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 200. In one embodiment the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 180, and a VL encoded by the nucleotide sequence of SEQ ID NO: 190. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 196, and a VL, encoded by the nucleotide sequence under SEQ ID NO: 200.

In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 181 or an amino acid sequence that is at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 181. In one embodiment, the anti-TIM-3 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 191 or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical in with respect to SEQ ID NO: 191. In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 197 or an amino acid sequence of at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 197. In one embodiment, the anti-TIM-3 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 201 or an amino acid sequence of at least 85%, 90%, 95 % or 99% or greater identical to SEQ ID NO: 201. In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 181 and a light chain comprising the amino acid sequence of SEQ ID NO: 191. In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 197 and a light chain comprising the amino acid sequence of SEQ ID NO: 201.

In one embodiment, the antibody molecule contains a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 182 or a nucleotide sequence that is at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 182. In one embodiment, the antibody molecule contains a light chain encoded by the nucleotide sequence of SEQ ID NO: 192 or a nucleotide sequence that is at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 192. In one embodiment, the antibody molecule contains a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 198 or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 198. In one embodiment, the antibody molecule contains a light chain encoded by the nucleotide sequence of SEQ ID NO: 202 or a nucleotide sequence that is at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO: 202. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 182 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 192. In one embodiment, the antibody molecule contains a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 198, and the light chain encoded by the nucleotide sequence of SEQ ID NO: 202.

The antibody molecules described herein can be produced using the vectors, host cells and methods described in US 2015/0218274, incorporated by reference in its entirety.

Table 9. Amino acid and nucleotide sequences of exemplary anti-TIM-3 antibody molecules ABTIM3-hum11 SEQ ID NO: 174 (Kabat) HCDR1 SYNMH SEQ ID NO: 175 (Kabat) HCDR2 DIYPGNGDTSYNQKFKG SEQ ID NO: 176 (Kabat) HCDR3 VGGAFMDY SEQ ID NO: 177 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 178 (Chothia) HCDR2 YPGNGD SEQ ID NO: 176 (Chothia) HCDR3 VGGAFMDY SEQ ID NO: 179 VH QVQLVQSGAEVKKPGSSVKVSCKASGYTFTSYNMHWVRQAPGQGLEWMGDIYPGNGDTSYNQKFKGRVTITADKSTSTVYMELSSLRSEDTAVYYCARVGGAFMDYWGQGTTVTVSS SEQ ID NO: 180 DNA encoding VH CAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAACCCGGCTCTAGCGTGAAAGTTTCTTGTAAAGCTAGTGGCTACACCTTCACTAGCTATAATATGCACTGGGTTCGCCAGGCCCAGGGCAAGGCCTCGAGTGGATGGGCGATATCTACCCCGGGAACGGCGACACTAGTTATAATCAGAAGTTTAAGGGTAGAGTCACTATCACCGCCGATAAGTCTACTAGCACCGTCTATATGGA ACTGAGTTCCCTGAGGTCTGAGGACACCGCCGTCTACTACTGCGCTAGAGTGGGCGGAGCCTTCCCTATGGACTACTGGGGTCAAGGCACTACCGTGACCGTGTCTAGC SEQ ID NO: 181 Heavy chain QVQLVQSGAEVKKPGSSVKVSCKASGYTFTSYNMHWVRQAPGQGLEWMGDIYPGNGDTSYNQKFKGRVTITADKSTSTVYMELSSLRSEDTAVYYCARVGGAFPMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 182 DNA encoding the heavy chain CAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAACCCGGCTCTAGCGTGAAAGTTTCTTGTAAAGCTAGTGGCTACACCTTCACTAGCTATAATATGCACTGGGTTCGCCAGGCCCAGGGCAAGGCCTCGAGTGGATGGGCGATATCTACCCCGGGAACGGCGACACTAGTTATAATCAGAAGTTTAAGGGTAGAGTCACTATCACCGCCGATAAGTCTACTAGCACCGTCTATATGGA ACTGAGTTCCCTGAGGTCTGAGGACACCGCCGTCTACTACTGCGCTAGAGTGGGCGGAGCCTTCCCTATGGACTACTGGGGTCAAGGCACTACCGTGACCGTGTCTAGCGCTAGCACTAAGGGCCCGTCCGTGTTCCCCCTGGCACCTTGTAGCCGGAGCACTAGCGAATCCACCGCTGCCCTCGGCTGCCTGGTCAAGGATTACTTCCCGGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACC TCCGGAGTGCACACCTTCCCCGCTGTGCTGCAGAGCTCCGGGCTGTACTCGCTGTCGTCGGTGGTCACGGTGCCTTCATCTAGCCTGGGTACCAAGACCTACACTTGCAACGTGGACCACAAGCCTTCCAACACTAAGGTGGACAAGCGCGTCGAATCGAAGTACGGCCCACGTGCCCGCCTTGTCCCGCGCCGGAGTTCCTCGGCGGTCCCTCGGTCTTTCTGTTCCCACCGAAGCCCAAG GACACTTTGATGATTTCCCGCACCCCTGAAGTGACATGCGTGGTCGTGGACGTGTCACAGGAAGATCCGGAGGTGCAGTTCAATTGGTACGTGGATGGCGTCGAGGTGCACAACGCCAAAACCAAGCCGAGGGAGGAGCAGTTCAACTCCACTTACCGCGTCGTGTCCGTGCTGACGGTGCTGCATCAGGACTGGCTGAACGGGAAGGAGTACAAGTGCAAAGTGTCCAACAAGGGACTTC CTAGCTCAATCGAAAAGACCATCTCGAAAGCCAAGGGACAGCCCCGGGAACCCCAAGTGTATACCCTGCCACCGAGCCAGGAAGAAATGACTAAGAACCAAGTCTCATTGACTTGCCTTGTGAAGGGCTTCTACCCATCGGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCGGAAAACAACTACAAGACCACCCCTCCGGTGCTGGACTCAGACGGATCCTTCTTCCCTACTCGCGGCTGACCGTGGATA AGAGCAGATGGCAGGAGGGAAATGTGTTCAGCTGTTCTGTGATGCATGAAGCCCTGCACAACCACTACACTCAGAAGTCCCTGTCCCTCTCCCTGGGA SEQ ID NO: 183 (Kabat) LCDR1 RASESVEYYGTSLMQ SEQ ID NO: 184 (Kabat) LCDR2 AASNVES SEQ ID NO: 185 (Kabat) LCDR3 QQSRKDPST SEQ ID NO: 186 (Chothia) LCDR1 SESVEYYGTSL SEQ ID NO: 187 (Chothia) LCDR2 A.A.S. SEQ ID NO: 188 (Chothia) LCDR3 SRKDPS SEQ ID NO: 189 VL AIQLTQSPSSLSSASVGDRVTITCRASESVEYYGTSLMQWYQQKPGKAPKLLIYAASNVESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSRKDPSTFGGGTKVEIK SEQ ID NO: 190 DNA encoding VL GCTATTCAGCTGACTCAGTCACCTAGTAGCCTGAGCGCTAGTGTGGGCGATAGAGTGACTATCACCTGTAGAGCTAGTGAATCAGTCGAGTACTACGGCACTAGCCTGATGCAGTGGTATCAGCAGAAGCCCGGGAAAGCCCCTAAGCTGCTGATCTACGCCGCCTCTAACGTGGAATCAGGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCACCCTGACTATCTCTAGCC TGCAGCCCGAGGACTTCGCTACCTACTTCTGTCAGCAGTCTAGGAAGGACCCTAGCACCTTCGGCGGAGGCACTAAGGTCGAGATTAAG SEQ ID NO: 191 Light chain AIQLTQSPSSLSASVGDRVTITCRASESVEYYGTSLMQWYQQKPGKAPKLLIYAASNVESGVPSRFSGSGSGTDFTISSLQPEDFATYFCQQSRKDPSTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 192 DNA encoding the light chain GCTATTCAGCTGACTCAGTCACCTAGTAGCCTGAGCGCTAGTGTGGGCGATAGAGTGACTATCACCTGTAGAGCTAGTGAATCAGTCGAGTACTACGGCACTAGCCTGATGCAGTGGTATCAGCAGAAGCCCGGGAAAGCCCCTAAGCTGCTGATCTACGCCGCCTCTAACGTGGAATCAGGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCACCCTGACTATCTCTAGCC TGCAGCCCGAGGACTTCGCTACCTACTTCTGTCAGCAGTCTAGGAAGGACCCTAGCACCTTCGGCGGAGGCACTAAGGTCGAGATTAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAG CCAGGAGACGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC ABTIM3-hum03 SEQ ID NO: 174 (Kabat) HCDR1 SYNMH SEQ ID NO: 193 (Kabat) HCDR2 DIYPGQGDTSYNQKFKG SEQ ID NO: 176 (Kabat) HCDR3 VGGAFMDY SEQ ID NO: 177 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 194 (Chothia) HCDR2 YPGQGD SEQ ID NO: 176 (Chothia) HCDR3 VGGAFMDY SEQ ID NO: 195 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYNMHWVRQAPGQGLEWIGDIYPGQGDTSYNQKFKGRATMTADKSTSTVYMELSSLRSEDTAVYYCARVGGAFPMDYWGQGTLVTVSS SEQ ID NO: 196 DNA encoding VH CAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAACCCGGCCTAGTGTGAAAGTTAGCTGTAAAGCTAGTGGCTATACTTTCACTTCTTATAATATGCACTGGGTCCGCCAGGCCCCAGGTCAAGGCCTCGAGTGGATCGGCGATATCTACCCCGGTCAAGGCGACACTTCCTATAATCAGAAGTTTAAGGGTAGAGCTACTATGACCGCCGATAAGTCTACTTCTACCGTCTATATGGA ACTGAGTTCCCTGAGGTCTGAGGACACCGCCGTCTACTACTGCGCTAGAGTGGGCGGAGCCTTCCCAATGGACTACTGGGGTCAAGGCACCCTGGTCACCGTGTCTAGC SEQ ID NO: 197 Heavy chain QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYNMHWVRQAPGQGLEWIGDIYPGQGDTSYNQKFKGRATMTADKSTSTVYMELSSLRSEDTAVYYCARVGGAFPMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTK TYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 198 DNA encoding the heavy chain CAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAACCCGGCCTAGTGTGAAAGTTAGCTGTAAAGCTAGTGGCTATACTTTCACTTCTTATAATATGCACTGGGTCCGCCAGGCCCCAGGTCAAGGCCTCGAGTGGATCGGCGATATCTACCCCGGTCAAGGCGACACTTCCTATAATCAGAAGTTTAAGGGTAGAGCTACTATGACCGCCGATAAGTCTACTTCTACCGTCTATATGGA ACTGAGTTCCCTGAGGTCTGAGGACACCGCCGTCTACTACTGCGCTAGAGTGGGCGGAGCCTTCCCAATGGACTACTGGGGTCAAGGCACCCTGGTCACCGTGTCTAGCGCTAGCACTAAGGGCCCGTCCGTGTTCCCCCTGGCACCTTGTAGCCGGAGCACTAGCGAATCCACCGCTGCCCTCGGCTGCCTGGTCAAGGATTACTTCCCGGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACC TCCGGAGTGCACACCTTCCCCGCTGTGCTGCAGAGCTCCGGGCTGTACTCGCTGTCGTCGGTGGTCACGGTGCCTTCATCTAGCCTGGGTACCAAGACCTACACTTGCAACGTGGACCACAAGCCTTCCAACACTAAGGTGGACAAGCGCGTCGAATCGAAGTACGGCCCACGTGCCCGCCTTGTCCCGCGCCGGAGTTCCTCGGCGGTCCCTCGGTCTTTCTGTTCCCACCGAAGCCCAAG GACACTTTGATGATTTCCCGCACCCCTGAAGTGACATGCGTGGTCGTGGACGTGTCACAGGAAGATCCGGAGGTGCAGTTCAATTGGTACGTGGATGGCGTCGAGGTGCACAACGCCAAAACCAAGCCGAGGGAGGAGCAGTTCAACTCCACTTACCGCGTCGTGTCCGTGCTGACGGTGCTGCATCAGGACTGGCTGAACGGGAAGGAGTACAAGTGCAAAGTGTCCAACAAGGGACTTC CTAGCTCAATCGAAAAGACCATCTCGAAAGCCAAGGGACAGCCCCGGGAACCCCAAGTGTATACCCTGCCACCGAGCCAGGAAGAAATGACTAAGAACCAAGTCTCATTGACTTGCCTTGTGAAGGGCTTCTACCCATCGGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCGGAAAACAACTACAAGACCACCCCTCCGGTGCTGGACTCAGACGGATCCTTCTTCCCTACTCGCGGCTGACCGTGGATA AGAGCAGATGGCAGGAGGGAAATGTGTTCAGCTGTTCTGTGATGCATGAAGCCCTGCACAACCACTACACTCAGAAGTCCCTGTCCCTCTCCCTGGGA SEQ ID NO: 183 (Kabat) LCDR1 RASESVEYYGTSLMQ SEQ ID NO: 184 (Kabat) LCDR2 AASNVES SEQ ID NO: 185 (Kabat) LCDR3 QQSRKDPST SEQ ID NO: 186 (Chothia) LCDR1 SESVEYYGTSL SEQ ID NO: 187 (Chothia) LCDR2 A.A.S. SEQ ID NO: 188 (Chothia) LCDR3 SRKDPS SEQ ID NO: 199 VL DIVLTQSPDSLAVSLGERATINCRASESVEYYGTSLMQWYQQKPGQPPKLLIYAASNVESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSRKDPSTFGGGTKVEIK SEQ ID NO: 200 DNA encoding VL GATATCGTCCTGACTCAGTCACCCGATAGCCTGGCCGTCAGCCTGGGCGAGCGGGCTACTATTAACTGTAGAGCTAGTGAATCAGTCGAGTACTACGGCACTAGCCTGATGCAGTGGTATCAGCAGAAGCCCGGTCAACCCCCTAAGCTGCTGATCTACGCCGCCTCTAACGTGGAATCAGGCGTGCCCGATAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCACCCTGACTATTAGTAGC CTGCAGGCCGAGGACGTGGCCGTCTACTACTGTCAGCAGTCTAGGAAGGACCCTAGCACCTTCGGCGGAGGCACTAAGGTCGAGATTAAG SEQ ID NO: 201 Light chain DIVLTQSPDSLAVSLGERATINCRASESVEYYGTSLMQWYQQKPGQPPKLLIYAASNVESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSRKDPSTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK VYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 202 DNA encoding the light chain GATATCGTCCTGACTCAGTCACCCGATAGCCTGGCCGTCAGCCTGGGCGAGCGGGCTACTATTAACTGTAGAGCTAGTGAATCAGTCGAGTACTACGGCACTAGCCTGATGCAGTGGTATCAGCAGAAGCCCGGTCAACCCCCTAAGCTGCTGATCTACGCCGCCTCTAACGTGGAATCAGGCGTGCCCGATAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCACCCTGACTATTAGTAGC CTGCAGGCCGAGGACGTGGCCGTCTACTACTGTCAGCAGTCTAGGAAGGACCCTAGCACCTTCGGCGGAGGCACTAAGGTCGAGATTAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAAC AGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC

Other exemplary TIM-3 inhibitors

In one embodiment, the anti-TIM-3 antibody molecule is TSR-022 (AnaptysBio/Tesaro). In one embodiment, the anti-TIM-3 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a TSR-022 heavy chain or light chain sequence. In one embodiment, the anti-TIM-3 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence of APE5137 or APE5121, e.g. disclosed in Table 10. APE5137, APE5121 and other anti-TIM-3 antibodies are disclosed in WO 2016/161270, incorporated by reference in its entirety.

In one embodiment, the anti-TIM-3 antibody molecule is an antibody of clone F38-2E2. In one embodiment, the anti-TIM-3 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or an F38-2E2 heavy chain or light chain sequence.

Additional known antibodies to TIM-3 include those described, for example, in WO 2016/111947, WO 2016/071448, WO 2016/144803, US 8552156, US 8841418 and US 9163087, incorporated by reference in their entirety.

In one embodiment, an anti-TIM-3 antibody is an antibody that competes for binding and/or binds to the same epitope on TIM-3 as one of the anti-TIM-3 antibodies described herein.

Table 10. Amino acid sequences of other exemplary anti-TIM-3 antibody molecules APE5137 SEQ ID NO: 203 VH EVQLLESGGGLVQPGGSLRLSCAAASGFTFSSYDMSWVRQAPGKGLDWVSTISGGGTYTYYQDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASMDYWGQGTTVTVSSA SEQ ID NO: 204 VL DIQMTQSPSSLSSASVGDRVTITCRASQSIRRYLNWYHQKPGKAPKLLIYGASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFAVYYCQQSHSAPLTFGGGTKVEIKR APE5121 SEQ ID NO: 205 VH EVQVLESGGGLVQPGGSLRLYCVASGFTFSGSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKKYYVGPADYWGQGTLVTVSSG SEQ ID NO: 206 VL DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQHKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSSPLTFGGGTKIEVK

Cytokines

In yet another embodiment, the compounds of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof of the present invention are used in combination with one or more cytokines, including but not limited to interferon, IL-2, IL-15, IL-7 or IL21. In certain embodiments, compounds of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof are administered in combination with the IL-15/IL-15Ra complex. In some embodiments, the IL-15/IL-15Ra complex is selected from NIZ985 (Novartis), ATL-803 (Altor), or CYP0150 (Cytune).

Exemplary IL-15/IL-15Ra complexes

In one embodiment, the cytokine is IL-15 complexed with a soluble form of IL-15 receptor alpha (IL-15Ra). The IL-15/IL-15Ra complex may contain IL-15 covalently or non-covalently associated with a soluble form of IL-15Ra. In a specific embodiment, human IL-15 is non-covalently associated with a soluble form of IL-15Ra. In a specific embodiment, the human IL-15 formulation comprises the amino acid sequence of SEQ ID NO: 207 in Table 11, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO : 207, and the soluble form of human IL-15Ra contains the amino acid sequence of SEQ ID NO: 208 in Table 11 or an amino acid sequence that is at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO : 208, described in WO 2014/066527, incorporated by reference in its entirety. The molecules described herein can be produced using the vectors, host cells and methods described in WO 2007084342, incorporated by reference in its entirety.

Table 11. Amino acid and nucleotide sequences of exemplary IL-15/IL-15Ra complexes NIZ985 SEQ ID NO: 207 Human IL-15 NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS SEQ ID NO: 208 Soluble form of human IL-15Ra ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLTECVLNKATNVAHWTTPSLKCIRDPALVHQRPAPPSTVTTAGVTPQPESLSPSGKEPAASSPSSNNTAATTAAIVPGSQLMPSKSPSTGTTEISSHESSHGTPSQTTAKNWELTASASHQPPGVYPQG

Other Exemplary IL-15/IL-15Ra Complexes

In one embodiment, the IL-15/IL-15Ra complex is an ALT-803 IL-15/IL-15Ra and Fc fusion protein (IL-15N72D:IL-15RaSu/Fc soluble complex). ALT-803 is described in WO 2008/143794, incorporated by reference in its entirety. In one embodiment, the IL-15/IL-15Ra and Fc fusion protein contains the sequences disclosed in Table 12.

In one embodiment, the IL-15/IL-15Ra complex contains IL-15 fused to the Sushi domain of IL-15Ra (CYP0150, Cytune). The Sushi domain of IL-15Ra refers to the domain starting from the first cysteine residue after the signal peptide of IL-15Ra and ending with the fourth cysteine residue after the signal peptide. The IL-15 complex fused to the Sushi domain of IL-15Ra is described in WO 2007/04606 and WO 2012/175222, incorporated by reference in their entirety. In one embodiment, the IL-15/Sushi domain IL-15Ra fusion protein contains the sequences disclosed in Table 12.

Table 12. Amino acid sequences of other exemplary IL-15/IL-15Ra complexes ALT-803 SEQ ID NO: 209 IL-15N72D NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANDSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS SEQ ID NO: 210 IL-15RaSu/Fc ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLTECVLNKATNVAHWTTPSLKCIREPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK IL-15/Sushi domain IL-15Ra fusion protein (CYP0150) SEQ ID NO: 211 Human IL-15 NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEXKNIKEFLQSFVHIVQMFINTS
Where X represents E or K SEQ ID NO: 212 Sushi domain and hinge domain of human IL-15Ra ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLTECVLNKATNVAHWTTPSLKCIRDPALVHQRPAPP

In yet another embodiment, the compounds of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof of the present invention are used in combination with one or more toll-like receptor agonists (TLR, eg TLR7, TLR8, TLR9) for treating a disease such as cancer. In some embodiments, a compound of the present invention may be used in combination with a TLR7 agonist or a TLR7 agonist conjugate.

In some embodiments, the TLR7 agonist includes a compound disclosed in International Application Publication No. WO2011/049677, which is incorporated by reference in its entirety. In some embodiments, the TLR7 agonist includes 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid. In some embodiments, the TLR7 agonist includes a compound of the formula:

In another embodiment, the compounds of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof herein are used in combination with one or more angiogenesis inhibitors for the treatment of cancer, for example, bevacizumab (Avastin®), axitinib (Inlyta®); brivanib alaninate (BMS-582664, ( S )-(( R )-1-(4-(4-fluoro-2-methyl- 1H- indol-5-yloxy)-5-methylpyrrolo[2,1- f ] [1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate); sorafenib (Nexavar®); pazopanib (Votrient®); sunitinib malate (Sutent®); cediranib (AZD2171, CAS 288383-20-1); vargatef (BIBF1120, CAS 928326-83-4); foretinib (GSK1363089); telatinib (BAY57-9352, CAS 332012-40-5); apatinib (YN968D1, CAS 811803-05-1); imatinib (Gleevec®); ponatinib (AP24534, CAS 943319-70-8); tivozanib (AV951, CAS 475108-18-0); regorafenib (BAY73-4506, CAS 755037-03-7); vatalanib dihydrochloride (PTK787, CAS 212141-51-0); brivanib (BMS-540215, CAS 649735-46-6); vandetanib (Caprelsa® or AZD6474); motesanib diphosphate (AMG706, CAS 857876-30-3, N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide , described in publication according to PCT No. WO 02/066470); dovitinib with lactyl lactic acid (TKI258, CAS 852433-84-2); linfanib (ABT869, CAS 796967-16-3); cabozantinib (XL184, CAS 849217-68-1); lestaurtinib (CAS 111358-88-4); N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (BMS38703, CAS 345627-80-7); (3R,4R)-4-amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-3 -olom (BMS690514); N -(3,4-dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aα,5β,6aα)-octahydro-2-methylcyclopenta[ c ]pyrrol-5-yl]methoxy]-4-quinazolinamine (XL647, CAS 781613-23-8); 4-methyl-3-[[1-methyl-6-(3-pyridinyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-yl]amino]- N -[3-(trifluoromethyl)phenyl] -benzamide (BHG712, CAS 940310-85-0) or aflibercept (Eylea®).

In another embodiment, the compounds of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof of the present invention are used in combination with one or more heat shock protein inhibitors for the treatment of cancer, for example, tanespimicion (17-allylamino-17-demethoxygeldamycin, also known as KOS-953 and 17-AAG, available from SIGMA and described in US patent No. 4261989); retaspimycin (IPI504), ganetespib (STA-9090); [6-chloro-9-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-9H-purin-2-yl]amine (BIIB021 or CNF2024, CAS 848695-25-0); ester trans -4-[[2-(aminocarbonyl)-5-[4,5,6,7-tetrahydro-6,6-dimethyl-4-oxo-3-(trifluoromethyl)-1 H -indazole-1- yl]phenyl]amino]cyclohexylglycine (SNX5422 or PF04929113, CAS 908115-27-5); 5-[2,4-dihydroxy-5-(1-methylethyl)phenyl] -N -ethyl-4-[4-(4-morpholinylmethyl)phenyl]-3-isoxazolecarboxamide (AUY922, CAS 747412-49-3) or 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG).

In yet another embodiment, the compounds of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof of the present invention are used in combination with one or more HDAC inhibitors or other epigenetic modifiers. Exemplary HDAC inhibitors include, but are not limited to, voninostat (Zolinza®); romidepsin (Istodax®); Treychostatin A (TSA); oxamflatin; vorinostat (Zolinza®, suberoylanilide hydroxamic acid); pyroxamide (siberoyl-3-aminopyridinamidehydroxamic acid); trapoxin A (RF-1023A); trapoxin B (RF-10238); cyclo[(αS,2S)-α-amino-η-oxo-2-oxiranoctanoyl-O-methyl-D-tyrosyl-L-isoleucyl-L-prolyl] (Cyl-1); cyclo[(αS,2S)-α-amino-η-oxo-2-oxiranoctanoyl-O-methyl-D-tyrosyl-L-isoleucyl-(2S)-2-piperidinecarbonyl] (Cyl-2); cyclic [L-alanyl-D-alanyl-(2S)-η-oxo-L-α-aminooxiranoctanoyl-D-prolyl] (HC-toxin); cyclo[(αS,2S)-α-amino-η-oxo-2-oxiranoctanoyl-D-phenylalanyl-L-leucyl-(2S)-2-piperidinecarbonyl] (WF-3161); chlamydocin ((S)-cyclic(2-methylalanyl-L-phenylalanyl-D-prolyl-η-oxo-L-α-aminooxiranoctanoyl); apicidin (cyclo(8-oxo-L-2-aminodecanoyl-1-methoxy-L -tryptophil-L-isoleucyl-D-2-piperidinecarbonyl); romidepsin (Istodax®, FR-901228); 4-phenylbutyrate; spiruchostatin A; milproine (valproic acid); entinostat (MS-275, N-(2-aminophenyl) -4-[N-(pyridin-3-ylmethoxycarbonyl)-aminomethyl]benzamide); depudecin (4,5:8,9-dianhydro-1,2,6,7,11-pentadeoxy-D-trio-D-ido-undeca-1,6-dienitol); 4-(acetylamino)-N-(2-aminophenyl)-benzamide (also known as CI-994); N1-(2-aminophenyl)-N8-phenyloctanediamide (also known as BML-210); 4-(dimethylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide (also known as M344); (E)-3-(4-(((2-(1H-indol-3-yl)ethyl)(2-hydroxyethyl)amino)-methyl)phenyl)-N-hydroxyacrylamide; panobinostat (Farydak®); mocetinostat and belinostat (also known as PXD101, Beleodaq® or (2E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide) or chidamide (also known as CS055 or HBI-8000, (E)-N-(2-amino-5-fluorophenyl)-4-( (3-(pyridin-3-yl)acrylamido)methyl)benzamide). Other epigenetic modifiers include, but are not limited to, inhibitors of EZH2 (zeste homolog enhancer 2), EED (embryo ectoderm development protein), or LSD1 (lysine-specific histone demethylase 1A or KDM1A).

In yet another embodiment, the compounds of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof of the present invention are used in combination with one or more indoleamine pyrrole-2 inhibitors, 3-dioxygenase (IDO), e.g. indoximod (also known as NLG-8189), α-cyclohexyl-5H-imidazo[5,1-a]isoindole-5-ethanol (also known as NLG919) or (4E)-4 -[(3-chloro-4-fluoroanilino)-nitrosomethylidene]-1,2,5-oxadiazol-3-amine (also known as INCB024360), for the treatment of cancer.

Chimeric antigen receptors

The present invention provides compounds of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof for use in combination with adoptive immunotherapy methods and reagents such as immune effector cells with chimeric antigen receptor (CAR), for example, T cells or chimeric TCR-transduced immune effector cells, for example, T cells. This section describes CAR technology that is generally applicable in combination with compounds of formula (I') or formula (I) or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs thereof, stereoisomers or tautomers thereof, and describes CAR reagents, for example cells and compositions and methods.

In general, aspects of the present invention relate to or provide an isolated nucleic acid molecule encoding a chimeric antigen receptor (CAR), wherein the CAR contains an antigen binding domain (e.g., an antibody or antibody fragment, TCR or TCR fragment) that binds to a tumor antigen, described herein, a transmembrane domain (e.g., a transmembrane domain described herein) and an intracellular signaling domain (e.g., an intracellular signaling domain described herein) (e.g., an intracellular signaling domain containing a costimulatory domain (e.g., a costimulatory domain described herein) and/or a primary signaling domain (eg, the primary signaling domain described herein)). In other aspects, the present invention includes host cells containing the above nucleic acids, and isolated proteins encoded by such nucleic acid molecules. The nucleic acid constructs for CARs, the proteins they encode, vectors containing them, host cells, pharmaceutical compositions, and methods of administration and treatment associated with the present invention are disclosed in detail in International Patent Application Publication No. WO2015142675, which is incorporated by reference in its entirety.

In one aspect, the invention provides an isolated nucleic acid molecule encoding a chimeric antigen receptor (CAR), wherein the CAR contains an antigen-binding domain (e.g., an antibody or antibody fragment, TCR or TCR fragment) that binds to a tumor-maintaining antigen (e.g., an antigen tumor maintenance domain described herein), a transmembrane domain (e.g., a transmembrane domain described herein), and an intracellular signaling domain (e.g., an intracellular signaling domain described herein) (e.g., an intracellular signaling domain containing a costimulatory domain (eg, a costimulatory domain described herein) and/or a primary signaling domain (eg, a primary signaling domain described herein)). In some embodiments, the tumor maintenance antigen is an antigen present on a stromal cell or a myeloid-derived suppressor cell (MDSC). In other aspects of the present invention, polypeptides encoded by such nucleic acids and host cells containing such nucleic acids and/or polypeptides are described.

Alternatively, aspects of the present invention relate to an isolated nucleic acid encoding a chimeric T cell receptor (TCR) comprising a TCR alpha chain and/or TCR beta chain variable domain with specificity for a cancer antigen described herein. See, for example, Dembic et al., Nature, 320, 232-238 (1986), Schumacher, Nat. Rev. Immunol., 2, 512-519 (2002), Kershaw et al., Nat. Rev. Immunol., 5, 928-940 (2005), Xue et al., Clin. Exp. Immunol., 139, 167-172 (2005), Rossig et al., Mol. Ther., 10, 5-18 (2004) and Murphy et al., Immunity, 22, 403-414 (2005); (Morgan et al. J. Immunol., 171, 3287-3295 (2003), Hughes et al., Hum. Gene Ther., 16, 1-16 (2005), Zhao et al., J. Immunol., 174 , 4415-4423 (2005), Roszkowski et al., Cancer Res, 65, 1570-1576 (2005) and Engels et al., Hum. Gene Ther., 16, 799-810 (2005); US2009/03046557, contents which are incorporated herein by reference in their entirety.Such chimeric TCRs can recognize, for example, cancer antigens such as MART-1, gp-100, p53 and NY-ESO-1, MAGE A3/A6, MAGEA3, SSX2, HPV-16 E6 or HPV-16 E7 In other aspects of the present invention, polypeptides encoded by such nucleic acids and host cells containing such nucleic acids and/or polypeptides are described.

Sequences of non-limiting examples of various components that may be part of a CAR are listed in Table 11a, where "a.k." stands for amino acids, and "n.k." denotes the nucleic acids that encode the corresponding peptide.

Table 11a. Sequences of various CAR components (a.k. - amino acid sequence, n.k. - nucleic acid sequence) SEQ ID NO: Description Subsequence SEQ ID NO: 270 EF-1 promoter (n.k.) CGTGAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACAC AGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACCTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTG TCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTTG CCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTC GAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGA SEQ ID NO: 268 Leader sequence (a.k.) MALPVTALLLPLALLLHAARP SEQ ID NO:
287 Leader sequence (n.k.) ATGGCCCTGCCTGTGACAGCCCTGCTGCTGCCTCTGGCTCTGCTGCTGCATGCCGCTAGACCC SEQ ID NO:
288 Leader sequence (n.k.) atggccctccctgtcaccgccctgctgcttccgctggctcttctgctccacgccgctcggccc SEQ ID NO: 250 Hinge region CD8 (a.k.) TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD SEQ ID NO: 254 Hinge region CD8 (n.k.) ACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCCCACCATCGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGTGCCGGCCAGCGGCGGGGGGGCGCAGTGCACACGAGGGGGCTGGACTTCGCCTGTGAT SEQ ID NO: 253 IgG4 hinge region (a.k.) ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKM SEQ ID NO: 255 IgG4 hinge region (n.k.) GAGAGCAAGTACGGCCCTCCCTGCCCCCCTTGCCCTGCCCCCGAGTTCCTGGGCGGACCCAGCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCCGGACCCCCGAGGTGACCTGTGTGGTGGTGGACGTGTCCCAGGAGGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCCGGGAGGAGCAGTTCAATAGC ACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAATACAAGTGTAAGGTGTCCAACAAGGGCCTGCCCAGCAGCATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCTCGGGAGCCCCAGGTGTACACCCTGCCCCCTAGCCAAGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTG GGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCCGGCTGACCGTGGACAAGAGCCGGTGGCAGGAGGGCAACGTCTTTAGCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCTGGGCAAGATG SEQ ID NO: 256 IgD hinge region (a.k.) RWPESPKAQASSVPTAQPQAEGSLAKATTAPATTRNTGRGGEEKKKEKEKEEQEERETKTPECPSHTQPLGVYLLTPAVQDLWLRDKATFTCFVVGSDLKDAHLTWEVAGKVPTGGVEEGLLERHSNGSQSQHSRLTLPRSLWNAGTSVTCTLNHPSLPPQRLMALREPAAQAPVKLSLNLLASSDPPEAASWLLCEVSGFSP PNILLMWLEDQREVNTSGFAPARPPPQPGSTTFWAWSVLRVPAPPSPQPATYTCVVSHEDSRTLLNASRSLEVSYVTDH SEQ ID NO: 257 Hinge region IgD (n.k.) AGGTGGCCCGAAAGTCCCAAGGCCCAGGCATCTAGTGTTCCTACTGCACAGCCCCAGGCAGAAGGCAGCCTAGCCAAAGCTACTACTGCACCTGCCACTACGCGCAATACTGGCCGTGGCGGGGAGGAGAAGAAAAAGGAGAAAGAGAAAGAAGAACAGGAAGAGAGGGAGACCAAGACCCCTGAATGTCCATCCCATACCCAGCCGCTGGGCGTCTATCTCTTGACTCCCGCAGTACAGGACTTGTGGCTT AGAGATAAGGCCACCTTTACATGTTTCGTCGTGGGCTCTGACCTGAAGGATGCCCATTTGACTTGGGAGGTTGCCGGAAAGGTACCCACAGGGGGGGTTGAGGAAGGGTTGCTGGAGCGCCATTCCAATGGCTCTCAGAGCCAGCACTCAAGACTCACCCTTCCGAGATCCCTGTGGAACGCCGGGACCTCTGTCACATGTACTCTAAATCATCCTAGCCTGCCCCCACAGCGTCTGATGGCCCTTA GAGAGCCAGCCGCCCAGGCACCAGTTAAGCTTAGCCTGAATCTGCTCGCCAGTAGTGATCCCCCAGAGGCCGCCAGCTGGCTCTTATGCGAAGTGTCCGGCTTTAGCCCGCCCAACATCTTGCTCATGTGGCTGGAGGACCAGCGAGAAGTGAACACCAGCGGCTTCGCTCCAGCCCGGCCCCCACCCCAGCCGGGTTCTACCACATTCTGGGCCTGGAGTGTCTTAAGGGTCCCAGCACCACCTAGCC CCCAGCCAGCCACATACACCTGTGTTGTGTCCCATGAAGATAGCAGGACCCTGCTAAATGCTTCTAGGAGTCTGGAGGTTTCCTACGTGACTGACCATT SEQ ID NO: 258 Hinge region/linker GS (a.k.) GGGGSGGGGS SEQ ID NO: 259 Hinge region/linker GS (n.k.) GGTGGCGGAGGTTCTGGAGGTGGAGGTTCC SEQ ID NO: 251 CD8 transmembrane domain (a.k.) IYIWAPLAGTCGVLLLSLVITLYC SEQ ID NO: 252 CD8 transmembrane domain (n.c.) ATCTACATCTGGGCGCCCTTGGCCGGGACTTGTGGGGTCCTTCTCCTGTCACTGGTTATCACCCTTTACTGC SEQ ID NO: 289 CD8 transmembrane domain (n.c.) ATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGT SEQ ID NO: 264 Intracellular domain 4-1BB (a.k) KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL SEQ ID NO: 266 Intracellular domain 4-1BB (n.k.) AAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTG SEQ ID NO: 290 Intracellular domain 4-1BB (n.k.) aagcgcggtcggaagaagctgctgtacatctttaagcaacccttcatgaggcctgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggaaggcggctgcgaactg SEQ ID NO: 265 CD27 (a.k.) QRRKYRSNKGESPVEPAEPCRYSCPREEEGSTIPIQEDYRKPEPACSP SEQ ID NO: 267 CD27 (n.k.) Caacgaaggaaatatagatcaaacaaaggagaaagtcctgtggagcctgcagagccttgtcgttacagctgccccagggaggagggagggcagcaccatccccatccaggaggattaccgaaaaccggagcctgcctgctccccc SEQ ID NO: 260 CD3-zeta (a.k.) RVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR SEQ ID NO: 262 CD3-zeta (n.k.) AGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACAAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGG AGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGC SEQ ID NO: 291 CD3-zeta (n.k.) CGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAG GCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGCCCTGCCGCCTCGG SEQ ID NO: 261 CD3-zeta (a.k.) RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR SEQ ID NO: 263 CD3-zeta (n.k.) AGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGG AGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGC SEQ ID NO: 292 Linker (a.k.) GGGGS SEQ ID NO: 293 Extracellular domain of PD-1 (a.k.) Pgwfldspdrpwnpptfspallvvtegdnatftcsfsntsesfvlnwyrmspsnqtdklaafpedrsqpgqdcrfrvtqlpngrdfhmsvvrarrndsgtylcgaislapkaqikeslraelrvterraevptahpspsprpagqfqtlv SEQ ID NO: 294 PD-1 extracellular domain (nc) Cccggatggtttctggactctccggatcgcccgtggaatcccccaaccttctcaccggcactcttggttgtgactgagggcgataatgcgaccttcacgtgctcgttctccaacacctccgaatcattcgtgctgaactggtaccgcatgagcccgtcaaaccagaccgacaagctcgccgcgtttccggaagatcggtcg caaccgggacaggattgtcggttccgcgtgactcaactgccgaatggcagagacttccacatgagcgtggtccgcgctaggcgaaacgactccgggacctacctgtgcggagccatctcgctggcgcctaaggcccaaatcaaagagagcttgaggggccgaactgagagtgaccgagcgcagagctgaggtgccaactgcacatccatccccat cgcctcggcctgcggggcagtttcagaccctggtc SEQ ID NO: 295 CAR for PD-1 with signal sequence (a.s.) Malpvtalllplalllhaarppgwfldspdrpwnpptfspallvvtegdnatftcsfsntsesfvlnwyrmspsnqtdklaafpedrsqpgqdcrfrvtqlpngrdfhmsvvrarrndsgtylcgaislapkaqikeslraelrvterraevptahpspsprpagqfqtlvtttpaprpptpaptiasq please tydalhmqalppr SEQ ID NO: 296 CAR for PD-1 (n.k.) Atggccctccctgtcactgccctgcttctccccctcgcactcctgctccacgccgctagaccacccggatggtttctggactctccggatcgcccgtggaatcccccaaccttctcaccggcactcttggttgtgactgagggcgataatgcgaccttcacgtgctcgttctccaacacctccgaatcattcgtgctgaactggtacc gcatgagcccgtcaaaccagaccgacaagctcgccgcgtttccggaagatcggtcgcaaccgggacaggattgtcggttccgcgtgactcaactgccgaatggcagagacttccacatgagcgtggtccgcgctaggcgaaacgactccgggacctacctgtgcggagccatctcgctggcgcctaaggcccaaatcaaagagag cttgagggccgaactgagagtgaccgagcgcagagctgaggtgccaactgcacatccatccccatcgcctcggcctgcggggcagtttcagaccctggtcacgaccactccggcgccgcgcccaccgactccggccccaactatcgcgagccagcccctgtcgctgaggccggaagcatgccgccctgccgccggaggtgctgtgcatacc cggggattggacttcgcatgcgacatctacatttgggctcctctcgccggaacttgtggcgtgctccttctgtccctggtcatcaccctgtactgcaagcggggtcggaaaaagcttctgtacattttcaagcagcccttcatgaggcccgtgcaaaccacccaggaggaggacggttgctcctgccggttccccgaagaggaagaagga ggttgcgagctgcgcgtgaagttctcccggagcgccgacgcccccgcctataagcagggccagaaccagctgtacaacgaactgaacctgggacggcgggaagagtacgatgtgctggacaagcggcgcggccgggaccccgaaatgggcgggaagcctagaagaaagaaccctcaggaaggcctgtataacgagctgcagaaggacaagat ggccgaggcctactccgaaattgggatgaagggagagcggcggaggggaaaggggcacgacggcctgtaccaaggactgtccaccgccaccaaggacacatacgatgccctgcacatgcaggcccttccccctcgc SEQ ID NO: 297 Linker (a.k.) (Gly-Gly-Gly-Ser)n, where n=1-10 SEQ ID NO: 215 Linker (a.k.) (Gly4 Ser)4 SEQ ID NO: 216 Linker (a.k.) (Gly4 Ser)3 SEQ ID NO: 297 Linker (a.k.) (Gly3Ser) SEQ ID NO: 298 polyA (n.k.) [a] _50-5000 SEQ ID NO: 299 CAR for PD1 (a.k.) Pgwfldspdrpwnpptfspallvvtegdnatftcsfsntsesfvlnwyrmspsnqtdklaafpedrsqpgqdcrfrvtqlpngrdfhmsvvrarrndsgtylcgaislapkaqikeslraelrvterraevptahpspsprpagqfqtlv tttpaprpptpaptiasqplslrpeacrpaaggav htrgldfacdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapaykqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr SEQ ID NO: 300 Intracellular domain ICOS (a.k.) TKKKYSSSVHDPNGEYMFMRAVNTAKKSRLTDVTL SEQ ID NO: 301 Intracellular domain ICOS (n.k.) ACAAAAAAGAAGTATTCATCCAGTGTGCACGACCCTAACGGTGAATACATGTTCATGAGAGCAGTGAACACAGCCAAAAAATCCAGACTCACAGATGTGACCCTA SEQ ID NO: 302 TM-domain ICOS (a.k.) TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDFWLPIGCAAFVVVCILGCILICWL SEQ ID NO: 303 TM-domain ICOS (n.k.) ACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCCCACCATCGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGTGCCGGCCAGCGGCGGGGGGCGCAGTGCACACGAGGGGGCTGGACTTCGCCTGTGATTTCTGGTTACCCATAGGATGTGCAGCCTTTGTTGTAGTCTGCATTTTGGGATGCATACTTATTTGTTGGCTT SEQ ID NO: 304 Intracellular domain of CD28 (a.k) RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS SEQ ID NO: 305 CD28 intracellular domain (nc) AGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCCGGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCC

Targets

The present invention provides cells, e.g., immune effector cells (e.g., T cells, NK cells), that contain or have at any time contained a gRNA molecule or CRISPR system described herein, which are further engineered to contain one or multiple CARs that direct immune effector cells to unwanted cells (eg, cancer cells). This is achieved by an antigen-binding domain in the CAR, which is specific for cancer-associated antigen. There are two classes of cancer-associated antigens (tumor antigens) that can be targeted by the CARs of the present invention: (1) cancer-associated antigens that are expressed on the surface of cancer cells; and (2) cancer-associated antigens, which are themselves intracellular, but a fragment of such antigen (peptide) is presented on the surface of cancer cells by MHC (major histocompatibility complex).

In some embodiments, the tumor antigen is selected from one or more of CD19; CD123; CD22; CD30; CD171; CS-1 (also called CD2 subgroup protein 1, CRACC, SLAMF7, CD319 and 19A24); C-type lectin-like molecule 1 (CLL-1 or CLECL1); CD33; epidermal growth factor receptor variant III (EGFRvIII); ganglioside G2 (GD2); ganglioside GD3 (aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)Cer); B-cell maturation antigen (BCMA), which is a member of the TNF receptor family; Tn antigen ((Ag Tn) or (GalNAcα-Ser/Thr)); prostate specific membrane antigen (PSMA); orphan receptor tyrosine kinase-like 1 (ROR1); Fms-like tyrosine kinase 3 (FLT3); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; carcinoembryonic antigen (CEA); epithelial cell adhesion molecules (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor alpha 2 subunit (IL-13Ra2 or CD213A2); mesothelin; interleukin 11 receptor alpha subunit (IL-11Ra); prostate stem cell antigen (PSCA); serine protease 21 (testisin or PRSS21); vascular endothelial growth factor receptor 2 (VEGFR2); Lewis system antigen (Y); CD24; platelet-derived growth factor receptor beta (PDGFR-beta); stage-specific embryonic antigen 4 (SSEA-4); CD20; folate receptor alpha; receptor tyrosine protein kinase ERBB2 (Her2/neu); cell surface associated mucin 1 (MUC1); epidermal growth factor receptor (EGFR); nerve cell adhesion molecules (NCAM); prostases; prostatic acid phosphatase (PAP); elongation factor 2 mutant (ELF2M); ephrin B2; fibroblast activation protein alpha (FAP); insulin-like growth factor receptor 1 (IGF-I receptor), carbonic anhydrase IX (CAIX); proteasome (prosome, multicatalytic protease) beta type 9 subunit (LMP2); glycoprotein 100 (gp100); an oncogenic fusion protein consisting of the break point cluster region (BCR) and the Abelson murine leukemia virus (Abl) oncogene homolog 1 (bcr-abl); tyrosinase; ephrin A-type receptor 2 (EphA2); fucosyl-GM1; adhesion molecule, which is a sialylated Lewis antigen (sLe); ganglioside GM3 (aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)Cer); transglutaminase 5 (TGS5); high molecular weight melanoma-associated antigen (HMWMAA); ganglioside o-acetyl-GD2 (OAcGD2); folic acid receptor beta; tumor endothelial marker 1 (TEM1/CD248); tumor endothelial marker 7-related protein (TEM7R); claudin 6 (CLDN6); thyroid stimulating hormone receptor (TSHR); group D representative of class C G-protein coupled receptors (GPRC5D); protein encoded by X chromosome open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); polysialic acid; placenta-specific protein 1 (PLAC1); the hexasaccharide part of the glycoceramide globoH (GloboH); breast differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); hepatitis A virus cellular receptor 1 (HAVCR1); beta-3 adrenergic receptor (ADRB3); pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); lymphocyte antigen complex 6 locus antigen K9 (LY6K); olfactory receptor 51E2 (OR51E2); protein encoded by the TCR-gamma alternative reading frame (TARP); Wilms tumor protein (WT1); cancer testicular antigen 1 (NY-ESO-1); cancer testicular antigen 2 (LAGE-1a); melanoma-associated antigen 1 (MAGE-A1); protein encoded by translocation variant 6 of the ETS gene, localized in the p-arm of chromosome 12 (ETV6-AML); sperm protein 17 (SPA17); X antigen family member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (TIE-2); melanoma cancer-testicular antigen 1 (MAD-CT-1); melanoma cancer-testicular antigen 2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53 (p53); mutant p53; prostein; survivina; telomerase; prostate carcinoma tumor antigen 1 (PCTA-1 or galectin 8), melanoma T-cell recognized antigen 1 (MelanA or MART1); mutant rat sarcoma antigen (Ras); human telomerase reverse transcriptase (hTERT); sarcoma antigen with point breaks during translocation; melanoma inhibitor of apoptosis (ML-IAP); ERG (a fusion gene product of transmembrane serine protease 2 (TMPRSS2) and ETS); N-acetylglucosaminyltransferase V (NA17); protein with paired box domain Pax-3 (PAX3); androgen receptor; cyclin B1; neuroblastoma homologue of the avian myelocytomatosis virus v-myc (MYCN) oncogene; member C of the Ras homolog family (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P450 1B1 (CYP1B1); CCCTC-binding factor-like protein (zinc finger protein) (BORIS or brother of imprinted site regulator), squamous cell carcinoma antigen 3 recognized by T cells (SART3); protein with paired box domain Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES1); lymphocyte-specific protein tyrosine kinase (LCK); anchor kinase protein 4 A (AKAP-4); synovial sarcoma antigen 2 with point break in the X chromosome (SSX2); receptor for advanced glycation end products (RAGE-1); renal ubiquitous protein 1 (RU1); renal ubiquitous protein 2 (RU2); legumaina; E6 human papillomavirus (E6 HPV); E7 human papillomavirus (E7 HPV); intestinal carboxylesterase; mutant heat shock protein 70-2 (mut-hsp70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin receptor 1 (LAIR1); IgA Fc receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A representative 2 (LILRA2); member f of the CD300 molecule-like protein family (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); mucin-like hormone receptor-containing EGF-like module protein 2 (EMR2); lymphocyte antigen 75 (LY75); glypican-3 (GPC3); Fc receptor-like antigen 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1).

A CAR described herein may contain an antigen binding domain (eg, an antibody or antibody fragment, a TCR or TCR fragment) that binds to a tumor maintenance antigen (eg, a tumor maintenance antigen described herein). In some embodiments, the tumor maintenance antigen is an antigen present on a stromal cell or a myeloid-derived suppressor cell (MDSC). Stromal cells can secrete growth factors to promote cell division in the microenvironment. MDSC cells can suppress T cell proliferation and activation. Without being limited by theory, in some embodiments, CAR-expressing cells destroy tumor maintenance cells, thereby indirectly inhibiting tumor growth or survival.

In embodiments, the stromal cell-expressed antigen is selected from one or more of bone marrow stromal cell-expressed antigen 2 (BST2), fibroblast activation protein (FAP), and tenascin. In one embodiment, the FAP-specific antibody is, competes with, or contains the same CDRs for binding to sibrotuzumab. In embodiments, the antigen expressed by the MDSC is selected from one or more of CD33, CD11b, C14, CD15, and CD66b. Accordingly, in some embodiments, the tumor maintenance antigen is selected from one or more of bone marrow stromal cell-expressed antigen 2 (BST2), fibroblast activation protein (FAP) or tenascin, CD33, CD11b, C14, CD15, and CD66b.

Structures of the antigen binding domain

In some embodiments, the antigen binding domain of the encoded CAR molecule comprises an antibody, antibody fragment, scFv, Fv, Fab, (Fab')2, single domain antibody (SDAB), VH or VL domain, camelid VHH domain, or bifunctional (e.g., bispecific ) hybrid antibody (eg, Lanzavecchia et al., Eur. J. Immunol. 17, 105 (1987)).

In some cases, scFv can be prepared in accordance with a method known in the art (see, for example, Bird et al., (1988) Science 242:423-426 and Huston et al., (1988) Proc. Natl. Acad. Sci USA 85:5879-5883). ScFv molecules can be prepared by linking the VH and VL regions to each other using flexible polypeptide linkers. scFv molecules contain a linker (eg, a Ser-Gly linker) with optimized length and/or amino acid composition. Linker length can greatly influence the folding and interaction of scFv variable regions. In fact, if a short polypeptide linker is used (eg, 5-10 amino acids long), folding within a single chain is prevented. Interstrand folding is also required to bring two variable regions together to form a functional epitope-binding site. For examples of linker orientation and size, see, for example, Hollinger et al. 1993 Proc Natl Acad. Sci. U.S.A. 90:6444-6448, US Patent Application Publications Nos. 2005/0100543, 2005/0175606, 2007/0014794, and PCT Publications Nos. WO2006/020258 and WO2007/024715, incorporated herein by reference.

scFv may contain a linker of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50 or more amino acid residues between its VL and VH regions. The linker sequence may contain any naturally occurring amino acid. In some embodiments, the linker sequence comprises the amino acids glycine and serine. In another embodiment, the linker sequence contains groups of glycine and serine repeats, such as (Gly ₄ Ser)n, where n is a positive integer equal to 1 or greater (SEQ ID NO: 217). In one embodiment, the linker may be (Gly ₄ Ser) ₄ (SEQ ID NO: 215) or (Gly ₄ Ser) ₃ (SEQ ID NO: 216). By changing the linker length, activity can be maintained or enhanced, leading to improved performance in activity assays.

In another aspect, the antigen binding domain is a T cell receptor ("TCR") or a fragment thereof, such as a single chain TCR (scTCR). Methods for producing such TCRs are known in the art. See, for example, Willemsen RA et al, Gene Therapy 7: 1369-1377 (2000); Zhang T et al, Cancer Gene Ther 11: 487-496 (2004); Aggen et al, Gene Ther. 19(4):365-74 (2012) (the literature is included in this document in its entirety). For example, a scTCR can be constructed that contains the Vα and Vβ genes from a T cell clone linked by a linker (eg, a flexible peptide). This approach is very useful for a cancer-associated target that is itself intracellular, but a fragment of such antigen (peptide) is presented on the surface of cancer cells by MHC.

In certain embodiments, the encoded antigen binding domain has a KD binding affinity of 10 ^-4 M to 10 ^-8 M.

In one embodiment, the encoded CAR molecule contains an antigen binding domain that has a KD binding affinity for the target antigen of 10 ^-4 M to 10 ^-8 M, e.g., 10 ^-5 M to 10 ^-7 M, e.g. 10 ^-6 M or 10 ^-7 M. In one embodiment, the antigen binding domain has a binding affinity that is at least five times, 10 times, 20 times, 30 times, 50 times, 100 times, or 1000 times less than that of the reference antibody , for example, the antibodies described herein. In one embodiment, the encoded antigen binding domain has a binding affinity that is at least 5 times less than that of a reference antibody (eg, the antibody from which the antigen binding domain is derived). In one aspect, such antibody fragments are functional in the sense that they provide a biological response, which may include, but is not limited to, activation of an immune response, inhibition of the onset of signaling from their target antigen, inhibition of kinase activity, and the like, as will be appreciated by one skilled in the art. in this field of technology.

In one aspect, the antigen binding domain of a CAR is a scFv antibody fragment that is humanized from the murine scFv sequence from which it is derived.

In one aspect, the antigen binding domain of a CAR of the present invention (eg, scFv) is encoded by a nucleic acid molecule whose sequence has been codon-optimized for expression in a mammalian cell. In one aspect, the entire CAR construct of the present invention is encoded by a nucleic acid molecule whose entire sequence has been codon-optimized for expression in a mammalian cell. Codon optimization refers to the discovery that the frequency of occurrence of synonymous codons (i.e., codons that code for the same amino acid) in coding DNA is biased across species. This codon degeneracy makes it possible to encode an identical polypeptide with different nucleotide sequences. Various codon optimization methods are known in the art and include, for example, those disclosed in at least US Pat. Nos. 5,786,464 and 6,114,148.

Antigen binding domains (and target antigens)

In one embodiment, the antigen binding domain for CD19 is an antigen binding portion, for example a CDR, CAR, antibody or antigen binding fragment thereof, as described, for example, in PCT publication WO2012/079000; publications according to PCT WO2014/153270; Kochenderfer, J.N. et al., J. Immunother. 32(7), 689-702 (2009); Kochenderfer, J.N., et al., Blood, 116 (20), 4099-4102 (2010); publications according to PCT WO2014/031687; Bejcek, Cancer Research, 55, 2346-2351, 1995 or US Patent No. 7446190.

In one embodiment, the antigen binding domain for mesothelin is an antigen binding portion, for example a CDR, antibody, antigen binding fragment or CAR, as described, for example, in PCT publication WO2015/090230. In one embodiment, the antigen binding domain for mesothelin is an antigen binding portion, for example a CDR, antibody, antigen binding fragment or CAR, as described, for example, in PCT publication WO1997/025068, WO1999/028471, WO2005/014652, WO2006/099141, WO2009/ 045957, WO2009/068204, WO2013/142034, WO2013/040557 or WO2013/063419. In one embodiment, the antigen binding domain for mesothelin is an antigen binding portion, for example, a CDR, antibody, antigen binding fragment or CAR described in WO/2015/090230.

In one embodiment, the antigen binding domain for CD123 is an antigen binding portion, for example a CDR, antibody, antigen binding fragment or CAR, as described, for example, in PCT publication WO2014/130635. In one embodiment, the antigen binding domain for CD123 is an antigen binding portion, for example a CDR, antibody, antigen binding fragment or CAR, as described, for example, in PCT publication WO2014/138805, WO2014/138819, WO2013/173820, WO2014/144622, WO2001/ 66139, WO2010/126066, WO2014/144622 or US2009/0252742. In one embodiment, the antigen binding domain for CD123 is an antigen binding portion, for example, a CDR, antibody, antigen binding fragment or CAR described in WO/2016/028896.

In one embodiment, the antigen binding domain for EGFRvIII is an antigen binding portion, for example, a CDR, antibody, antigen binding fragment or CAR, described, for example, in WO/2014/130657.

In one embodiment, the antigen binding domain for CD22 is an antigen binding portion, for example a CDR, of an antibody described, for example, in Haso et al., Blood, 121(7): 1165-1174 (2013); Wayne et al., Clin Cancer Res 16(6): 1894-1903 (2010); Kato et al., Leuk Res 37(1):83-88 (2013); Creative BioMart (creativebiomart.net): MOM-18047-S(P).

In one embodiment, the antigen binding domain for CS-1 is the antigen binding portion, eg, CDR, of elotuzumab (BMS), see, for example, Tai et al., 2008, Blood 112(4):1329-37; Tai et al., 2007, Blood. 110(5):1656-63.

In one embodiment, the antigen binding domain for CLL-1 is an antigen binding portion, for example, a CDR, antibody available from R&D, ebiosciences, Abcam, for example, PE-CLL1-hu cat. No. 353604 (BioLegend) and PE-CLL1 (CLEC12A) with cat. No. 562566 (BD). In one embodiment, the antigen binding domain for CLL-1 is an antigen binding portion, for example, a CDR, antibody, antigen binding fragment or CAR described in WO/2016/014535.

In one embodiment, the antigen binding domain for CD33 is the antigen binding portion, e.g., CDR, of an antibody described, for example, in Bross et al., Clin Cancer Res 7(6):1490-1496 (2001) (gemtuzumab-ozogamicin, hP67. 6), Caron et al., Cancer Res 52(24):6761-6767 (1992) (lintuzumab, HuM195), Lapusan et al., Invest New Drugs 30(3):1121-1131 (2012) (AVE9633), Aigner et al., Leukemia 27(5): 1107–1115 (2013) (AMG330, CD33 BiTE), Dutour et al., Adv hematol 2012:683065 (2012), and Pizzitola et al., Leukemia doi:10.1038/Lue .2014.62 (2014). In one embodiment, the antigen binding domain for CD33 is an antigen binding portion, for example, a CDR, antibody, antigen binding fragment or CAR described in WO/2016/014576.

In one embodiment, the antigen binding domain for GD2 is an antigen binding portion, for example, a CDR, of an antibody described, for example, in Mujoo et al., Cancer Res. 47(4):1098-1104 (1987); Cheung et al., Cancer Res 45(6):2642-2649 (1985), Cheung et al., J Clin Oncol 5(9):1430-1440 (1987), Cheung et al., J Clin Oncol 16(9 ):3053-3060 (1998), Handgretinger et al., Cancer Immunol Immunother 35(3):199-204 (1992). In some embodiments, the antigen binding domain for GD2 is the antigen binding portion of an antibody selected from mAbs 14.18, 14G2a, ch14.18, hu14.18, 3F8, hu3F8, 3G6, 8B6, 60C3, 10B8, ME36.1, and 8H9, see for example, WO2012033885, WO2013040371, WO2013192294, WO2013061273, WO2013123061, WO2013074916 and WO201385552. In some embodiments, the antigen binding domain for GD2 is the antigen binding portion of an antibody described in US Patent Application Publication No. 20100150910 or PCT Publication No. WO 2011160119.

In one embodiment, the antigen binding domain for BCMA is the antigen binding portion, for example, a CDR, of an antibody described, for example, in WO2012163805, WO200112812 and WO2003062401. In one embodiment, the antigen binding domain for BCMA is an antigen binding portion, for example, a CDR, antibody, antigen binding fragment or CAR described in WO/2016/014565.

In one embodiment, the antigen binding domain for a Tn antigen is the antigen binding portion, e.g., CDR, of an antibody described, for example, in US 8,440,798, Brooks et al., PNAS 107(22):10056-10061 (2010) and Stone et al. ., OncoImmunology 1(6):863–873(2012).

In one embodiment, the antigen binding domain for PSMA is the antigen binding portion, e.g., CDR, of an antibody described, for example, in Parker et al., Protein Expr Purif 89(2):136-145 (2013), US 20110268656 (J591 ScFv) ; Frigerio et al., European J. Cancer 49(9):2223–2232 (2013) (scFvD2B); WO 2006125481 (mAbs 3/A12, 3/E7 and 3/F11), and single chain antibody fragments (scFv A5 and D7).

In one embodiment, the antigen binding domain for ROR1 is an antigen binding portion, for example a CDR, of an antibody described, for example, in Hudecek et al., Clin Cancer Res 19(12):3153-3164 (2013); WO2011159847 and US20130101607.

In one embodiment, the antigen binding domain for FLT3 is the antigen binding portion, e.g., CDR, of an antibody described, for example, in WO2011076922, US5777084, EP0754230, US20090297529 and several commercial antibody catalogs (R&D, Ebiosciences, Abcam).

In one embodiment, the antigen binding domain for TAG72 is the antigen binding portion, eg, CDR, of an antibody described, for example, in Hombach et al., Gastroenterology 113(4):1163-1170 (1997); and ab691 from Abcam.

In one embodiment, the antigen binding domain for FAP is the antigen binding portion, e.g., CDR, of an antibody described, for example, in Ostermann et al., Clinical Cancer Research 14:4584-4592 (2008) (FAP5), US Patent Application Publication No. 2009/0304718; sibrotuzumab (see, for example, Hofheinz et al., Oncology Research and Treatment 26(1), 2003); and Tran et al., J Exp Med 210(6):1125–1135 (2013).

In one embodiment, the antigen binding domain for CD38 is the antigen binding portion, e.g., CDR, of daratumumab (see, e.g., Groen et al., Blood 116(21):1261-1262 (2010); MOR202 (see, e.g., U.S. 8263746); or antibodies described in US 8362211.

In one embodiment, the antigen binding domain for CD44v6 is an antigen binding portion, for example, a CDR, of an antibody described, for example, in Casucci et al., Blood 122(20):3461-3472 (2013).

In one embodiment, the antigen binding domain for CEA is the antigen binding portion, for example, a CDR, of an antibody described, for example, in Chmielewski et al., Gastoenterology 143(4):1095-1107 (2012).

In one embodiment, the antigen binding domain for EPCAM is the antigen binding portion, for example, CDR, of an antibody selected from MT110, a bispecific Ab to EpCAM-CD3 (see, for example, clinicaltrials.gov/ct2/show/NCT00635596); edrecolomab; 3622W94; ING-1 and adecatumumab (MT201).

In one embodiment, the antigen binding domain for PRSS21 is an antigen binding portion, such as a CDR, of an antibody described in US Pat. No. 8,080,650.

In one embodiment, the antigen binding domain for B7H3 is an antigen binding portion, for example, the CDR of antibody MGA271 (Macrogenics).

In one embodiment, the antigen binding domain for KIT is the antigen binding portion, such as a CDR, of an antibody described, for example, in US7915391, US20120288506 and several commercial antibody catalogs.

In one embodiment, the antigen binding domain for IL-13Ra2 is the antigen binding portion, e.g., CDR, of an antibody described, for example, in WO2008/146911, WO2004087758, several commercial antibody catalogs, and WO2004087758.

In one embodiment, the antigen binding domain for CD30 is an antigen binding portion, for example, a CDR, of an antibody described, for example, in US7090843 B1 and EP0805871.

In one embodiment, the antigen binding domain for GD3 is an antigen binding portion, for example, a CDR, of an antibody described, for example, in US7253263; US 8207308; US 20120276046; EP1013761; WO2005035577 and US6437098.

In one embodiment, the antigen binding domain for CD171 is an antigen binding portion, for example, a CDR, of an antibody described, for example, in Hong et al., J Immunother 37(2):93-104 (2014).

In one embodiment, the antigen binding domain for IL-11Ra is an antigen binding portion, for example, a CDR, of an antibody available from Abcam (cat. no. ab55262) or Novus Biologicals (cat. no. EPR5446). In another embodiment, the antigen binding domain for IL-11Ra is a peptide, see, for example, Huang et al., Cancer Res 72(1):271-281 (2012).

In one embodiment, the antigen binding domain for PSCA is the antigen binding portion, eg, CDR, of an antibody described, for example, in Morgenroth et al., Prostate 67(10):1121-1131 (2007) (scFv 7F5); Nejatollahi et al., J of Oncology 2013(2013), Article ID 839831 (scFv C5-II); and publication of US Patent Application No. 20090311181.

In one embodiment, the antigen binding domain for VEGFR2 is the antigen binding portion, for example, a CDR, of an antibody described, for example, in Chinnasamy et al., J Clin Invest 120(11):3953-3968 (2010).

In one embodiment, the antigen binding domain for the Lewis Y system is the antigen binding portion, e.g., CDR, of an antibody described, for example, in Kelly et al., Cancer Biother Radiopharm 23(4):411-423 (2008) (Ab hu3S193 (scFvs )); Dolezal et al., Protein Engineering 16(1):47–56 (2003) (NC10 scFv).

In one embodiment, the antigen binding domain for CD24 is an antigen binding portion, for example, a CDR, of an antibody described, for example, in Maliar et al., Gastroenterology 143(5):1375-1384 (2012).

In one embodiment, the antigen binding domain for PDGFR-beta is an antigen binding portion, for example, the CDR, antibody ab32570 from Abcam.

In one embodiment, the antigen binding domain for SSEA-4 is an antigen binding portion, for example, a CDR, antibody MC813 (Cell Signaling) or other commercially available antibodies.

In one embodiment, the antigen binding domain for CD20 is an antigen binding portion, such as a CDR, rituximab, ofatumumab, ocrelizumab, veltuzumab, or GA101 antibody.

In one embodiment, the antigen binding domain for folate receptor alpha is an antigen binding portion, for example, the CDR of antibody IMGN853 or the antibody described in US20120009181; US4851332, LK26: US5952484.

In one embodiment, the antigen binding domain for ERBB2 (Her2/neu) is an antigen binding portion, for example, a CDR of a trastuzumab or pertuzumab antibody.

In one embodiment, the antigen binding domain for MUC1 is the antigen binding portion, for example, the CDR, of the SAR566658 antibody.

In one embodiment, the antigen binding domain for EGFR is an antigen binding portion, such as a CDR, of a cetuximab, panitumumab, zalutumumab, nimotuzumab, or matuzumab antibody.

In one embodiment, the antigen binding domain for NCAM is the antigen binding portion, for example, CDR, of antibody clone 2-2B: MAB5324 (EMD Millipore).

In one embodiment, the antigen binding domain for ephrin B2 is an antigen binding portion, for example, a CDR, of an antibody described, for example, in Abengozar et al., Blood 119(19):4565-4576 (2012).

In one embodiment, the antigen binding domain for the IGF-I receptor is the antigen binding portion, for example, a CDR, of an antibody described, for example, in US8344112 B2; EP2322550 A1; WO 2006/138315 or PCT/US2006/022995.

In one embodiment, the antigen binding domain for CAIX is the antigen binding portion, eg, CDR, of antibody clone 303123 (R&D Systems).

In one embodiment, the antigen binding domain for LMP2 is the antigen binding portion, for example, a CDR, of an antibody described, for example, in US7410640 or US20050129701.

In one embodiment, the antigen binding domain for gp100 is an antigen binding portion, for example, a CDR, an HMB45 antibody, an NKI/beta B antibody, or an antibody described in WO2013165940 or US20130295007.

In one embodiment, the antigen binding domain for tyrosinase is an antigen binding portion, for example, a CDR, of an antibody described, for example, in US5843674 or US19950504048.

In one embodiment, the antigen binding domain for EphA2 is an antigen binding portion, for example, a CDR, of an antibody described, for example, in Yu et al., Mol Ther 22(1):102-111 (2014).

In one embodiment, the antigen binding domain for GD3 is an antigen binding portion, for example, a CDR, of an antibody described, for example, in US7253263; US 8207308; US 20120276046; EP1013761 A3; 20120276046; WO2005035577 or US6437098.

In one embodiment, the antigen binding domain for fucosyl-GM1 is an antigen binding portion, for example, a CDR, of an antibody described, for example, in US20100297138 or WO2007/067992.

In one embodiment, the antigen binding domain for sLe is the antigen binding portion, for example, the CDR, of antibody G193 (for Lewis Y antigen), see Scott AM et al, Cancer Res 60: 3254-61 (2000), also described in Neeson et al. al, J Immunol May 2013 190 (Meeting Abstract Supplement) 177.10.

In one embodiment, the antigen binding domain for GM3 is an antigen binding portion, for example, the CDR of antibody CA 2523449 (mAb 14F7).

In one embodiment, the antigen binding domain for HMWMAA is the antigen binding portion, e.g., CDR, of an antibody described, for example, in Kmiecik et al., Oncoimmunology 3(1):e27185 (2014) (PMID: 24575382) (mAb9.2.27); US6528481; WO2010033866 or US 20140004124.

In one embodiment, the antigen binding domain for o-acetyl-GD2 is the antigen binding portion, for example, the CDR, of antibody 8B6.

In one embodiment, the antigen binding domain for TEM1/CD248 is an antigen binding portion, for example, a CDR, of an antibody described, for example, in Marty et al., Cancer Lett 235(2):298-308 (2006); Zhao et al., J Immunol Methods 363(2):221–232 (2011).

In one embodiment, the antigen binding domain for CLDN6 is an antigen binding portion, for example, the CDR, antibody IMAB027 (Ganymed Pharmaceuticals), see, for example, clinicaltrial.gov/show/NCT02054351.

In one embodiment, the antigen binding domain for TSHR is an antigen binding portion, for example, a CDR, of an antibody described, for example, in US8603466, US8501415 or US8309693.

In one embodiment, the antigen binding domain for GPRC5D is an antigen binding portion, such as the CDR antibody FAB6300A (R&D Systems) or LS-A4180 (Lifespan Biosciences).

In one embodiment, the antigen binding domain for CD97 is an antigen binding portion, for example a CDR, of an antibody described, for example, in US6846911; de Groot et al., J. Immunol. 183(6):4127-4134 (2009); or antibodies from R&D: MAB3734.

In one embodiment, the antigen binding domain for ALK is an antigen binding portion, for example, a CDR, of an antibody described, for example, in Mino-Kenudson et al., Clin Cancer Res 16(5):1561-1571 (2010).

In one embodiment, the antigen binding domain for polysialic acid is an antigen binding portion, for example, a CDR, of an antibody described, for example, in Nagae et al., J Biol Chem 288(47):33784-33796 (2013).

In one embodiment, the antigen binding domain for PLAC1 is the antigen binding portion, for example, a CDR, of an antibody described, for example, in Ghods et al., Biotechnol Appl Biochem 2013 doi:10.1002/bab.1177.

In one embodiment, the antigen binding domain for GloboH is the antigen binding portion of a VK9 antibody or an antibody described, for example, in Kudryashov V et al., Glycoconj J.15(3):243-9 (1998), Lou et al., Proc Natl. Acad Sci USA 111(7):2482-2487 (2014); MBr1: Bremer E-G et al. J Biol Chem 259:14773–14777 (1984).

In one embodiment, the antigen binding domain for NY-BR-1 is an antigen binding portion, for example, a CDR, of an antibody described, for example, in Jager et al., Appl Immunohistochem Mol Morphol 15(1):77-83 (2007).

In one embodiment, the antigen binding domain for WT-1 is the antigen binding portion, e.g., CDR, of an antibody described, for example, in Dao et al., Sci Transl Med 5(176):176ra33 (2013) or WO2012/135854.

In one embodiment, the antigen binding domain for MAGE-A1 is the antigen binding portion, e.g., CDR, of an antibody described, for example, in Willemsen et al., J Immunol 174(12):7853-7858 (2005) (TCR-like scFv) .

In one embodiment, the antigen binding domain for sperm protein 17 is an antigen binding portion, for example, a CDR, of an antibody described, for example, in Song et al., Target Oncol 2013 Aug 14 (PMID: 23943313); Song et al., Med Oncol 29(4):2923–2931 (2012).

In one embodiment, the antigen binding domain for Tie 2 is an antigen binding portion, for example, a CDR, antibody AB33 (Cell Signaling Technology).

In one embodiment, the antigen binding domain for MAD-CT-2 is an antigen binding portion, for example, a CDR, of an antibody described, for example, in PMID: 2450952; US7635753.

In one embodiment, the antigen binding domain for Fos-related antigen 1 is an antigen binding portion, for example, the CDR of antibody 12F9 (Novus Biologicals).

In one embodiment, the antigen binding domain for MelanA/MART1 is the antigen binding portion, for example, a CDR, of an antibody described in EP2514766 A2 or US 7749719.

In one embodiment, the antigen binding domain for translocation punctate sarcoma antigens is the antigen binding portion, eg, CDR, of an antibody described, for example, in Luo et al, EMBO Mol. Med. 4(6):453-461 (2012).

In one embodiment, the antigen binding domain for TRP-2 is an antigen binding portion, for example, a CDR, of an antibody described, for example, in Wang et al, J Exp Med. 184(6):2207-16 (1996).

In one embodiment, the antigen binding domain for CYP1B1 is the antigen binding portion, for example, a CDR, of an antibody described, for example, in Maecker et al, Blood 102 (9): 3287-3294 (2003).

In one embodiment, the antigen binding domain for RAGE-1 is an antigen binding portion, for example, the CDR of antibody MAB5328 (EMD Millipore).

In one embodiment, the antigen binding domain for human telomerase reverse transcriptase is an antigen binding portion, for example, a CDR, antibody cat. no. LS-B95-100 (Lifespan Biosciences)

In one embodiment, the antigen binding domain for intestinal carboxylesterase is an antigen binding portion, for example, CDR, antibody 4F12 cat. no. LS-B6190-50 (Lifespan Biosciences).

In one embodiment, the antigen binding domain for mut hsp70-2 is the antigen binding portion, e.g., CDR, of a monoclonal antibody from Lifespan Biosciences Cat. No. LS-C133261-100 (Lifespan Biosciences).

In one embodiment, the antigen binding domain for CD79a is the antigen binding portion, for example, CDR, of the antibody [HM47/A9], which is an anti-CD79a antibody (ab3121), available from Abcam; antibody No. 3351, which is an anti-CD79A antibody available from Cell Signalling Technology; or antibody HPA017748, which is an anti-CD79A antibody produced in rabbit, available from Sigma Aldrich.

In one embodiment, the antigen binding domain for CD79b is the antigen binding portion, e.g., CDR, of the anti-CD79b antibody polatuzumab vedotin described in Dornan et al., "Therapeutic potential of an anti-CD79b antibody-drug conjugate, anti-CD79b -vc-MMAE, for the treatment of non-Hodgkin lymphoma" Blood. 2009 Sep 24;114(13):2721-9. doi: 10.1182/blood-2009-02-205500. Epub 2009 Jul 24 or the anti-CD79b/CD3 bispecific antibody described in "4507 Pre-Clinical Characterization of T Cell-Dependent Bispecific Antibody Anti-CD79b/CD3 As a Potential Therapy for B Cell Malignancies" Abstracts of ^{the 56th} ASH Annual Meeting and Exposition , San Francisco, CA December 6-9 2014.

In one embodiment, the antigen binding domain for CD72 is the antigen binding portion, for example, the CDR, of antibody J3-109 described in Myers and Uckun, "An anti-CD72 immunotoxin against therapeutic-refractory B-lineage acute lymphoblastic leukemia." Leuk Lymphoma. 1995 Jun;18(1-2):119-22, or anti-CD72 antibodies (10D6.8.1, mIgG1) described in Polson et al., "Antibody-Drug Conjugates for the Treatment of Non-Hodgkin's Lymphoma: Target and Linker -Drug Selection" Cancer Res March 15, 2009 69; 2358.

In one embodiment, the antigen binding domain for LAIR1 is the antigen binding portion, for example, the CDR, of the anti-LAIR1 antibody ANT-301 available from ProSpec; or anti-human CD305 (LAIR1) available from BioLegend.

In one embodiment, the antigen binding domain for FCAR is an antigen binding portion, e.g., CDR, anti-CD89 antibody/anti-FCAR antibody (Cat. No. 10414-H08H), available from Sino Biological Inc.

In one embodiment, the antigen binding domain for LILRA2 is the antigen binding portion of, for example, the CDR of the anti-LILRA2 monoclonal antibody (M17), clone 3C7, available from Abnova, or the mouse anti-LILRA2 monoclonal antibody (2D7), available from Lifespan Biosciences.

In one embodiment, the antigen binding domain for CD300LF is the antigen binding portion of, for example, the CDR of the mouse monoclonal antibody against CMRF35-like molecule 1 [UP-D2], available from BioLegend, or the rat monoclonal antibody against CMRF35-like molecule 1 [234903], available from R&D Systems.

In one embodiment, the antigen binding domain for CLEC12A is an antigen binding portion, e.g., a CDR, a scFv antibody in a bispecific activator engaging T cells (BiTE) format, and an ADC described in Noordhuis et al., “Targeting of CLEC12A In Acute Myeloid Leukemia by Antibody-Drug-Conjugates and Bispecific CLL-1xCD3 BiTE Antibody" ^53rd ASH Annual Meeting and Exposition, December 10-13, 2011, and MCLA-117 (Merus).

In one embodiment, the antigen binding domain for BST2 (also referred to as CD317) is the antigen binding portion of, for example, the CDR of the anti-CD317 mouse monoclonal antibody [3H4], available from Antibodies-Online, or the anti-CD317 mouse monoclonal antibody [696739], available from R&D Systems.

In one embodiment, the antigen binding domain for EMR2 (also referred to as CD312) is the antigen binding portion of, for example, the CDR of anti-CD312 mouse monoclonal antibody [LS-B8033], available from LifeSpan Biosciences, or anti-CD312 mouse monoclonal antibody [494025], available from R&D Systems.

In one embodiment, the antigen binding domain for LY75 is the antigen binding portion of, for example, the CDR of the mouse monoclonal antibody against lymphocyte antigen 75 [HD30], available from EMD Millipore, or the mouse monoclonal antibody against lymphocyte antigen 75 [A15797], available from Life Technologies.

In one embodiment, the antigen binding domain for GPC3 is the antigen binding portion, for example, the CDR, of the hGC33 antibody described in Nakano K, Ishiguro T, Konishi H, et al. Generation of a humanized anti-glypican 3 antibody by CDR grafting and stability optimization. Anticancer Drugs. 2010 Nov;21(10):907-916, or MDX-1414, HN3 or YP7, all three of which are described in Feng et al., "Glypican-3 antibodies: a new therapeutic target for liver cancer." FEBS Lett. 2014 Jan 21;588(2):377-82.

In one embodiment, the antigen binding domain for FCRL5 is the antigen binding portion, for example, the CDR, of an anti-FcRL5 antibody described in Elkins et al., "FcRL5 as a target of antibody-drug conjugates for the treatment of multiple myeloma" Mol Cancer Ther. 2012 Oct;11(10):2222-32. In one embodiment, the antigen binding domain for FCRL5 is the antigen binding portion, e.g., CDR, of an anti-FcRL5 antibody described, for example, in WO2001/038490, WO/2005/117986, WO2006/039238, WO2006/076691, WO2010/114940, WO2010 /120561 or WO2014/210064.

In one embodiment, the antigen binding domain for IGLL1 is the antigen binding portion, for example, the CDR, of a mouse monoclonal antibody to immunoglobulin lambda-like polypeptide 1 [AT1G4], available from LifeSpan Biosciences, a mouse monoclonal antibody to immunoglobulin lambda-like polypeptide 1 [HSL11], available from BioLegend.

In one embodiment, the antigen binding domain comprises one, two, three (e.g., all three) heavy chain CDRs, CDR1 HC, CDR2 HC, and CDR3 HC, from the antibody above, and/or one, two, three (e.g., all three ) light chain CDRs, CDR1 LC, CDR2 LC and CDR3 LC, from the antibody above. In one embodiment, the antigen binding domain comprises a heavy chain variable region and/or a light chain variable region of an antibody as defined above.

In another aspect, the antigen binding domain comprises a humanized antibody or antibody fragment. In some aspects, a non-human antibody is humanized if specific sequences or regions of the antibody are modified to increase similarity to an antibody naturally produced in humans, or a fragment thereof. In one aspect, the antigen binding domain is humanized.

In one embodiment, the antigen binding domain of a CAR, for example, a CAR expressed by a cell of the present invention, binds to CD19. CD19 is found on B cells during lineage differentiation from the pro/pre-B cell stage to the terminally differentiated plasma cell stage. In one embodiment, the antigen binding domain is a mouse scFv domain that binds to human CD19, such as the CTL019 antigen binding domain (eg, SEQ ID NO: 218). In one embodiment, the antigen binding domain is a humanized antibody or antibody fragment, for example, a scFv domain derived from a mouse CTL019 scFv. In one embodiment, the antigen binding domain is a human antibody or antibody fragment that binds to human CD19. Exemplary scFv domains (and their sequences, eg, CDR, VL and VH sequences) that bind CD19 are presented in Table 12a. The scFv domain sequences shown in Table 12 include a light chain variable region (VL) and a heavy chain variable region (VH). VL and VH are connected using a linker containing the sequence GGGGSGGGGSGGGGS (SEQ ID NO: 216), for example, in the following orientation: VL-linker-VH.

Table 12a. Antigen-binding domains that bind CD19 Antigen Name Amino acid sequence SEQ ID NO: CD19 muCTL019 DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGGGGSGGGGSGGGGSEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNS KSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSS 218 CD19 huscFv1 EIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNS KNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSS 219 CD19 huscFv2 EIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKD NSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSS 220 CD19 huscFv3 QVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGI PARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIK 221 CD19 huscFv4 QVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHS GIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIK 222 CD19 huscFv5 EIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISK DNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSS 223 CD19 huscFv6 EIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTIS KDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSS 224 CD19 huscFv7 QVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTS RLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIK 225 CD19 huscFv8 QVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYH TSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIK 226 CD19 huscFv9 EIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISK DNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSS 227 CD19 Hu
scFv10 QVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTS RLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIK 228 CD19 Hu
scFv11 EIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISKDNS KNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSS 229 CD19 HuscFv12 QVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGI PARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIK 230

The CDR sequences of the scFv domains from the CD19 antigen binding domains presented in Table 12a are shown in Table 12b for the heavy chain variable domains and in Table 12c for the light chain variable domains. "ID" denotes the corresponding SEQ ID NO for each CDR.

Table 12b. Heavy chain variable domain CDRs Description FW HCDR1 ID HCDR2 ID HCDR3 ID Mouse_CART19 GVSLPDYGVS 306 VIWGSETTYYNSALKS 307 HYYYGGSYAMDY 231 Humanized CART19 a VH4 GVSLPDYGVS 306 VIWGSETTYY S S S LKS 308 HYYYGGSYAMDY 231 Humanized CART19 b VH4 GVSLPDYGVS 306 VIWGSETTYY Q S S LKS 309 HYYYGGSYAMDY 231 Humanized CART19 c VH4 GVSLPDYGVS 306 VIWGSETTYYNS S LKS 310 HYYYGGSYAMDY 231

Table 12c. Light chain variable domain CDR Description FW LCDR1 ID LCDR2 ID LCDR3 ID Mouse_CART19 RASQDISKYLN 311 HTSRLHS 312 QQGNTLPYT 232 Humanized CART19 a VK3 RASQDISKYLN 311 HTSRLHS 312 QQGNTLPYT 232 Humanized CART19 b VK3 RASQDISKYLN 311 HTSRLHS 312 QQGNTLPYT 232 Humanized CART19 c VK3 RASQDISKYLN 311 HTSRLHS 312 QQGNTLPYT 232

In one embodiment, the antigen binding domain comprises an anti-CD19 antibody or fragment thereof, for example, a scFv. For example, the antigen binding domain contains a heavy chain variable region and a light chain variable region shown in Table 12d. The linker sequence connecting the heavy chain variable region and the light chain variable region may be any of the linker sequences described herein, or alternatively may be GSTSGSGKPGSGEGSTKG (SEQ ID NO: 233). The light chain variable region and the heavy chain variable region of the scFv may, for example, be in any of the following orientations: light chain variable region-linker-heavy chain variable region or heavy chain variable region-linker-light chain variable region.

Table 12d. Additional CD19-binding antibody domains Title Ab VH sequence VL sequence SJ25-C1 QVQLLESGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIYPGDGDTNYNGKFKGQATLTADKSSSTAYMQLSGLTSEDSAVYSCARKTISSVVDFYFDYWGQGTTVT (SEQ ID NO: 234) ELVLTQSPKFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQSPKPLIYSATYRNSGVPDRFTGSGSGTDFTLTITNVQSKDLADYFYFCQYNRYPYTSGGGTKLEIKRRS (SEQ ID NO: 235) ScFv sequence SJ25-C1
scFv QVQLLESGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIYPGDGDTNYNGKFKGQATLTADKSSSTAYMQLSGLTSEDSAVYSCARKTISSVVDFYFDYWGQGTTVTGSTSGSGKPGSGEGSTKGELVLTQSPKFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQSPKPLIYSATY RNSGVPDRFTGSGSGTDFTLTITNVQSKDLADYFYFCQYNRYPYTSGGGTKLEIKRRS (SEQ ID NO: 236)

In one embodiment, the CD19 binding domain comprises one or more (e.g., all three) of light chain complementarity determining region 1 (CDR1 LC), light chain complementarity determining region 2 (CDR2 LC), and complementarity determining region 3 (CDR2 LC). , the light chain (CDR3 LC) of the CD19 binding domain described herein, for example, those presented in Table 12a or 15, and/or one or more (e.g., all three) of the complementarity determining region 1 of the heavy chain (CDR1 HC ), the heavy chain complementarity determining region 2 (CDR2 HC) and the heavy chain complementarity determining region 3 (CDR3 HC) of the CD19 binding domain described herein, such as those presented in Table 12a or 16. In one embodiment The CD19 binding domain comprises one, two or all of CDR1 LC, CDR2 LC and CDR3 LC with any of the amino acid sequences shown in Table 12c, incorporated herein by reference; and one, two or all of CDR1 HC, CDR2 HC and CDR3 HC with any of the amino acid sequences presented in table 12b.

To construct a CAR in accordance with the present invention, any CD19 CAR known in the art can be used, for example, a CD19 antigen binding domain from any known CD19 CAR. For example, the CAR for CD19, LG-740, is described in US Pat. No. 8,399,645; US Patent No. 7446190; Xu et al., Leuk Lymphoma. 2013 54(2):255-260(2012); Cruz et al., Blood 122(17):2965-2973 (2013); Brentjens et al., Blood, 118(18):4817–4828 (2011); Kochenderfer et al., Blood 116(20):4099–102 (2010); Kochenderfer et al., Blood 122 (25):4129-39 (2013) and 16th Annu Meet Am Soc Gen Cell Ther (ASGCT) (May 15-18, Salt Lake City) 2013, Abst 10. In one embodiment, the antigen binding domain for CD19 is an antigen-binding part, for example a CDR, CAR, antibody or antigen-binding fragment thereof, described, for example, in PCT publication WO2012/079000; publications according to PCT WO2014/153270; Kochenderfer, J.N. et al., J. Immunother. 32(7), 689-702 (2009); Kochenderfer, J.N., et al., Blood, 116 (20), 4099-4102 (2010); publications according to PCT WO2014/031687; Bejcek, Cancer Research, 55, 2346-2351, 1995 or US Patent No. 7446190.

In one embodiment, the antigen binding domain of a CAR, for example, a CAR expressed by a cell of the present invention, binds to BCMA. BCMA is found predominantly in mature B lymphocytes. In one embodiment, the antigen binding domain is a mouse scFv domain that binds to human BCMA. In one embodiment, the antigen binding domain is a humanized antibody or antibody fragment, such as a scFv domain, that binds to human BCMA. In one embodiment, the antigen binding domain is a human antibody or antibody fragment that binds to human BCMA. In embodiments, exemplary CAR constructs for BCMA are generated using the VH and VL sequences from PCT publication WO2012/0163805 (the contents of which are incorporated herein by reference in their entirety). In embodiments, additional exemplary CAR constructs for BCMA are generated using the VH and VL sequences from PCT publication WO2016/014565 (the contents of which are incorporated herein by reference in their entirety). In embodiments, additional exemplary CAR constructs for BCMA are generated using the VH and VL sequences from PCT publication WO2014/122144 (the contents of which are incorporated herein by reference in their entirety). In embodiments, additional exemplary CAR constructs for BCMA are generated using CAR molecules and/or VH and VL sequences from PCT publication WO2016/014789 (the contents of which are incorporated herein by reference in their entirety). In embodiments, additional exemplary CAR constructs for BCMA are prepared using CAR molecules and/or VH and VL sequences from PCT publication WO2014/089335 (the contents of which are incorporated herein by reference in their entirety). In embodiments, additional exemplary CAR constructs for BCMA are generated using CAR molecules and/or VH and VL sequences from PCT publication WO2014/140248 (the contents of which are incorporated herein by reference in their entirety).

In accordance with the present invention, any known BMCA CAR can be used, for example, a BMCA antigen binding domain from any BMCA CAR known in the art. For example, those described in this document.

Exemplary CAR molecules

In one aspect, a CAR, for example, a CAR expressed by a cell of the present invention, provides a CAR molecule containing an antigen binding domain that binds to a B cell antigen, for example, described herein, such as CD19 or BCMA.

In one embodiment, the CAR provides a CAR molecule comprising an antigen binding domain for CD19 (e.g., a murine, human, or humanized antibody or antibody fragment that specifically binds to CD19), a transmembrane domain, and an intracellular signaling domain (e.g., an intracellular signaling domain comprising a co-stimulatory domain and/or primary signaling domain).

Exemplary CAR molecules described herein are presented in Table 12e. The CAR molecules in Table 12e contain an antigen binding domain for CD19, for example, with the amino acid sequence of any antigen binding domain for CD19 presented in Table 12a.

Table 12e. Exemplary CAR molecules for CD19 Antigen Name Amino acid sequence SEQ ID NO: CD19 CTL019 MALPVTALLLPLALLLHAARPDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGGGGSGGGGSGGGGSEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTY YNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGR REEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 237 CD19 CAR 1 MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTY YSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNL GRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 238 CD19 CAR 2 MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTY YQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNEL NLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 239 CD19 CAR 3 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQK PGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKTTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNL GRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 240 CD19 CAR 4 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQ KPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKTTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNEL NLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 241 CD19 CAR 5 MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGS ETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYN ELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 242 CD19 CAR 6 MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGS ETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLY NELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 243 CD19 CAR 7 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWY QQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKTTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLY NELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 244 CD19 CAR 8 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNW YQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKTTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQ LYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 245 CD19 CAR 9 MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGS ETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYN ELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 246 CD19 CAR 10 MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGS ETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYN ELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 247 CD19 CAR 11 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWY QQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKTTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLY NELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 248 CD19 CAR 12 MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTY YNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNL GRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 249

In one aspect, a CAR, e.g., a CAR expressed by a cell of the present invention, comprises a CAR molecule comprising an antigen binding domain that binds to BCMA, e.g., comprising a BCMA antigen binding domain (e.g., a murine, human, or humanized antibody or antibody fragment that specifically binds with BCMA, eg human BCMA), a transmembrane domain and an intracellular signaling domain (eg an intracellular signaling domain containing a co-stimulatory domain and/or a primary signaling domain).

Exemplary CAR molecules for the CAR molecule described herein are presented in Table 1 of WO2016/014565, which is incorporated herein by reference.

Transmembrane domains

With respect to the transmembrane domain, in various embodiments, the CAR can be designed to contain a transmembrane domain attached to an extracellular domain of the CAR. The transmembrane domain may contain one or more additional amino acids adjacent to the transmembrane region, for example, one or more amino acids related to the extracellular region of the protein from which the transmembrane domain is derived (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and up to 15 amino acids of the extracellular region), and/or one or more additional amino acids related to the intracellular region of the protein from which the transmembrane domain is derived (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and up to 15 amino acids of the intracellular region). In one aspect, the transmembrane domain is a domain associated with one of the other domains of the CAR, for example, in one embodiment, the transmembrane domain can be derived from the same protein from which the signaling domain, costimulatory domain, or hinge domain is derived. In another aspect, the transmembrane domain is not derived from the same protein from which any other CAR domain is derived. In some cases, the transmembrane domain can be selected or modified by amino acid substitution to avoid binding of such domains to the transmembrane domains of the same or other membrane surface proteins, for example, to minimize interactions with other components of the receptor complex. In one aspect, the transmembrane domain is capable of homodimerizing with another CAR on the cell surface of a cell expressing the CAR. In another aspect, the amino acid sequence of the transmembrane domain can be modified or replaced so as to minimize interactions with the binding domains of a native binding partner present in the same cell expressing the CAR.

The transmembrane domain can be obtained from a natural or recombinant source. If the source is natural, the domain can be derived from any membrane-bound or transmembrane protein. In one aspect, the transmembrane domain is capable of transmitting a signal to the intracellular domain(s) whenever the CAR has bound a target. A transmembrane domain particularly useful in the present invention may include at least transmembrane region(s), for example, T cell receptor alpha, beta or zeta chains, CD28, CD27, CD3 epsilon, CD45, CD4 , CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154. In some embodiments, the transmembrane domain may include at least transmembrane region(s), e.g., KIRDS2, OX40, CD2, CD27, LFA-1 (CD11a, CD18), ICOS (CD278), 4-1BB (CD137) , GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD160, CD19, IL2R-beta, IL2R-gamma, IL7R-α, ITGA1, VLA1, CD49a, ITGA4, IA4 , CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2 , DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, PAG/Cbp, NKG2D, NKG2C.

In some cases, the transmembrane domain may be attached to the extracellular region of the CAR, such as the antigen binding domain of the CAR, via a hinge region, such as a human protein hinge region. For example, in one embodiment, the hinge region may be a human Ig (immunoglobulin) hinge region (e.g., an IgG4 hinge region, an IgD hinge region), a GS linker (e.g., a GS linker described herein), a KIR2DS2 hinge region, or a hinge region CD8a. In one embodiment, the hinge region or spacer comprises (e.g., consists of) the amino acid sequence of SEQ ID NO: 250. In one aspect, the transmembrane domain comprises (e.g., consists of) the transmembrane domain of SEQ ID NO: 251.

In certain embodiments, the encoded transmembrane domain comprises a CD8 transmembrane domain amino acid sequence comprising at least one, two, or three modifications, but not more than 20, 10, or 5 modifications of the amino acid sequence of SEQ ID NO: 251 or the sequence of at least 95 % identical to the amino acid sequence of SEQ ID NO: 251. In one embodiment, the encoded transmembrane domain contains the sequence of SEQ ID NO: 251.

In other embodiments, the CAR-encoding nucleic acid molecule comprises a CD8 transmembrane domain nucleotide sequence, for example, the sequence of SEQ ID NO: 252 or SEQ ID NO: 289, or a sequence that is at least 95% identical thereto.

In certain embodiments, the encoded antigen binding domain is connected to the transmembrane domain by a hinge region. In one embodiment, the encoded hinge region comprises a CD8 hinge region amino acid sequence, for example, SEQ ID NO: 250; or an IgG4 hinge region amino acid sequence, such as SEQ ID NO: 253, or a sequence at least 95% identical to SEQ ID NO: 250 or SEQ ID NO: 253. In other embodiments, the nucleic acid sequence encoding the hinge region comprises the sequence of SEQ ID NO: 254 or SEQ ID NO: 255 corresponding to the CD8 hinge region or the IgG4 hinge region, respectively, or a sequence at least 95% identical to SEQ ID NO: 254 or 255.

In one aspect, the hinge region or spacer includes an IgG4 hinge region. For example, in one embodiment, the hinge region or spacer comprises a hinge region with the amino acid sequence ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKM (SEQ ID NO: 253). In some embodiments, the hinge region or spacer comprises a hinge region encoded by the nucleotide sequence GAGAGCAAGTACGGCCCTCCCTGCCCCCCTTGCCCTGCCCCCGAGTTCCTGGGCGGACCCAGCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCCGGACCCCCGAGGTGACCTGTGTGGTGGTGGACGTGTCCCAGGAGGACCCCGAGGTCCAGTTCAACTGGTACG TGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCCGGGAGGAGCAGTTCAATAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAATACAAGTGTAAGGTGTCCAACAAGGGCCTGCCCAGCAGCATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCTCGGGAGCCCCAGGTGTACACCCTGCCCCCTAGCCAAGAGGATGACCAAGAAC CAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCCGGCTGACCGTGGACAAGAGCCGGTGGCAGGAGGGCAACGTCTTTAGCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGCCTGAGCCTGTC CCTGGGCAAGATG (SEQ ID NO: 255).

In one aspect, the hinge region or spacer includes an IgD hinge region. For example, in one embodiment, the hinge region or spacer comprises a hinge region with the amino acid sequence RWPESPKAQASSVPTAQPQAEGSLAKATTAPATTRNTGRGGEEKKKEKEKEEQEERETKTPECPSHTQPLGVYLLTPAVQDLWLRDKATFTCFVVGSDLKDAHLTWEVAGKVPTGGVEEGLLERHSNGSQSQHSRLTLPRSLWNAGTSVTCTLN HPSLPPQRLMALREPAAQAPVKLSLNLLASSDPPEAASWLLCEVSGFSPPNILLMWLEDQREVNTSGFAPARPPPQPGSTTFWAWSVLRVPAPPSPQPATYTCVVSHEDSRTLLNASRSLEVSYVTDH (SEQ ID NO: 256). In some embodiments, the hinge region or spacer comprises a hinge region encoded by the nucleotide sequence AGGTGGCCCGAAAGTCCCAAGGCCCAGGCATCTAGTGTTCCTACTGCACAGCCCCAGGCAGAAGGCAGCCTAGCCAAAGCTACTACTGCACCTGCCACTACGCGCAATACTGGCCGTGGCGGGGAGGAGAAGAAAAAGGAGAAAGAGAAAGAAGAACAGGAAGAGAGGGAGACCAAGACCCCTGAATGTC CATCCCATACCCAGCCGCTGGGCGTCTATCTCTTGACTCCCGCAGTACAGGACTTGTGGCTTAGAGATAAGGCCACCTTTACATGTTTCGTCGTGGGCTCTGACCTGAAGGATGCCCATTTGACTTGGGAGGTTGCCGGAAAGGTACCCACAGGGGGGGTTGAGGAAGGGTTGCTGGAGCGCCATTCCAATGGCTCTCAGAGCCAGCACTCAAGACTCACCCTTCCGAGATCCCTGTGGAACGCCGGGA CCTCTGTCACATGTACTCTAAATCATCCTAGCCTGCCCCCACAGCGTCTGATGGCCCTTAGAGAGCCAGCCGCCCAGGCACCAGTTAAGCTTAGCCTGAATCTGCTCGCCAGTAGTGATCCCCCAGAGGCCGCCAGCTGGCTCTTATGCGAAGTGTCCGGCTTTAGCCCGCCCAACATCTTGCTCATGTGGCTGGAGGACCAGCGAGAAGTGAACACCAGCGGCTTCGCTCCAGCCCGGCCCCCACCCCA GCCGGGTTCTACCACATTCTGGGCCTGGAGTGTCTTAAGGGTCCCAGCACCACCTAGCCCCCAGCCAGCCACATACACCTGTGTTGTGTCCCATGAAGATAGCAGGACCCTGCTAAATGCTTCTAGGAGTCTGGAGGTTTCCTACGTGACTGACCATT (SEQ ID NO: 257).

In one aspect, the transmembrane domain may be recombinant, in which case it will contain primarily hydrophobic residues such as leucine and valine. In one aspect, a triplet of phenylalanine, tryptophan and valine may be present at each end of the recombinant transmembrane domain.

A short oligo- or polypeptide linker of 2 to 10 amino acids in length may optionally form a link between the transmembrane domain and the cytoplasmic region of the CAR. A glycine-serine doublet is a particularly suitable linker. For example, in one aspect, the linker contains the amino acid sequence GGGGSGGGGS (SEQ ID NO: 258). In some embodiments, the linker is encoded by the nucleotide sequence GGTGGCGGAGGTTCTGGAGGTGGAGGTTCC (SEQ ID NO: 259).

In one aspect, the hinge region or spacer includes a KIR2DS2 hinge region.

Signaling domains

Embodiments of the present invention provide an intracellular signaling domain, such as a domain that may comprise, for example, one or more of a primary signaling domain and/or a co-stimulatory signaling domain. In some embodiments, the intracellular signaling domain comprises a sequence encoding a primary signaling domain. In some embodiments, the intracellular signaling domain comprises a co-stimulatory signaling domain. In some embodiments, the intracellular signaling domain comprises a primary signaling domain and a co-stimulatory signaling domain.

Intracellular signal sequences in the cytoplasmic portion of the CAR of the present invention may be associated with each other in a random or established order. A short oligo- or polypeptide linker, for example, 2 to 10 amino acids in length (eg, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids) may optionally form a link between intracellular signal sequences. In one embodiment, a glycine-serine doublet may be used as a suitable linker. In one embodiment, a single amino acid, eg alanine, glycine, can be used as a suitable linker.

In one aspect, the intracellular signaling domain is designed to contain two or more, such as 2, 3, 4, 5 or more, co-stimulatory signaling domains. In one embodiment, two or more, such as 2, 3, 4, 5, or more, co-stimulatory signaling domains are separated by a linker molecule, such as the linker molecule described herein. In one embodiment, the intracellular signaling domain comprises two co-stimulatory signaling domains. In some embodiments, the linker molecule is a glycine residue. In some embodiments, the linker is an alanine residue.

Primary signaling domains

The primary signaling domain regulates the primary activation of the TCR complex in either a stimulatory or inhibitory manner. Primary intracellular signaling domains that act in a stimulatory manner may contain signaling motifs known as immunoreceptor tyrosine activating motifs or ITAMs.

Examples of ITAM-containing primary intracellular signaling domains that are particularly useful in the present invention include CD3 -zeta, FcR gamma chain common (FCER1G), Fc-gamma RIIa, FcR-beta (Fc-epsilon R1b) , CD3-gamma domains. , CD3-delta, CD3-epsilon , CD79a, CD79b, DAP10 and DAP12. In one embodiment, the CAR of the present invention contains an intracellular signaling domain, for example, a CD3-zeta primary signaling domain.

In one embodiment, the encoded primary signaling domain comprises a functional CD3-zeta signaling domain. The encoded primary CD3 zeta signal domain may comprise an amino acid sequence containing at least one, two or three modifications, but not more than 20, 10 or 5 modifications of the amino acid sequence of SEQ ID NO: 260 or SEQ ID NO: 261 or sequences of at least 95% identical to the amino acid sequence of SEQ ID NO: 260 or SEQ ID NO: 261. In some embodiments, the encoded primary signal domain comprises the sequence of SEQ ID NO: 260 or SEQ ID NO: 261. In other embodiments, the nucleic acid sequence , encoding the primary signaling domain, comprises the sequence of SEQ ID NO: 262, SEQ ID NO: 291 or SEQ ID NO: 263 or a sequence at least 95% identical thereto.

Costimulatory signaling domains

In some embodiments, the encoded intracellular signaling domain comprises a co-stimulatory signaling domain. For example, the intracellular signaling domain may comprise a primary signaling domain and a co-stimulatory signaling domain. In some embodiments, the encoded costimulatory signaling domain comprises a functional signaling domain of a protein selected from one or more of CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen 1 ( LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds to CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD160, CD19 , CD4, CD8-alpha, CD8-beta, IL2R-beta, IL2R-gamma, IL7R-alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103 , ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84 , CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, NKp44, NKp30, NKp46 or NKG2D.

In certain embodiments, the encoded co-stimulatory signaling domain comprises an amino acid sequence having at least one, two, or three modifications, but not more than 20, 10, or 5 modifications of the amino acid sequence of SEQ ID NO: 264 or SEQ ID NO: 265 or sequences at at least 95% identical to the amino acid sequence of SEQ ID NO: 264 or SEQ ID NO: 265. In one embodiment, the encoded co-stimulatory signaling domain comprises the sequence of SEQ ID NO: 264 or SEQ ID NO: 265. In other embodiments, the nucleic acid sequence acid encoding a co-stimulatory signaling domain contains the sequence of SEQ ID NO: 266, SEQ ID NO: 290 or SEQ ID NO: 267 or a sequence at least 95% identical thereto.

In other embodiments, the encoded intracellular domain comprises the sequence of SEQ ID NO: 264 or SEQ ID NO: 265 and the sequence of SEQ ID NO: 260 or SEQ ID NO: 261, wherein the sequences forming the intracellular signaling domain are expressed in the same reading frame and in the form of a single polypeptide chain.

In certain embodiments, the nucleic acid sequence encoding the intracellular signaling domain comprises the sequence of SEQ ID NO: 266, SEQ ID NO: 290, or SEQ ID NO: 267, or a sequence at least 95% identical thereto, and the sequence of SEQ ID NO: 262, SEQ ID NO: 291 or SEQ ID NO: 263 or a sequence at least 95% identical thereto.

In some embodiments, the nucleic acid molecule further encodes a leader sequence. In one embodiment, the leader sequence comprises the sequence of SEQ ID NO: 268.

In one aspect, the intracellular signaling domain is designed to comprise a CD3-zeta signaling domain and a CD28 signaling domain. In one aspect, the intracellular signaling domain is designed to comprise a CD3-zeta signaling domain and a 4-1BB signaling domain. In one aspect, the 4-1BB signaling domain is the signaling domain of SEQ ID NO: 264. In one aspect, the CD3-zeta signaling domain is the signaling domain of SEQ ID NO: 260.

In one aspect, the intracellular signaling domain is designed to comprise a CD3-zeta signaling domain and a CD27 signaling domain. In one aspect, the CD27 signaling domain comprises the amino acid sequence QRRKYRSNKGESPVEPAEPCRYSCPREEEGSTIPIQEDYRKPEPACSP (SEQ ID NO: 265). In one aspect, the CD27 signaling domain is encoded by the nucleic acid sequence Caacgaaggaaatatagatcaaacaaaggagaaagtcctgtggagcctgcagagccttgtcgttacagctgccccagggaggagggcagcaccatccccatccaggaggattaccgaaaaccggagcctgcctgctccccc (SEQ ID NO: 267).

Vectors

In another aspect, the present invention provides a vector containing a nucleic acid sequence encoding a CAR described herein. In one embodiment, the vector is selected from a DNA vector, RNA vector, plasmid, lentiviral vector, adenoviral vector, or retroviral vector. In one embodiment, the vector is a lentiviral vector. Such vectors or portions thereof may, among other things, be used to generate nucleic acid templates described herein for use with the CRISPR systems described herein. Alternatively, vectors can be used to deliver a nucleic acid directly into a cell, eg an immune effector cell, eg a T cell, eg an allogeneic T cell, independent of the CRISPR system.

The present invention also provides vectors into which the DNA of the present invention is inserted. Vectors derived from retroviruses, such as lentivirus, are suitable tools for achieving long-term gene transfer, as they ensure long-term stable integration of the transgene and its propagation in daughter cells. Lentiviral vectors have the additional advantage over vectors derived from oncoretroviruses such as murine leukemia viruses in that they can be transduced into non-proliferating cells such as hepatocytes. They also have the added benefit of low immunogenicity. The retroviral vector may also be, for example, a gamma retroviral vector. The gamma retroviral vector may contain, for example, a promoter, a packaging signal (ψ), a primer binding site (PBS), one or more (eg, two) long terminal repeats (LTRs), and a transgene of interest, such as a gene encoding a CAR . The gammaretroviral vector may lack viral structural genes such as gag, pol and env. Exemplary gamma retroviral vectors include murine leukemia virus (MLV), spleen necrosis virus (SFFV), and myeloproliferative sarcoma virus (MPSV), as well as vectors derived from them. Other gammaretroviral vectors are described, for example, in Tobias Maetzig et al., "Gammaretroviral Vectors: Biology, Technology and Application" Viruses. 2011 Jun; 3(6): 677-713.

In another embodiment, the vector containing the nucleic acid encoding the desired CAR of the present invention is an adenoviral vector (A5/35). In another embodiment, expression of nucleic acids encoding CARs can be achieved using transposons such as Sleeping Beauty, CRISPR, CAS9 and zinc finger nucleases. See below June et al. 2009 Nature Reviews Immunology 9.10: 704-716, which is incorporated herein by reference.

Nucleic acid can be cloned into many types of vectors. For example, the nucleic acid can be cloned into a vector including, but not limited to, a plasmid, phagemid, phage derivative, animal virus, and cosmid. Vectors of particular interest include expression vectors, replication vectors, probe generation vectors, and sequencing vectors.

Disclosed herein are methods for producing in vitro transcribed RNA encoding a CAR. The present invention also includes an RNA construct encoding a CAR that can be introduced by direct transfection into a cell. A method for producing mRNA for use in transfection may involve in vitro transcription (IVT) of a template using specially designed primers followed by the addition of poly(A) to produce a construct containing 3' and 5' untranslated sequences ("UTRs"), 5' -cap and/or internal ribosome entry site (IRES), a nucleic acid to be expressed, and a poly(A) tail, typically 50-2000 bases in length (SEQ ID NO: 269). Using RNA obtained in this way, various types of cells can be effectively transfected. In one aspect, the matrix contains sequences for CARs.

Non-viral delivery methods

In some aspects, non-viral methods can be used to deliver a nucleic acid encoding a CAR described herein into a cell or tissue or body of a subject.

In some embodiments, the non-viral method includes the use of a transposon (also called a mobile genetic element). In some embodiments, a transposon is a piece of DNA that can self-insert at a specific location in the genome, such as a piece of DNA that is capable of self-replicating and inserting a copy of itself into the genome, or a piece of DNA that can be excised from a longer length by splicing. nucleic acid and inserted elsewhere in the genome. For example, a transposon contains a DNA sequence consisting of inverted repeats flanking the genes to be transposed.

In some embodiments, cells, e.g., T or NK cells, that express a CAR described herein are generated through a combination of gene insertion using SBTS and genetic editing using a nuclease (e.g., zinc finger nucleases (ZFNs) ), transcription activator-like effector nucleases (TALENs), the CRISPR/Cas system, or engineered meganucleases, which are reconstituted homing endonucleases).

In some embodiments, cells of the present invention, e.g., T or NK cells, e.g., allogeneic T cells, e.g., those described herein (e.g., that express the CAR described herein), are generated by bringing the cells into contact with (a) a composition comprising one or more gRNA molecules, for example, as described herein, and one or more Cas molecules, for example, a Cas9 molecule, for example, as described herein, and (b) a nucleic acid containing a coding sequence A CAR, for example, as described herein (such as a template nucleic acid molecule described herein). Without being limited to any theory, the above composition (a) will induce a break in or near the genomic DNA targeted by the targeting domain of the gRNA molecule(s), and the nucleic acid (b) will be incorporated, for example, partially or completely, into the genome at or near the site of said break so that upon integration, the encoded CAR molecule is expressed. In embodiments, CAR expression will be controlled by promoters or other regulatory elements endogenous to the genome (eg, promoter-controlled expression from a gene into which nucleic acid (b) has been inserted). In other embodiments, the nucleic acid (b) further comprises a promoter and/or other regulatory elements, such as those described herein, for example, an EF1-alpha promoter operably linked to a CAR coding sequence such that upon integration, expression of the CAR is controlled this promoter and/or other regulatory elements. Additional features of the present invention relate to the use of CRISPR/Cas9 systems, such as those described herein, the direct incorporation of a nucleic acid sequence encoding a CAR, such as those described herein, are described elsewhere in this application, for example, in the section relating to to gene insertion and homologous recombination. In embodiments, composition a) above is a composition comprising RNPs containing one or more gRNA molecules. In embodiments, RNPs containing gRNAs targeting unique target sequences are introduced into a cell simultaneously, for example, as a mixture of RNPs containing one or more gRNAs. In embodiments, RNPs containing gRNAs targeting unique target sequences are introduced into a cell sequentially.

In some embodiments, the use of a non-viral delivery method allows cells, such as T or NK cells, to be reprogrammed and the cells to be directly infused into a subject. Advantages of non-viral vectors include, but are not limited to, ease and relatively low cost of obtaining sufficient quantities to meet patient population requirements, storage stability, and lack of immunogenicity.

Promoters

In one embodiment, the vector further comprises a promoter. In some embodiments, the promoter is selected from the EF-1 promoter, the CMV IE gene promoter, the EF-1α promoter, the ubiquitin C promoter, or the phosphoglycerate kinase (PGK) promoter. In one embodiment, the promoter is an EF-1 promoter. In one embodiment, the EF-1 promoter contains the sequence of SEQ ID NO: 270.

Host cells for CAR expression

As stated above, in some aspects, the present invention relates to a cell, e.g., an immune effector cell (e.g., a population of cells, e.g., a population of immune effector cells) comprising a nucleic acid molecule, a CAR polypeptide molecule, or a vector described herein.

In certain aspects of the present invention, immune effector cells, such as T cells, can be obtained from a unit of blood collected from a subject using any number of techniques known to one of ordinary skill in the art, such as Ficoll™ separation. In one preferred aspect, cells from the circulating blood of an individual are obtained by apheresis. The apheresis product typically contains lymphocytes, including T cells, monocytes, granulocytes, B cells, other nucleated leukocytes, red blood cells, and platelets. In one aspect, cells collected by apheresis can be washed to remove the blood plasma fraction and optionally place the cells in an appropriate buffer or medium for subsequent processing steps. In one embodiment, the cells are washed with phosphate buffered saline (PBS). In an alternative embodiment, the wash solution lacks calcium and may lack magnesium or may lack many, if not all, divalent cations.

The initial stages of activation in the absence of calcium may result in increased activation. As will be apparent to those of ordinary skill in the art, the washing step can be accomplished using methods known to those skilled in the art, such as using a semi-automated "flow" centrifuge (e.g., Cobe 2991 cell processor, Baxter's CytoMate or Cell Saver 5 from Haemonetics) according to the manufacturer's instructions. After washing, the cells can be resuspended in a variety of biocompatible buffers, such as Ca-free, Mg-free PBS, PlasmaLyte A, or other saline solution with or without buffer. Alternatively, unwanted components from the apheresis sample can be removed and the cells can be directly resuspended in culture medium.

It is recognized that methods of use may employ culture media conditions comprising human serum AB at a concentration of 5% or less, such as 2%, and use known culture media conditions and compositions, such as those described in Smith et al ., "Ex vivo expansion of human T cells for adoptive immunotherapy using the novel Xeno-free CTS Immune Cell Serum Replacement", Clinical & Translational Immunology (2015) 4, e31; doi:10.1038/cti.2014.31.

In one aspect, T cells are isolated from peripheral blood lymphocytes by lysing red blood cells and depleting the monocyte population, for example, by PERCOLL™ gradient centrifugation or by countercurrent elutriation centrifugation.

The methods described herein may include, for example, selecting a specific subpopulation of immune effector cells, for example, T cells, which is a population of cells depleted of regulatory T cells with depletion of CD25+ cells, using, for example, a negative selection, such as those described in this document. The regulatory T cell depleted population preferably contains less than 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1% CD25+ cells.

In one embodiment, regulatory T cells, eg, CD25+ T cells, are removed from the population using an anti-CD25 antibody or fragment thereof or a CD25-binding IL-2 ligand. In one embodiment, an anti-CD25 antibody or fragment thereof or a CD25-binding ligand is conjugated to a substrate, such as a microbead, or otherwise applied to a substrate, such as a microbead. In one embodiment, the anti-CD25 antibody or fragment thereof is conjugated to a substrate described herein.

In one embodiment, regulatory T cells, eg, CD25+ T cells, are removed from the population using CD25 depletion reagent from Miltenyi™. In one embodiment, the ratio of cells to CD25 depletion reagent is 1e7 cells per 20 μl, or 1e7 cells per 15 μl, or 1e7 cells per 10 μl, or 1e7 cells per 5 μl, or 1e7 cells per 2.5 μl, or 1e7 cells per 1.25 µl. In one embodiment, for example, more than 500 million cells/ml is used to deplete regulatory T cells, eg CD25+. In a further aspect, a cell concentration of 600, 700, 800 or 900 million cells/ml is used.

In one embodiment, the population of immune effector cells to be depleted contains approximately 6×10 ⁹ CD25+ T cells. In other aspects, the population of immune effector cells to be depleted contains from about 1×10 ⁹ to 1×10 ¹⁰ CD25+ T cells, including any integer value in between. In one embodiment, the resulting regulatory T cell-depleted population contains 2 x 10 ⁹ regulatory T cells, e.g., CD25+ cells, or less (e.g., 1 x 10 ⁹ , 5 x 10 ⁸ , 1 x 10 ⁸ , 5 ×10 ⁷ , 1 × 10 ⁷ or fewer CD25+ cells).

In one embodiment, regulatory T cells, such as CD25+ cells, are removed from the population using a CliniMACS system with a depletion tube set, such as, for example, 162-01 tubes. In one embodiment, the CliniMACS system operates with depletion parameters set, such as, for example, DEPLETION2.1.

Without wishing to be bound by any particular theory, it is believed that by reducing the level of immune cell negative regulators (e.g., reducing the number of undesirable immune cells, e.g., T _REG cells) in a subject prior to apheresis or during manufacture of a CAR-expressing cell product , the subject's risk of relapse can be reduced. For example, methods for depleting a population of T _REG cells are known in the art. Methods for reducing the number of T _REG cells include, but are not limited to, the use of cyclophosphamide, an anti-GITR antibody (the anti-GITR antibody described herein), a CD25 depletion reagent, and combinations thereof.

In some embodiments, manufacturing methods include reducing the amount (e.g., depleting a population) of T_REG-cells before producing a CAR-expressing cell. For example, manufacturing methods involve contacting a sample, such as an apheresis sample, with an anti-GITR antibody and/or an anti-CD25 antibody (or a fragment or CD25-binding ligand thereof), for example, to deplete T_REG-cells before production product based on a cell (eg, T cells, NK cells) expressing CAR.

In one embodiment, the subject is pretreated with one or more therapies that reduce the number of T _REG cells before harvesting the cells to make a CAR-expressing cell product, thereby reducing the subject's risk of relapse when treated with using cells expressing CAR. In one embodiment, methods of reducing the number of T _REG cells include, but are not limited to, administering to a subject one or more of cyclophosphamide, an anti-GITR antibody, a CD25 depletion reagent, or a combination thereof. Administration of one or more of cyclophosphamide, anti-GITR antibody, CD25 depletion reagent, or a combination thereof may occur before, during, or after infusion of the CAR-expressing cell product.

In one embodiment, the subject is pretreated with cyclophosphamide prior to harvesting the cells to make a CAR-expressing cell product, thereby reducing the subject's risk of relapse when treated with the CAR-expressing cells. In one embodiment, the subject is pretreated with an anti-GITR antibody before harvesting cells to make a CAR-expressing cell product, thereby reducing the subject's risk of relapse when treated with the CAR-expressing cells.

In one embodiment, the population of cells to be removed is neither regulatory T cells nor tumor cells, but rather cells that otherwise adversely affect the proliferation and/or function of CAR-T cells, e.g., cells expressing CD14, CD11b, CD33, CD15 or other markers expressed by potentially immunosuppressive cells. In one embodiment, it is contemplated that such cells are removed in parallel with regulatory T cells and/or tumor cells, or after said depletion, or in another order.

The methods described herein may include more than one selection step, for example, more than one depletion step. Enrichment of the T cell population by negative selection can be accomplished, for example, by using a combination of antibodies directed to surface markers unique to cells under negative selection. One method is cell sorting and/or selection by negative magnetic immunoadhesion or flow cytometry, which uses a cocktail of monoclonal antibodies directed to cell surface markers present on cells undergoing negative selection. For example, to enrich for CD4+ cells by negative selection, the monoclonal antibody mixture may contain antibodies to CD14, CD20, CD11b, CD16, HLA-DR and CD8.

The methods described herein may further include removing from the population cells that express a tumor antigen, such as a tumor antigen that does not include CD25, such as CD19, CD30, CD38, CD123, CD20, CD14, or CD11b, thereby obtaining a population of cells depleted of regulatory T cells, eg, CD25+ cell-depleted and tumor antigen-depleted cells, that are suitable for expressing a CAR, eg, the CAR described herein. In one embodiment, tumor antigen expressing cells are removed simultaneously with regulatory T cells, such as CD25+ cells. For example, an anti-CD25 antibody or fragment thereof and an anti-tumor antigen antibody or fragment thereof may be attached to the same substrate, such as a microbead, which can be used to remove cells, or an anti-CD25 antibody or fragment thereof, or an anti-tumor antigen antibody or its fragment can be attached to individual microbeads, a mixture of which can be used to remove cells. In other embodiments, the removal of regulatory T cells, eg, CD25+ cells, and the removal of tumor antigen expressing cells are sequential and can occur, for example, in any order.

Also provided are methods that include removing, for example, one or more of PD1+ cells, LAG3+ cells, and TIM3+ cells from a population of cells expressing an immune checkpoint inhibitor, such as an immune checkpoint inhibitor described herein, thereby obtaining a population depleted of regulatory T cells, eg, depleted of CD25+ cells and depleted of immune checkpoint inhibitor cells, eg, depleted of PD1+, LAG3+ and/or TIM3+ cells. Exemplary immune checkpoint inhibitors include B7-H1, B7-1, CD160, P1H, 2B4, PD1, TIM3, CEACAM (eg, CEACAM-1, CEACAM-3 and/or CEACAM-5), LAG3, TIGIT, CTLA- 4, BTLA and LAIR1. In one embodiment, cells expressing an immune checkpoint inhibitor are removed simultaneously with regulatory T cells, such as CD25+ cells. For example, an anti-CD25 antibody or fragment thereof and an anti-immune checkpoint inhibitor antibody or fragment thereof can be attached to the same microbead that can be used to remove cells, or an anti-CD25 antibody or fragment thereof and an anti-immune checkpoint inhibitor antibody. response or a fragment thereof can be attached to individual microbeads, a mixture of which can be used to remove cells. In other embodiments, the removal of regulatory T cells, such as CD25+ cells, and the removal of cells expressing an immune checkpoint inhibitor are sequential and can occur, for example, in any order.

The methods described herein may include a positive selection step. For example, T cells can be isolated by incubation with anti-CD3/anti-CD28 conjugated microbeads (e.g., 3x28), such as DYNABEADS® M-450 CD3/CD28 T, for a period of time sufficient for positive selection required T cells. In one embodiment, the time period is approximately 30 minutes. In a further embodiment, the time period is in the range of 30 minutes to 36 hours or greater and includes all integer values within that range. In a further embodiment, the time period is at least 1, 2, 3, 4, 5 or 6 hours. In yet another embodiment, the time period is from 10 to 24 hours, for example, 24 hours. Longer incubation times can be used to isolate T cells in any situation in which T cells are few in number relative to other cell types, such as when isolating tumor infiltrating lymphocytes (TILs) from tumor tissue or from individuals with weakened immunity. In addition, using longer incubation times may increase the capture efficiency of CD8+ T cells. Thus, simply shortening or lengthening the time that T cells are able to bind to anti-CD3/CD28 microbeads and/or increasing or decreasing the microbead to T cell ratio (as further described herein) can advantageously perform positive or negative selection of T cell subpopulations at the beginning of culture or at other times during the process. In addition, by increasing or decreasing the relative amount of anti-CD3 antibodies and/or anti-CD28 antibodies on the microbeads or other surface, positive or negative selection of T cell subsets can be preferentially achieved at the start of culture or at other desired times.

In one embodiment, you can select a population of T cells that express one or more of IFN-γ, TNFα, IL-17A, IL-2, IL-3, IL-4, GM-CSF, IL-10, IL-13 , granzyme B and perforin or other relevant molecules, such as other cytokines. Screening methods for cellular expression can be determined, for example, using the methods described in the publication according to PCT No. WO 2013/126712

Cell concentration and surface (eg, particles such as microbeads) can be varied to select the desired cell population by positive or negative selection. In certain aspects, it may be desirable to significantly reduce the volume in which the microbeads and cells are mixed with each other (eg, increase the concentration of cells) to ensure maximum contact of cells and microbeads. For example, in one aspect, a concentration of 10 billion cells/ml, 9 billion/ml, 8 billion/ml, 7 billion/ml, 6 billion/ml, or 5 billion/ml is used. In one aspect, a concentration of 1 billion cells/ml is used. In yet another aspect, a cell concentration of 75, 80, 85, 90, 95 or 100 million cells/ml is used. In additional aspects, concentrations of 125 or 150 million cells/ml may be used.

The use of high concentrations can lead to increased cell yield, cell activation, and cell proliferation rates. In addition, the use of high cell concentrations allows for more efficient capture of cells that may have poor expression of target antigens of interest, such as CD28-negative T cells, or cells from samples in which many tumor cells are present (eg, leukemic blood , tumor tissue, etc.). Such cell populations may have therapeutic value and may be desirable to obtain. For example, using a high concentration of cells allows for more efficient selection of CD8+ T cells, which typically have weaker CD28 expression.

In a related aspect, it may be necessary to use lower concentrations of cells. By significantly diluting the mixture of T cells and surface (eg particles such as microbeads), particle-cell interactions are minimized. In this case, cells are selected that express the required antigens in high quantities, which will bind to the particles. For example, CD4+ T cells express CD28 at higher levels and are taken up at weak concentrations more efficiently than CD8+ T cells. In one aspect, the cell concentration used is 5×10 ⁶ /ml. In other aspects, the concentration used may be from about 1×10 ⁵ /ml to 1×10 ⁶ /ml, including any integer value in between.

In other aspects, cells can be incubated on a rotator for various periods of time at various speeds at 2-10°C or at room temperature.

T cells for stimulation can also be frozen after the washing step. Without being limited to any theory, it is believed that the freezing and thawing step provides a more uniform product by removing granulocytes and to some extent monocytes from the cell population. After a washing step in which blood plasma and platelets are removed, the cells can be suspended in a freezing solution. Although many freezing solutions and parameters for freezing are known in the art and will be applicable here, one method involves the use of PBS containing 20% DMSO and 8% human serum albumin, or culture media containing 10% dextran 40 in 5% dextrose. 20% human serum albumin and 7.5% DMSO or 31.25% PlasmaLyte-A, 31.25% 5% dextrose in 0.45% NaCl, 10% dextran 40 in 5% dextrose, 20% human serum albumin and 7.5% DMSO, or other suitable cell freezing media containing, for example, Hespan and PlasmaLyte A, and then the cells are frozen to -80°C at a rate of 1° per minute and stored in the vapor phase in a liquid nitrogen storage tank . Other methods of controlled freezing can be used, as well as uncontrolled freezing immediately at -20°C or in liquid nitrogen.

In certain aspects, cryopreserved cells are thawed and washed as described herein and left for one hour at room temperature before activation using the methods of the present invention.

It is also within the scope of the present invention to collect blood samples or apheresis product from a subject at a time before the expanded cells described herein may be needed. In view of this, the source of cells to be expanded can be collected at any time required, and the required cells, such as T cells, can be isolated and frozen for subsequent use in immune effector cell therapy for any diseases or conditions that would benefit. therapy using immune effector cells, such as those described herein. In one aspect, a blood sample or apheresis sample is collected from an otherwise healthy subject. In certain aspects, a blood sample or apheresis sample is collected from an otherwise healthy subject who is at risk for developing the disease but who has not yet developed the disease, and the cells of interest are isolated and frozen for later use. In certain aspects, T cells can be expanded, frozen, and used at a later time. In certain aspects, samples are collected from a patient shortly after diagnosis of a particular disease described herein, but before any treatment is administered. In a further aspect, the cells are isolated from a blood or apheresis sample from a subject prior to any number of appropriate treatments, including but not limited to treatments such as natalizumab, efalizumab, antivirals, chemotherapy, radiation therapy, immunosuppressive agents. agents such as cyclosporine, azathioprine, methotrexate, mycophenolate and FK506, antibodies or other immunosuppressive agents such as CAMPATH, anti-CD3 antibodies, cytoxan, fludarabine, cyclosporine, FK506, rapamycin, mycophenolic acid, steroids, FR901228 and radiation.

In a further aspect of the present invention, T cells are obtained from a patient immediately after treatment in which the subject retains functional T cells. In this regard, it has been observed that after certain types of cancer treatments, in particular types of treatments with drugs that damage the immune system, shortly after treatment during the period when patients are usually recovering from treatment, the quality of the resulting T cells may be optimal or improved in regarding their ability to reproduce ex vivo. Likewise, when manipulated ex vivo using the methods described herein, these cells may be in a state favorable for enhanced engraftment and proliferation in vivo . Thus, it is within the scope of the present invention to collect blood cells, including T cells, dendritic cells or other hematopoietic lineage cells, during this recovery phase. Additionally, in certain aspects, mobilization (eg, mobilization with GM-CSF) and conditioning regimens can be used to create a state in a subject in which the repopulation, recycling, regeneration and/or proliferation of certain cell types is favorable, especially during a certain time window after therapy. Exemplary cell types include T cells, B cells, dendritic cells, and other cells of the immune system.

In one embodiment, immune effector cells expressing a CAR molecule, such as the CAR molecule described herein, are obtained from a subject who has received a low dose of an immune-enhancing mTOR inhibitor. In one embodiment, a population of immune effector cells, e.g., T cells, to be engineered to express a CAR is collected after a sufficient amount of time or after sufficient administration of a low dose of an immune-enhancing mTOR inhibitor such that the level of PD1-negative immune effector cells, e.g., T cells, or the ratio of PD1-negative immune effector cells, e.g., T cells, and PD1-positive immune effector cells, e.g., T cells, in the subject or in material collected from the subject, was at least transiently increased.

In other embodiments, a population of immune effector cells, e.g., T cells that have been or will be engineered to express a CAR, can be treated ex vivo by contacting it with an amount of mTOR inhibitor that provides an increase in the number of PD1-negative immune effector cells. cells, eg T cells, or provides an increase in the ratio of PD1-negative immune effector cells, eg T cells, and PD1-positive immune effector cells, eg T cells.

In one embodiment, the T cells in the population are characterized by diacylglycerol kinase (DGK) deficiency. DGK-deficient cells include cells that do not express DGK as RNA or protein or have reduced or inhibited DGK activity. DGK deficient cells can be generated using genetic approaches, for example, by introducing RNA interference agents such as siRNA, shRNA, miRNA to reduce or prevent DGK expression. Alternatively, DGK-deficient cells can be generated by treatment with the DGK inhibitors described herein.

In one embodiment, the T cells in the population are deficient in Ikaros. Ikaros-deficient cells include cells that do not express Ikaros as RNA or protein or have reduced or inhibited Ikaros activity; Ikaros-deficient cells can be generated using genetic approaches, for example, by introducing RNA interference agents such as siRNA, shRNA, miRNA to reduce or prevent Ikaros expression. Alternatively, Ikaros-deficient cells can be generated by treatment with Ikaros inhibitors, such as lenalidomide.

In embodiments, the T cells in the population are characterized by DGK deficiency and Ikaros deficiency, e.g., do not express DGK and Ikaros or have reduced or inhibited DGK and Ikaros activity. Such DGK and Ikaros deficient cells can be obtained by any of the methods described herein.

In one embodiment, the NK cells are obtained from a subject. In another embodiment, the NK cells are an NK cell line, for example, the NK-92 cell line (Conkwest).

In some aspects, the cells of the present invention (e.g., immune effector cells of the present invention, e.g., CAR expressing cells of the present invention) are induced pluripotent stem cells ("iPSCs") or embryonic stem cells (ESCs) or are T -cells derived from (eg, differentiated from) said iPSCs and/or ESCs. iPSCs can be obtained, for example, using methods known in the art, from peripheral blood T lymphocytes, for example, peripheral blood T lymphocytes isolated from a healthy volunteer. Also, such cells can be differentiated into T cells using methods known in the art. See, for example, Themeli M. et al., Nat. Biotechnol ., 31, pp. 928-933 (2013); doi:10.1038/nbt.2678; WO2014/165707, the contents of each of which are incorporated herein by reference in their entirety.

In another embodiment, the compounds of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof of the present invention are used in combination with one or more of the therapeutic agents listed in Table 13, or listed in the patent and patent applications cited in Table 13, for the treatment of cancer. Each publication listed in Table 13 is incorporated herein by reference in its entirety, including all structural formulas therein.

Table 13 . No. of the second remedy Nonproprietary name
Trade name Connection structure Patents/Publication of Patent Applications A1 Sotrastaurin EP 1682103
US 2007/142401
WO 2005/039549 A2 Nilotinib Monohydrate-HCl
TASIGNA®
HCl• _H2O WO 2004/005281
US 7169791 A3 WO2011/023773 A4 WO2012/149413 A6 WO 2010/029082 A7 WO2015/107493 A8 WO2015/107495 A9 WO 2011/076786 A10 Deferasirox
EXJADE® WO 1997/049395 A11 Letrozole
FEMARA® US 4978672 A12 WO 2013/124826 US 2013/0225574 A13 WO 2013/111105 A14 WO2007/121484 A15 Imatinib mesylate
GLEEVEC®
Mesilate WO 1999/003854 A16 Capmatinib
Dihydrochloride salt EP 2099447
US 7767675
US 8420645 A17 JAKAFI® Ruxolitinib Phosphate _{H3PO4 ​} WO 2007/070514 EP 2474545 US 7598257 WO 2014/018632 A18 Panobinostat WO 2014/072493
WO 2002/022577
EP 1870399 A20 WO 2008/016893 EP 2051990
US 8552003 A21 WO2015/022662 A22 Ceritinib
ZYKADIA™ WO 2008/073687
US 8039479 A23 Ribociclib
KISQALI® US 8415355
US 8685980 A24 WO 2010/007120 A26 WO 2011/101409 A27 Human monoclonal antibody to HER3 WO 2012/022814 EP 2606070
US 8735551 A28 Antibody drug conjugate (ADC) WO 2014/160160 A29 Monoclonal antibody or Fab directed against M-CSF WO 2004/045532 A30 Midostaurin WO 2003/037347 EP 1441737
US 2012/252785 A31 Everolimus AFINITOR® WO 1994/009010
WO 2014/085318 A32 WO 2007/030377 US 7482367 A34 WO 2006/122806 A35 WO 2008/073687 US 8372858 A36 Valspodar
AMDRAY™ EP 296122 A37 Vatalanib succinate
Succinate WO 98/35958 A38 WO2014/141104 A39 Asciminib WO2013/171639 WO2013/171640 WO2013/171641 WO2013/171642 A42
or its choline salt WO2010/015613 WO2013030803
US 7989497 A43 WO 2017/025918
WO2011/121418
US 8796284 A44 WO2010/101849 A45 WO2014/130310 A46 Trametinib WO2005/121142
US 7378423 A47 Dabrafenib WO 2009/137391
US 7994185 A49 Octreotide US 4395403
EP 0029579 A50 WO 2016/103155
US 9580437
EP 3237418 A51 US 9512084
WO/2015/079417 A52 WO 2010/002655
US 8519129 A53 WO 2010/002655 US 8519129 A54 WO 2010/002655

Estrogen receptor antagonists

In some embodiments, an estrogen receptor (ER) antagonist is used in combination with compounds of formula (I') or formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for the treatment of a disease, such as cancer . In some embodiments, the estrogen receptor antagonist is a selective estrogen receptor disruptor (SERD). SERDs are estrogen receptor antagonists that bind to the receptor and result in, for example, disruption or suppression of receptor function (Boer K. et al., (2017) Therapeutic Advances in Medical Oncology 9(7): 465-479). ER is a hormone-activated transcription factor important, for example, in the growth, development and physiology of the human reproductive system. The ER is activated, for example, by the hormone estrogen (17-beta-estradiol). ER expression and signaling are involved in cancers (eg, breast cancer), such as ER-positive (ER+) breast cancer. In some embodiments, the SERD is selected from LSZ102, fulvestrant, brilanestrant, or elacestrant.

Exemplary Estrogen Receptor Antagonists

In some embodiments, SERD provides for a compound disclosed in International Application Publication No. WO 2014/130310, which is incorporated herein by reference in its entirety. In some embodiments, the SERD provides LSZ102. LSZ102 has the chemical name (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid.

Other Illustrative Estrogen Receptor Antagonists

In some embodiments, the SERD comprises fulvestrant (CAS Registration Number: 129453-61-8) or a compound disclosed in International Application Publication No. WO 2001/051056, which is incorporated herein by reference in its entirety. Fulvestrant is also known as ICI 182780, ZM 182780, FASLODEX® or (7α,17β)-7-{9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl}estra-1,3,5( 10)-triene-3,17-diol. Fulvestrant is a high-affinity estrogen receptor antagonist with an IC50 of 0.29 nM.

In some embodiments, the SERD provides elacestrant (CAS Registration Number: 722533-56-4) or a compound disclosed in US Pat. No. 7,612,114, which is incorporated by reference in its entirety. Elacestrant is also known as RAD1901, ER-306323 or (6R)-6-{2-[ethyl({4-[2-(ethylamino)ethyl]phenyl}methyl)amino]-4-methoxyphenyl}-5,6,7 ,8-tetrahydronaphthalene-2-ol. Elacestrant is a non-steroidal combination selective estrogen receptor modulator (SERM) and SERD characterized by oral bioavailability. Elacestrant is also disclosed, for example, in Garner F et al., (2015) Anticancer Drugs 26(9):948-56.

In some embodiments, the SERD is brilanestrant (CAS Registration Number: 1365888-06-7) or a compound disclosed in International Application Publication No. WO 2015/136017, which is incorporated by reference in its entirety. Brilanestrant is also known as GDC-0810, ARN810, RG-6046, RO-7056118 or (2E)-3-{4-[(1E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazole -5-yl)but-1-en-1-yl]phenyl}prop-2-enoic acid. Brilanestrant is a new generation selective SERD characterized by oral bioavailability with an IC50 of 0.7 nM. Brilanestrant is also disclosed, for example, in Lai A. et al. (2015) Journal of Medicinal Chemistry 58(12): 4888-4904.

In some embodiments, the SERD is selected from RU 58668, GW7604, AZD9496, bazedoxifene, pipendoxifene, arzoxifene, OP-1074, or acolbifene, for example, as disclosed in McDonell et al. (2015) Journal of Medicinal Chemistry 58(12) 4883-4887. Other exemplary estrogen receptor antagonists are disclosed, for example, in WO 2011/156518, WO 2011/159769, WO 2012/037410, WO 2012/037411 and US 2012/0071535, all of which are incorporated herein by reference in their entirety.

CDK4/6 inhibitors

In some embodiments, a cyclin-dependent kinase 4 or 6 (CDK4/6) inhibitor is used in combination with compounds of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer thereof, or a tautomer to treat a disease, such as cancer. In some embodiments, the CDK4/6 inhibitor is selected from ribociclib, abemaciclib (Eli Lilly), or palbociclib.

Exemplary CDK4/6 inhibitors

In some embodiments, the CDK4/6 inhibitor provides ribociclib (CAS registration number: 1211441-98-3) or a compound disclosed in US Pat. Nos. 8,415,355 and 8,685,980, which are incorporated by reference in their entirety.

In some embodiments, the CDK4/6 inhibitor provides a compound disclosed in International Application Publication No. WO 2010/020675 and US Patent Nos. 8,415,355 and 8,685,980, which are incorporated by reference in their entirety.

In some embodiments, the CDK4/6 inhibitor comprises ribociclib (CAS registration number: 1211441-98-3). Ribociclib is also known as LEE011, KISQALI® or 7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d ]pyrimidine-6-carboxamide.

Other exemplary CDK4/6 inhibitors

In some embodiments, the CDK4/6 inhibitor includes abemaciclib (CAS registration number: 1231929-97-7). Abemaciclib is also known as LY835219 or N-[5-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2-methyl-1-(1-methylethyl) )-1H-benzimidazol-6-yl]-2-pyrimidinamine. Abemaciclib is a CDK inhibitor selective for CDK4 and CDK6 and is disclosed e.g. in Torres-Guzman Ret al. (2017)Oncotarget 10.18632/oncotarget.17778.

In some embodiments, the CDK4/6 inhibitor includes palbociclib (CAS registration number: 571190-30-2). Palbociclib is also known as PD-0332991, IBRANCE® or 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(1-piperazinyl)-2-pyridinyl]amino}pyrido[2,3-d]pyrimidine -7(8H)-on. Palbociclib inhibits CDK4 with an IC50 of 11 nM and inhibits CDK6 with an IC50 of 16 nM and is disclosed e.g. in Finnet al. (2009)Breast Cancer Research 11(5):R77.

CXCR2 inhibitors

In some embodiments, a chemokine (C-X-C motif) receptor 2 (CXCR2) inhibitor is used in combination with compounds of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof to treating a disease such as cancer. In some embodiments, the CXCR2 inhibitor is selected from 6-chloro-3-((3,4-dioxo-2-(pentan-3-ylamino)cyclobut-1-en-1-yl)amino)-2-hydroxy-N- methoxy-N-methylbenzenesulfonamide, danirixin, reparixin or navarixin.

Exemplary CXCR2 inhibitors

In some embodiments, the CXCR2 inhibitor comprises a compound disclosed in US Patent Nos. 7989497, 8288588, 8329754, 8722925, 9115087, US Patent Application Publications Nos. US 2010/0152205, US 2011/0251205 and US 2011/0251206, and International Publications applications No. WO 2008/061740, WO 2008/061741, WO 2008/062026, WO 2009/106539, WO 2010/063802, WO 2012/062713, WO 2013/168108, WO 2010/015613 and WO 2013/030803. In some embodiments, the CXCR2 inhibitor comprises 6-chloro-3-((3,4-dioxo-2-(pentan-3-ylamino)cyclobut-1-en-1-yl)amino)-2-hydroxy-N-methoxy -N-methylbenzenesulfonamide or its choline salt. In some embodiments, the CXCR2 inhibitor comprises the choline salt 6-chloro-3-((3,4-dioxo-2-(pentan-3-ylamino)cyclobut-1-en-1-yl)amino)-2-hydroxy-N -methoxy-N-methylbenzenesulfonamide. In some embodiments, the CXCR2 inhibitor is 2-hydroxy-N,N,N-trimethylethane-1-aminium-3-chloro-6-({3,4-dioxo-2-[(pentan-3-yl)amino] cyclobut-1-en-1-yl}amino)-2-(N-methoxy-N-methylsulfamoyl)phenolate (i.e. choline salt 6-chloro-3-((3,4-dioxo-2-(pentane -3-ylamino)cyclobut-1-en-1-yl)amino)-2-hydroxy-N-methoxy-N-methylbenzenesulfonamide) and has the following chemical structure:

.

Other exemplary CXCR2 inhibitors

In some embodiments, the CXCR2 inhibitor includes danirixin (CAS registration number: 954126-98-8). Danirixin is also known as GSK1325756 or 1-(4-chloro-2-hydroxy-3-piperidin-3-ylsulfonylphenyl)-3-(3-fluoro-2-methylphenyl)urea. Danirixin is disclosed, e.g. in Milleret al. Eur J Drug Metab Pharmacokinet (2014) 39:173–181; and Milleret al. BMC Pharmacology and Toxicology (2015), 16:18.

In some embodiments, the CXCR2 inhibitor comprises reparixin (CAS Registration Number: 266359-83-5). Reparixin is also known as repertaxin or (2R)-2-[4-(2-methylpropyl)phenyl]-N-methylsulfonylpropanamide. Reparixin is a non-competitive allosteric inhibitor of CXCR1/2. Reparixin is disclosed, e.g. in Zarbocket al. Br J Pharmacol.2008; 155(3):357-64.

In some embodiments, the CXCR2 inhibitor includes navarixin. Navarixin is also known as MK-7123, SCH 527123, PS291822 or 2-hydroxy-N,N-dimethyl-3-[[2-[[(1R)-1-(5-methylfuran-2-yl)propyl]amino] -3,4-dioxocyclobuten-1-yl]amino]benzamide. Navarixin is disclosed, for example, in Ninget al. Mol Cancer Ther. 2012; 11(6):1353-64.

CSF-1/1R binders

In some embodiments, the CSF-1/1R binding agent is used in combination with compounds of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof for the treatment of a disease , such as cancer. In some embodiments, the CSF-1/1R binding agent is selected from a macrophage colony-stimulating factor (M-CSF) inhibitor, e.g. monoclonal antibody or Fab to M-CSF (e.g. MCS110), a CSF-1R tyrosine kinase inhibitor (e.g. 4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide or BLZ945), a receptor tyrosine kinase (RTK) inhibitor (e.g. pexidartinib) or an antibody targeting CSF-1R (e.g. emactuzumab or FPA008). In some embodiments, the CSF-1/1R inhibitor is BLZ945. In some embodiments, the CSF-1/1R binding agent is MCS110. In other embodiments, the CSF-1/1R binding agent is pexidartinib.

Exemplary CSF-1 Binding Agents

In some embodiments, the CSF-1/1R binding agent comprises a macrophage colony-stimulating factor (M-CSF) inhibitor. M-CSF is also sometimes known as CSF-1. In certain embodiments, the CSF-1/1R binding agent is an anti-CSF-1 antibody (eg, MCS110). In other embodiments, the CSF-1/1R binding agent is a CSF-1R inhibitor (eg, BLZ945).

In some embodiments, the CSF-1/1R binding agent comprises an anti-M-CSF monoclonal antibody or Fab (e.g. MCS110/H-RX1) or CSF-1 binding agent disclosed in International Application Publications Nos. WO 2004/045532 and WO 2005/068503, including H-RX1 or 5H4 (e.g. anti-M-CSF antibody molecule or Fab fragment), and US9079956, which applications and patent are incorporated by reference in their entirety.

Table 13a . Amino acid and nucleotide sequences of an exemplary anti-M-CSF antibody molecule (MCS110) (H-RX1)HC QVQLQESGPGLVKPSQTLSLTCTVSDYSITSDYAWNWIRQFPGKGLEWMGYISYSGSTSYNPSLKSRITISRDTSKNQFSLQLNSVTAADTAVYYCASFDYAHAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 271) (H-RX1)LC DIVLTQSPAFLSVTPGEKVTFTCQASQSIGTSIHWYQQKTDQAPKLLIKYASESISGIPSRFSGSGSGTDFTISSVEAEDAADYYCQQINSWPTTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC (SEQ ID NO: 272) Heavy chain
CDR1 (Kabat) SDYAWN (SEQ ID NO: 273) Heavy chain
CDR2 (Kabat) YISYSGSTSYNPSLKS (SEQ ID NO: 274) Heavy chain
CDR3 (Kabat) FDYAHAMDY (SEQ ID NO: 275) Light chain
CDR1 (Kabat) QASQSIGTSIH (SEQ ID NO: 276) Light chain
CDR2 (Kabat) YASESIS (SEQ ID NO: 277) Light chain
CDR3 (Kabat) QQINSWPTT (SEQ ID NO: 278)

In another embodiment, the CSF-1/1R binding agent comprises a CSF-1R tyrosine kinase inhibitor, 4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl) oxy)-N-methylpicolinamide (BLZ945), or the compound disclosed in International Application Publication No. WO 2007/121484 and US Patent Nos. 7,553,854, 8,173,689 and 8,710,048, which are incorporated by reference in their entirety.

Other exemplary CSF-1/1R binding agents

In some embodiments, the CSF-1/1R binding agent is pexidartinib (CAS registration number 1029044-16-3). Pexidartinib is also known as PLX3397 or 5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl) pyridine-2-amine. Pexidartinib is a small molecule inhibitor of the receptor tyrosine kinases (RTKs) KIT, CSF1R and FLT3. FLT3, CSF1R, and FLT3 are overexpressed or mutated in multiple types of cancer cells and play important roles in tumor cell proliferation and metastasis. PLX3397 can bind to stem cell growth factor receptor (KIT), colony stimulating factor-1 receptor (CSF1R) and FMS-like tyrosine kinase 3 (FLT3) and inhibit their phosphorylation, which may lead to suppression of tumor cell proliferation and negative modulation of macrophages, osteoclasts and mast cells involved in osteolytic metastatic disease.

In some embodiments, the CSF-1/1R binding agent is emactuzumab. Emactuzumab is also known as RG7155 or RO5509554. Emactuzumab is a humanized IgG1 mAb that targets CSF1R. In some embodiments, the CSF-1/1R binding agent is FPA008. FPA008 is a humanized mAb that inhibits CSF1R.

A2aR antagonists

In some embodiments, an adenosine A2a receptor (A2aR) antagonist (e.g. A2aR pathway inhibitor, e.g. adenosine inhibitor, e.g. A2aR inhibitor or CD-73) is used in combination with compounds of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof for the treatment of a disease, such as cancer. In some embodiments, the A2aR antagonist is selected from PBF509 (NIR178) (Palobiofarma/Novartis), CPI444/V81444 (Corvus/Genentech), AZD4635/HTL-1071 (AstraZeneca/Heptares), Vipadenant (Redox/Juno), GBV-2034 (Globavir ), AB928 (Arcus Biosciences), theophylline, istradefylline (Kyowa Hakko Kogyo), tosadenant/SYN-115 (Acorda), KW-6356 (Kyowa Hakko Kogyo), ST-4206 (Leadiant Biosciences) and preladenant/SCH 420814 (Merck/ Schering).

Illustrative A2aR antagonists

In some embodiments, the A2aR antagonist comprises PBF509 (NIR178) or a compound disclosed in US Pat. No. 8,796,284 or International Application Publication No. WO 2017/025918, incorporated herein by reference in its entirety. PBF509 (NIR178) is also known as NIR178.

Other illustrative A2aR antagonists

In certain embodiments, the A2aR antagonist comprises CPI444/V81444. CPI-444 and other A2aR antagonists are disclosed in International Application Publication No. WO 2009/156737, incorporated herein by reference in its entirety. In certain embodiments, the A2aR antagonist is (S)-7-(5-methylfuran-2-yl)-3-((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl )-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine. In certain embodiments, the A2aR antagonist is (R)-7-(5-methylfuran-2-yl)-3-((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl )-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine or its racemate. In certain embodiments, the A2aR antagonist is 7-(5-methylfuran-2-yl)-3-((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidin-5-amine.

In certain embodiments, the A2aR antagonist is AZD4635/HTL-1071. A2aR antagonists are disclosed in International Application Publication No. WO 2011/095625, which is incorporated herein by reference in its entirety. In certain embodiments, the A2aR antagonist is 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine.

In certain embodiments, the A2aR antagonist is ST-4206 (Leadiant Biosciences). In certain embodiments, the A2aR antagonist is the A2aR antagonist described in US Pat. No. 9,133,197, incorporated herein by reference in its entirety.

In certain embodiments, the A2aR antagonist is the A2aR antagonist described in U.S. Patent Nos. 8,114,845 and 9,029,393, U.S. Patent Application Publications Nos. 2017/0015758 and 2016/0129108, incorporated herein by reference in their entirety.

In some embodiments, the A2aR antagonist is istradefylline (CAS registration number: 155270-99-8). Istradefylline is also known as KW-6002 or 8-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6 -dion. Istradefylline is disclosed, e.g. at LeWittet al. (2008)Annals of Neurology 63 (3): 295-302.

In certain embodiments, the A2aR antagonist is tosadenant (Biotie). Tozadenant is also known as SYN115 or 4-hydroxy-N-(4-methoxy-7-morpholin-4-yl-1,3-benzothiazol-2-yl)-4-methylpiperidin-1-carboxamide. Tozadenant blocks the effect of endogenous adenosine on the A2a receptor, which leads to an increase in the effect of dopamine on the D2 receptor and suppression of the effect of glutamate on the mGluR5 receptor. In some embodiments, the A2aR antagonist is preladenant (CAS registration number: 377727-87-2). Preladenant is also known as SCH 420814 or 2-(2-furanyl)-7-[2-[4-[4-(2-methoxyethoxy)phenyl]-1-piperazinyl]ethyl]7H-pyrazolo[4,3-e] [1,2,4]triazolo[1,5-c]pyrimidin-5-amine. Preladenant was developed as a drug that acts as an effective and selective antagonist of the adenosine A2A receptor.

In some embodiments, the A2aR antagonist is vipadenant. Vipadenant is also known as BIIB014, V2006 or 3-[(4-amino-3-methylphenyl)methyl]-7-(furan-2-yl)triazolo[4,5-d]pyrimidin-5-amine. Other exemplary A2aR antagonists include, for example, ATL-444, MSX-3, SCH-58261, SCH-412,348, SCH-442,416, VER-6623, VER-6947, VER-7835, CGS-15943, and ZM-241,385.

In some embodiments, the A2aR antagonist is an antagonist of the A2aR pathway (e.g. CD-73 inhibitor, e.g. antibodies to CD73) is MEDI9447. MEDI9447 is a monoclonal antibody specific for CD73. Targeting extracellular adenosine production by CD73 may attenuate the immunosuppressive effects of adenosine. MEDI9447 has been reported to have a number of forms of activity, e.g. inhibition of CD73 ectonucleotidase activity, weakening of AMP-mediated suppression of lymphocytes and suppression of the growth of syngeneic tumors. MEDI9447 can drive changes in both myeloid and lymphoid populations of infiltrating leukocytes in the tumor microenvironment. These changes include, for example, an increase in the number of CD8 effector cells and activated macrophages, as well as a decrease in the proportion of myeloid-derived suppressor cells (MDSC) and regulatory T lymphocytes.

IDO inhibitors

In some embodiments, an indoleamine 2,3-dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TDO) inhibitor is used in combination with compounds of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate thereof , solvate, prodrug thereof, stereoisomer or tautomer thereof for the treatment of a disease such as cancer. In some embodiments, the IDO inhibitor is selected from (4E)-4-[(3-chloro-4-fluoroanilino)-nitrosomethylidene]-1,2,5-oxadiazol-3-amine (also known as epacadostat or INCB24360), indoximod ( ), (1-methyl-D-tryptophan), α-cyclohexyl-5H-imidazo[5,1-a]isoindole-5-ethanol (also known as NLG919), indoximod and BMS-986205 (formerly F001287).

Exemplary IDO Inhibitors

In some embodiments, the IDO/TDO inhibitor is indoximod (New Link Genetics). Indoximod, which is the D-isomer of 1-methyltryptophan, is an orally administered small molecule inhibitor of the indoleamine 2,3-dioxygenase (IDO) pathway that disrupts the mechanisms by which tumors escape immune-mediated destruction.

In some embodiments, the IDO/TDO inhibitor is NLG919 (New Link Genetics). NLG919 is a potent inhibitor of the IDO (indoleamine (2,3)-dioxygenase) pathway with a Ki/EC50 of 7 nM/75 nM in cell-free assays.

In some embodiments, the IDO/TDO inhibitor is epacadostat (CAS registration number: 1204669-58-8). Epacadostat is also known as INCB24360 or INCB024360 (Incyte). Epacadostat is a potent and selective inhibitor of indoleamine 2,3-dioxygenase (IDO1) with an IC50 of 10 nM, with high selectivity compared to other related enzymes such as IDO2 or tryptophan 2,3-dioxygenase (TDO).

In some embodiments, the IDO/TDO inhibitor is F001287 (Flexus/BMS). F001287 is a small molecule inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1).

STING agonists

In some embodiments, a STING agonist is used in combination with compounds of formula (I') or formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for the treatment of a disease, such as cancer. In some embodiments, the STING agonist is a cyclic dinucleotide, e.g. a cyclic dinucleotide that contains purine or pyrimidine nucleotide bases (for example, adenosine, guanine, uracil, thymine or cytosine nucleotide bases). In some embodiments, the nucleotide bases of the cyclic dinucleotide include the same nucleotide base or different nucleotide bases.

In some embodiments, the STING agonist comprises an adenosine or guanosine nucleotide base. In some embodiments, the STING agonist comprises one adenosine nucleotide base and one guanosine nucleotide base. In some embodiments, the STING agonist contains two adenosine nucleotide bases or two guanosine nucleotide bases.

In some embodiments, the STING agonist comprises a modified cyclic dinucleotide, e.g. containing a modified nucleotide base, modified ribose, or modified phosphate bond. In some embodiments, the modified cyclic dinucleotide contains a modified phosphate bond, e.g. thiophosphate.

In some embodiments, the STING agonist comprises a cyclic dinucleotide (e.g. modified cyclic dinucleotide) with 2',5'- or 3',5'-phosphate bonds. In some embodiments, the STING agonist comprises a cyclic dinucleotide (e.g. modified cyclic dinucleotide) with Rp or Sp stereochemistry around phosphate bonds.

In some embodiments, the STING agonist is MK-1454 (Merck). MK-1454 is a cyclic dinucleotide stimulator of interferon genes (STING), an agonist that activates the STING pathway. An exemplary STING agonist is disclosed, for example, in the publication of PCT application No. WO 2017/027645.

Galectin inhibitors

In some embodiments, a galectin inhibitor, e.g. galectin-1 or galectin-3, is used in combination with compounds of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof for the treatment of a disease, such as cancer. In some embodiments, the combination contains a galectin-1 inhibitor and a galectin-3 inhibitor. In some embodiments, the combination contains a bispecific inhibitor (e.g. bispecific antibody molecule) that specifically targets both galectin-1 and galectin-3. In some embodiments, the galectin inhibitor is selected from an anti-galectin antibody molecule, GR-MD-02 (Galectin Therapeutics), Galectin-3C (Mandal Med), Anginex, or OTX-008 (OncoEthix, Merck). Galectins are a family of proteins that bind to beta-galactosidase sugars.

The galectin family of proteins includes at least galectin-1, galectin-2, galectin-3, galectin-4, galectin-7 and galectin-8. Galectins are also called S-type lectins and they are soluble proteins having e.g. intracellular and extracellular functions.

Galectin-1 and galectin-3 are expressed at high levels in various tumor types. Galectin-1 and galectin-3 may stimulate angiogenesis and/or reprogram myeloid cells toward a protumor phenotype, e.g. enhance immunosuppression from myeloid cells. The soluble form of galectin-3 can also inactivate and/or bind to infiltrating T cells.

Exemplary Galectin Inhibitors

In some embodiments, the galectin inhibitor is an antibody molecule. In one embodiment, the antibody molecule is a monospecific antibody molecule and binds a single epitope. For example, a monospecific antibody molecule characterized by multiple immunoglobulin variable domain sequences, each of which binds the same epitope. In one embodiment, the galectin inhibitor is an anti-galectin antibody molecule, e.g. antibodies to galectin-1 or antibodies to galectin-3. In some embodiments, the galectin inhibitor is an anti-galectin-1 antibody molecule. In some embodiments, the galectin inhibitor is an anti-galectin-3 antibody molecule.

In one embodiment, the antibody molecule is a multispecific antibody molecule, e.g. it contains a plurality of immunoglobulin variable domain sequences, wherein a first immunoglobulin variable domain sequence of the plurality is characterized by binding specificity to a first epitope, and a second immunoglobulin variable domain sequence of the plurality is characterized by binding specificity to a second epitope. In one embodiment, the first and second epitopes are on the same antigen, e.g. on the same protein (or subunit of a multimeric protein). In one embodiment, the first and second epitopes overlap. In one embodiment, the first and second epitopes do not overlap. In one embodiment, the first and second epitopes are on different antigens, e.g. different proteins (or different subunits of a multimeric protein). In one embodiment, the multispecific antibody molecule contains third, fourth or fifth immunoglobulin variable domains. In one embodiment, the multispecific antibody molecule is a bispecific antibody molecule, a trispecific antibody molecule, or a tetraspecific antibody molecule.

In one embodiment, the galectin inhibitor is a multispecific antibody molecule. In one embodiment, the multispecific antibody molecule is a bispecific antibody molecule. A bispecific antibody is characterized by specificity for no more than two antigens. The bispecific antibody molecule is characterized by the presence of a first immunoglobulin variable domain sequence, which is characterized by binding specificity to a first epitope, and a second immunoglobulin variable domain sequence, which is characterized by binding specificity to a second epitope. In one embodiment, the first and second epitopes are on the same antigen, e.g. on the same protein (or subunit of a multimeric protein). In one embodiment, the first and second epitopes overlap. In one embodiment, the first and second epitopes do not overlap. In one embodiment, the first and second epitopes are on different antigens, e.g. different proteins (or different subunits of a multimeric protein). In one embodiment, the bispecific antibody molecule comprises a heavy chain variable domain sequence and a light chain variable domain sequence that have binding specificity to a first epitope, and a heavy chain variable domain sequence and a light chain variable domain sequence that have binding specificity to a second epitope. In one embodiment, the bispecific antibody molecule comprises a half-antibody having binding specificity to a first epitope and a half-antibody having binding specificity to a second epitope. In one embodiment, a bispecific antibody molecule comprises a half-antibody or fragment thereof having binding specificity to a first epitope and a half-antibody or fragment thereof having binding specificity to a second epitope. In one embodiment, the bispecific antibody molecule comprises a scFv or fragment thereof having a binding specificity to a first epitope, and a scFv or fragment thereof having a binding specificity to a second epitope. In one embodiment, the galectin inhibitor is a bispecific antibody molecule. In one embodiment, the first epitope is located on galectin-1 and the second epitope is located on galectin-3.

Protocols for the production of bispecific or heterodimeric antibody molecules are known in the art, including without limitation, for example, the trench-to-trench approach described in e.g. in US5731168; Fc pairing using targeted electrostatic interaction as described e.g. in WO 09/089004, WO 06/106905 and WO 2010/129304; formation of heterodimers by strand exchange domain engineering (SEED) as described e.g. in WO 07/110205; exchange of Fab fragments as described, e.g. in WO 08/119353, WO 2011/131746 and WO 2013/060867; double antibody conjugates, such as those obtained by cross-linking antibodies to create a bispecific structure using a heterobifunctional reagent containing a reactive amino group and a reactive sulfhydryl group, as described, for example, in US4433059; bispecific antibody determinants created by recombination of half-antibodies (heavy-light chain pairs or Fabs) from different antibodies through a cycle of reduction and oxidation of disulfide bonds between two heavy chains, as described e.g. in US 4444878; trifunctional antibodies, e.g. three Fab' fragments cross-linked with reactive sulfhydryl groups as described e.g. in US5273743; biosynthetic binding proteins, e.g. a pair of scFvs cross-linked at the C-terminal tails, preferably by chemical cross-linking via disulfide bonds or reactive amino groups, as described e.g. in US5534254; bifunctional antibodies, e.g. Fab fragments with different binding specificities dimerized with leucine zippers (e.g. c-fos and c-jun), replacing the constant domain, as described, for example, in US5582996; bispecific and oligospecific mono- and oligovalent receptors, e.g. VH-CH1 regions of two antibodies (two Fab fragments), linked by a polypeptide spacer between the CH1 region of one antibody and the VH region of another antibody, usually with associated light chains, as described, for example, in US5591828; bispecific DNA-antibody conjugates, e.g. obtained by cross-linking antibodies or Fab fragments with a double-stranded DNA fragment, as described, for example, in US5635602; bispecific fusion proteins, e.g. an expression construct containing two scFvs with a hydrophilic coiled-coil peptide linker between them and a complete constant region, as described, for example, in US5637481; polyvalent and polyspecific binding proteins, e.g. a dimer of polypeptides having a first domain with an Ig heavy chain variable region binding region and a second domain with an Ig light chain variable region binding region, generally referred to as diabodies (higher order structures for creating bispecific, trispecific or tetraspecific molecules are also covered, as described For example, in US5837242; mini-antibody constructs with linked VL and VH chains, further connected by peptide spacers to the antibody hinge region and CH3 region, which can be dimerized to form bispecific/multivalent molecules, as described, for example, in US5837821; VH and VL domains linked by a short peptide linker (e.g. 5 or 10 amino acids) or without a linker at all, in any orientation, which can form dimers to form bispecific diabodies; trimers and tetramers as described e.g. in US5844094; a thread of VH domains (or VL domains in members of the family) connected by peptide bonds with cross-linking groups at the C-terminus, further associated with VL domains to form sequentially connected Fvs (or scFvs), as described, for example, in US5864019; and single chain binding polypeptides with both VH and VL domains linked by a peptide linker, combined into multivalent structures by non-covalent or chemical cross-linking to form, e.g. homobivalent, heterobivalent, trivalent and tetravalent structures using both scFv type and diabody type format as described e.g. in US5869620. Additional illustrative multispecific and bispecific molecules and methods for their preparation can be found, for example, in US5910573, US5932448, US5959083, US5989830, US6005079, US6239259, US6294353, US6333396, US6476198, US6511663, US6670453 , US6743896, US6809185, US6833441, US7129330, US7183076, US7521056, US7527787, US7534866, US7612181, US2002/004587A1, US2002/076406A1, US2002/103345A1, US2003/207346A1, US2003/211078A1, US2004/219643A1, US2004/2 20388A1, US2004/242847A1, US2005/003403A1, US2005/004352A1, US2005/069552A1, US2005/079170A1, US2005/100543A1, US2005/136049A1, US2005/136051A1, US2005/163782A1, US2005/266425A1, US2006/083747A1, US2006/120960A1, US200 6/204493A1, US2006/263367A1, US2007/004909A1, US2007/087381A1, US2007/ 128150A1, US2007/141049A1, US2007/154901A1, US2007/274985A1, US2008/050370A1, US2008/069820A1, US2008/152645A1, US2008/171855A1, US2008/241 884A1, US2008/254512A1, US2008/260738A1, US2009/130106A1, US2009/148905A1, US2009/155275A1, US2009/162359A1, US2009/162360A1, US2009/175851A1, US2009/175867A1, US2009/232811A1, US2009/234105A1, US2009/263392A1, US200 9/274649A1, EP346087A2, WO00/06605A2, WO02/072635A2, WO04/081051A1, WO06/020258A2, WO2007/044887A2, WO2007/095338A2, WO2007/137760A2, WO2008/119353A1, WO2009/021754A2, WO2009/068630A1, WO91/03493A1, W O93/23537A1, WO94/09131A1, WO94/12625A2, WO95/09917A1, WO96/ 37621A2, WO99/64460A1. The contents of the foregoing applications are incorporated herein by reference in their entirety.

In other embodiments, an anti-galectin antibody molecule, e.g. antibodies to galectin-1 or antibodies to galectin-3, (for example, monospecific, bispecific or polyspecific antibody molecule) is covalently linked, e.g. merged with another partner, for example, with protein, for example, in the form of a fusion molecule, for example a fusion protein. In one embodiment, the bispecific antibody molecule has a first binding specificity for a first target (e.g. galectin-1) and a second binding specificity to a second target (e.g. galectin-3).

The present invention provides an isolated nucleic acid molecule encoding any of the above antibody molecules, vectors and their host cells. The nucleic acid molecule includes, but is not limited to, RNA, genomic DNA and cDNA.

In some embodiments, the galectin inhibitor is a peptide, e.g. a protein that can bind to galectin, e.g. galectin-1 or galectin-3, and inhibit its function. In some embodiments, a galectin inhibitor is a peptide that can bind to galectin-3 and inhibit its function. In some embodiments, the galectin inhibitor is a galectin-3C peptide. In some embodiments, the galectin inhibitor is a galectin-3 inhibitor disclosed in US Pat. No. 6,770,622, which is incorporated herein by reference in its entirety.

Galectin-3C is an N-terminally truncated galectin-3 protein and acts e.g. as a competitive inhibitor of galectin-3. Galectin-3C prevents the binding of endogenous galectin-3, e.g. with laminin on the surface, e.g. cancer cells and other beta-galactosidase glycoconjugates in the extracellular matrix (ECM). Galectin-3C and other exemplary galectin inhibitory peptides are disclosed in US Pat. No. 6,770,622.

In some embodiments, galectin-3C comprises the amino acid sequence of SEQ ID NO: 279 or an amino acid substantially identical (e.g. 90, 95 or 99%) to her.

GAPAGPLIVPYNLPLPGGVVPRMMLITILGTVKPNANRIALDFQRGNDVAFHFNPRFNENNRRVIVCNTKLDNNWGREERQSVFPFESGKPFKIQVLVEPDHFKVAVNDAHLLQYNHRVKKLNEISKLGISGDIDITSASYTMI (SEQ ID NO: 279).

In some embodiments, a galectin inhibitor is a peptide that can bind to galectin-1 and inhibit its function. In some embodiments, the galectin inhibitor is an anginex peptide: anginex is an antiangiogenic peptide that binds to galectin-1 (Salomonsson E, et al., (2011) Journal of Biological Chemistry, 286(16):13801-13804). The binding of anginex to galectin-1 may be inhibited by e.g. proangiogenic effects of galectin-1.

In some embodiments, a galectin inhibitor, e.g. galectin-1 or galectin-3, is a non-peptide topomimetic molecule. In some embodiments, the non-peptide topomimetic galectin inhibitor is OTX-008 (OncoEthix). In some embodiments, the non-peptide topomimetic is the non-peptide topomimetic disclosed in US Pat. No. 8,207,228, which is incorporated herein by reference in its entirety. OTX-008, also known as PTX-008 or calixarene 0118, is a selective allosteric inhibitor of galectin-1. OTX-008 has a chemical name: N-[2-(dimethylamino)ethyl]-2-{[26,27,28-tris({[2-(dimethylamino)ethyl]carbamoyl}methoxy)pentacyclo[19.3.1.1,7.1 ,.15,]octacose-1(25),3(28),4,6,9(27),1012,15,17,19(26),21,23-dodecan-25-yl]oxy}acetamide .

In some embodiments, a galectin inhibitor, e.g. galectin-1 or galectin-3, is a carbohydrate-based compound. In some embodiments, the galectin inhibitor is GR-MD-02 (Galectin Therapeutics).

In some embodiments, GR-MD-02 is a galectin-3 inhibitor. GR-MD-02 is a polysaccharide containing galactose, also called e.g. galactoarabino-rhamnogalacturonate. GR-MD-02 and other polymers containing galactose, e.g. galactoarabino-rhamnogalacturonates are disclosed in US Patent No. 8236780 and US Patent Application Publication No. 2014/0086932, the contents of which are incorporated herein by reference in their entirety.

MEK inhibitors

In some embodiments, a MEK inhibitor is used in combination with compounds of formula (I') or formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof, for the treatment of a disease, such as cancer. In some embodiments, the MEK inhibitor is selected from trametinib, selumetinib, AS703026, BIX 02189, BIX 02188, CI-1040, PD0325901, PD98059, U0126, XL-518, G-38963, or G02443714. In some embodiments, the MEK inhibitor is trametinib.

Exemplary MEK Inhibitors

In some embodiments, the MEK inhibitor is trametinib. Trametinib is also known as JTP-74057, TMT212, N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3 ,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide or Mekinist (CAS number 871700-17-3).

Other exemplary MEK inhibitors

In some embodiments, the MEK inhibitor includes selumetinib, which has the chemical name: (5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole- 6-Carboxamide Selumetinib is also known as AZD6244 or ARRY 142886, e.g. described in PCT Application Publication No. WO2003077914.

In some embodiments, the MEK inhibitor includes AS703026, BIX 02189, or BIX 02188.

In some embodiments, the MEK inhibitor comprises 2-[(2-chloro-4-iodophenyl)amino]-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (also known as CI-1040 or PD184352), e.g. described in PCT Application Publication No. WO2000035436).

In some embodiments, the MEK inhibitor comprises N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide (also known as PD0325901), For example, described in PCT Application Publication No. WO2002006213).

In some embodiments, the MEK inhibitor includes 2'-amino-3'-methoxyflavone (also known as PD98059), which is available from Biaffin GmbH & Co., KG, Germany.

In some embodiments, the MEK inhibitor comprises 2,3-bis[amino[(2-aminophenyl)thio]methylene]-butane dinitrile (also known as U0126), e.g. described in US Patent No. 2779780).

In some embodiments, the MEK inhibitor includes XL-518 (also known as GDC-0973), which has CAS No. 1029872-29-4 and is available from ACC Corp.

In some embodiments, the MEK inhibitor includes G-38963.

In some embodiments, the MEK inhibitor includes G02443714 (also known as AS703206)

Additional examples of MEK inhibitors are disclosed in WO 2013/019906, WO 03/077914, WO 2005/121142, WO 2007/04415, WO 2008/024725 and WO 2009/085983, the contents of which are incorporated herein by reference. Additional examples of MEK inhibitors include, but are not limited to, 2,3-bis[amino[(2-aminophenyl)thio]methylene]-butane dinitrile (also known as U0126 and described in US Pat. No. 2,779,780); (3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine- 1,7(8H)-dione] (also known as E6201, described in PCT Application Publication No. WO2003076424); vemurafenib (PLX-4032, CAS 918504-65-1); (R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H) -dione (TAK-733, CAS 1035555-63-5); pimasertib (AS-703026, CAS 1204531-26-9); 2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (AZD 8330) and 3,4-difluoro- 2-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)-5-[(3-oxo-[1,2]oxazinan-2-yl)methyl]benzamide (CH 4987655 or Ro 4987655).

c-MET inhibitors

In some embodiments, a c-MET inhibitor is used in combination with compounds of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof for the treatment of a disease, such as cancer. c-MET, a receptor tyrosine kinase overexpressed or mutated in multiple tumor cell types, has key functions in tumor cell proliferation, survival, invasion, metastasis, and tumor angiogenesis. Inhibition of c-MET can induce cell death among tumor cells overexpressing c-MET protein or expressing constitutively activated c-MET protein.

In some embodiments, the c-MET inhibitor is selected from capmatinib (INC280), JNJ-3887605, AMG 337, LY2801653, MSC2156119J, crizotinib, tivantinib, or golvatinib.

Exemplary c-MET inhibitors

In some embodiments, the c-MET inhibitor includes capmatinib (INC280) or a compound described in US Pat. No. 7,767,675 and US Pat. No. 8,461,330, which are incorporated by reference in their entirety.

Other exemplary c-MET inhibitors

In some embodiments, the c-MET inhibitor includes JNJ-38877605. JNJ-38877605 is an orally available small molecule c-MET inhibitor. JNJ-38877605 selectively binds to c-MET, thereby inhibiting c-MET phosphorylation and disrupting c-MET-mediated signal transduction pathways.

In some embodiments, the c-MET inhibitor is AMG 208. AMG 208 is a selective small molecule inhibitor of c-MET. AMG 208 inhibits ligand-dependent and ligand-independent activation of c-MET by inhibiting its tyrosine kinase activity, which may result in inhibition of cell growth in tumors that overexpress c-MET.

In some embodiments, the c-Met inhibitor comprises AMG 337. AMG 337 is a c-MET inhibitor having oral bioavailability. AMG 337 selectively binds to c-MET, thereby disrupting c-MET-mediated signal transduction pathways.

In some embodiments, the c-Met inhibitor includes LY2801653. LY2801653 is an orally available small molecule c-MET inhibitor. LY2801653 selectively binds to c-MET, thereby inhibiting c-MET phosphorylation and disrupting c-MET-mediated signal transduction pathways.

In some embodiments, the c-Met inhibitor includes MSC2156119J. MSC2156119J is a c-MET inhibitor with oral bioavailability. MSC2156119J selectively binds to c-MET, resulting in inhibition of c-MET phosphorylation and disruption of c-MET-mediated signal transduction pathways.

In some embodiments, the c-MET inhibitor is capmatinib. Capmatinib is also known as INCB028060. Capmatinib is a c-MET inhibitor with oral bioavailability. Capmatinib selectively binds to c-MET, thereby inhibiting c-MET phosphorylation and disrupting c-MET-mediated signal transduction pathways.

In some embodiments, the c-MET inhibitor includes crizotinib. Crizotinib is also known as PF-02341066. Crizotinib is an aminopyridine inhibitor of receptor tyrosine kinase anaplastic lymphoma kinase (ALK) and c-MET/hepatocyte growth factor receptor (HGFR) with oral availability. Crizotinib binds to and inhibits ALK kinase and ALK-based fusion proteins in an ATP-competitive manner. In addition, crizotinib inhibits c-MET kinase and disrupts the c-MET signaling pathway. In general, this drug suppresses the growth of tumor cells.

In some embodiments, the c-MET inhibitor includes golvatinib. Golvatinib is a dual c-MET and VEGFR-2 kinase inhibitor with potential antitumor activity and oral bioavailability. Golvatinib binds to both c-MET and VEGFR-2 and inhibits their activity, which may result in tumor cell growth and survival of tumor cells that overexpress these receptor tyrosine kinases.

In some embodiments, the c-MET inhibitor is tivantinib. Tivantinib is also known as ARQ 197. Tivantinib is a small molecule c-MET inhibitor with oral bioavailability. Tivantinib binds to c-MET protein and disrupts c-MET-mediated signal transduction pathways, which may induce cell death in tumor cells that overexpress c-MET protein or express constitutively activated c-MET protein.

TGF-β inhibitors

In some embodiments, a transforming growth factor beta inhibitor (also known as TGF-β, TGFβ, TGFb, or TGF-beta, used interchangeably herein) is used in combination with compounds of formula (I') or formula (I) or a pharmaceutically acceptable salt thereof , hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof for the treatment of a disease such as cancer. In certain embodiments, the combination described herein comprises an inhibitor of transforming growth factor beta (also known as TGF-β, TGFβ, TGFb, or TGF-beta, used interchangeably herein).

TGF-β belongs to a large family of structurally related cytokines including, e.g. bone morphogenetic proteins (BMPs), growth and differentiation factors, activins and inhibins. In some embodiments, the TGF-β inhibitors described herein can bind and/or inhibit one or more TGF-β isoforms (e.g. one, two or all of TGF-β1, TGF-β2 or TGF-β3).

Under normal conditions, TGF-β maintains homeostasis and limits the growth of epithelial, endothelial, neural and hematopoietic cell lines, e.g. by inducing antiproliferative and apoptotic responses. Canonical and non-canonical signaling pathways are involved in cellular responses to TGF-β. Activation of the canonical TGF-β/Smad pathway may mediate the antiproliferative effects of TGF-β. The non-canonical TGF-β pathway may activate additional intracellular pathways, e.g. Mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3-kinases/protein kinases B, Rho-like GTPases (Tianet al. Cell Signal. 2011; 23(6):951-62; Blobeet al. N Engl J Med. 2000; 342(18):1350-8), thereby modulating epithelial-mesenchymal transition (EMT) and/or cell motility.

Alterations in the TGF-β signaling pathway are associated with human diseases, e.g. cancers, cardiovascular diseases, fibrosis, reproductive disorders and wound healing. Without being limited by theory, it is believed that in some embodiments, the role of TGF-β in cancer depends on the disease setting (eg, tumor stage and genetic alteration) and/or cellular environment. For example, in advanced stages of cancer, TGF-β may modulate a cancer-related process, e.g. by stimulating tumor growth (eg inducing EMT), blocking antitumor immune responses, enhancing tumor-associated fibrosis, or enhancing angiogenesis (Wakefield and HillNat Rev Cancer. 2013; 13(5):328-41). In certain embodiments, a combination containing a TGF-β inhibitor described herein is used to treat advanced cancer, metastatic cancer, or advanced cancer.

Preclinical data indicate that TGF-β has an important function in immune regulation (Wojtowicz-PragaInvest New Drugs. 2003; 21(1):21-32; Yanget al. Trends Immunol. 2010; 31(6):220-7). TGF-β may negatively regulate the host immune response through several mechanisms, for example shifting the balance of T helper cells towards the Th2 immune phenotype; inhibition of antitumor responses of Th1-type and M1-type macrophages; suppressing the functions of cytotoxic CD8+ T lymphocytes (CTL), NK lymphocytes and dendritic cells, generating regulatory CD4+CD25+ T cells or stimulating M2 macrophages through protumor activity mediated by the secretion of immunosuppressive cytokines (e.g. IL10 or VEGF), pro-inflammatory cytokines (e.g. IL6, TNFα or IL1), and the formation of reactive oxygen species (ROS) with genotoxic activity (Yanget al. Trends Immunol. 2010; 31(6):220-7; Truty and UrrutiaPancreatology. 2007; 7(5-6):423-35; Achyutet al Gastroenterology. 2011; 141(4):1167-78).

Exemplary TGF- β inhibitors

In some embodiments, the TGF-β inhibitor includes XOMA 089 or a compound disclosed in International Application Publication No. WO 2012/167143, which is incorporated by reference in its entirety.

XOMA 089 is also known as XPA.42.089. XOMA 089 is a fully human monoclonal antibody that specifically binds and neutralizes TGF-beta ligands 1 and 2.

The heavy chain variable region of XOMA 089 has the following amino acid sequence: QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGLWEVRALPSVYWGQGTLVTVSS (SEQ ID NO: 284) (disclosed under SEQ ID NO: 6 in W O 2012/167143). The light chain variable region of XOMA 089 has the following amino acid sequence: SYELTQPPSVSVAPGQTARITCGANDIGSKSVHWYQQKAGQAPVLVVSEDIIRPSGIPERISGSNSGNTATLTISRVEAGDEADYYCQVWDRDSDQYVFGTGTKVTVLG (SEQ ID NO: 285) (disclosed under SEQ ID NO: 8 in WO 201 2/167143).

XOMA 089 binds to human TGF-β isoforms with high affinity. In general, XOMA 089 binds with high affinity to TGF-β1 and TGF-β2 and to a lesser extent to TGF-β3. In Biacore _KD assays, XOMA 089 interacts with human TGF-β at 14.6 pM for TGF-β1, 67.3 pM for TGF-β2, and 948 pM for TGF-β3. Given the high binding affinity to all three TGF-β isoforms, in certain embodiments, XOMA 089 is expected to bind to TGF-β1, 2 and 3 at the dose of XOMA 089 described herein. XOMA 089 cross-reacts with rodent and cynomolgus TGF-β and demonstrates functional activity in vitro and in vivo , making rodents and cynomolgus monkeys relevant species for toxicology studies.

Other exemplary TGF-β inhibitors

In some embodiments, the TGF-β inhibitor comprises frezolimumab (CAS Registration Number: 948564-73-6). Frezolimumab is also known as GC1008. Frezolimumab is a human monoclonal antibody that binds to and inhibits TGF-beta isoforms 1, 2 and 3.

The heavy chain of fresolimumab has the amino acid sequence: QVQLVQSGAEVKKPGSSVKVSCKASGYTFSSNVISWVRQAPGQGLEWMGGVIPIVDIANYAQRFKGRVTITADESTSTTYMELSSLRSEDTAVYYCASTLGLVLDAMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVHTTVSWNSGALTSGVFPAV LQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 280).

The light chain of fresolimumab has the amino acid sequence: ETVLTQSPGTLSLSPGERATLSCRASQSLGSSYLAWYQQKPGQAPRLLIYGASSRAPGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYADSPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 281).

Frezolimumab is disclosed, e.g. in International Application Publication No. WO 2006/086469 and US Patent Nos. 8,383,780 and 8,591,901, which are incorporated by reference in their entirety.

IL-1 β inhibitors

Cytokines of the interleukin-1 (IL-1) family are a group of secreted pleiotropic cytokines that play a central role in inflammation and the immune response. Increased levels of IL-1 are observed in several clinical situations, including cancer (Apte et al. (2006) Cancer Metastasis Rev. p. 387-408; Dinarello (2010) Eur. J. Immunol. p. 599-606) . The IL-1 family includes IL-1 beta (IL-1b) and IL-1 alpha (IL-1a), among others. IL-1b levels are increased in lung cancer, breast cancer and colorectal cancer (Voronov et al. (2014) Front Physiol. p. 114) and are associated with poor prognosis (Apte et al. (2000) Adv. Exp. Med. Biol . p. 277-88). Without being limited by theory, it is believed that in some embodiments, secreted IL-1b derived from the tumor microenvironment and malignant cells promotes tumor cell proliferation, increases invasiveness, and attenuates the antitumor immune response, in part through the recruitment of inhibitory neutrophils (Apte et al. (2006) Cancer Metastasis Rev. p. 387-408; Miller et al. (2007) J. Immunol. p. 6933-42). Experimental evidence indicates that inhibition of IL-1b leads to a reduction in tumor burden and metastasis (Voronov et al. (2003) Proc. Natl. Acad. Sci. USA p. 2645-50).

In some embodiments, an interleukin-1-beta (IL-1β) inhibitor is used in combination with compounds of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof to treating a disease such as cancer. In some embodiments, the IL-1β inhibitor is selected from canakinumab, gevokizumab, anakinra, or rilonacept. In some embodiments, the IL-1β inhibitor is canakinumab.

Exemplary IL-1 β inhibitors

In some embodiments, the IL-1β inhibitor is canakinumab. Canakinumab is also known as ACZ885 or ILARIS®. Canakinumab is a human IgG1/κ monoclonal antibody that neutralizes the bioactivity of human IL-1β.

Canakinumab is disclosed, e.g. in WO 2002/16436, US 7446175 and EP 1313769. The heavy chain variable region of canakinumab has the following amino acid sequence: MEFGLSWVFLVALLRGVQCQVQLVESGGGVVQPGRSLRLSCAASGFTFSVYGMNWVRQAPGKGLEWVAIIWYDGDNQYYADSVKGRFTISRDNSKNTLYLQMNGLRA EDTAVYYCARDLRTGPFDYWGQGTLVTVSS (SEQ ID NO: 282) (disclosed as SEQ ID NO: 1 in US 7446175). The canakinumab light chain variable region has the following amino acid sequence: MLPSQLIGFLLLWVPASRGEIVLTQSPDFQSVTPKEKVTITCRASQSIGSSLHWYQQKPDQSPKLLIKYASQSFSGVPSRFSGSGSGTDFTLTINSLEAEDAAAYYCHQSSSLPFTFGPGTKVDIK (SEQ ID NO: 283) (disclosed under SEQ ID NO: 2 in US 7446175).

Canakinumab has been used, for example, for the treatment of cryopyrin-associated periodic syndromes (CAPS) in adults and children, for the treatment of systemic juvenile idiopathic arthritis (SJIA), for the symptomatic treatment of attacks of acute gouty arthritis in adults and for other inflammatory diseases caused by IL-1β. Without being limited by theory, it is believed that in some embodiments, IL-1β inhibitors, e.g. canakinumab may enhance the antitumor immune response, e.g. by blocking one or more functions of IL-1b, including, e.g. recruiting immunosuppressive neutrophils into the tumor microenvironment, stimulating tumor angiogenesis and/or promoting metastasis (Dinarello (2010)Eur. J. Immunol. p. 599-606).

In some embodiments, the combination described herein includes an IL-1β inhibitor, canakinumab, or a compound disclosed in WO 2002/16436, and an immune checkpoint molecule inhibitor, e.g. PD-1 inhibitor (eg anti-PD-1 antibody molecule). IL-1 is a secreted pleiotropic cytokine that plays a central role in inflammation and the immune response. Increased levels of IL-1 have been observed in several clinical situations, including cancer (Apteet al. (2006)Cancer Metastasis Rev. p. 387-408; Dinarello (2010)Eur. J. Immunol. p. 599-606). The level of IL-1b is increased in lung cancer, breast cancer and colorectal cancer (Voronovet al. (2014)Front Physiol. p. 114) and is associated with a poor prognosis (Apteet al. (2000)Adv. Exp. Med. Biol.p. 277-88). Without being limited by theory, it is believed that in some embodiments, secreted IL-1b derived from the tumor microenvironment and malignant cells promotes tumor cell proliferation, increases invasiveness, and attenuates the antitumor immune response, in part through the recruitment of inhibitory neutrophils (Apteet al. (2006)Cancer Metastasis Rev. p. 387-408; Milleret al. (2007) J. Immunol. p. 6933-42). Experimental data indicate that inhibition of IL-1b leads to a decrease in tumor burden and metastasis (Voronovet al. (2003)Proc. Natl. Acad. Sci. USA p. 2645-50). Canakinumab can bind IL-1β and inhibit IL-1-mediated signaling. Accordingly, in certain embodiments, an IL-1β inhibitor, e.g. canakinumab, enhances the immune-mediated antitumor effect of a PD-1 inhibitor (e.g. antibody molecules to PD-1) or used to enhance it.

In some embodiments, each of an IL-1β inhibitor, canakinumab, or a compound disclosed in WO 2002/16436 and an immune checkpoint molecule inhibitor, e.g. PD-1 inhibitor (eg anti-PD-1 antibody molecules) are administered at a dose and/or timing that, in combination, achieve the desired antitumor activity.

MDM2 inhibitors

In some embodiments, a murine dual microprotein homolog 2 (MDM2) inhibitor is used in combination with compounds of formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof, stereoisomer or tautomer thereof for the treatment of a disease , such as cancer. The human homologue of MDM2 is also known as HDM2. In some embodiments, an MDM2 inhibitor described herein is also known as an HDM2 inhibitor. In some embodiments, the MDM2 inhibitor is selected from HDM201 or CGM097.

In one embodiment, the MDM2 inhibitor includes (S)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-(methyl(((1r,4S)-4-(4-methyl-3 -oxopiperazin-1-yl)cyclohexyl)methyl)amino)phenyl)-1,2-dihydroisoquinolin-3(4H)-one (also known as CGM097) or a compound disclosed in PCT Publication No. WO 2011/076786, for the treatment violations, for example violations described in this document). In one embodiment, a therapeutic agent disclosed herein is used in combination with CGM097.

In one embodiment, the MDM2 inhibitor involves interaction of a p53 and/or p53/Mdm2 inhibitor. In one embodiment, the MDM2 inhibitor includes (S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2, 4-dimethoxypyrimidin-5-yl)-1-isopropyl-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one (also known as HDM201) or a compound disclosed in PCT Publication No. WO2013/ 111105, for the treatment of a disorder, e.g. violations described in this document. In one embodiment, a therapeutic agent disclosed herein is used in combination with HDM201. In some embodiments, HDM201 is administered orally.

In one embodiment, the combination disclosed herein is suitable for the treatment of cancerin vivo. For example, the combination can be used to inhibit the growth of cancerous tumors. The combination may also be used in combination with one or more of the following: standard of care treatments (eg, for cancers or infectious disorders), vaccine (e.g. therapeutic cancer vaccine), cell-based therapy, radiation therapy, surgery or any other therapeutic agent or treatment for the treatment of a disorder described herein. For example, to achieve antigen-specific immune enhancement, the combination can be administered together with an antigen of interest.

EXAMPLES

The invention is further illustrated by the following examples and synthesis schemes, which should not be construed as limiting the scope or spirit of the present invention to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain embodiments and that this does not constitute any limitation on the scope of the invention. It is further understood that various other embodiments, modifications and equivalents thereof may be contemplated by those skilled in the art without departing from the spirit of the present invention and/or the scope of the appended claims.

The compounds of the present invention can be prepared using methods known in the art of organic synthesis. All methods assume that protecting groups can be applied to labile or reactive groups as needed, in accordance with general principles of chemistry. Protecting groups are processed according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (1999) Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons). These groups are removed at a suitable stage in the synthesis of the compound using methods obvious to those skilled in the art.

Analytical methods, materials and instruments

Unless otherwise stated, reagents and solvents were used as received from the suppliers. Proton nuclear magnetic resonance (NMR) spectra were acquired on either a Bruker Avance spectrometer or a Varian Oxford 400 MHz spectrometer unless otherwise stated. Spectra are given in ppm(δ) and coupling constants, J , are given in hertz. Tetramethylsilane (TMS) was used as an internal standard. Chemical shifts are given in ppm relative to dimethyl sulfoxide (δ 2.50), methanol (δ 3.31), chloroform (δ 7.26) or other solvent specified in the NMR data. A small amount of dry sample (2-5 mg) was dissolved in a suitable deuterated solvent (1 ml). Chemical names were generated using ChemBioDraw Ultra v14 from CambridgeSoft.

Mass spectra (electrospray ionization MS) were acquired using a Waters System (Acquity UPLC and Micromass ZQ mass spectrometer) or an Agilent-1260 Infinity (6120 Quadrupole); all masses reported are the mass/charge ratio of the protonated parent ions unless otherwise noted. The sample was dissolved in a commercial solvent such as MeCN, DMSO or MeOH and injected directly onto the column using an automatic sample feeder.

Abbreviations used in the following examples and other sections:

AIBN azo-bis-isobutyronitrile

aq. water

Bn benzyl

Br wide

d doublet

DCE 1,2-dichloroethane

DCM dichloromethane

dd doublet of doublets

ddd doublet doublet doublets

DIPEA N, N-diisopropylethylamine

DPPA diphenylphosphoryl azide

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

dq doublet quartets

dt doublet of triplets

dtd doublet triplet doublets

EC ₅₀ half-maximal effective concentration (relative)

Et ethyl

Et ₂ O diethyl ether

EtOAc ethyl acetate

EtOH ethanol or ethyl alcohol

Et ₃ N triethylamine

eq. equivalents

hour hour

hept heptet

HPLC high performance liquid chromatography

HRMS high resonance mass spectrometry

g gram

i-Pr isopropyl

i -PrOH isopropanol or isopropyl alcohol

i -Pr ₂ NEt N, N-diisopropylethylamine

LCMS liquid chromatography with mass spectrometry

LiAlH ₄ lithium aluminum hydride

MeCN acetonitrile

MeOH methanol

m multiplet

M molar

Me methyl

MeCN acetonitrile

mg milligram

MHz megahertz

min. minutes

ml milliliter

mmol millimole

MS mass spectrometry

MTBE methyl tert-butyl ether

NaBH(OAc) ₃ sodium triacetoxyborohydride

NBS N-bromosuccinimide

NMR nuclear magnetic resonance

NMP N-methyl-2-pyrrolidone

PhMe toluene

q quartet

quint quintet

quintd doublet quintet

room temperature

RT retention time

RuPhos 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl

RuPhos Pd G2 chloro-(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-

biphenyl)-[2-(2'-amino-1,1'-biphenyl)]palladium(II)

s singlet

sat. saturated

SFC supercritical fluid chromatography

SPA scintillation proximity analysis

t-Bu tert-butyl

t triplet

t-BuONa sodium tert-butoxide

tdd triplet doublet of doublets

TEA triethylamine

TFA trifluoroacetic acid

TFE 2,2,2-trifluoroethanol

THF tetrahydrofuran

TMP 2,2,6,6-tetramethylpiperidine

ttd triplet triplet doublets

UPLC ultra performance liquid chromatography

Example 1. Racemic salt of HC(O)OH and trans-3-(5-(methyl-(2-(methylamino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (I- 9)

Stage 1. 3-(5-Iodo-1-oxo-isoindolin-2-yl)piperidin-2,6-dione (1-2a)

A 3 L three neck round bottom flask, purged with nitrogen and kept under an inert nitrogen atmosphere, was charged with methyl 4-iodo-2-methyl benzoate ( 1-1a , 170 g, 616 mmol), MeCN (1.0 L), AIBN ( 10.1 g, 61.5 mmol) and NBS (131.56 g, 739.18 mmol). The resulting solution was stirred overnight at 80°C. The reaction mixture was cooled to room temperature and the solids were filtered off. The resulting mixture was then concentrated to dryness. The crude material was purified by silica gel chromatography eluting with 0% to 10% EtOAc/petroleum ether and the collected fractions were concentrated under reduced pressure to give 1-2a (50 g, 141 mmol, 23% yield) as a white solid. ^1H NMR (300 MHz, DMSO- d6 ) δ 8.04-8.01 (m, _1H ), 7.88-7.81 (m, 1H), 7.67-7.59 (m, 1H ), 4.96 (s, 2H), 3.87 (s, 3H).

Stage 2. 3-(5-Iodo-1-oxo-isoindolin-2-yl)piperidin-2,6-dione (1-4a)

Compound 1-2a (50 g, 141 mmol), CF ₃ CO ₂ H salt and 3-aminopiperidine-2,6-dione ( 1-3a , 34.18 g, 141.2 mmol) were charged into a 1 L three-neck round bottom flask ), DMF (500 ml) and Et ₃ N (42.4 g, 419 mmol) and the resulting solution was stirred for 48 hours at 60°C. The reaction mixture was then cooled to room temperature and quenched by adding 500 mL of water/ice. The pH of the solution was adjusted to 5 using 1 M aq. HCl. The resulting solids were collected by filtration, washed with 3 x 500 mL EtOAc and dried in vacuo to give 1-4a (13 g, 35 mmol, 25% yield) as a gray solid. [M+H] ⁺ = 371.0. ^1H NMR (300 MHz, DMSO- d6 ) δ 11.00 (s, 1H), 8.06 (s, 1H), 7.90 ₍ d, J =7.8 Hz, 1H), 7.52 (d, J =7.8 Hz, 1H), 5.14-5.08 (m, 1H), 4.47-4.28 (m, 2H), 2.97-2.85 (m, 1H ), 2.73-2.01 (m, 2H), 1.98-1.20 (m, 1H) .

Stage 3. Racemic salt HC(O)OH and trance -3-(5-(methyl-(2-(methylamino)cyclohexyl)amino)-1-oxo-isoindolin-2-yl)piperidin-2,6-dione (I-9)

_{DMF (} 4 ml) and racemic trans- -N1,N2-dimethylcyclohexane-1,2-diamine ( 1-5a , 132 mg, 0.928 mmol) and the resulting reaction mixture was stirred for 48 hours at room temperature. The reaction mixture was then diluted with MeCN:DCM (v/v = 2:1), filtered and concentrated under reduced pressure. The crude material was purified by reverse phase HPLC (eluting with MeCN/H ₂ O with 0.1% formic acid). Fractions containing the product were combined and lyophilized to obtain the formate salt of compound I-9 (5.0 mg, 0.011 mmol, 7%) as a white powder. MS [M+H] ⁺ = 385.1. ¹ H NMR (400 MHz, acetonitrile- d ₃ ) δ 8.36 (s, 1H), 7.52 (dd, J = 8.6, 1.3 Hz, 1H), 7.08 (dd, J = 7.2, 2.3 Hz, 1H), 7.03 (dt, J =8.6, 2.4 Hz, 1H), 5.00 (dd, J =13.4, 5.1 Hz, 1H ), 4.29 (d, J =16.5 Hz, 1H), 4.19 (d, J =16.4 Hz, 1H), 3.90 (td, J =11.1, 4.0 Hz , 1H), 2.99-2.89 (m, 1H), 2.81 (s, 3H), 2.80-2.66 (m, 2H), 2.44 (s, 3H), 2, 42-2.30 (m, 1H), 2.24-2.14 (m, 1H), 2.13-2.03 (m, 1H), 1.84-1.64 (m, 3H), 1.64-1.50 (m, 1H), 1.50-1.20 (m, 3H).

Example 2. Salt of HC(O)OH and 3-(5-(methyl((1S,2S)-2-(methylamino)cyclohexyl)amino)-1-oxo-isoindolin-2-yl)piperidin-2,6- dione (I-8)

Stage 1. Ethyl 4-bromo-2-(chloromethyl)benzoate (2-2)

SOCl ₂ (2.40 L, 33.0 mol) was added dropwise to a stirred suspension of 5-bromophthalide ( 2-1 , 1200 g, 5.633 mol) in EtOH (12 L), heated to 68-72°C, over period of 7 hours. The reaction mixture was concentrated under reduced pressure to approximately 4 L and then water (5 L) was added followed by MTBE (5 L) and the resulting mixture was stirred for 40 minutes. The layers were separated and the aqueous layer was extracted with MTBE (1 x 5 L). The combined organic layers were washed with 5% aq. NaHCO ₃ (5 L), dried over Na ₂ SO ₄ , filtered and concentrated to dryness to give 2-2 (1450 g, 5.25 mol, 93% yield) as a pale brown solid. MS [M+Na] ⁺ = 298.9. ^1H NMR (400 MHz, chloroform- d ) δ 7.85 (d, J =8.4 Hz, 1H), 7.72 (d, J =2.0 Hz, 1H), 7.52 (dd, J =8.3, 2.0 Hz, 1H), 5.00 (s, 2H), 4.38 (q, J =7.1 Hz, 2H), 1.40 (t, J =7.1 Hz, 3H).

Stage 2. 3-(5-Bromo-1-oxo-isoindolin-2-yl)piperidin-2,6-dione (2-3)

Into a stirred suspension of 3-aminopiperidine-2,6-dione hydrochloride ( 1-3a , 596.3 g, 3.623 mol) and

i -Pr ₂ NEt (2.50 L, 14.3 mol) in DMF (5.0 L) was added compound 2-2 (1000 g, 3.623 mmol) and the resulting reaction mixture was stirred at 85-90°C for 24 h. The reaction mixture was cooled to room temperature, then water (20 L) was added and the resulting mixture was stirred for 12 hours. The resulting precipitate was filtered and washed with water (5 L), then with MeOH (2 L). The crude solid was suspended in MeOH (5 L) for 1 hour, filtered and washed with MeOH (2 L). The solid was taken up with EtOAc (10 L) and stirred for 1 hour. The resulting suspension was then filtered, washed with EtOAc (5 L) and dried under reduced pressure at 45-50°C to give compound 2-3 (740 g , 2.29 mol, 63% yield) as an off-white solid. MS [M+H] ⁺ = 323.2. ^1H NMR (400 MHz, DMSO- d6 ) δ 10.99 (s, 1H), _7.91-7.88 (m, 1H), 7.72 (dd, J =8.1, 1.6 Hz, 1H), 7.67 (d, J =8.0 Hz, 1H), 5.11 (dd, J =13.3, 5.1 Hz, 1H), 4.47 (d, J =17 .7 Hz, 1H), 4.34 (d, J =17.7 Hz, 1H), 2.98-2.83 (m, 1H), 2.65-2.55 (m, 1H), 2 .45-2.29 (m, 1H), 2.01 (dtd, J = 12.7, 5.3, 2.3 Hz, 1H).

Stage 3. Salt of HC(O)OH and 3-(5-(methyl((1S,2S)-2-(methylamino)cyclohexyl)amino)-1-oxo-isoindolin-2-yl)piperidin-2,6-dione (I -8)

To 3-(5-bromo-1-oxoisoindolin-2-yl)piperidin-2,6-dione ( 2-3 , 200 mg, 0.619 mmol), CuI (35.4 mg, 0.186 mmol), Cs ₂ CO ₃ (403 mg, 1.24 mmol) and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine ( (S,S)-1-5a , 132 mg, 0.928 mmol) DMF was added under a nitrogen atmosphere ( 4 ml) and the resulting reaction mixture was stirred for 72 hours at room temperature. The reaction mixture was then heated to 85°C and stirred at this temperature for an additional 72 hours. The resulting mixture was then filtered, concentrated and redissolved in DMSO. The resulting DMSO solution was directly purified by reverse phase HPLC (elution with MeCN/H ₂ O with 0.1% formic acid). Fractions containing the product were combined and lyophilized to give the formate salt of compound I-8 (14.1 mg, 0.032 mmol, 5% yield) as a white powder. MS [M+H] ⁺ = 385.1. ¹ H NMR (400 MHz, deuterium oxide) δ 7.73-7.67 (m, 1H), 7.16-7.10 (m, 2H), 5.12 (dd, J = 13.3, 5 ,3 Hz, 1H), 4.65-4.38 (m, 2H), 3.95 (td, J =11.2, 4.0 Hz, 1H), 3.50 (td, J =11, 2, 4.2 Hz, 1H), 3.00-2.83 (m, 2H), 2.89 (s, 3H), 2.71 (s, 3H), 2.57-2.45 (m , 1H), 2.40-2.32 (m, 1H), 2.29-2.22 (m, 1H), 1.94-1.76 (m, 3H), 1.72-1.61 (m, 1H), 1.57-1.44 (m, 1H), 1.43-1.32 (m, 2H).

Example 3. Salt of HC(O)OH and 3-(5-(methyl-((1R,2R)-2-(methylamino)cyclohexyl)amino)-1-oxoindolin-2-yl)piperidin-2,6-dione (I-2)

Into a stirred suspension of 3-(5-iodo-1-oxoisoindolin-2-yl)piperidin-2,6-dione ( 1-4a , 60 mg, 0.16 mmol), CuI (9 mg, 0.05 mmol), Cs ₂ CO ₃ (106 mg, 0.324 mmol) and DMF (1 ml) (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine ( (R,R)-1-5a , 69 mg, 0.49 mmol) and the resulting reaction mixture was stirred for 48 hours at room temperature. The reaction mixture was then diluted with MeCN:DCM (v/v = 3:1), filtered and concentrated to dryness. The resulting crude material was purified by reverse phase HPLC (elution with MeCN/H ₂ O with 0.1% formic acid). Fractions containing the desired product were combined and lyophilized to give the formate salt of Compound I-2 (15.1 mg, 0.034 mmol, 21% yield) as a white solid. MS [M+H] ⁺ = 385.3. ^1H NMR (400 MHz, deuterium oxide) δ 8.46 (s, 1H), 7.69 (d, J =7.5 Hz, 1H), 7.20-7.07 (m, 2H), 5 .11 (dd, J =13.3, 5.2 Hz, 1H), 4.54 (dd, J =17.3, 4.3 Hz, 1H), 4.44 (dd, J =17.3 , 5.2 Hz, 1H), 3.94 (td, J =11.2, 3.9 Hz, 1H), 3.47 (td, J =11.1, 4.1 Hz, 1H), 2 .99-2.84 (m, 2H), 2.89 (s, 3H), 2.70 (s, 3H), 2.52 (qd, J =13.0, 5.3 Hz, 1H), 2.39-2.31 (m, 1H), 2.29-2.20 (m, 1H), 2.01-1.74 (m, 3H), 1.72-1.60 (m, 1H ), 1.55-1.43 (m, 1H), 1.43-1.31 (m, 2H).

Example 4. Salt of HC(O)OH and 3-(5-(((1S,2S)-2-(benzyl(methyl)amino)cyclohexyl)(methyl)amino)-1-oxoindolin-2-yl)piperidin- 2,6-diones (I-6)

To a stirred solution of compound I-8 (62.3 mg, 0.162 mmol) and benzaldehyde ( 4-1 , 0.10 ml, 0.97 mmol) in DMF (2 ml) was added one portion of NaBH(OAc) ₃ (206 mg , 0.972 mmol) and the resulting reaction mixture was stirred vigorously at room temperature overnight. The reaction mixture was then concentrated to dryness. The resulting crude material was purified by reverse phase HPLC (elution with MeCN/H ₂ O with 0.1% formic acid). Fractions containing the desired product were combined and lyophilized to give the formate salt of compound I-6 (7.1 mg, 0.014 mmol, 8% yield) as a white solid. MS [M+H] ⁺ = 475.4. ^1H NMR (400 MHz, DMSO- d6 ) δ 10.92 (s, 1H), 7.44 (dd, J = _8.5 , 2.3 Hz, 1H), 7.21-7.10 ( m, 3H), 7.10-7.02 (m, 2H), 6.97-6.86 (m, 2H), 5.13-4.89 (m, 1H), 4.29 (dd, J =21.7, 16.6 Hz, 1H), 4.18 (dd, J =16.6, 9.3 Hz, 1H), 3.98-3.88 (m, 1H), 3.56 (d, J =13.2 Hz, 1H), 2.95-2.84 (m, 1H), 2.83 (s, 3H), 2.64-2.53 (m, 1H), 2, 42-2.27 (m, 1H), 2.00-1.95 (m, 1H), 1.94 (s, 3H), 1.82-1.65 (m, 3H), 1.59- 1.29 (m, 3H), 1.30-1.16 (m, 1H).

Example 5. Salt of HC(O)OH and 3-(5-(((1S,2S)-2-aminocyclohexyl)amino)-1-oxoindolin-2-yl)piperidin-2,6-dione (I-7)

To 3-(5-bromo-1-oxoisoindolin-2-yl)piperidin-2,6-dione ( 2-3 , 100 mg, 0.309 mmol), CuI (17.7 mg, 0.093 mmol), Cs ₂ CO ₃ (202 mg, 0.619 mmol) and (1S,2S)-cyclohexane-1,2-diamine ( 5-1 , 70.7 mg, 0.619 mmol) DMF (2 ml) was added under nitrogen atmosphere and the resulting reaction mixture was stirred for 24 hours at 70°C. The reaction mixture was diluted with MeCN and formic acid (0.05 ml) was added. The reaction mixture was then filtered and concentrated to dryness. The resulting crude material was purified by reverse phase HPLC (elution with MeCN/H ₂ O with 0.1% formic acid). Fractions containing the desired product were combined and lyophilized to give the formate salt of Compound I-7 (43.1 mg, 0.107 mmol, 35% yield) as a white solid. MS [M+H] ⁺ = 357.2. ^1H NMR (400 MHz, deuterium oxide) δ 8.36 (s, 1H), 7.51 (d, J =8.5 Hz, 1H), 6.89-6.70 (m, 2H), 4 .99 (dd, J =13.3, 5.2 Hz, 1H), 4.40 (d, J =17.4 Hz, 1H), 4.30 (d, J =17.1 Hz, 1H) , 3.53-3.35 (m, 1H), 3.02 (td, J =11.1, 3.8 Hz, 1H), 2.91-2.70 (m, 2H), 2.40 (qd, J =12.9, 5.2 Hz, 1H), 2.19-1.99 (m, 3H), 1.82-1.62 (m, 2H), 1.52-1.37 (m, 1H), 1.35-1.25 (m, 2H), 1.23-1.08 (m, 1H).

Example 6. Salt of HC(O)OH and 3-(5-(((1S,2S)-2-(benzylamino)cyclohexyl)amino)-1-oxoindolin-2-yl)piperidin-2,6-dione (I -3)

In a stirred solution of the compoundI-7 (55 mg, 0.14 mmol) and benzaldehyde (4-1, 0.014 ml, 0.14 mmol) in DMF (1 ml) was added NaBH(OAc)₃ (87 mg, 0.41 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then quenched with 1 M aq. formic acid (0.4 ml) and the resulting solution was directly purified by reverse phase HPLC (eluting with MeCN/H₂O with 0.1% formic acid). Fractions containing the desired product were combined and lyophilized to give the formate salt of the compoundI-3 (5.4 mg, 0.011 mmol, 8% yield) as a white powder. MS [M+H]⁺ = 447.2.¹H NMR (400 MHz, DMSO-d ₆ and 1 drop D₂O) δ 7.42 (d,J=8.9 Hz, 1H), 7.35-7.18 (m, 5H), 6.84-6.63 (m, 2H), 5.05-4.92 (m, 1H), 4, 29 (dd,J=16.9, 11.5 Hz, 1H), 4.15 (dd,J=16.9, 7.4 Hz, 1H), 3.85 (dd,J=13.1, 2.6 Hz, 1H), 3.47-3.26 (m, 1H), 2.87 (ddd,J=18.0, 13.6, 5.4 Hz, 1H), 2.72-2.55 (m, 2H), 2.35 (qd,J=13.2, 4.5 Hz, 1H), 2.12-1.90 (m, 3H), 1.78-1.59 (m, 2H), 1.48-1.06 (m, 4H ).

Example 7. Salt of HC(O)OH and 3-(5-(((1S,2S)-2-(benzyloxy)cyclohexyl)amino)-1-oxoindolin-2-yl)piperidin-2,6-dione (I -4)

Into a stirred mixture of compound 2-3 (120 mg, 0.371 mmol), (1S,2S)-2-(benzyloxy)cyclohexane-1-amine ( 7-1 , 107 mg, 0.520 mmol) and RuPhos Pd G2 catalyst (28, 8 mg, 0.037 mmol) in 1,4-dioxane (6 ml) under nitrogen atmosphere, 1 M t -BuONa in THF (0.85 ml, 0.85 mmol) was added and the resulting reaction mixture was stirred overnight at 80°C . The reaction mixture was then filtered through Celite® and washed with EtOAc and then with DCM/ i -PrOH. The filtrate solution was then concentrated to dryness and the resulting crude material was purified by reverse phase HPLC (eluting with MeCN/H ₂ O with 0.1% formic acid). Fractions containing the desired product were combined and lyophilized to give Compound I-4 (18 mg, 0.037 mmol, 10% yield) as a white solid. MS [M+H] ⁺ = 448.5. ^1H NMR (400 MHz, Acetonitrile- d3 ) δ 8.82 (br s, _1H ), 7.54-7.39 (m, 1H), 7.30-7.15 (m, 5H), 6 .83-6.62 (m, 2H), 5.13-4.87 (m, 2H), 4.65-4.62 (m, 1H), 4.49-4.45 (m, 1H) , 4.29-4.25 (m, 1H), 3.59-3.22 (m, 2H), 3.00-2.68 (m, 2H), 2.50-2.26 (m, 2H), 2.14-2.06 (m, 2H), 1.83-1.65 (m, 2H), 1.48-1.27 (m, 4H).

Example 8. 3-(5-(((1S,2S)-2-Hydroxycyclohexyl)amino)-1-oxoindolin-2-yl)piperidin-2,6-dione (I-1)

Compound solutionI-4 (6 mg, 0.013 mmol) in EtOH (6 ml) was passed through an H-Cube (25°C, 5 atm, 1 hour, Pd/C, 1 ml/min). The resulting solution containing the desired product was concentrated to dryness. The crude material was purified by silica gel chromatography eluting with a gradient of 0% to 100% EtOAc in heptane to give the compoundI-1 (1.4 mg, 3.7 µmol, 29% yield) as a white solid. MS [M+H]⁺ = 358.5.¹H NMR (400 MHz, acetonitrile-d ₃ ) δ 8.65 (br s, 1H), 7.34 (d,J=8.31 Hz, 1H), 6.76-6.49(m, 2H), 5.03-4.71 (m, 2H), 4.24-3.98 (m, 2H), 3.38 -3.22 (m, 1H), 3.17-3.01 (m, 1H), 2.63-2.52 (m, 2H), 2.28-2.25 (m, 2H), 1 .99-1.92 (m, 3H), 1.63-1.50 (m, 2H), 1.38-1.15 (m, 3H).

Example 9. Salt of HC(O)OH and 3-(5-(((1S,2S)-2-(methylamino)cyclohexyl)amino)-1-oxoindolin-2-yl)piperidin-2,6-dione (I-10)

Stage 1. 3-(5-(((1S,2S)-2-Aminocyclohexyl)amino)-1-oxoindolin-2-yl)piperidin-2,6-dione (I-7)

Combine 3-(5-bromo-1-oxoisoindolin-2-yl)piperidin-2,6-dione ( 2-3 , 2000 mg, 6.19 mmol), CuI (354 mg, 1.86 mmol), Cs ₂ CO ₃ (4.03 g, 12.4 mmol) and (1S,2S)-cyclohexane-1,2-diamine ( 5-1 , 1.41 g, 12.4 mmol) under nitrogen and DMF (25 ml). The resulting mixture was stirred at 70°C overnight and then filtered through a pad of Celite®, and concentrated to dryness. The crude material was purified by silica gel chromatography eluting with a gradient of 0 to 100% EtOH (with 1% Et ₃ N as modifier) in DCM to give compound I-7 (1273 mg, 3.45 mmol, 56% yield) in as a light green solid. MS [M+H] ⁺ = 357.1.

Stage 2. 3-(5-(((1S,2S)-2-(Benzyl(methyl)amino)cyclohexyl)amino)-1-oxoindolin-2-yl)piperidin-2,6-dione (I-11)

To 3-(5-(((1S,2S)-2-aminocyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione ( I-7 , 100 mg, 0.281 mmol) and NaBH( OAc) ₃ (119 mg, 0.561 mmol) in TFE (1.0 ml) under nitrogen atmosphere, benzaldehyde ( 4-1 , 0.086 ml, 0.84 mmol) was added in one portion. The resulting mixture was stirred at room temperature overnight and then formaldehyde in H ₂ O (37 wt.%, 0.031 ml, 0.42 mmol) was added, followed by the addition of another portion of NaBH(OAc) ₃ (89 mg, 0.42 mmol). The reaction mixture was stirred at RT for 30 minutes and then diluted with DCM and H ₂ O. The aqueous phase was treated with saturated aqueous NaHCO ₃ to adjust the pH to ~8-9. The resulting mixture was extracted with DCM (×3) and the combined organic extracts were concentrated to dryness. The crude material was purified by silica gel chromatography eluting with a gradient of 0 to 100% EtOAc:EtOH (v/v = 3:1) in DCM to give compound I-11 (26 mg, 0.056 mmol, 20% yield) in as a white solid. MS [M+H] ⁺ = 461.5.

Stage 3. 3-(5-(((1S,2S)-2-(Methylamino)cyclohexyl)amino)-1-oxoindolin-2-yl)piperidin-2,6-dione (I-10)

To 3-(5-(((1S,2S)-2-(benzyl(methyl)amino)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione ( I-11 , 24 mg , 0.052 mmol) in acetic acid (6 μl, 0.1 mmol) and DMF (1.0 ml) under nitrogen, Pd/C (10 wt.%, 10.1 mg, 9.5 μmol) was added followed by triethylsilane (0.025 ml, 0.16 mmol). The resulting reaction mixture was stirred at room temperature overnight and then filtered through a pad of Celite®. The Celite® precipitate was washed with DCM (2 x 5 ml) and the filtrate was concentrated to dryness. The crude material was purified by reverse phase HPLC (column: Xbridge C18 OBD 5 µm, 30 x 50 mm; conditions: water/acetonitrile with 5 mM NH ₄ OH at 75 ml/min; injection volume 1.5 ml; gradient: from 15 to 40% MeCN in 3.5 min) with collection in test tubes containing ~2 drops of formic acid, obtaining the formate salt of compound I-10 (2.4 mg, 5.5 µmol, 11% yield) as a white powder . MS [M+H] ⁺ = 371.1. ¹ H NMR (400 MHz, deuterium oxide) δ 8.44 (s, 2H), 7.63 (d, J= 8.3 Hz, 1H), 6.96-6.83 (m, 2H), 5 ,14-5.07 (m, 1H), 4.51 (d, J= 17.3 Hz, 1H), 4.41 (d, J= 17.3 Hz, 1H), 3.62 (td, J= 10.8, 4.2 Hz, 1H), 3.09 (td, J= 11.1, 4.0 Hz, 1H), 3.00-2.82 (m, 2H), 2.72 (s, 3H), 2.51 (qd, J= 13.0, 5.3 Hz, 1H), 2.37-2.11 (m, 3H), 1.97-1.85 (m, 1H ), 1.86-1.72 (m, 1H), 1.59-1.44 (m, 1H), 1.44-1.33 (m, 2H), 1.34-1.19 (m , 1H).

Example 10. Salt of HC(O)OH and 3-(5-(((1S,2S)-2-((cyclohexylmethyl)amino)cyclohexyl)amino)-1-oxoindolin-2-yl)piperidin-2,6-dione (I -12)

Into a solution of 3-(5-(((1S,2S)-2-aminocyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione ( I-7 , 100 mg, 0.281 mmol) in DMF (1.4 ml) cyclohexanecarbaldehyde (0.041 ml, 0.34 mmol) was added. The resulting mixture was stirred at room temperature for 15 minutes and then sodium triacetoxyborohydride (0.089 g, 0.42 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and then concentrated on Celite®. The crude material was purified by silica gel chromatography eluting with 0 to 100% EtOAc:EtOH (v/v = 3:1, with 1% Et ₃ N modifier) in heptane. The resulting material was further purified using reverse phase HPLC (column: X-bridge C18 OBD 5 μm 30 × 50 mm; conditions: water/acetonitrile with 0.1% formic acid at 75 ml/min; injection volume 1.5 ml; gradient: 10 to 30% MeCN, 3.5 min gradient) to give the formate salt of compound I-12 (23 mg, 0.041 mmol, 15% yield) as a white solid. MS [M+H] ⁺ = 453.3. ^1H NMR (400 MHz, DMSO- d6 ) δ 10.92 (s, 1H), 8.19 (s, 1H), 7.38 ₍ d, J= 8.8 Hz, 1H), 6.77 -6.64 (m, 2H), 6.12 (d, J= 8.9 Hz, 1H), 5.01 (dd, J= 13.2, 5.0 Hz, 1H), 4.26 ( dd, J= 16.7, 10.0 Hz, 1H), 4.13 (dd, J= 16.7, 8.1 Hz, 1H), 3.25-3.17 (m, 1H), 2 .89 (ddd, J= 17.2, 13.6, 5.5 Hz, 1H), 2.63-2.54 (m, 1H), 2.46-2.26 (m, 4H), 2 .01-1.88 (m, 3H), 1.75-1.53 (m, 7H), 1.36-1.03 (m, 8H), 0.90-0.72 (m, 2H) .

Example 11. Salt of HC(O)OH and 3-(1-oxo-5-(((1S,2S)-2-(piperidin-1-yl)cyclopentyl)amino)isoindolin-2-yl)piperidin-2,6-dione (I-14)

Step 1. 3-(5-(((1S,2S)-2-Aminocyclopentyl)amino)-1-oxoindolin-2-yl)piperidin-2,6-dione (I-13 )

Combined 3-(5-bromo-1-oxoisoindolin-2-yl)piperidin-2,6-dione ( 2-3 , 1000 mg, 3.09 mmol), CuI (177 mg, 0.928 mmol), Cs ₂ CO ₃ (3025 mg, 9.28 mmol) and (1S,2S)-cyclopentane-1,2-diamine ( 11-1 , 803 mg, 4.64 mmol) under nitrogen and DMF (12 ml) was added. The resulting mixture was stirred at 70°C for 2 days and then concentrated on Celite®. The crude product was purified by silica gel chromatography eluting with a gradient of 0 to 100% EtOH (with 1% TEA as modifier) in DCM to give I-13 (174 mg, 0.508 mmol, 16% yield) as a green solid. . MS [M+H] ⁺ = 343.1.

Stage 2. 3-(1-Oxo-5-(((1S,2S)-2-(piperidin-1-yl)cyclopentyl)amino)isoindolin-2-yl)piperidin-2,6-dione (I-14)

To 3-(5-(((1S,2S)-2-aminocyclopentyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione ( I-13 , 173 mg, 0.457 mmol) and NaBH( OAc) ₃ (290 mg, 1.37 mmol) in DMF (1.0 ml) under nitrogen atmosphere, glutaraldehyde in H ₂ O (0.10 ml, 0.55 mmol) was added in one portion. The resulting mixture was stirred at room temperature for 5 minutes and then concentrated to dryness. The crude material was purified by reverse phase HPLC (column: X-bridge C18 OBD, 5 µm, 30 × 50 mm; conditions: water/acetonitrile with 0.1% formic acid at 75 ml/min; injection volume 1.5 ml ; gradient: 2 to 12% MeCN, 3.5 min gradient) to obtain the formate salt of compound I-14 (11.2 mg, 0.025 mmol, 5% yield) as a white powder. MS [M+H] ⁺ = 411.3. ^1H NMR (400 MHz, DMSO- d6 ) δ 10.92 (s, 1H), 8.15 (s, 1H), 7.37 ₍ d, J= 8.8 Hz, 1H), 6.72 -6.63 (m, 2H), 6.41 (d, J= 7.1 Hz, 1H), 5.01 (dd, J= 13.3, 5.1 Hz, 1H), 4.27 ( dd, J= 16.7, 7.4 Hz, 1H), 4.13 (dd, J= 16.7, 6.1 Hz, 1H), 3.74-3.65 (m, 1H), 2 .89 (ddd, J= 18.0, 13.5, 5.4 Hz, 1H), 2.80-2.72 (m, 1H), 2.60 (s, 1H), 2.57-2 .42 (Asymmetric DMSO signal indicates uninterrupted 1H), 2.34 (qd, J= 13.2, 4.5 Hz, 1H), 2.04-1.89 (m, 2H), 1.89-1 .79 (m, 1H), 1.70-1.43 (m, 7H), 1.42-1.29 (m, 3H).

Example 12. 3-(5-(((1S,2S)-2-(Isobutylamino)cyclohexyl)amino)-1-oxoindolin-2-yl)piperidin-2,6-dione (I-15)

Into a solution of 3-(5-(((1S,2S)-2-aminocyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione ( I-7 , 100 mg, 0.281 mmol) in DMF (1.4 ml) isobutyraldehyde (0.031 ml, 0.34 mmol) was added. The resulting mixture was stirred at room temperature for 15 minutes and then sodium triacetoxyborohydride (0.089 g, 0.42 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and concentrated on Celite®. The crude material was purified by silica gel chromatography with a gradient of 0 to 100% EtOAc:EtOH (v/v = 3:1, with 1% Et ₃ N modifier) in heptane to give I-15 (29 .9 mg, 0.067 mmol, 24% yield) as a white solid. MS [M+H] ⁺ = 413.3. ^1H NMR (400 MHz, DMSO- d6 ) δ 10.92 (s, 1H), _7.38 (d, J= 8.8 Hz, 1H), 6.81-6.63 (m, 2H) , 6.12 (d, J= 8.8 Hz, 1H), 5.01 (dd, J= 13.2, 5.2 Hz, 1H), 4.26 (dd, J= 16.7, 9 ,2 Hz, 1H), 4.13 (dd, J= 16.7, 7.8 Hz, 1H), 3.25-3.15 (m, 1H), 2.89 (ddd, J= 17, 4, 13.6, 5.4 Hz, 1H), 2.58 (ddd, J= 17.3, 4.3, 2.2 Hz, 1H), 2.47-2.26 (m, 4H) , 2.02-1.90 (m, 3H), 1.72-1.49 (m, 3H), 1.36-1.07 (m, 4H), 0.81 (dd, J= 6, 6, 5.1 Hz, 6H).

Example 13. Salt HC(O)OH and 3-(5-(methyl-((1S,6S)-6-(methylamino)cyclohex-3-en-1-yl)amino)-1-oxoindolin-2-yl)piperidin- 2,6-dione (I-16) and salt HC(O)OH and 3-(5-(methyl-((1R,6R)-6-(methylamino)cyclohex-3-en-1-yl)amino) -1-oxoindolin-2-yl)piperidin-2,6-dione (I-17)

Step 1. rac - Di-tert-butyl-((trans)-cyclohex-4-ene-1,2-diyl)dicarbamate (13-2)

Add di-tert-butyl dicarbonate (1.57 mL, 6.75 mmol) to the mixture of rac- (trans)-cyclohex-4-ene-1,2-diamine dihydrochloride ( 13-1a and 13-1b , 500 mg, 2.70 mmol) and Et ₃ N (2.0 ml, 14 mmol) in DCM (20 ml). The resulting mixture was stirred at room temperature for 2 days. The reaction solution was then poured into a saturated aqueous NH ₄ Cl solution (20 ml). The phases were separated and the aqueous phase was extracted with DCM (3 x 20 ml). The combined organic phases were washed with brine, passed through a phase separation column and concentrated to dryness to give 13-2 (908 mg, 2.70 mmol, quantitative yield) as a brown beige solid. The product was transferred to the next step without further purification. ^1H NMR (400 MHz, Chloroform- d ) δ 5.62-5.52 (m, 2H), 4.87 (s, 2H), 3.66 (s, 2H), 2.48 (d, J = 16.7 Hz, 2H), 1.97 (dt, J= 15.5, 4.8 Hz, 2H), 1.43 (s, 18H).

Step 2. rac - Di-tert-butyl-((trans)-cyclohex-4-ene-1,2-diyl)bis(methylcarbamate) (13-3)

Add LiHMDS (1 M in THF) (4.60 mL, 4.60 mmol) to a solution of di-tert-butyl- rac -((trans)-cyclohex-4-ene-1,2-diyl)dicarbamate ( 13- 2 , 575 mg, 1.84 mmol) in THF (12.0 ml) at 0°C and stirred for 15 min. MeI (0.35 mL, 5.5 mmol) was then added and the resulting mixture was allowed to warm to room temperature and then stirred at room temperature for 17 hours. The reaction solution was cooled to 0°C, quenched with saturated aqueous NH ₄ Cl solution (10 ml) and the phases were separated. The aqueous phase was extracted with EtOAc (3 x 10 ml). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The crude material was purified by silica gel chromatography eluting with a gradient of 0 to 60% EtOAc in heptane to give 13-3 (254 mg, 0.747 mmol, 41% yield) as a white solid. ^1H NMR (400 MHz, Chloroform- d ) δ 5.65-5.50 (m, 2H), 4.44 (s, 1H), 4.22 (s, 1H), 2.77-2.62 (m, 6H), 2.22 (s, 4H), 1.46 (d, J =4.7 Hz, 18H).

Step 3. rac - trans-N1,N2-Dimethylcyclohex-4-ene-1,2-diamine dihydrochloride (13-4)

Added 1 M HCl to Et₂O (2.04 ml, 2.04 mmol) into a solution of di-tert-butyl-((trance)-cyclohex-4-ene-1,2-diyl)bis(methylcarbamate) (13-3, 139 mg, 0.408 mmol) in Et₂O (2 ml). The resulting mixture was stirred at room temperature for 17 hours. Then an additional amount of 1 M HCl in Et was added₂O (2.0 ml, 2.0 mmol) and the solution was stirred at room temperature for 24 hours. The mixture was concentrated, 4 M HCl in dioxane (2.0 ml, 8.0 mmol) was added and the reaction mixture was stirred at kt. within 5 days. The reaction mixture was diluted with Et₂O and filtered. The resulting precipitate was washed with Et₂O and dried in vacuum at 50°C to obtain the dihydrochloride salt of the compound13-4 (83 mg, 0.39 mmol, 96% yield) as a white solid. MS [M+H]⁺ = 141.1.¹H NMR (400 MHz, DMSO-d ₆ ) δ 9.32 (s, 4H), 5.67 (d,J=1.6 Hz, 2H), 3.67 (s, 2H), 2.62 (s, 8H), 2.40 (d,J=18.6 Hz, 2H).

Stage 4. Salt HC(O)OH and 3-(5-(methyl-((1S,2S)-6-(methylamino)cyclohex-3-en-1-yl)amino)-1-oxoindolin-2-yl)piperidin- 2,6-dione (I-16) and salt HC(O)OH and 3-(5-(methyl-((1R,6R)-6-(methylamino)cyclohex-3-en-1-yl)amino) -1-oxoindolin-2-yl)piperidin-2,6-dione (I-17)

Combined 3-(5-bromo-1-oxoisoindolin-2-yl)piperidin-2,6-dione ( 2-3 , 50 mg, 0.155 mmol), rac -trans-N1,N2-dimethylcyclohex-4-ene-1 ,2-diamine ( 13-4 , 83 mg, 0.39 mmol), copper(I) iodide (8.8 mg, 0.046 mmol) and Cs ₂ CO ₃ (202 mg, 0.619 mmol) and purged with nitrogen gas . DMF (1 ml) was added and the resulting mixture was stirred at 70°C for 22 hours. The reaction mixture was then cooled to room temperature and concentrated on Celite®. The crude material was purified by silica gel chromatography eluting with a gradient of 0 to 100% EtOAc/EtOH (v/v = 3:1, with 1% Et ₃ N as modifier) in heptane. The crude material was further purified by reverse phase HPLC (column: X-bridge C18 OBD 5 μm 30 × 50 mm; conditions: water/acetonitrile with 0.1% formic acid at 75 ml/min; injection volume 1.5 ml; gradient: 5 to 20% MeCN, 3.5 min gradient) to give the formate salt of a mixture of compound I-16 and compound I-17 (10.5 mg, 0.023 mmol, 15% yield) as a white solid. MS [M+H] ⁺ = 383.1. ^1H NMR (400 MHz, DMSO- d6 ) δ 10.93 (s, 1H), 8.25 (s, 1H), 7.49 ₍ d, J =8.5 Hz, 1H), 7.06 -6.88 (m, 2H), 5.76-5.53 (m, 2H), 5.03 (dd, J =13.3, 5.1 Hz, 1H), 4.30 (d, J =17.8 Hz, 1H), 4.18 (d, J =16.3 Hz, 1H), 3.99 (td, J =10.3, 5.5 Hz, 1H), 3.05-2 .95 (m, 1H), 2.90 (ddd, J =17.1, 13.5, 5.3 Hz, 1H), 2.82 (s, 3H), 2.63-2.55 (m , 1H), 2.40-2.22 (m, 5H), 2.16-2.06 (m, 1H), 2.06-1.90 (m, 2H).

Example 14. Salt of HC(O)OH and 3-(4-fluoro-5-(methyl-((1S,2S)-2-(methylamino)cyclohexyl)amino)-1-oxoindolin-2-yl)piperidin-2 ,6-dione (I-163)

Stage 1. 5-Bromo-4-fluoro-3-hydroxy-isobenzofuran-1(3H)-one (14-2)

To a stirred solution of TMP (57 ml, 57 mmol) in THF (40 ml) under nitrogen atmosphere, BuLi (2.7 M in heptane, 20.3 ml, 54.7 mmol) was added dropwise at 0°C and the resulting mixture was stirred within 30 min. at 0°C. The reaction mixture was then cooled to approximately -45°C (using a dry ice/MeCN bath) and 4-bromo-3-fluorobenzoic acid ( 14-1 , 4.99 g, 22.8 mmol) dissolved in THF (15 ml), and stirring was continued at -45°C for 5 hours. DMF (2.65 ml, 34.2 mmol) was then added dropwise and the reaction mixture was allowed to warm to room temperature and stirred for nights. The reaction mixture was quenched with 3 M aq. HCl solution (40 ml) at 0°C and extracted with DCM (×3). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The crude product was purified by silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in heptane to give 14-2 (2.91 g, 11.4 mmol, 50% yield) as a pale brown solid. MS [M+H] ⁺ = 247.0. ¹ H NMR (400 MHz, Acetonitrile- d ₃ ) δ 7.90 (dd, J= 8.0, 5.8 Hz, 1H), 7.56 (d, J= 8.0 Hz, 1H), 6 .72 (s, 1H), 5.92 (br s, 1H).

Stage 2. 3-(5-Bromo-4-fluoro-1-oxoindolin-2-yl)piperidin-2,6-dione (14-3)

To a stirred solution of compound 14-2 (2.90 g, 11.7 mmol) in DMF (20 ml) was added HCl salt and 3-aminopiperidine-2,6-dione ( 1-3a , 2.90 g, 17.6 mmol) and NaBH(OAc) ₃ (6.22 g, 29.3 mmol) and the resulting mixture was stirred for 2 days at RT. The reaction mixture was diluted with H ₂ O (50 ml) and cooled to 0°C using a water/ice bath, which resulted in the formation of sediment. The resulting mixture was filtered and the dark blue solid was washed with Et ₂ O (×3). The resulting solid was dried in a vacuum oven to give 14-3 (1.89 g, 5.31 mmol, 45% yield) as a gray solid. MS [M+H] ⁺ = 341.1. ^1H NMR (400 MHz, DMSO- d6 ) δ 11.02 (s, 1H), 7.88 (dd, J= 8.0, 6.0 Hz, 1H) _, 7.55 (d, J= 8.0 Hz, 1H), 5.12 (dd, J= 13.3, 5.1 Hz, 1H), 4.62 (d, J= 17.6 Hz, 1H), 4.45 (d, J= 17.6 Hz, 1H), 2.99-2.85 (m, 1H), 2.66-2.55 (m, 1H), 2.47-2.36 (m, 1H), 2 .05-1.96 (m, 1H).

Stage 3. Salt of HC(O)OH and 3-(4-fluoro-5-(methyl-((1S,2S)-2-(methylamino)cyclohexyl)amino)-1-oxoindolin-2-yl)piperidin-2,6- Dione (I-163)

Into a vial containing compound 14-3 (200 mg, 0.586 mmol), CuI (33.5 mg, 0.176 mmol), Cs ₂ CO ₃ (382 mg, 1.17 mmol) and (1S,2S)-N1,N2 -dimethylcyclohexane-1,2-diamine ( (S,S)-1-5a , 167 mg, 1.17 mmol), DMF (3 ml) was added under nitrogen and the resulting mixture was stirred overnight at 90°C. Celite® was then added and the reaction mixture was concentrated to dryness. The crude product was purified by reverse phase HPLC (eluting with MeCN/H ₂ O with 0.1% formic acid). Fractions containing the desired product were combined and lyophilized to give the formate salt of compound I-163 (8.0 mg, 0.017 mmol, 3% yield) as a white solid. MS [M+H] ⁺ = 403.4. ¹ H NMR (400 MHz, Acetonitrile- d _{3 +} 1 drop D ₂ O) δ 8.32 (s, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.20 (t, J =7.9 Hz, 1H), 4.97 (dd, J =13.4, 5.2 Hz, 1H), 4.38 (d, J =16.9 Hz, 1H), 4.32 ( d, J =17.0 Hz, 1H), 3.27 (td, J =11.3, 3.9 Hz, 1H), 2.84-2.72 (m, 1H), 2.68 (s , 3H), 2.67-2.62 (m, 1H), 2.57 (s, 3H), 2.36 (qd, J =13.3, 5.0 Hz, 1H), 2.21- 2.14 (m, 1H), 2.11-2.02 (m, 1H), 1.76-1.59 (m, 3H), 1.51 (q, J = 12.0 Hz, 1H) , 1.37-1.25 (m, 1H), 1.23-1.13 (m, 2H).

Example 15. Salt of HC(O)OH and 2-(2,6-dioxopiperidin-3-yl)-5-(methyl-(3-(methylamino)bicyclo[2.2.1]hept-5-en-2-yl )amino)isoindoline-1,3-dione (I-158)

Stage 1. Dibenzyl-( rac-trans -bicyclo[2.2.1]hept-5-ene-2,3-diyl)dicarbamate ( rac -15-2)

i ​ ​ -Pr ₂ NEt (0.96 ml, 5.5 mmol) and DPPA (0.95 ml, 4.4 mmol) and the resulting mixture was stirred for 4 hours at room temperature. BnOH (0.57 ml) was then added , 5.5 mmol) and continued stirring at 90°C for 12 hours, then at 100°C for 24 hours. The reaction mixture was cooled to 0°C, quenched by slowly adding 1 M NaOH (6 ml) and provided heating it to temperature with stirring. The reaction mixture was then extracted (×3) with EtOAc and the combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The crude product was purified by silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in heptane to give racemic compound 15-2 (356 mg, 0.889 mmol, 41% yield) as a white solid. MS [M+H] ⁺ = 393.4. ¹ H NMR (400 MHz, Chloroform- d ) δ 7.40-7.29 (m, 10H), 6.41-6.27 (m, 1H), 6.16 (dd, J= 5.8, 2.8 Hz, 1H), 5.12-5.05 (m, 4H), 4.72-4.57 (m, 1H), 3.85 (s, 1H), 3.17 (s, 1H ), 2.97 (s, 1H), 2.87 (s, 1H), 1.75-1.66 (m, 1H).

Stage 2. rac - trance -N2,N3-Dimethylbicyclo[2.2.1]hept-5-ene-2,3-diamine ( rac -15-3)

To a stirred solution of rac- 15-2 (264 mg, 0.673 mmol) in THF (2 ml) under nitrogen atmosphere, LiAlH ₄ in THF (2.0 ml, 4.0 mmol) was added dropwise at 0°C and the resulting mixture was stirred overnight at room temperature. The reaction mixture was then cooled to 0°C, diluted with THF (20 ml) and Na ₂ SO ₄ ·10H ₂ O (200 mg x 4) was added slowly in portions. After stirring for 10 min. another portion of Na ₂ SO ₄ ·10H ₂ O (approximately 500 mg) was added. The reaction mixture was stirred for 30 minutes, filtered through a pad of Celite® and concentrated to dryness. The crude product was dissolved in THF (5 ml) and 4 M HCl in dioxane (2 ml) was added. A white precipitate formed immediately and was collected by filtration, washed with Et ₂ O and dried under high vacuum to give rac - 15-3 (144 mg, 0.640 mmol, 95% yield) as a white powder. ^1H NMR (400 MHz, deuterium oxide) δ 6.56 (dd, J= 5.8, 3.5 Hz, 1H), 6.41 (dd, J= 5.8, 2.7 Hz, 1H) , 3.94 (t, J= 3.2 Hz, 1H), 3.49-3.40 (m, 1H), 3.38-3.31 (m, 1H), 3.21 (t, J = 2.5 Hz, 1H), 2.90 (s, 3H), 2.82 (s, 3H), 1.98 (dq, J = 10.8, 2.0 Hz, 1H), 1.88 -1.82 (m, 1H).

Stage 3. Salt of HC(O)OH and 2-(2,6-dioxopiperidin-3-yl)-5-(methyl-(3-(methylamino)bicyclo[2.2.1]hept-5-en-2-yl)amino) isoindoline-1,3-dione (I-158)

A suspension of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione ( 15-4 , 220 mg, 0.796 mmol), rac - 15-3 (179 mg, 0.796 mmol) and DIPEA (0.28 ml, 1.6 mmol) in NMP (1.5 ml) for 3 hours at 200°C in the microwave. The crude product was purified by reverse phase HPLC (eluting with MeCN/H ₂ O with 0.1% NH ₃ modifier) with fractions collected in tubes containing ~1 drop of formic acid. Fractions containing the desired product were concentrated using a lyophilizer to obtain I-158 formate salt (2.2 mg, 4.7 μmol, 0.6% yield) as a yellow powder. The compound was obtained as a mixture of diastereoisomers ~5:1 at the bridging position. MS [M+H] ⁺ = 409.3. ¹ H NMR (400 MHz, Acetonitrile- d ₃ , main diastereoisomer) δ 8.19 (s, 1H), 7.64 (d, J= 8.6 Hz, 1H), 7.30 (t, J= 2 ,4 Hz, 1H), 7.13 (dd, J= 8.7, 2.5 Hz, 1H), 6.31 (dd, J= 5.7, 3.3 Hz, 1H), 6.15 (dd, J= 5.7, 2.8 Hz, 1H), 5.02-4.86 (m, 1H), 4.17 (t, J= 3.4 Hz, 1H), 3.09 ( s, 1H), 3.04 (s, 1H), 2.92-2.89 (m, 3H), 2.86 (s, 3H), 2.74-2.70 (m, 3H), 2 .36 (s, 3H), 2.13-2.05 (m, 1H), 1.56 (dd, J= 9.2, 2.0 Hz, 1H).

Example 16

A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (15-4, 200 mg, 0.724 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine ((S, S)-1-5a, 0.24 ml, 1.5 mmol) and DIPEA (0.63 ml, 3.6 mmol) in NMP (3.0 ml) at 180°C for 6 hours in the microwave. The reaction mixture was concentrated and the resulting precipitate was purified by reverse phase HPLC with an elution gradient of 5 to 100% water/MeCN with 0.1% TFA as modifier. The required fractions were collected, neutralized with sat. aq. sodium bicarbonate solution, extracted with DCM and then further purified by silica gel chromatography eluting with a gradient of 0 to 40% EtOAc:EtOH (v/v = 3:7, with 2% Et₃N as a modifier) in DCM to obtain the required productI-114 (230 mg, 0.577 mmol, 80% yield) as a light yellow solid. MS [M+H]⁺ = 399.6.¹H NMR (400 MHz, Acetonitrile-d ₃) δ 7.63 (d,J=8.4 Hz, 1H), 7.25 (d,J=2.5 Hz, 1H), 7.09 (dd,J=8.7, 2.5 Hz, 1H), 4.99-4.91 (m, 1H), 2.93 (s, 3H), 2.82-2.55 (m, 4H), 2, 29 (s, 3H), 2.23-2.05 (m, 3H), 1.83-1.56 (m, 4H), 1.53-1.06 (m, 3H).

Example 17. 5-(((1S,2S)-2-Aminocyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione hydrochloride (I-99)

Stage 1. rubs -Butyl-((1S,2S)-2-(methylamino)cyclohexyl)carbamate (17-3)

To tert-butyl-((1S,2S)-2-aminocyclohexyl)carbamate ( 17-1 , 1.00 g, 4.67 mmol), (1H-benzo[d][1,2,3]triazole-1 -yl)methanol ( 17-2 , 0.696 g, 4.67 mmol) and 4 M HCl in dioxane (1.17 ml, 4.67 mmol) in EtOH (30 ml) was added sodium borohydride (0.353 g, 9.33 mmol) and the resulting mixture was stirred overnight. The reaction mixture was concentrated and the resulting residue was purified by RP-C18 reverse phase column chromatography with a gradient elution of 5 to 60% MeCN in water to give compound 17-3 (230 mg, 1.03 mmol, 22% yield) as white solid. ^1H NMR (400 MHz, methylene chloride- d2 ) δ 4.85-4.39 (m, 1H), 3.26-2.87 ( _m , 1H), 2.27 (s, 3H), 2, 13-1.92 (m, 3H), 1.68-1.54 (m, 2H), 1.34 (s, 9H), 1.25-0.92 (m, 4H).

Stage 2. tert-Butyl-((1S,2S)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoindolin-5-yl)(methyl)amino)cyclohexyl)carbamate (17- 4)

A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-isoindoline-1,3-dione (15-4, 800 mg, 2.90 mmol), tert-butyl-((1S,2S)-2-(methylamino)cyclohexyl)carbamate (17-3, 1323 mg, 5.79 mmol) and DIPEA (4.05 ml, 23.2 mmol) in NMP (3.5 ml) at 170°C for 4 hours in the microwave. The reaction mixture was concentrated and the resulting residue was purified using RP-C18 reverse phase column chromatography with a gradient elution of 5 to 100% MeCN in water with 0.1% TFA as a modifier. Fractions containing the desired product were collected and neutralized with sat. aq. sodium bicarbonate solution. The mixture was extracted with DCM and then further purified by silica gel column chromatography with a 0 to 100% EtOAc/heptane elution gradient to obtain the desired product17-4 (160 mg, 0.348 mmol, 12% yield) as a yellow solid. MS [M+H]⁺ = 485.7.¹H NMR (400 MHz, Chloroform-d) δ 7.90 (d,J=5.7 Hz, 1H), 7.53 (d,J=8.7 Hz, 1H), 7.07 (d,J=2.4 Hz, 1H), 6.77 (dd,J=8.6, 2.5 Hz, 1H), 4.83 (dt,J=12.4, 5.4 Hz, 1H), 4.24 (d,J=8.8 Hz, 1H), 3.69-3.39 (m, 2H), 2.80 (s, 3H), 2.77-2.56 (m, 3H), 2.12-1, 97 (m, 2H), 1.84-1.58 (m, 4H), 1.57-1.35 (m, 1H), 1.14 (s, 9H).

Stage 3. 5-(((1S,2S)-2-Aminocyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride (I-99)

To tert-butyl-((1S,2S)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)(methyl)amino)cyclohexyl)carbamate ( 17 -4 , 160 mg, 0.330 mmol) in DCE (4 ml), 4 M HCl in dioxane (1.65 ml, 6.60 mmol) was added and the resulting mixture was stirred at 40°C for 30 min. The reaction mixture was concentrated to dryness to obtain the hydrochloride salt of compound I-99 (150 mg, 0.31 mmol, 94% yield) as a light yellow solid. MS [M+H] ⁺ = 385.5. ^1H NMR (400 MHz, DMSO- d6 ) δ 11.08 (s, 1H), _8.09-7.82 (m, 3H), 7.71 (d, J =8.4 Hz, 1H) , 7.37 (d, J =2.4 Hz, 1H), 7.20 (dd, J =8.8, 2.4 Hz, 1H), 5.08 (dd, J =13.0, 5 .4 Hz, 1H), 3.94 (m, 1H), 3.83-3.63 (m, 1H), 2.90 (m, 4H), 2.65-1.95 (m, 3H) , 1.81-1.28 (m, 7H).

Example 18 )

Acetic acid (trace amount) was added to the mixture of 5-(((1S,2S)-2-aminocyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione hydrochloride (I-99, 30 mg, 0.066 mmol) and acetaldehyde (18-1, 4.33 mg, 0.098 mmol) in TFE (1 ml) and DCM (1 ml). Sodium triacetoxyborohydride (27.8 mg, 0.131 mmol) was then added and the resulting mixture was stirred overnight at room temperature. Additional acetaldehyde (18-1, 20 equiv.) and sodium triacetoxyborohydride (10 equiv.) and continued stirring for 1 day. The reaction mixture was concentrated and the resulting precipitate was partitioned between DCM and sat. aq. ammonium chloride solution. The aqueous phase was extracted with DCM (×3) and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography eluting with a gradient of 0 to 30% EtOAc:EtOH (v/v = 3:7, with 2% Et₃N as a modifier) in DCM to obtain the required productI-104 (13 mg, 0.03 mmol, 46% yield) as a yellow solid. MS [M+H]⁺= 413.5.¹H NMR (400 MHz, Acetonitrile-d ₃) δ 7.64 (d,J=8.8 Hz, 1H), 7.26 (d,J=2.6 Hz, 1H), 7.10 (dd,J=8.8, 2.5 Hz, 1H), 5.19-4.72 (m, 1H), 3.86-3.64 (m, 1H), 2.93 (s, 3H), 2, 83-2.61 (m, 5H), 2.49 (m, 1H), 1.83-1.55 (m, 5H), 1.46-1.42 (m, 1H), 1.37- 1.08 (m, 3H), 0.96 (t,J=7.1 Hz, 3H).

Example 19 -dion (I-143)

Add sodium triacetoxyborohydride (27.8 mg, 0.131 mmol) to the mixture of 5-(((1S,2S)-2-aminocyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1 ,3-dione hydrochloride (I-99, 30 mg, 0.066 mmol), acetic acid (trace) and nicotinaldehyde (19-1, 10.5 mg, 0.098 mmol) in TFE (1 ml) and DCM (1 ml). The resulting mixture was stirred overnight at room temperature. An additional amount of nicotinaldehyde was added (18-1, 3 equiv.) and sodium triacetoxyborohydride (5 equiv.) and continued stirring for 1 day. The reaction mixture was concentrated and the resulting precipitate was partitioned between DCM and sat. aq. ammonium chloride solution. The aqueous phase was extracted with DCM (×3) and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0 to 40% EtOAc:EtOH (v/v = 3:7, with 2% Et₃N as a modifier) in DCM to obtain the required productI-143 (8 mg, 0.017 mmol, 25% yield) as a light yellow solid. MS [M+H]⁺ = 476.4.¹H NMR (400 MHz, Acetonitrile-d ₃) δ 8.89 (s, 1H), 8.47-8.32 (m, 2H), 7.63 (d,J=8.8 Hz, 1H), 7.58 (dt,J=7.8, 2.0 Hz, 1H), 7.27 (d,J=2.5 Hz, 1H), 7.24 (dd,J=7.8, 4.7 Hz, 1H), 7.10 (dd,J=8.8, 2.4 Hz, 1H), 5.03-4.88 (m, 1H), 3.89-3.73 (m, 2H), 3.67 (d,J=13.7 Hz, 1H), 2.83 (s, 3H), 2.80-2.65 (m, 4H), 1.83-1.68 (m, 3H), 1.66-1, 38 (m, 3H), 1.29-1.17 (m, 3H).

Example 20. ((1S,2S)-2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoindolin-5-yl)(methyl)amino)cyclohexyl)glycine (I-148 )

To 5-(((1S,2S)-2-aminocyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride (I-99, 30 mg, 0.066 mmol) and 2-oxoacetic acid (20-1, 120 mg, 1.32 mmol) in TFE (1 ml) was added sodium triacetoxyborohydride (139 mg, 0.65 mmol) and the resulting mixture was stirred overnight at RT. The reaction mixture was concentrated and the crude product was purified with RP- C18 column reverse phase chromatography with gradient elution from 5 to 60% MeCN in water to obtain the desired productI-148 (1.4 mg, 0.003 mmol, 4.6% yield) as a light yellow solid. MS [M+H]⁺ = 443.5.¹H NMR (400 MHz, Acetonitrile-d ₃) δ 7.77 (d,J=8.5 Hz, 1H), 7.45 (d,J=2.6 Hz, 1H), 7.20 (dd,J=8.8, 2.5 Hz, 1H), 5.08-4.95 (m, 1H), 4.11-3.89 (m, 1H), 3.47-3.26 (m, 3H ), 3.15-2.77 (m, 5H), 2.25-1.83 (m, 4H), 1.67-1.58 (m, 3H), 1.28-1.08 (m , 3H),

Example 21 ).

Add sodium triacetoxyborohydride (42 mg, 0.20 mmol) to the mixture of 5-(((1S,2S)-2-aminocyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1 ,3-dione hydrochloride (I-99, 30 mg, 0.066 mmol), acetic acid (trace) and benzaldehyde (4-1, 10 mg, 0.098 mmol) in TFE (1 ml) and DCM (1 ml). The resulting reaction mixture was stirred overnight at room temperature. Additional benzaldehyde was added (4-1, 3 equiv.) and sodium triacetoxyborohydride (5 equiv.) and continued stirring for 1 day. The reaction mixture was concentrated and the resulting precipitate was partitioned between DCM and sat. aq. ammonium chloride solution. The aqueous phase was extracted with DCM (×3) and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography eluting with a gradient of 0 to 30% EtOAc:EtOH (v/v = 3:7, with 2% Et₃N as a modifier) in DCM to obtain the required productI-133 (3 mg, 0.007 mmol, 10% yield) as a light yellow solid. MS [M+H]⁺ = 475.4.¹H NMR (400 MHz, Acetonitrile-d ₃) δ 8.88 (s, 1H), 7.64 (d,J=8.4 Hz, 1H), 7.37-7.20 (m, 6H), 7.13 (dd,J=8.4, 2.5 Hz, 1H), 5.16-4.84 (m, 1H), 3.88-3.77 (m, 2H), 3.67 (d,J=13.3 Hz, 1H), 2.84 (s, 3H), 2.80-2.68 (m, 4H), 1.88-1.72 (m, 3H), 1.67-1, 39 (m, 3H), 1.30-1.17 (m, 3H).

Example 22 -1,3-dione (I-138)

Add sodium triacetoxyborohydride (42 mg, 0.20 mmol) to the mixture of 5-(((1S,2S)-2-aminocyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1 ,3-dione hydrochloride (I-99, 30 mg, 0.066 mmol), acetic acid (trace amount) and 1-(trifluoromethyl)cyclopropane-1-carbaldehyde (22-1, 14 mg, 0.098 mmol) in TFE (1 ml) and DCM (1 ml). The resulting reaction mixture was stirred overnight at room temperature. Additional 1-(trifluoromethyl)cyclopropane-1-carbaldehyde was added (22-1, 3 equiv.) and sodium triacetoxyborohydride (5 equiv.) and continued stirring for 1 day. The reaction mixture was concentrated and the resulting precipitate was partitioned between DCM and sat. aq. ammonium chloride solution. The aqueous phase was extracted with DCM (×3) and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified using Column chromatography on silica gel with an elution gradient of 0 to 20% EtOAc:EtOH (v/v = 3:7, with 2% Et₃N as a modifier) in DCM to obtain the required productI-138 (4 mg, 0.008 mmol, 12% yield) as a light yellow solid. MS [M+H]⁺ = 507.2.¹H NMR (400 MHz, Acetonitrile-d ₃) δ 7.63 (d,J=8.7 Hz, 1H), 7.26 (d,J=2.4 Hz, 1H), 7.09 (dd,J=8.5, 2.6 Hz, 1H), 5.10-4.89 (m, 1H), 3.87-3.52 (m, 1H), 2.93 (s, 3H), 2, 92-2.77 (m, 3H), 2.77-2.64 (m, 3H), 1.84-1.56 (m, 6H), 1.53-1.26 (m, 4H), 1.21-1.05 (m, 3H)

Example 23 (I-168)

Stage 1. 2-(2,6-Dioxopiperidin-3-yl)-5,6-difluoro-isoindoline-1,3-dione (23-2)

A mixture of 5,6-difluoro-isobenzofuran-1,3-dione ( 23-1 , 1.00 g, 5.43 mmol), HCl salt and 3-aminopiperidine-2,6-dione ( 1-3a , 0.939 g) was stirred , 5.70 mmol) and potassium acetate (0.586 g, 5.98 mmol) in acetic acid (20 ml) at 90°C overnight. The reaction mixture was cooled to room temperature, concentrated, and the resulting precipitate was stirred in 20 mL of water for 3 hours. The resulting precipitate was collected to give crude product 23-2 (1.5 g, 5.1 mmol, 94% yield) as dark brown solid, which was carried to the next step without purification. MS [MH] ⁻ = 293.3. ^1H NMR (400 MHz, DMSO- d6 ) δ 11.15 (s, 1H), _8.16 (t, J =7.7 Hz, 2H), 5.17 (dd, J =12.8, 5.4 Hz, 1H), 2.89 (ddd, J = 17.1, 13.9, 5.5 Hz, 1H), 2.70-2.52 (m, 1H), 2.07 (dtd , J =13.1, 5.4, 2.3 Hz, 1H).

Stage 2. rubs -Butyl-methyl-((1S,2S)-2-(methylamino)cyclohexyl)carbamate (23-3)

(1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine ( (S,S)-1-5a , 1 g, 7.03 mmol) was added to conc. a solution of HCl (0.58 ml, 7.03 mmol) and MeOH (15 ml) at 0°C. The resulting solution was then warmed to room temperature and Boc anhydride (1.63 mL, 7.03 mmol) in MeOH (15 mL) was added dropwise over 20 min. The reaction mixture was stirred overnight, concentrated and then treated with 1 M aq. NaOH to bring the pH to 8-9. The resulting mixture was then extracted with DCM (3 x 30 ml) and the combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by RP-C18 reverse phase column chromatography with a gradient elution of 10 to 80% MeCN in water with 0.1% NH ₄ OH as modifier to give the desired product 23-3 (665 mg, 2.74 mmol, yield 39%) as a white solid. MS [M+H] ⁺ = 243.2.

Stage 3. rubs -Butyl-((1S,2S)-2-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoindolin-5-yl)(methyl)amino)cyclohexyl)( methyl)carbamate (23-4)

A mixture of 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoro-isoindoline-1,3-dione ( 23-2 , 100 mg, 0.340 mmol), tert-butylmethyl-((1S,2S) )-2-(methylamino)cyclohexyl)carbamate ( 23-3 , 165 mg, 0.680 mmol) and DIPEA (0.30 ml, 1.7 mmol) in i -PrOH (3 ml) at 150°C for 2 h ... in the microwave. The reaction mixture was concentrated and the crude residue was purified by RP-C18 reverse phase column chromatography with a gradient elution of 5 to 100% MeCN in water with 0.1% TFA as modifier. Fractions containing the desired product were collected and neutralized with sat. aq. sodium bicarbonate solution. The resulting mixture was extracted with DCM and then further purified by silica gel column chromatography eluting with a gradient of 0 to 100% EtOAc in heptane to provide the desired product 23-4 (25 mg, 0.048 mmol, 14%) as a light yellow solid. substances. MS [M+H] ⁺ = 517.5. ¹ H NMR (400 MHz, Acetonitrile- d ₃ ) δ 8.85 (s, 1H), 7.44 (d, J =12.1 Hz, 1H), 7.23 (dd, J =7.5, 2.9 Hz, 1H), 4.91 (dd, J =12.4, 5.2 Hz, 1H), 4.41-3.95 (m, 1H), 3.60 (br, 1H), 2.88 (s, 3H), 2.77-2.55 (m, 4H), 2.29-2.19 (m, 2H), 2.15 (s, 3H), 1.66-1, 80 (m, 4H), 1.64-1.48 (m, 2H), 1.24 (s, 9H).

Stage 4. 2-(2,6-Dioxopiperidin-3-yl)-5-fluoro-6-(methyl-((1S,2S)-2-

(methylamino)cyclohexyl)amino)isoindoline-1,3-dione hydrochloride (I-168)

K tert-butyl-((1S,2S)-2-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)(methyl)amino)cyclohexyl )(methyl) carbamate ( 23-4 , 24 mg, 0.046 mmol) in DCE (1 ml), 4 M HCl in dioxane (0.23 ml, 0.93 mmol) was added and the resulting mixture was stirred at 40°C for 30 min. The reaction mixture was then concentrated to dryness to obtain the hydrochloride salt of compound I-168 (18 mg, 0.037 mmol, 81%) as a light yellow solid. MS [M+H] ⁺ = 417.4. ^1H NMR (400 MHz, DMSO- d6 ) δ 11.11 (s, 1H), 8.47 (s, 1H), _8.26 (s, 1H), 7.82 (d, J =11, 9 Hz, 1H), 7.58 (d, J =7.5 Hz, 1H), 5.12 (dd, J =12.8, 5.5 Hz, 1H), 3.76-3.60 ( m, 1H), 2.87 (s, 3H), 2.77-2.65 (m, 3H) 2.56 (s, 3H), 2.30-2.10 (m, 2H), 2, 10-1.97 (m, 1H), 1.68-1.48 (m, 4H), 1.31 (m, 3H).

Example 24 ​ )

Add formaldehyde in H ₂ O (37 wt.%, 90 μl, 1.3 mmol) to a mixture of 2-(2,6-dioxopiperidin-3-yl)-5-(methyl-((1S,2S)-2- (methylamino)cyclohexyl)amino)-isoindoline-1,3-dione ( I-114 , 25 mg, 0.063 mmol) and acetic acid (4 µl, 0.06 mmol) in DCE (2 ml) followed by sodium triacetoxyborohydride ( 200 mg, 0.94 mmol). The resulting mixture was stirred overnight at room temperature and then concentrated to dryness. The crude residue was partitioned between DCM and sat. aq. ammonium chloride solution. The aqueous phase was extracted with DCM (×3) and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography with a gradient of 0 to 30% EtOAc:EtOH (v/v = 3:7, with 2% Et ₃ N as modifier) in DCM to give the desired product I-96 (19 mg, 0.043 mmol, 69% yield) as a light yellow solid. MS [M+H] ⁺ = 413.5. ¹ H NMR (400 MHz, Acetonitrile- d ₃ ) δ 8.89 (s, 1H), 7.62 (d, J =8.7 Hz, 1H), 7.19 (d, J =2.4 Hz , 1H), 7.03 (dd, J =8.8, 2.5 Hz, 1H), 5.05-4.86 (m, 1H), 3.87 (td, J =11.0, 3 .8 Hz, 1H), 2.90 (s, 3H), 2.82-2.65 (m, 4H), 2.17 (s, 3H), 2.13 (s, 3H), 1.95 -1.72 (m, 4H), 1.67-1.55 (m, 1H), 1.52-1.41 (m, 1H), 1.38-1.20 (m, 3H).

Example 25 5-(((1S,2S)-2-(Dimethylamino)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (I-153)

Stage 1. rubs -Butyl-((1S,2S)-2-(dimethylamino)cyclohexyl)carbamate (25-1)

To tert -butyl-((1S,2S)-2-aminocyclohexyl)carbamate ( 17-1 , 500 mg, 2.33 mmol) in EtOH (30 ml) was added (1H-benzo[d][1,2,3 ]triazol-1-yl)methanol ( 17-2 , 750 mg, 4.67 mmol) and the resulting mixture was stirred for 3 hours. Sodium borohydride (265 mg, 7.00 mmol) was then added and stirring was continued overnight. The reaction mixture was concentrated and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by RP-C18 reverse phase column chromatography with a gradient of 10 to 100% MeCN in water with 0.1% NH ₄ OH modifier to give product 25-1 (250 mg, 1.03 mmol , yield 44%) as a white solid. MS [M+H] ⁺ = 243.2.

Stage 2. (1S,2S)-N1,N1-Dimethylcyclohexane-1,2-diamine hydrochloride (25-2)

To tert -butyl-((1S,2S)-2-(dimethylamino)cyclohexyl)carbamate ( 25-1 , 170 mg, 0.701 mmol) in DCE (3 ml) was added 4 M HCl in dioxane (1.75 ml, 7 01 mmol) and the resulting mixture was stirred overnight and then concentrated to give the crude product, which was carried to the next step without purification.

Stage 3. 5-(((1S,2S)-2-(Dimethylamino)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (I-153)

A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-isoindoline-1,3-dione (15-4, 30 mg, 0.11 mmol), (1S,2S)-N1,N1-dimethylcyclohexane-1,2-diamine (25-2, 31 mg, 0.22 mmol) and DIPEA (0.095 ml, 0.54 mmol) ini-PrOH (1 ml) at 170°C for 4 hours in the microwave. The reaction mixture was concentrated and the resulting residue was purified using RP-C18 reverse phase column chromatography with a gradient elution of 5 to 100% MeCN in water with 0.1% TFA as a modifier. Fractions containing the desired product were collected and neutralized with sat. aq. sodium bicarbonate solution. The resulting mixture was extracted with DCM and then further purified by silica gel column chromatography eluting with a gradient of 0 to 40% EtOAc:EtOH (v/v = 3:7, with 2% Et₃N as a modifier) in DCM to obtain the required productI-153 (4 mg, 0.01 mmol, 9% yield) as a light yellow solid. MS [M+H]⁺ = 399.4.¹H NMR (400 MHz, Acetonitrile-d ₃) δ 8.88 (s, 1H), 7.56 (d,J=8.3 Hz, 1H), 6.99 (d,J=2.3 Hz, 1H), 6.88 (dd,J=8.4, 2.1 Hz, 1H), 5.80 (d,J=5.2 Hz, 1H), 5.09-4.82 (m, 1H), 3.35-3.28 (m, 1H), 2.86-2.64 (m, 3H), 2, 52-2.45 (m, 1H), 2.36-2.27 (m, 1H), 2.22 (s, 6H), 2.14-2.06 (m, 2H), 1.75- 1.68 (m, 1H), 1.50-1.26 (m, 3H), 1.26-1.09 (m, 2H).

Example 26 Salt CF ₃ C(O)OH and rac - trance -2-(2,6-dioxopiperidin-3-yl)-5-(octahydroquinoxalin-1(2H)-yl)isoindolin-1,3-dione (I-282)

A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (15-4, 50 mg, 0.18 mmol),rac-trance-decahydroquinoxaline (51 mg, 0.36 mmol) and DIPEA (0.25 ml, 1.4 mmol) ini-PrOH (2 ml) at 200°C for 4 hours in the microwave. The reaction mixture was concentrated to dryness and the residue was purified by RP-C18 reverse phase column chromatography with a gradient elution of 5 to 100% MeCN in water with 0.1% TFA modifier to give the productI-282 as TFA salt (5 mg, 0.01 mmol, 5% yield) as a yellow solid. MS [M+H]⁺ = 397.1.¹H NMR (400 MHz, Acetonitrile-d ₃) δ 8.83 (s, 1H), 8.44 (br, 2H), 7.70 (d,J=8.0 Hz, 1H), 7.44 (d,J=2.0 Hz, 1H), 7.35 (dd,J=8.0, 2.1 Hz, 1H), 5.01-4.83 (m, 1H), 3.44-3.17 (m, 4H), 2.77-2.50 (m, 4H ), 2.09-1.90 (m, 2H), 1.80-1.70 (m, 2H), 1.65-1.43 (m, 2H), 1.39-1.19 (m , 3H), 1.16-0.99 (m, 1H).

Example 27 2-(2,6-Dioxopiperidin-3-yl)-5-(methyl-((1S,2S)-2-(methylamino)cycloheptyl)amino)isoindoline-1,3-dione (I-109)

Step 1. rac - N, N'-( trans -Cycloheptane-1,2-diyl)bis(4-nitrobenzenesulfonamide) (27-3)

To a solution of rac - trans- cycloheptane-1,2-diamine ( 27-1 , 250 mg, 1.24 mmol) in DCM (10 ml) at 0°C was added Et ₃ N (1.73 ml, 12.4 mmol ), then 4-nitrobenzenesulfonyl chloride ( 27-2 , 661 mg, 2.98 mmol). The resulting mixture was stirred at room temperature for 3 hours and then quenched with water. The resulting precipitate was collected by filtration to give the desired product 27-3 (450 mg, 0.907 mmol, 73% yield) as a beige solid. The product was carried to the next stage without purification. MS [MH] ⁻ = 497.1.

Step 2. rac - N, N'-( trans -Cycloheptane-1,2-diyl)bis(N-methyl-4-nitrobenzenesulfonamide) (27-4)

Into a solution of rac -N, N'-( trans -cycloheptane-1,2-diyl)bis(4-nitrobenzenesulfonamide)

( 27-3 , 450 mg, 0.903 mmol) Cesium carbonate (1765 mg, 5.42 mmol) was added to DMF (5 ml) followed by iodomethane (0.45 ml, 7.2 mmol). The resulting mixture was stirred at room temperature for 2 hours and then quenched with water. The resulting precipitate was collected by filtration to give the desired product 27-4 (450 mg, 0.858 mmol, 95% yield) as a beige solid. The product was carried to the next stage without purification. MS [M+H] ⁺ = 527.3.

Step 3. rac - trans -N1,N2-Dimethylcycloheptane-1,2-diamine (27-5)

To a suspension of rac -N, N'-( trans -cycloheptane-1,2-diyl)bis(N-methyl-4-nitrobenzenesulfonamide) (450 mg, 0.855 mmol) in MeCN (30 ml) and MeOH (5.0 ml ) cesium carbonate (3340 mg, 10.3 mmol) was added followed by dropwise addition of mercaptoacetic acid (0.48 ml, 6.8 mmol). The resulting mixture was stirred for 4 hours and then concentrated to dryness. The residue was divided between DCM and sat. aq. ammonium chloride solution and the organic phase was washed with sat. aq. sodium carbonate solution, dried over sodium sulfate, filtered and concentrated to give crude product 27-5 (80 mg, 0.51 mmol, 60% yield) as an off-white solid, which was used in the next step without further purification. MS [M+H] ⁺ = 157.1.

Stage 4. 2-(2,6-Dioxopiperidin-3-yl)-5-(methyl-((1S,2S)-2-(methylamino)cycloheptyl)amino)isoindoline-1,3-dione (I-109)

A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-isoindoline-1,3-dione (15-4, 80 mg, 0.29 mmol),rac-trance-N1,N2-dimethylcycloheptane-1,2-diamine (27-5, 54 mg, 0.377 mmol) and DIPEA (0.40 ml, 2.3 mmol) in NMP (0.3 ml) at 180°C for 6 hours in the microwave. The resulting mixture was concentrated and the crude residue was purified by RP-C18 reverse phase column chromatography with a gradient elution of 5 to 100% MeCN in water with 0.1% TFA as modifier. Fractions containing the desired product were collected and neutralized with sat. aq. sodium bicarbonate solution. The resulting mixture was extracted with DCM and then further purified by silica gel column chromatography eluting with a gradient of 0 to 40% EtOAc:EtOH (v/v = 3:7, with 2% Et₃N as a modifier) in DCM to obtain the required productI-109 (3 mg, 0.06 mmol, 2% yield) as a yellow solid. MS [M+H]⁺ = 413.5.¹H NMR (400 MHz, Acetonitrile-d ₃) δ 7.63 (d,J=8.4 Hz, 1H), 7.22 (d,J=2.4 Hz, 1H), 7.08 (dd,J=8.7, 2.4 Hz, 1H), 5.05-4.86 (m, 1H), 3.81 (td,J=9.5, 3.2 Hz, 1H), 2.93 (s, 3H), 2.83-2.64 (m, 5H), 2.29 (s, 3H), 2.15-2, 07 (m, 2H), 1.91-1.64 (m, 3H), 1.64-1.47 (m, 3H), 1.37-1.05 (m, 3H).

Example 28

Stage 1. Di- rubs -butyl-((1S,2S)-cyclopentane-1,2-diyl)dicarbamate (28-2)

Add Boc anhydride (0.64 ml, 2.8 mmol) in DCM (10 ml) to a mixture of tert-butyl ((1S,2S)-2-aminocyclopentyl)carbamate ( 28-1 , 500 mg, 2.50 mmol) in DCM (5 ml) at 0°C and the resulting mixture was heated to RT. The reaction mixture was then washed with 1 M HCl solution, water and saline. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give crude product 28-2 (750 mg, 2.50 mmol, 100% yield) as an off-white solid. The product was carried to the next step without purification. MS [M+H] ⁺ = 301.6.

Stage 2. Di- rubs -butyl-((1S,2S)-cyclopentane-1,2-diyl)bis(methylcarbamate) (28-3)

Add potassium tert -butoxide (2.56 ml, 2.56 mmol) to a mixture of di- tert -butyl-((1S,2S)-cyclopentane-1,2-diyl)dicarbamate ( 28-2 , 350 mg, 1. 17 mmol) and iodomethane (0.22 ml, 3.5 mmol) in DMF (5 ml) at 0°C and the resulting mixture was stirred overnight. Additional potassium tert -butoxide (2.56 mL, 2.56 mmol) and iodomethane (0.22 mL, 3.5 mmol) were added and stirring was continued overnight. The reaction mixture was diluted with EtOAc and then washed with 1 M HCl, water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give crude product 28-3 (380 mg, 1.16 mmol, 100% yield) as an off-white solid. The product was carried to the next stage without purification. MS [M+H] ⁺ = 329.6.

Stage 3. (1S,2S)-N1,N2-Dimethylcyclopentane-1,2-diamine (28-4)

Add 4 M HCl in dioxane (2.91 ml, 11.7 mmol) to a solution of di- tert -butyl-((1S,2S)-cyclopentane-1,2-diyl)bis(methylcarbamate ( 28-3 , 0.383 g , 1.17 mmol) in EtOAc (4 ml) and the resulting mixture was stirred overnight.The reaction mixture was concentrated to give crude product 28-4 , which was carried to the next step without purification.

Step 4. 2-(2,6-Dioxopiperidin-3-yl)-5-(methyl-((1S,2S)-2-(methylamino)cyclopentyl)amino)isoindoline-1,3-dione ( I-128)

A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-isoindoline-1,3-dione (15-4, 60 mg, 0.22 mmol), (1S,2S)-N1,N2-dimethylcyclopentane-1,2-diamine28-4 (55.7 mg, 0.434 mmol) and DIPEA (0.27 ml, 1.5 mmol) ini-PrOH (2 ml) at 170°C for 4 hours in the microwave. The reaction mixture was concentrated and the residue was purified by C18 reverse phase chromatography with an elution gradient of 5 to 100% MeCN/water (with 0.1% TFA as modifier). The required fractions were collected and neutralized with saturated aq. sodium bicarbonate solution. The mixture was extracted with DCM, then further purified by flash chromatography with a gradient elution of 0 to 40% EtOAc:EtOH (v/v = 3:7, with 1% Et₃N as a modifier) in DCM to obtain the required productI-128 (4 mg, 0.009 mmol, 4%) as a light yellow powder. MS [M+H]⁺ = 385.3.¹H NMR (400 MHz, Acetonitrile-d ₃) δ 7.63 (d,J=8.7 Hz, 1H), 7.26 (d,J=2.4 Hz, 1H), 7.09 (dd,J=8.7, 2.5 Hz, 1H), 5.09-4.84 (m, 1H), 4.15 (q,J=8.5 Hz, 1H), 3.10 (q,J=8.1 Hz, 1H), 2.96 (s, 3H), 2.84-2.62 (m, 4H), 2.30 (s, 3H), 1.82-1.64 (m, 4H), 1.47-1.39 (m, 2H).

Example 29. 3-(5-(((1S,2S)-2-(Isopropylamino)cyclohexyl)amino)-1-oxoindolin-2-yl)piperidin-2,6-dione ( I-45 )

Add acetone (0.062 ml, 0.84 mmol) to a mixture of compound I-7 (120 mg, 0.337 mmol), MgSO ₄ (81 mg, 0.67 mmol) and acetic acid (1 drop) in DMF (2.0 ml ) and stirred at room temperature for 30 minutes. The reaction mixture was then cooled to 0°C before sodium triacetoxyborohydride (143 mg, 0.673 mmol) was added. The mixture was allowed to warm to room temperature for 4 hours and then it was concentrated to dryness. The crude material was purified by silica gel chromatography with a gradient of 0 to 100% EtOAc:EtOH (v/v = 3:1, with 1% Et ₃ N modifier) in DCM to give I-45 (86 .4 mg, 0.195 mmol, 58% yield) as a light green solid. MS [M+H] ⁺ = 399.4 ^1H NMR (400 MHz, methylene chloride- d ₂ ) δ 7.44 (s, 1H), 6.75 (s, 1H), 6.65 (d, J = 8.5 Hz, 1H), 5.14-4.99 (m, 1H), 4.23 (s, 2H), 3.31 (s, 1H), 3.17 (s, 1H), 2, 91-2.64 (m, 3H), 2.41-2.24 (m, 1H), 2.24-2.04 (m, 4H), 1.86-1.66 (m, 2H), 1.46-1.28 (m, 3H), 1.26-1.05 (m, 8H).

Example 30. Salt HC(O)OH and 3-(5-(((1S,2S)-2-(ethylamino)cyclohexyl)amino)-1-oxoindolin-2-yl)piperidin-2,6-dione (I-40)

Add acetaldehyde (0.024 ml, 0.42 mmol) to a mixture of compound I-7 (60 mg, 0.17 mmol), MgSO ₄ (40.5 mg, 0.337 mmol) and acetic acid (1 drop) in DMF (1, 0 ml) and stirred at room temperature for 30 min. The resulting mixture was then cooled to 0°C before sodium triacetoxyborohydride (71 mg, 0.38 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 29 hours. Additional acetaldehyde (0.095 mL, 1.68 mmol) was added, the mixture was stirred at room temperature for 19 hours and then concentrated to dryness. The crude material was purified by reverse phase HPLC (eluting with MeCN/H ₂ O with 0.1% NH ₄ OH as modifier). The resulting material was further purified by reverse phase HPLC (eluting with MeCN/H ₂ O with 0.1% formic acid modifier) to give the formate salt of compound I-40 (1.7 mg, 4.2 µmol, yield 2.5%) as a white solid. MS [M+H] ⁺ = 385.2. ¹ H NMR (400 MHz, Acetonitrile- d ₃ ) δ 9.27 (d, J =45.4 Hz, 1H), 8.80 (s, 1H), 7.46 (d, J =8.3 Hz , 1H), 6.83 (s, 1H), 6.75 (dd, J = 8.5, 2.0 Hz, 1H), 5.29 (s, 1H), 5.01 (dd, J = 13.4, 5.1 Hz, 1H), 4.36-4.08 (m, 2H), 3.76-3.58 (m, 1H), 3.22-3.10 (m, 1H) , 3.10-2.92 (m, 2H), 2.81 (ddd, J =18.3, 13.3, 5.3 Hz, 1H), 2.71 (ddd, J =17.6, 4.8, 2.5 Hz, 1H), 2.37 (qd, J =13.2, 4.8 Hz, 3H), 2.25-2.13 (m, 2H), 1.79-1 .69 (m, 1H), 1.60 (q, J =12.4, 11.3 Hz, 1H), 1.37 (qd, J =11.4, 9.8, 2.9 Hz, 2H ), 1.31-1.12 (m, 4H).

Example 31. Salt of HC(O)OH and 3-(5-(ethyl-((1S,2S)-2-(ethylamino)cyclohexyl)amino)-1-oxoindolin-2-yl)piperidin-2,6-dione (I-55)

To 3-(5-bromo-1-oxoisoindolin-2-yl)piperidin-2,6-dione ( 2-3 , 40 mg, 0.12 mmol), CuI (7 mg, 0.04 mmol), Cs ₂ CO ₃ (161 mg, 0.495 mmol) and (1S,2S)-N1,N2-diethylcyclohexane-1,2-diamine dihydrochloride salt ( S,S-31-1 , 60 mg, 0.25 mmol) were added under nitrogen atmosphere DMF (0.7 ml) and the resulting reaction mixture was stirred for 72 hours at 90°C. The reaction mixture was diluted with DMSO (0.7 ml), filtered and directly purified by reverse phase HPLC (eluting with MeCN/H ₂ O with 0.1% formic acid). Fractions containing the desired product were combined and lyophilized to give the formate salt of compound I-55 (5.4 mg, 0.012 mmol, 10% yield) as a white solid. MS [M+H] ⁺ = 413.5. ^1H NMR (400 MHz, methylene chloride- d2 ) δ 8.27 (s, 1H), 7.59 (d, J =8.6 Hz _, 1H), 7.14-7.01 (m, 1H) , 6.97 (dt, J =8.6, 2.1 Hz, 1H), 5.06 (ddd, J =13.3, 5.2, 2.8 Hz, 1H), 4.27 (s , 2H), 3.99-3.74 (m, 1H), 3.47-3.20 (m, 2H), 3.06-2.84 (m, 2H), 2.83-2.61 (m, 3H), 2.37-2.24 (m, 1H), 2.22-2.06 (m, 2H), 1.91-1.73 (m, 3H), 1.66-1 .45 (m, 2H), 1.42-1.20 (m, 2H), 1.18-1.10 (m, 6H).

Example 32 Salt CF ₃ C(O)OH and 3-(5-(methyl-((1S,6S)-6-(methylamino)cyclohex-3-en-1-yl)amino)-1-oxoindolin-2-yl)piperidin-2 ,6-dione (I-119) and CF salt ₃ C(O)OH and 2-(2,6-dioxopiperidin-3-yl)-5-(methyl-((1R,6R)-6-(methylamino)cyclohex-3-en-1-yl)amino)isoindoline -1,3-dione (I-121)

A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-isoindoline-1,3-dione ( 15-4 , 100 mg, 0.362 mmol), rac -trans-N1,N2-dimethylcyclohex-4 was stirred -ene-1,2-diamine ( 13-4 , 146 mg, 0.685 mmol) and DIPEA (0.32 ml, 1.8 mmol) in i -PrOH (1 ml) at 180°C in the microwave for 6 h. Celite® was added to the solution and the mixture was concentrated to dryness. The crude product was purified by silica gel chromatography eluting with a gradient of 0 to 100% EtOAc:EtOH (v/v = 3:1, with 0.5% Et ₃ N) in DCM. The resulting material was further purified by reverse phase HPLC (eluting with H ₂ O/MeCN with 0.1% TFA modifier) to give the CF ₃ C(O)OH salt of a mixture of I-119 and I-121 (9 .4 mg, 0.017 mmol, 5% yield) as a bright yellow solid. MS [M+H] ⁺ = 397.4. ^1H NMR (400 MHz, DMSO- d6 ) δ 11.08 (s, 1H), 8.59 (s, 2H), 7.73 ₍ d, J =8.5 Hz, 1H), 7.43 (d, J =2.4 Hz, 1H), 7.25 (dd, J =8.7, 2.4 Hz, 1H), 5.80-5.57 (m, 2H), 5.08 ( dd, J =12.9, 5.4 Hz, 1H), 4.38 (td, J =10.4, 5.8 Hz, 1H), 3.76 (s, 1H), 2.96-2 .82 (m, 4H), 2.74-2.63 (m, 1H), 2.58 (q, J =6.6 Hz, 4H), 2.36 (d, J =13.2 Hz, 2H), 2.19 (d, J =17.1 Hz, 1H), 2.07-1.96 (m, 1H).

Biological assays and data

The activity of the compound of the present invention can be assessed by the following in vitro methods.

Example 33. Quantitative determination of IKZF1, IKZF2 or GSPT1 protein levels in 293GT cells using Prolabel

DiscoverX's Prolabel system was used to develop high-throughput and quantitative assays to measure changes in protein levels of IKZF1, IKZF2 and GSPT1 in response to exposure to compounds. The Prolabel was derived from the alpha portion of beta-galactosidase and has the following protein sequence: mssnslavvlqrrdwenpgvtqlnrlaahppfaswrnseeartdrpsqqlrslnge. A complementary beta-galactosidase fragment (from DiscoverX) was added to the Prolabel to form an active beta-galactosidase enzyme whose activity can be accurately measured. This allows the levels of Prolabel fusion protein in cell lysates to be quantified.

Lentiviral vectors were constructed based on the pLenti6.2/V5-DEST backbone from Invitrogen, in which a Prolabel tag was placed upstream of IKZF1, IKZF2, or GSPT1, and the fusion protein was expressed under the control of the CMV promoter.

To ensure moderate and sustained expression of the Prolabel fusion proteins in all cells in the population, stable cell lines were constructed from cells expressing one copy of the construct. Lentivirus with packaged constructs was produced using the ViraPower kit from Invitrogen. Highly adherent 293GT cells, GripTite 293 MSR cells from Thermo Fisher Scientific (catalog number: R79507), were infected with virus at a low multiplicity of infection and selected with 5 μg/ml blasticidin for 2 weeks.

Levels of Prolabel-tagged fusion proteins in compound-treated cell lines were measured as follows.

On day 1, cells were diluted to 1.0 x 10 ⁶ cells/ml in normal growth medium. 17.5 μl of cells were seeded into each well of an opaque white 384-well plate. The plates were incubated overnight in a tissue culture incubator at 37°C.

On day 2, serial dilutions of compounds were prepared in 384-well plates from 10 mM stock solutions. 15 μL of DMSO was added to each well of a 384-well plate. 15 μl of compound stock solution was added to the first column. The solution was mixed and 15 μl was transferred to the next column. This was repeated until 20 two-fold dilutions were obtained. 2.5 μl of diluted compounds was transferred into 60 μl of cell culture medium in another 384-well plate and mixed well. 2.5 μl of this mixture was added to the cells seeded in the plate. The final concentration of DMSO was 0.5% and the highest concentration of compound was 50 μM. The plates were incubated overnight (eg, for approximately 14 hours, 18 hours or 24 hours) in a tissue culture incubator at 37°C.

On day 3, plates were removed from the incubator and allowed to equilibrate at room temperature for 30 minutes. Prolabel substrate (Prolabel PathHunter Detection Kit from DiscoverX, User Manual: 93-0180) was added as described in the manufacturer's protocols. The plates were incubated at room temperature for three hours and luminescence readings were read using an Envision plate reader (Perkin Elmer). Data were analyzed and visualized using the Spotfire software package.

Table 14 shows the degradation activity of Helios (IKZF2), Ikaros (IKZF1), and G1 to S phase transition protein 1 (GSPT1) for compounds of the present invention in Prolabel assays in 293GT cells (% degradation reported at 10 μM).

Connection no. Chemical structure IKZF2
E.C. ₅₀ (µM) IKZF2
% reduction
protein level at 10
µM, 24 h. IKZF1
E.C. ₅₀ (µM) GSPT1
E.C. ₅₀ (µM) I-1 - 20% >30 >30 I-2 >30 0% >30 >30 I-3 0.029 65% >30 >30 I-4 - - - >30 I-9 0.113 65% >50 >50 I-6 0.043 65% >50 N. d. I-7 0.183 thirty% >50 N. d. I-8 0.103 65% >50 >50 I-40 1.67 45% >30 N. d. I-45 0.10 70% >30 >50 I-55 - 10% >30 N. d. I-12 0.036 65% >30 N. d. I-14 0.73 40% >30 N. d. I-15 0.094 60% >30 N. d. Blend of I-16 & I-17
0.23 65% 0.12 >50 I-114 0.024 70% 0.29 >50 I-99 0.15 70% 5.20 >50 I-104 0.049 80% 0.051 >50 I-109 0.23 70% >30 >50 Mixture
I-119 &
I-121
0.67 65% 0.63 >50 I-133 0.45 75% >30 N. d. I-143 23.1 40% >30 N. d. I-138 - thirty% >30 N. d. I-163 0.066 80% 0.57 N. d. I-128 >30 thirty% >30 N. d. I-10 0.99 50% >30 >50 I-96 1.57 50% 2.37 >50 I-153 0.41 50% >30 >50 I-148 11.3 40% >30 N. d.

Example 34. Quantification of inhibitory activity in vitro primary human regulatory T cells expanded in the presence of compounds

Materials and methods

Treg cell sorting

Human buffy coats were obtained from BioreclamationIVT in the USA. CD4+ T cells were isolated from the indicated buffy coats using RosetteSep human CD4+ T cell enrichment cocktail (StemCell Technologies, USA) and gradient centrifugation in Ficoll Paque Plus (GE Healthcare LifeSciences, USA) according to the manufacturer's recommendations. Cells were resuspended in RPMI medium supplemented with 1% penicillin-streptomycin solution, 10% fetal bovine serum, HEPES (10 mM), MEM NEAA (100 nM), sodium pyruvate (1 mM) (all supplements from Thermo Fisher Scientific, USA) , hereafter referred to as complete RPMI medium (cRPMI), and left overnight at 37°C, 5% CO ₂ in the presence of 2 U/ml rhIL-2 (Proleukin, Novartis). Cells were collected and resuspended in autoMACS running buffer supplemented with BSA (Miltenyi Biotec, USA) and labeled with FITC-conjugated anti-CD4 antibody (clone RPA-T4), APC-conjugated anti-CD25 antibody (clone M-A251) ( Biolegend), and microbeads with anti-CD25 antibody (Miltenyi Biotec, USA). CD25-enriched cells were then isolated using an autoMACS Pro separator. A highly purified Treg cell population was then obtained by further sorting CD4+ CD25Hi cells using a Sony SH800 cell sorter. The resulting Treg cell population was typically more than 90% pure as measured by FOXP3 expression.

Treg cell proliferation

Purified Treg cells were seeded in cRPMI in 96-well round-bottom plates at a density of 25,000-50,000 cells per well and activated in the presence of 500 U/ml rhIL2 and Treg expansion agent Dynabeads (Thermo Fisher Scientific, USA) according to the manufacturer's recommendations in in the presence or absence of 100 μM rapamycin (Thermo Fisher Scientific, USA). The compounds of the present invention were then added at a final concentration of 10 μM and DMSO was added as an inert control. Cells were incubated at 37°C, 5% CO ₂ for a total of 12-14 days. Compound and rhIL2 were replenished every 48 hours throughout the culture period.

Phenotypic analysis of expanded Treg cells

Cells were collected and counted, and the multiplication factor was calculated as (number of cells recovered)/(number of cells plated). A proportion of cells were fixed and permeabilized using the eBioscience Foxp3 Staining Buffer Kit (eBioscience, Thermo Fisher Scientific, USA) and stained with anti-Helios antibody conjugated to PE-cyanine 7 (clone 22F6). To determine IL2 expression, expanded Treg cells were further incubated in the presence of eBioscience cell stimulation cocktail with protein transport inhibitors (Thermo Fisher Scientific) for 4 hours, followed by fixation and staining with anti-IL2 antibody conjugated to BV711 (clone MQ1-17H12). (BioLegend, USA). Cell data was collected on LSRFortessa (Becton Dickinson, USA) and analysis was performed using FlowJo software (TreeStar, USA).

Functional analysis of expanded Treg cells

Primary human PBMCs were prepared from freshly prepared buffy coats (BioReclamationIVT) by gradient centrifugation in Ficoll Paque Plus according to the manufacturer's recommendations. Cells were then labeled with CFSE (5(6)-carboxyfluorescein diacetate N-succinimidyl ester, Sigma-Aldrich, USA) and seeded in triplicate in cRPMI in round-bottomed 96-well plates alone or with expanded Treg cells at a ratio of PBMC :Treg 1:2. The compounds of the present invention were then added at a final concentration of 10 μM and DMSO was added as an inert control. Cells were activated with soluble anti-CD3 antibody (clone OKT3) (eBioscience, ThermoFisher Scientific, USA) at a final concentration of 100 ng/ml. Cells were incubated at 37°C, 5% CO ₂ for a total of 4-5 days. Upon completion of culture, cells were stained with LIVE/DEAD blue viability dye (Thermo Fisher Scientific, USA) according to the manufacturer's instructions, followed by staining with BUV737-conjugated anti-CD4 antibody (clone SK3) (BD Biosciences, USA) and anti-CD4 antibody. CD8 conjugated to BV711 (clone RPA-T8) (Biolegend, USA). Cell data was collected on LSRFortessa (Becton Dickinson, USA) and analysis was performed using FlowJo software (TreeStar, USA). Proliferation was assessed in each population as the proportion of cells having dilute CFSE. Inhibition was assessed for each condition compared to immunoreactive cells plated individually.

Those skilled in the art will recognize many equivalents to the specific embodiments specifically described herein, or by merely routine experimentation will be able to ascertain such equivalents. Such equivalents are intended to be within the scope of the following claims.

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LIST OF SEQUENCES

<110> NOVARTIS AG

<120> 3-(5-AMINO-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE DERIVATIVES

AND THEIR APPLICATION

<130> PAT058179-WO-PCT

<140>

<141>

<150> 62/695,922

<151> 2018-07-10

<160> 314

<170> PatentIn version 3.5

<210> 1

<211> 121

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 1

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ser Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr

20 25 30

Gly Val Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Val Ile Trp Gly Gly Gly Gly Thr Tyr Tyr Ala Ser Ser Leu Met

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg His Ala Tyr Gly His Asp Gly Gly Phe Ala Met Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 2

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 2

Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Ser Ser Asn

20 25 30

Val Ala Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Gly Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gly Gln Ser Tyr Ser Tyr Pro Phe

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 3

<211> 451

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 3

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ser Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr

20 25 30

Gly Val Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Val Ile Trp Gly Gly Gly Gly Thr Tyr Tyr Ala Ser Ser Leu Met

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg His Ala Tyr Gly His Asp Gly Gly Phe Ala Met Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

115 120 125

Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala

130 135 140

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

145 150 155 160

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

165 170 175

Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

180 185 190

Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys

210 215 220

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly

225 230 235 240

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

245 250 255

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

260 265 270

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

275 280 285

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

290 295 300

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

305 310 315 320

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

325 330 335

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

340 345 350

Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser

355 360 365

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

370 375 380

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

385 390 395 400

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

405 410 415

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

420 425 430

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

435 440 445

Pro Gly Lys

450

<210> 4

<211> 214

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 4

Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Ser Ser Asn

20 25 30

Val Ala Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Gly Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gly Gln Ser Tyr Ser Tyr Pro Phe

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 5

<211> 363

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 5

gaggtgcagc tggtggaatc tggcggcgga ctggtgcagt ccggcggctc tctgagactg

60

tcttgcgctg cctccggctt ctccctgtcc tcttacggcg tggactgggt gcgacaggcc

120

cctggcaagg gcctggaatg ggtgggagtg atctggggcg gaggcggcac ctactacgcc

180

tcttccctga tgggccggtt caccatctcc cgggacaact ccaagaacac cctgtacctg

240

cagatgaact ccctgcgggc cgaggacacc gccgtgtact actgcgccag acacgcctac

300

ggccacgacg gcggcttcgc catggattat tggggccagg gcaccctggt gacagtgtcc

360

tcc

363

<210> 6

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 6

gagatcgtga tgacccagtc ccccgccacc ctgtctgtgt ctcccggcga gagagccacc

60

ctgagctgca gagcctccga gtccgtgtcc tccaacgtgg cctggtatca gcagagacct

120

ggtcaggccc ctcggctgct gatctacggc gcctctaacc gggccaccgg catccctgcc

180

agattctccg gctccggcag cggcaccgac ttcaccctga ccatctcccg gctggaaccc

240

gaggacttcg ccgtgtacta ctgcggccag tcctactcat accccttcac cttcggccag

300

ggcaccaagc tggaaatcaa g

321

<210> 7

<211> 1353

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 7

gaggtgcagc tggtggaatc tggcggcgga ctggtgcagt ccggcggctc tctgagactg

60

tcttgcgctg cctccggctt ctccctgtcc tcttacggcg tggactgggt gcgacaggcc

120

cctggcaagg gcctggaatg ggtgggagtg atctggggcg gaggcggcac ctactacgcc

180

tcttccctga tgggccggtt caccatctcc cgggacaact ccaagaacac cctgtacctg

240

cagatgaact ccctgcgggc cgaggacacc gccgtgtact actgcgccag acacgcctac

300

ggccacgacg gcggcttcgc catggattat tggggccagg gcaccctggt gacagtgtcc

360

tccgctagca ccaagggccc aagtgtgttt cccctggccc ccagcagcaa gtctacttcc

420

ggcggaactg ctgccctggg ttgcctggtg aaggactact tccccgagcc cgtgacagtg

480

tcctggaact ctggggctct gacttccggc gtgcacacct tccccgccgt gctgcagagc

540

agcggcctgt acagcctgag cagcgtggtg acagtgccct ccagctctct gggaacccag

600

acctatatct gcaacgtgaa ccacaagccc agcaacacca aggtggacaa gagagtggag

660

cccaagagct gcgacaagac ccacacctgc cccccctgcc cagctccaga actgctggga

720

gggccttccg tgttcctgtt cccccccaag cccaaggaca ccctgatgat cagcaggacc

780

cccgaggtga cctgcgtggt ggtggacgtg tcccacgagg acccagaggt gaagttcaac

840

tggtacgtgg acggcgtgga ggtgcacaac gccaagacca agcccagaga ggagcagtac

900

aacagcacct acagggtggt gtccgtgctg accgtgctgc accaggactg gctgaacggc

960

aaagaataca agtgcaaagt ctccaacaag gccctgccag ccccaatcga aaagacaatc

1020

agcaaggcca agggccagcc acgggagccc caggtgtaca ccctgccccc cagccgggag

1080

gagatgacca agaaccaggt gtccctgacc tgtctggtga agggcttcta ccccagcgat

1140

atcgccgtgg agtgggagag caacggccag cccgagaaca actacaagac caccccccca

1200

gtgctggaca gcgacggcag cttcttcctg tacagcaagc tgaccgtgga caagtccagg

1260

tggcagcagg gcaacgtgtt cagctgcagc gtgatgcacg aggccctgca caaccactac

1320

acccagaagt ccctgagcct gagccccggc aag

1353

<210> 8

<211> 642

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 8

gagatcgtga tgacccagtc ccccgccacc ctgtctgtgt ctcccggcga gagagccacc

60

ctgagctgca gagcctccga gtccgtgtcc tccaacgtgg cctggtatca gcagagacct

120

ggtcaggccc ctcggctgct gatctacggc gcctctaacc gggccaccgg catccctgcc

180

agattctccg gctccggcag cggcaccgac ttcaccctga ccatctcccg gctggaaccc

240

gaggacttcg ccgtgtacta ctgcggccag tcctactcat accccttcac cttcggccag

300

ggcaccaagc tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttccccccc

360

agcgacgagc agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac

420

ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag

480

gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc

540

ctgagcaagg ccgactacga gaagcataag gtgtacgcct gcgaggtgac ccaccagggc

600

ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc

642

<210> 9

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 9

Ser Tyr Gly Val Asp

15

<210> 10

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 10

Gly Phe Ser Leu Ser Ser Tyr

15

<210> 11

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 11

Val Ile Trp Gly Gly Gly Gly Thr Tyr Tyr Ala Ser Ser Leu Met Gly

1 5 10 15

<210> 12

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 12

Trp Gly Gly Gly Gly

15

<210> 13

<211> 13

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 13

His Ala Tyr Gly His Asp Gly Gly Phe Ala Met Asp Tyr

1 5 10

<210> 14

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 14

Arg Ala Ser Glu Ser Val Ser Ser Asn Val Ala

1 5 10

<210> 15

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 15

Ser Glu Ser Val Ser Ser Asn

15

<210> 16

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 16

Gly Ala Ser Asn Arg Ala Thr

15

<210> 17

<211> 3

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 17

Gly Ala Ser

1

<210> 18

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 18

Gly Gln Ser Tyr Ser Tyr Pro Phe Thr

15

<210> 19

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 19

Ser Tyr Ser Tyr Pro Phe

15

<210> 20

<211> 124

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 20

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Gly Ser Met Val Arg Gly Asp Tyr Tyr Tyr Gly Met Asp

100 105 110

Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 21

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 21

Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 22

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 22

Thr Tyr Trp Met His

15

<210> 23

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 23

Asn Ile Tyr Pro Gly Thr Gly Gly Ser Asn Phe Asp Glu Lys Phe Lys

1 5 10 15

Asn

<210> 24

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 24

Trp Thr Thr Gly Thr Gly Ala Tyr

15

<210> 25

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 25

Gly Tyr Thr Phe Thr Thr Tyr

15

<210> 26

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 26

Tyr Pro Gly Thr Gly Gly

15

<210> 27

<211> 117

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 27

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Thr Tyr

20 25 30

Trp Met His Trp Val Arg Gln Ala Thr Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Asn Ile Tyr Pro Gly Thr Gly Gly Ser Asn Phe Asp Glu Lys Phe

50 55 60

Lys Asn Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Trp Thr Thr Gly Thr Gly Ala Tyr Trp Gly Gln Gly Thr Thr

100 105 110

Val Thr Val Ser Ser

115

<210> 28

<211> 351

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 28

gaggtgcagc tggtgcagtc aggcgccgaa gtgaagaagc ccggcgagtc actgagaatt

60

agctgtaaag gttcaggcta caccttcact acctactgga tgcactgggt ccgccaggct

120

accggtcaag gcctcgagtg gatgggtaat atctaccccg gcaccggcgg ctctaacttc

180

gacgagaagt ttaagaatag agtgactatc accgccgata agtctactag caccgcctat

240

atggaactgt ctagcctgag atcagaggac accgccgtct actactgcac taggtggact

300

accggcacag gcgcctactg gggtcaaggc actaccgtga ccgtgtctag c

351

<210> 29

<211> 443

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 29

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Thr Tyr

20 25 30

Trp Met His Trp Val Arg Gln Ala Thr Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Asn Ile Tyr Pro Gly Thr Gly Gly Ser Asn Phe Asp Glu Lys Phe

50 55 60

Lys Asn Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Trp Thr Thr Gly Thr Gly Ala Tyr Trp Gly Gln Gly Thr Thr

100 105 110

Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu

115 120 125

Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys

130 135 140

Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser

145 150 155 160

Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser

165 170 175

Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser

180 185 190

Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn

195 200 205

Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro

210 215 220

Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe

225 230 235 240

Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val

245 250 255

Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe

260 265 270

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro

275 280 285

Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

290 295 300

Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val

305 310 315 320

Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala

325 330 335

Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln

340 345 350

Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

355 360 365

Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro

370 375 380

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser

385 390 395 400

Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu

405 410 415

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His

420 425 430

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly

435 440

<210> 30

<211> 1329

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 30

gaggtgcagc tggtgcagtc aggcgccgaa gtgaagaagc ccggcgagtc actgagaatt

60

agctgtaaag gttcaggcta caccttcact acctactgga tgcactgggt ccgccaggct

120

accggtcaag gcctcgagtg gatgggtaat atctaccccg gcaccggcgg ctctaacttc

180

gacgagaagt ttaagaatag agtgactatc accgccgata agtctactag caccgcctat

240

atggaactgt ctagcctgag atcagaggac accgccgtct actactgcac taggtggact

300

accggcacag gcgcctactg gggtcaaggc actaccgtga ccgtgtctag cgctagcact

360

aagggcccgt ccgtgttccc cctggcacct tgtagccgga gcactagcga atccaccgct

420

gccctcggct gcctggtcaa ggattacttc ccggagcccg tgaccgtgtc ctggaacagc

480

ggagccctga cctccggagt gcacaccttc cccgctgtgc tgcagagctc cgggctgtac

540

tcgctgtcgt cggtggtcac ggtgccttca tctagcctgg gtaccaagac ctacacttgc

600

aacgtggacc acaagccttc caacactaag gtggacaagc gcgtcgaatc gaagtacggc

660

ccaccgtgcc cgccttgtcc cgcgccggag ttcctcggcg gtccctcggt ctttctgttc

720

ccaccgaagc ccaaggacac tttgatgatt tcccgcaccc ctgaagtgac atgcgtggtc

780

gtggacgtgt cacaggaaga tccggaggtg cagttcaatt ggtacgtgga tggcgtcgag

840

gtgcacaacg ccaaaaccaa gccgagggag gagcagttca actccactta ccgcgtcgtg

900

tccgtgctga cggtgctgca tcaggactgg ctgaacggga aggagtacaa gtgcaaagtg

960

tccaacaagg gacttcctag ctcaatcgaa aagaccatct cgaaagccaa gggacagccc

1020

cgggaacccc aagtgtatac cctgccaccg agccaggaag aaatgactaa gaaccaagtc

1080

tcattgactt gccttgtgaa gggcttctac ccatcggata tcgccgtgga atgggagtcc

1140

aacggccagc cggaaaacaa ctacaagacc acccctccgg tgctggactc agacggatcc

1200

ttcttcctct actcgcggct gaccgtggat aagagcagat ggcaggaggg aaatgtgttc

1260

agctgttctg tgatgcatga agccctgcac aaccactaca ctcagaagtc cctgtccctc

1320

tccctggga

1329

<210> 31

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 31

Lys Ser Ser Gln Ser Leu Leu Asp Ser Gly Asn Gln Lys Asn Phe Leu

1 5 10 15

Thr

<210> 32

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 32

Trp Ala Ser Thr Arg Glu Ser

15

<210> 33

<211> 22

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 33

Tyr Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Leu Tyr Arg Ser Pro

1 5 10 15

Ala Met Pro Glu Asn Leu

20

<210> 34

<211> 13

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 34

Ser Gln Ser Leu Leu Asp Ser Gly Asn Gln Lys Asn Phe

1 5 10

<210> 35

<211> 3

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 35

Trp Ala Ser

1

<210> 36

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 36

Asp Tyr Ser Tyr Pro Tyr

15

<210> 37

<211> 113

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 37

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser

20 25 30

Gly Asn Gln Lys Asn Phe Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys

35 40 45

Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr

65 70 75 80

Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Asn

85 90 95

Asp Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile

100 105 110

Lys

<210> 38

<211> 339

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 38

gagatcgtcc tgactcagtc acccgctacc ctgagcctga gccctggcga gcgggctaca

60

ctgagctgta aatctagtca gtcactgctg gatagcggta atcagaagaa cttcctgacc

120

tggtatcagc agaagcccgg taaagcccct aagctgctga tctactgggc ctctactaga

180

gaatcaggcg tgccctctag gtttagcggt agcggtagtg gcaccgactt caccttcact

240

atctctagcc tgcagcccga ggatatcgct acctactact gtcagaacga ctatagctac

300

ccctacacct tcggtcaagg cactaaggtc gagattaag

339

<210> 39

<211> 220

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 39

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser

20 25 30

Gly Asn Gln Lys Asn Phe Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys

35 40 45

Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr

65 70 75 80

Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Asn

85 90 95

Asp Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile

100 105 110

Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp

115 120 125

Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn

130 135 140

Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu

145 150 155 160

Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp

165 170 175

Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr

180 185 190

Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser

195 200 205

Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215 220

<210> 40

<211> 660

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 40

gagatcgtcc tgactcagtc acccgctacc ctgagcctga gccctggcga gcgggctaca

60

ctgagctgta aatctagtca gtcactgctg gatagcggta atcagaagaa cttcctgacc

120

tggtatcagc agaagcccgg taaagcccct aagctgctga tctactgggc ctctactaga

180

gaatcaggcg tgccctctag gtttagcggt agcggtagtg gcaccgactt caccttcact

240

atctctagcc tgcagcccga ggatatcgct acctactact gtcagaacga ctatagctac

300

ccctacacct tcggtcaagg cactaaggtc gagattaagc gtacggtggc cgctcccagc

360

gtgttcatct tcccccccag cgacgagcag ctgaagagcg gcaccgccag cgtggtgtgc

420

ctgctgaaca acttctaccc ccgggaggcc aaggtgcagt ggaaggtgga caacgccctg

480

cagagcggca acagccagga gagcgtcacc gagcaggaca gcaaggactc cacctacagc

540

ctgagcagca ccctgaccct gagcaaggcc gactacgaga agcataaggt gtacgcctgc

600

gaggtgaccc accagggcct gtccagcccc gtgaccaaga gcttcaacag gggcgagtgc

660

<210> 41

<211> 113

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 41

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser

20 25 30

Gly Asn Gln Lys Asn Phe Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Ala Pro Arg Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr

65 70 75 80

Ile Ser Ser Leu Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Asn

85 90 95

Asp Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile

100 105 110

Lys

<210> 42

<211> 339

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 42

gagatcgtcc tgactcagtc acccgctacc ctgagcctga gccctggcga gcgggctaca

60

ctgagctgta aatctagtca gtcactgctg gatagcggta atcagaagaa cttcctgacc

120

tggtatcagc agaagcccgg tcaagcccct agactgctga tctactgggc ctctactaga

180

gaatcaggcg tgccctctag gtttagcggt agcggtagtg gcaccgactt caccttcact

240

atctctagcc tggaagccga ggacgccgct acctactact gtcagaacga ctatagctac

300

ccctacacct tcggtcaagg cactaaggtc gagattaag

339

<210> 43

<211> 220

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 43

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser

20 25 30

Gly Asn Gln Lys Asn Phe Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Ala Pro Arg Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr

65 70 75 80

Ile Ser Ser Leu Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Asn

85 90 95

Asp Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile

100 105 110

Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp

115 120 125

Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn

130 135 140

Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu

145 150 155 160

Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp

165 170 175

Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr

180 185 190

Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser

195 200 205

Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215 220

<210> 44

<211> 660

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 44

gagatcgtcc tgactcagtc acccgctacc ctgagcctga gccctggcga gcgggctaca

60

ctgagctgta aatctagtca gtcactgctg gatagcggta atcagaagaa cttcctgacc

120

tggtatcagc agaagcccgg tcaagcccct agactgctga tctactgggc ctctactaga

180

gaatcaggcg tgccctctag gtttagcggt agcggtagtg gcaccgactt caccttcact

240

atctctagcc tggaagccga ggacgccgct acctactact gtcagaacga ctatagctac

300

ccctacacct tcggtcaagg cactaaggtc gagattaagc gtacggtggc cgctcccagc

360

gtgttcatct tcccccccag cgacgagcag ctgaagagcg gcaccgccag cgtggtgtgc

420

ctgctgaaca acttctaccc ccgggaggcc aaggtgcagt ggaaggtgga caacgccctg

480

cagagcggca acagccagga gagcgtcacc gagcaggaca gcaaggactc cacctacagc

540

ctgagcagca ccctgaccct gagcaaggcc gactacgaga agcataaggt gtacgcctgc

600

gaggtgaccc accagggcct gtccagcccc gtgaccaaga gcttcaacag gggcgagtgc

660

<210> 45

<211> 15

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 45

acctactgga tgcac

15

<210> 46

<211> 51

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 46

aatatctacc ccggcaccgg cggctctaac ttcgacgaga agtttaagaa t

51

<210> 47

<211> 24

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 47

tggactaccg gcacaggcgc ctac

24

<210> 48

<211> 21

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic oligonucleotide"

<400> 48

ggctacacct tcactaccta c

21

<210> 49

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 49

taccccggca ccggcggc

18

<210> 50

<211> 51

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 50

aaatctagtc agtcactgct ggatagcggt aatcagaaga acttcctgac c

51

<210> 51

<211> 21

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 51

tggggcctcta ctagagaatc a

21

<210> 52

<211> 27

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 52

cagaacgact atagctaccc ctacacc

27

<210> 53

<211> 39

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 53

agtcagtcac tgctggatag cggtaatcag aagaacttc

39

<210> 54

<211> 9

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 54

tggggcctct

9

<210> 55

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 55

gactatagct accctac

18

<210> 56

<211> 440

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 56

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser

20 25 30

Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

100 105 110

Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser

115 120 125

Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp

130 135 140

Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr

145 150 155 160

Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr

165 170 175

Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys

180 185 190

Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp

195 200 205

Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala

210 215 220

Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

225 230 235 240

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

245 250 255

Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val

260 265 270

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

275 280 285

Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

290 295 300

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly

305 310 315 320

Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

325 330 335

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr

340 345 350

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

355 360 365

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

370 375 380

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

385 390 395 400

Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe

405 410 415

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

420 425 430

Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 57

<211> 214

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 57

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 58

<211> 447

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 58

Gln Val Gln Leu Val Gln Ser Gly Val Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe

50 55 60

Lys Asn Arg Val Thr Leu Thr Thr Asp Ser Ser Thr Thr Thr Ala Tyr

65 70 75 80

Met Glu Leu Lys Ser Leu Gln Phe Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro

210 215 220

Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val

225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu

260 265 270

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

275 280 285

Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser

290 295 300

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile

325 330 335

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

340 345 350

Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

370 375 380

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

385 390 395 400

Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg

405 410 415

Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

420 425 430

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440 445

<210> 59

<211> 218

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 59

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Gly Val Ser Thr Ser

20 25 30

Gly Tyr Ser Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro

35 40 45

Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Ser Arg

85 90 95

Asp Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg

100 105 110

Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln

115 120 125

Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr

130 135 140

Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser

145 150 155 160

Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr

165 170 175

Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys

180 185 190

His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro

195 200 205

Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 60

<211> 447

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 60

Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Gln Trp Met

35 40 45

Gly Trp Ile Asn Thr Asp Ser Gly Glu Ser Thr Tyr Ala Glu Glu Phe

50 55 60

Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Asn Thr Ala Tyr

65 70 75 80

Leu Gln Ile Thr Ser Leu Thr Ala Glu Asp Thr Gly Met Tyr Phe Cys

85 90 95

Val Arg Val Gly Tyr Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu

115 120 125

Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys

130 135 140

Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser

145 150 155 160

Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser

165 170 175

Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser

180 185 190

Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn

195 200 205

Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His

210 215 220

Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val

225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu

260 265 270

Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

275 280 285

Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser

290 295 300

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

305 310 315 320

Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile

325 330 335

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

340 345 350

Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

370 375 380

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

385 390 395 400

Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg

405 410 415

Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

420 425 430

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 61

<211> 213

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 61

Glu Ile Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Arg Ser Ser Val Ser Tyr Met

20 25 30

His Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Trp Ile Tyr

35 40 45

Arg Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Ser Tyr Cys Leu Thr Ile Asn Ser Leu Gln Pro Glu

65 70 75 80

Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg Ser Ser Phe Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro

100 105 110

Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr

115 120 125

Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys

130 135 140

Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu

145 150 155 160

Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser

165 170 175

Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala

180 185 190

Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe

195 200 205

Asn Arg Gly Glu Cys

210

<210> 62

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 62

Ser Tyr Trp Met Tyr

15

<210> 63

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 63

Arg Ile Asp Pro Asn Ser Gly Ser Thr Lys Tyr Asn Glu Lys Phe Lys

1 5 10 15

Asn

<210> 64

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 64

Asp Tyr Arg Lys Gly Leu Tyr Ala Met Asp Tyr

1 5 10

<210> 65

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 65

Gly Tyr Thr Phe Thr Ser Tyr

15

<210> 66

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 66

Asp Pro Asn Ser Gly Ser

15

<210> 67

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 67

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Arg Gly Gln Arg Leu Glu Trp Ile

35 40 45

Gly Arg Ile Asp Pro Asn Ser Gly Ser Thr Lys Tyr Asn Glu Lys Phe

50 55 60

Lys Asn Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Tyr Arg Lys Gly Leu Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 68

<211> 360

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 68

gaagtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggcgctac cgtgaagatt

60

agctgtaaag tctcaggcta caccttcact agctactgga tgtactgggt ccgacaggct

120

agaggcaaa gactggagtg gatcggtaga atcgacccta atagcggctc tactaagtat

180

aacgagaagt ttaagaatag gttcactatt agtagggata actctaagaa caccctgtac

240

ctgcagatga atagcctgag agccgaggac accgccgtct actactgcgc tagagactat

300

agaaagggcc tgtacgctat ggactactgg ggtcaaggca ctaccgtgac cgtgtcttca

360

<210> 69

<211> 446

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 69

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Arg Gly Gln Arg Leu Glu Trp Ile

35 40 45

Gly Arg Ile Asp Pro Asn Ser Gly Ser Thr Lys Tyr Asn Glu Lys Phe

50 55 60

Lys Asn Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Tyr Arg Lys Gly Leu Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro

210 215 220

Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val

225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu

260 265 270

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

275 280 285

Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser

290 295 300

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile

325 330 335

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

340 345 350

Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

370 375 380

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

385 390 395 400

Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg

405 410 415

Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

420 425 430

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly

435 440 445

<210> 70

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 70

Lys Ala Ser Gln Asp Val Gly Thr Ala Val Ala

1 5 10

<210> 71

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 71

Trp Ala Ser Thr Arg His Thr

15

<210> 72

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 72

Gln Gln Tyr Asn Ser Tyr Pro Leu Thr

15

<210> 73

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 73

Ser Gln Asp Val Gly Thr Ala

15

<210> 74

<211> 3

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 74

Trp Ala Ser

1

<210> 75

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 75

Tyr Asn Ser Tyr Pro Leu

15

<210> 76

<211> 1338

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 76

gaagtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggcgctac cgtgaagatt

60

agctgtaaag tctcaggcta caccttcact agctactgga tgtactgggt ccgacaggct

120

agaggcaaa gactggagtg gatcggtaga atcgacccta atagcggctc tactaagtat

180

aacgagaagt ttaagaatag gttcactatt agtagggata actctaagaa caccctgtac

240

ctgcagatga atagcctgag agccgaggac accgccgtct actactgcgc tagagactat

300

agaaagggcc tgtacgctat ggactactgg ggtcaaggca ctaccgtgac cgtgtcttca

360

gctagcacta agggcccgtc cgtgttcccc ctggcacctt gtagccggag cactagcgaa

420

tccaccgctg ccctcggctg cctggtcaag gattacttcc cggagcccgt gaccgtgtcc

480

tggaacagcg gagccctgac ctccggagtg cacaccttcc ccgctgtgct gcagagctcc

540

gggctgtact cgctgtcgtc ggtggtcacg gtgccttcat ctagcctggg taccaagacc

600

tacacttgca acgtggacca caagccttcc aacactaagg tggacaagcg cgtcgaatcg

660

aagtacggcc caccgtgccc gccttgtccc gcgccggagt tcctcggcgg tccctcggtc

720

tttctgttcc caccgaagcc caaggacact ttgatgattt cccgcacccc tgaagtgaca

780

tgcgtggtcg tggacgtgtc acaggaagat ccggaggtgc agttcaattg gtacgtggat

840

ggcgtcgagg tgcacaacgc caaaaccaag ccgagggagg agcagttcaa ctccacttac

900

cgcgtcgtgt ccgtgctgac ggtgctgcat caggactggc tgaacgggaa ggagtacaag

960

tgcaaagtgt ccaacaaggg acttcctagc tcaatcgaaa agaccatctc gaaagccaag

1020

ggacagcccc gggaacccca agtgtatacc ctgccaccga gccaggaaga aatgactaag

1080

aaccaagtct cattgacttg ccttgtgaag ggcttctacc catcggatat cgccgtggaa

1140

tgggagtcca acggccagcc ggaaaacaac tacaagacca cccctccggt gctggactca

1200

gacggatcct tcttcctcta ctcgcggctg accgtggata agagcagatg gcaggaggga

1260

aatgtgttca gctgttctgt gatgcatgaa gccctgcaca accactacac tcagaagtcc

1320

ctgtccctct ccctggga

1338

<210> 77

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 77

Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala

20 25 30

Val Ala Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile

35 40 45

Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Glu Ala

65 70 75 80

Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 78

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 78

gctattcagc tgactcagtc acctagtagc ctgagcgcta gtgtgggcga tagagtgact

60

atcacctgta aagcctctca ggacgtgggc accgccgtgg cctggtatct gcagaagcct

120

ggtcaatcac ctcagctgct gatctactgg gcctctacta gacacaccgg cgtgccctct

180

aggtttagcg gtagcggtag tggcaccgac ttcaccttca ctatctcttc actggaagcc

240

gaggacgccg ctacctacta ctgtcagcag tataatagct accccctgac cttcggtcaa

300

ggcactaagg tcgagattaa g

321

<210> 79

<211> 214

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 79

Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala

20 25 30

Val Ala Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile

35 40 45

Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Glu Ala

65 70 75 80

Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 80

<211> 642

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 80

gctattcagc tgactcagtc acctagtagc ctgagcgcta gtgtgggcga tagagtgact

60

atcacctgta aagcctctca ggacgtgggc accgccgtgg cctggtatct gcagaagcct

120

ggtcaatcac ctcagctgct gatctactgg gcctctacta gacacaccgg cgtgccctct

180

aggtttagcg gtagcggtag tggcaccgac ttcaccttca ctatctcttc actggaagcc

240

gaggacgccg ctacctacta ctgtcagcag tataatagct accccctgac cttcggtcaa

300

ggcactaagg tcgagattaa gcgtacggtg gccgctccca gcgtgttcat cttccccccc

360

agcgacgagc agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac

420

ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag

480

gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc

540

ctgagcaagg ccgactacga gaagcataag gtgtacgcct gcgaggtgac ccaccagggc

600

ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc

642

<210> 81

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 81

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Thr Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Arg Ile Asp Pro Asn Ser Gly Ser Thr Lys Tyr Asn Glu Lys Phe

50 55 60

Lys Asn Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Tyr Arg Lys Gly Leu Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 82

<211> 360

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 82

gaagtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggcgctac cgtgaagatt

60

agctgtaaag tctcaggcta caccttcact agctactgga tgtactgggt ccgacaggct

120

accggtcaag gcctggagtg gatgggtaga atcgacccta atagcggctc tactaagtat

180

aacgagaagt ttaagaatag agtgactatc accgccgata agtctactag caccgcctat

240

atggaactgt ctagcctgag atcagaggac accgccgtct actactgcgc tagagactat

300

agaaagggcc tgtacgctat ggactactgg ggtcaaggca ctaccgtgac cgtgtcttca

360

<210> 83

<211> 446

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 83

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Thr Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Arg Ile Asp Pro Asn Ser Gly Ser Thr Lys Tyr Asn Glu Lys Phe

50 55 60

Lys Asn Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Tyr Arg Lys Gly Leu Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro

210 215 220

Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val

225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu

260 265 270

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

275 280 285

Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser

290 295 300

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile

325 330 335

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

340 345 350

Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

370 375 380

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

385 390 395 400

Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg

405 410 415

Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

420 425 430

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly

435 440 445

<210> 84

<211> 1338

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 84

gaagtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggcgctac cgtgaagatt

60

agctgtaaag tctcaggcta caccttcact agctactgga tgtactgggt ccgacaggct

120

accggtcaag gcctggagtg gatgggtaga atcgacccta atagcggctc tactaagtat

180

aacgagaagt ttaagaatag agtgactatc accgccgata agtctactag caccgcctat

240

atggaactgt ctagcctgag atcagaggac accgccgtct actactgcgc tagagactat

300

agaaagggcc tgtacgctat ggactactgg ggtcaaggca ctaccgtgac cgtgtcttca

360

gctagcacta agggcccgtc cgtgttcccc ctggcacctt gtagccggag cactagcgaa

420

tccaccgctg ccctcggctg cctggtcaag gattacttcc cggagcccgt gaccgtgtcc

480

tggaacagcg gagccctgac ctccggagtg cacaccttcc ccgctgtgct gcagagctcc

540

gggctgtact cgctgtcgtc ggtggtcacg gtgccttcat ctagcctggg taccaagacc

600

tacacttgca acgtggacca caagccttcc aacactaagg tggacaagcg cgtcgaatcg

660

aagtacggcc caccgtgccc gccttgtccc gcgccggagt tcctcggcgg tccctcggtc

720

tttctgttcc caccgaagcc caaggacact ttgatgattt cccgcacccc tgaagtgaca

780

tgcgtggtcg tggacgtgtc acaggaagat ccggaggtgc agttcaattg gtacgtggat

840

ggcgtcgagg tgcacaacgc caaaaccaag ccgagggagg agcagttcaa ctccacttac

900

cgcgtcgtgt ccgtgctgac ggtgctgcat caggactggc tgaacgggaa ggagtacaag

960

tgcaaagtgt ccaacaaggg acttcctagc tcaatcgaaa agaccatctc gaaagccaag

1020

ggacagcccc gggaacccca agtgtatacc ctgccaccga gccaggaaga aatgactaag

1080

aaccaagtct cattgacttg ccttgtgaag ggcttctacc catcggatat cgccgtggaa

1140

tgggagtcca acggccagcc ggaaaacaac tacaagacca cccctccggt gctggactca

1200

gacggatcct tcttcctcta ctcgcggctg accgtggata agagcagatg gcaggaggga

1260

aatgtgttca gctgttctgt gatgcatgaa gccctgcaca accactacac tcagaagtcc

1320

ctgtccctct ccctggga

1338

<210> 85

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 85

Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Lys Ala Ser Gln Asp Val Gly Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 86

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 86

gacgtcgtga tgactcagtc acccctgagc ctgcccgtga ccctggggca gcccgcctct

60

attagctgta aagcctctca ggacgtgggc accgccgtgg cctggtatca gcagaagcca

120

gggcaagccc ctagactgct gatctactgg gcctctacta gacacaccgg cgtgccctct

180

aggtttagcg gtagcggtag tggcaccgag ttcaccctga ctatctcttc actgcagccc

240

gacgacttcg ctacctacta ctgtcagcag tataatagct accccctgac cttcggtcaa

300

ggcactaagg tcgagattaa g

321

<210> 87

<211> 214

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 87

Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Lys Ala Ser Gln Asp Val Gly Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 88

<211> 642

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 88

gacgtcgtga tgactcagtc acccctgagc ctgcccgtga ccctggggca gcccgcctct

60

attagctgta aagcctctca ggacgtgggc accgccgtgg cctggtatca gcagaagcca

120

gggcaagccc ctagactgct gatctactgg gcctctacta gacacaccgg cgtgccctct

180

aggtttagcg gtagcggtag tggcaccgag ttcaccctga ctatctcttc actgcagccc

240

gacgacttcg ctacctacta ctgtcagcag tataatagct accccctgac cttcggtcaa

300

ggcactaagg tcgagattaa gcgtacggtg gccgctccca gcgtgttcat cttccccccc

360

agcgacgagc agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac

420

ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag

480

gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc

540

ctgagcaagg ccgactacga gaagcataag gtgtacgcct gcgaggtgac ccaccagggc

600

ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc

642

<210> 89

<211> 15

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 89

agctactgga tgtac

15

<210> 90

<211> 51

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 90

agaatcgacc ctaatagcgg ctctactaag tataacgaga agtttaagaa t

51

<210> 91

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 91

gactatagaa agggcctgta cgctatggac tac

33

<210> 92

<211> 21

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 92

ggctacacct tcactagcta c

21

<210> 93

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 93

gaccctaata gcggctct

18

<210> 94

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 94

aaagcctctc aggacgtggg caccgccgtg gcc

33

<210> 95

<211> 21

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 95

tgggcctcta ctagacacac c

21

<210> 96

<211> 27

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 96

cagcagtata atagctaccc cctgacc

27

<210> 97

<211> 21

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 97

tctcaggacg tgggcaccgc c

21

<210> 98

<211> 9

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 98

tggggcctct

9

<210> 99

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 99

tataatagct accccctg

18

<210> 100

<211> 448

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 100

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser

20 25 30

Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro

115 120 125

Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly

130 135 140

Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn

145 150 155 160

Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln

165 170 175

Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser

180 185 190

Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser

195 200 205

Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr

210 215 220

His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser

225 230 235 240

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

245 250 255

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro

260 265 270

Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

275 280 285

Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val

290 295 300

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

305 310 315 320

Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr

325 330 335

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

340 345 350

Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

355 360 365

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

370 375 380

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

385 390 395 400

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser

405 410 415

Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

420 425 430

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 101

<211> 214

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 101

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 102

<211> 450

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 102

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp

210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly

225 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu

260 265 270

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

290 295 300

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

305 310 315 320

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

325 330 335

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

340 345 350

Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu

355 360 365

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

370 375 380

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

385 390 395 400

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

420 425 430

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

Gly Lys

450

<210> 103

<211> 216

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 103

Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr

20 25 30

Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser

85 90 95

Ser Thr Arg Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly Gln

100 105 110

Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu Glu

115 120 125

Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr

130 135 140

Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys

145 150 155 160

Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr

165 170 175

Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His

180 185 190

Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys

195 200 205

Thr Val Ala Pro Thr Glu Cys Ser

210 215

<210> 104

<211> 451

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 104

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr

20 25 30

Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Glu Gly Gly Trp Phe Gly Glu Leu Ala Phe Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

115 120 125

Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala

130 135 140

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

145 150 155 160

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

165 170 175

Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

180 185 190

Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys

210 215 220

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly

225 230 235 240

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

245 250 255

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

260 265 270

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

275 280 285

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

290 295 300

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

305 310 315 320

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile

325 330 335

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

340 345 350

Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser

355 360 365

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

370 375 380

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

385 390 395 400

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

405 410 415

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

420 425 430

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

435 440 445

Pro Gly Lys

450

<210> 105

<211> 215

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 105

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Arg Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Asp Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Leu Pro

85 90 95

Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala

100 105 110

Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser

115 120 125

Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu

130 135 140

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

145 150 155 160

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

165 170 175

Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val

180 185 190

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

195 200 205

Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 106

<211> 123

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 106

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Thr Ser Gly Asp Thr Phe Ser Thr Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Lys Ala His Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys

85 90 95

Ala Arg Lys Phe His Phe Val Ser Gly Ser Pro Phe Gly Met Asp Val

100 105 110

Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 107

<211> 106

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 107

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Thr

85 90 95

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 108

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 108

Asn Tyr Gly Met Asn

15

<210> 109

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 109

Trp Ile Asn Thr Asp Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe Lys

1 5 10 15

Gly

<210> 110

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 110

Asn Pro Pro Tyr Tyr Tyr Gly Thr Asn Asn Ala Glu Ala Met Asp Tyr

1 5 10 15

<210> 111

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 111

Gly Phe Thr Leu Thr Asn Tyr

15

<210> 112

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 112

Asn Thr Asp Thr Gly Glu

15

<210> 113

<211> 125

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 113

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Leu Thr Asn Tyr

20 25 30

Gly Met Asn Trp Val Arg Gln Ala Arg Gly Gln Arg Leu Glu Trp Ile

35 40 45

Gly Trp Ile Asn Thr Asp Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe

50 55 60

Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr

65 70 75 80

Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asn Pro Pro Tyr Tyr Tyr Gly Thr Asn Asn Ala Glu Ala Met

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120 125

<210> 114

<211> 375

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 114

caagtgcagc tggtgcagtc gggagccgaa gtgaagaagc ctggagcctc ggtgaaggtg

60

tcgtgcaagg catccggatt caccctcacc aattacggga tgaactgggt cagacaggcc

120

cggggtcaac ggctggagtg gatcggatgg attaacaccg acaccgggga gcctacctac

180

gcggacgatt tcaagggacg gttcgtgttc tccctcgaca cctccgtgtc caccgcctac

240

ctccaaatct cctcactgaa agcggaggac accgccgtgt actattgcgc gaggaacccg

300

ccctactact acggaaccaa caacgccgaa gccatggact actggggcca gggcaccact

360

gtgactgtgt ccagc

375

<210> 115

<211> 375

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 115

caggtgcagc tggtgcagtc tggcgccgaa gtgaagaaac ctggcgcctc cgtgaaggtg

60

tcctgcaagg cctctggctt caccctgacc aactacggca tgaactgggt gcgacaggcc

120

aggggccagc ggctggaatg gatcggctgg atcaacaccg acaccggcga gcctacctac

180

gccgacgact tcaagggcag attcgtgttc tccctggaca cctccgtgtc caccgcctac

240

ctgcagatct ccagcctgaa ggccgaggat accgccgtgt actactgcgc ccggaacccc

300

ccttactact acggcaccaa caacgccgag gccatggact attggggcca gggcaccacc

360

gtgaccgtgt cctct

375

<210> 116

<211> 451

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 116

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Leu Thr Asn Tyr

20 25 30

Gly Met Asn Trp Val Arg Gln Ala Arg Gly Gln Arg Leu Glu Trp Ile

35 40 45

Gly Trp Ile Asn Thr Asp Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe

50 55 60

Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr

65 70 75 80

Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asn Pro Pro Tyr Tyr Tyr Gly Thr Asn Asn Ala Glu Ala Met

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr

115 120 125

Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser

130 135 140

Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu

145 150 155 160

Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His

165 170 175

Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser

180 185 190

Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys

195 200 205

Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu

210 215 220

Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu

225 230 235 240

Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu

245 250 255

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser

260 265 270

Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu

275 280 285

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr

290 295 300

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn

305 310 315 320

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser

325 330 335

Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln

340 345 350

Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val

355 360 365

Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val

370 375 380

Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro

385 390 395 400

Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr

405 410 415

Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val

420 425 430

Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu

435 440 445

Ser Leu Gly

450

<210> 117

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 117

Ser Ser Ser Gln Asp Ile Ser Asn Tyr Leu Asn

1 5 10

<210> 118

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 118

Tyr Thr Ser Thr Leu His Leu

15

<210> 119

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 119

Gln Gln Tyr Tyr Asn Leu Pro Trp Thr

15

<210> 120

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 120

Ser Gln Asp Ile Ser Asn Tyr

15

<210> 121

<211> 3

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 121

Tyr Thr Ser

1

<210> 122

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 122

Tyr Tyr Asn Leu Pro Trp

15

<210> 123

<211> 1353

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 123

caagtgcagc tggtgcagtc gggagccgaa gtgaagaagc ctggagcctc ggtgaaggtg

60

tcgtgcaagg catccggatt caccctcacc aattacggga tgaactgggt cagacaggcc

120

cggggtcaac ggctggagtg gatcggatgg attaacaccg acaccgggga gcctacctac

180

gcggacgatt tcaagggacg gttcgtgttc tccctcgaca cctccgtgtc caccgcctac

240

ctccaaatct cctcactgaa agcggaggac accgccgtgt actattgcgc gaggaacccg

300

ccctactact acggaaccaa caacgccgaa gccatggact actggggcca gggcaccact

360

gtgactgtgt ccagcgcgtc cactaagggc ccgtccgtgt tccccctggc accttgtagc

420

cggagcacta gcgaatccac cgctgccctc ggctgcctgg tcaaggatta cttcccggag

480

cccgtgaccg tgtcctggaa cagcggagcc ctgacctccg gagtgcacac cttccccgct

540

gtgctgcaga gctccgggct gtactcgctg tcgtcggtgg tcacggtgcc ttcatctagc

600

ctgggtacca agacctacac ttgcaacgtg gaccacaagc cttccaacac taaggtggac

660

aagcgcgtcg aatcgaagta cggcccaccg tgcccgcctt gtcccgcgcc ggagttcctc

720

ggcggtccct cggtctttct gttcccaccg aagcccaagg acactttgat gatttcccgc

780

acccctgaag tgacatgcgt ggtcgtggac gtgtcacagg aagatccgga ggtgcagttc

840

aattggtacg tggatggcgt cgaggtgcac aacgccaaaa ccaagccgag ggagggagcag

900

ttcaactcca cttaccgcgt cgtgtccgtg ctgacggtgc tgcatcagga ctggctgaac

960

gggaaggagt acaagtgcaa agtgtccaac aagggacttc ctagctcaat cgaaaagacc

1020

atctcgaaag ccaagggaca gccccgggaa ccccaagtgt ataccctgcc accgagccag

1080

gaagaaatga ctaagaacca agtctcattg acttgccttg tgaagggctt ctacccatcg

1140

gatatcgccg tggaatggga gtccaacggc cagccggaaa acaactacaa gaccacccct

1200

ccggtgctgg actcagacgg atccttcttc ctctactcgc ggctgaccgt ggataagagc

1260

agatggcagg agggaaatgt gttcagctgt tctgtgatgc atgaagccct gcacaaccac

1320

tacactcaga agtccctgtc cctctccctg gga

1353

<210> 124

<211> 1353

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 124

caggtgcagc tggtgcagtc tggcgccgaa gtgaagaaac ctggcgcctc cgtgaaggtg

60

tcctgcaagg cctctggctt caccctgacc aactacggca tgaactgggt gcgacaggcc

120

aggggccagc ggctggaatg gatcggctgg atcaacaccg acaccggcga gcctacctac

180

gccgacgact tcaagggcag attcgtgttc tccctggaca cctccgtgtc caccgcctac

240

ctgcagatct ccagcctgaa ggccgaggat accgccgtgt actactgcgc ccggaacccc

300

ccttactact acggcaccaa caacgccgag gccatggact attggggcca gggcaccacc

360

gtgaccgtgt cctctgcttc taccaagggg cccagcgtgt tccccctggc cccctgctcc

420

agaagcacca gcgagagcac agccgccctg ggctgcctgg tgaaggacta cttccccgag

480

cccgtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc

540

gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc

600

ctgggcacca agacctacac ctgtaacgtg gaccacaagc ccagcaacac caaggtggac

660

aagaggtgg agagcaagta cggcccaccc tgccccccct gcccagcccc cgagttcctg

720

ggcggaccca gcgtgttcct gttccccccc aagcccaagg acaccctgat gatcagcaga

780

acccccgagg tgacctgtgt ggtggtggac gtgtcccagg aggaccccga ggtccagttc

840

aactggtacg tggacggcgt ggaggtgcac aacgccaaga ccaagcccag agaggagcag

900

tttaacagca cctaccgggt ggtgtccgtg ctgaccgtgc tgcaccagga ctggctgaac

960

ggcaaagagt acaagtgtaa ggtctccaac aagggcctgc caagcagcat cgaaaagacc

1020

atcagcaagg ccaagggcca gcctagagag ccccaggtct acaccctgcc acccagccaa

1080

gaggagatga ccaagaacca ggtgtccctg acctgtctgg tgaagggctt ctacccaagc

1140

gacatcgccg tggagtggga gagcaacggc cagcccgaga acaactacaa gaccaccccc

1200

ccagtgctgg acagcgacgg cagcttcttc ctgtacagca ggctgaccgt ggacaagtcc

1260

agatggcagg agggcaacgt ctttagctgc tccgtgatgc acgaggccct gcacaaccac

1320

tacacccaga agagcctgag cctgtccctg ggc

1353

<210> 125

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 125

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ser Ser Gln Asp Ile Ser Asn Tyr

20 25 30

Leu Asn Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Thr Leu His Leu Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Asn Leu Pro Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 126

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 126

gatattcaga tgactcagtc acctagtagc ctgagcgcta gtgtgggcga tagagtgact

60

atcacctgta gctctagtca ggatatctct aactacctga actggtatct gcagaagccc

120

ggtcaatcac ctcagctgct gatctactac actagcaccc tgcacctggg cgtgccctct

180

aggtttagcg gtagcggtag tggcaccgag ttcaccctga ctatctctag cctgcagccc

240

gacgacttcg ctacctacta ctgtcagcag tactataacc tgccctggac cttcggtcaa

300

ggcactaagg tcgagattaa g

321

<210> 127

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 127

gacatccaga tgacccagtc cccctccagc ctgtctgctt ccgtgggcga cagagtgacc

60

atcacctgtt cctccagcca ggacatctcc aactacctga actggtatct gcagaagccc

120

ggccagtccc ctcagctgct gatctactac acctccaccc tgcacctggg cgtgccctcc

180

agattttccg gctctggctc tggcaccgag tttaccctga ccatcagctc cctgcagccc

240

gacgacttcg ccacctacta ctgccagcag tactacaacc tgccctggac cttcggccag

300

ggcaccaagg tggaaatcaa g

321

<210> 128

<211> 214

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 128

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ser Ser Gln Asp Ile Ser Asn Tyr

20 25 30

Leu Asn Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Thr Leu His Leu Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Asn Leu Pro Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 129

<211> 642

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 129

gatattcaga tgactcagtc acctagtagc ctgagcgcta gtgtgggcga tagagtgact

60

atcacctgta gctctagtca ggatatctct aactacctga actggtatct gcagaagccc

120

ggtcaatcac ctcagctgct gatctactac actagcaccc tgcacctggg cgtgccctct

180

aggtttagcg gtagcggtag tggcaccgag ttcaccctga ctatctctag cctgcagccc

240

gacgacttcg ctacctacta ctgtcagcag tactataacc tgccctggac cttcggtcaa

300

ggcactaagg tcgagattaa gcgtacggtg gccgctccca gcgtgttcat cttccccccc

360

agcgacgagc agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac

420

ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag

480

gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc

540

ctgagcaagg ccgactacga gaagcataag gtgtacgcct gcgaggtgac ccaccagggc

600

ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc

642

<210> 130

<211> 642

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 130

gacatccaga tgacccagtc cccctccagc ctgtctgctt ccgtgggcga cagagtgacc

60

atcacctgtt cctccagcca ggacatctcc aactacctga actggtatct gcagaagccc

120

ggccagtccc ctcagctgct gatctactac acctccaccc tgcacctggg cgtgccctcc

180

agattttccg gctctggctc tggcaccgag tttaccctga ccatcagctc cctgcagccc

240

gacgacttcg ccacctacta ctgccagcag tactacaacc tgccctggac cttcggccag

300

ggcaccaagg tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttcccccca

360

agcgacgagc agctgaagag cggcaccgcc agcgtggtgt gtctgctgaa caacttctac

420

cccagggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag

480

gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc

540

ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gtgaggtgac ccaccagggc

600

ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc

642

<210> 131

<211> 125

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 131

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Leu Thr Asn Tyr

20 25 30

Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Asn Thr Asp Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe

50 55 60

Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr

65 70 75 80

Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asn Pro Pro Tyr Tyr Tyr Gly Thr Asn Asn Ala Glu Ala Met

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120 125

<210> 132

<211> 375

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 132

caggtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggcgctag tgtgaaagtc

60

agctgtaaag ctagtggctt caccctgact aactacggga tgaactggggt ccgccaggcc

120

ccaggtcaag gcctcgagtg gatgggctgg attaacaccg acaccggcga gcctacctac

180

gccgacgact ttaagggcag attcgtgttt agcctggaca ctagtgtgtc taccgcctac

240

ctgcagatct ctagcctgaa ggccgaggac accgccgtct actactgcgc tagaaacccc

300

ccctactact acggcactaa caacgccgag gctatggact actggggtca aggcactacc

360

gtgaccgtgt ctagc

375

<210> 133

<211> 375

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 133

caggtgcagc tggtgcagtc tggcgccgaa gtgaagaaac ctggcgcctc cgtgaaggtg

60

tcctgcaagg cctctggctt caccctgacc aactacggca tgaactgggt gcgacaggcc

120

cctggacagg gcctggaatg gatgggctgg atcaacaccg acaccggcga gcctacctac

180

gccgacgact tcaagggcag attcgtgttc tccctggaca cctccgtgtc caccgcctac

240

ctgcagatct ccagcctgaa ggccgaggat accgccgtgt actactgcgc ccggaacccc

300

ccttactact acggcaccaa caacgccgag gccatggact attggggcca gggcaccacc

360

gtgaccgtgt cctct

375

<210> 134

<211> 451

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 134

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Leu Thr Asn Tyr

20 25 30

Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Asn Thr Asp Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe

50 55 60

Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr

65 70 75 80

Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asn Pro Pro Tyr Tyr Tyr Gly Thr Asn Asn Ala Glu Ala Met

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr

115 120 125

Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser

130 135 140

Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu

145 150 155 160

Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His

165 170 175

Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser

180 185 190

Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys

195 200 205

Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu

210 215 220

Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu

225 230 235 240

Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu

245 250 255

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser

260 265 270

Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu

275 280 285

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr

290 295 300

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn

305 310 315 320

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser

325 330 335

Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln

340 345 350

Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val

355 360 365

Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val

370 375 380

Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro

385 390 395 400

Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr

405 410 415

Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val

420 425 430

Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu

435 440 445

Ser Leu Gly

450

<210> 135

<211> 1353

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 135

caggtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggcgctag tgtgaaagtc

60

agctgtaaag ctagtggctt caccctgact aactacggga tgaactggggt ccgccaggcc

120

ccaggtcaag gcctcgagtg gatgggctgg attaacaccg acaccggcga gcctacctac

180

gccgacgact ttaagggcag attcgtgttt agcctggaca ctagtgtgtc taccgcctac

240

ctgcagatct ctagcctgaa ggccgaggac accgccgtct actactgcgc tagaaacccc

300

ccctactact acggcactaa caacgccgag gctatggact actggggtca aggcactacc

360

gtgaccgtgt ctagcgctag cactaagggc ccgtccgtgt tccccctggc accttgtagc

420

cggagcacta gcgaatccac cgctgccctc ggctgcctgg tcaaggatta cttcccggag

480

cccgtgaccg tgtcctggaa cagcggagcc ctgacctccg gagtgcacac cttccccgct

540

gtgctgcaga gctccgggct gtactcgctg tcgtcggtgg tcacggtgcc ttcatctagc

600

ctgggtacca agacctacac ttgcaacgtg gaccacaagc cttccaacac taaggtggac

660

aagcgcgtcg aatcgaagta cggcccaccg tgcccgcctt gtcccgcgcc ggagttcctc

720

ggcggtccct cggtctttct gttcccaccg aagcccaagg acactttgat gatttcccgc

780

acccctgaag tgacatgcgt ggtcgtggac gtgtcacagg aagatccgga ggtgcagttc

840

aattggtacg tggatggcgt cgaggtgcac aacgccaaaa ccaagccgag ggagggagcag

900

ttcaactcca cttaccgcgt cgtgtccgtg ctgacggtgc tgcatcagga ctggctgaac

960

gggaaggagt acaagtgcaa agtgtccaac aagggacttc ctagctcaat cgaaaagacc

1020

atctcgaaag ccaagggaca gccccgggaa ccccaagtgt ataccctgcc accgagccag

1080

gaagaaatga ctaagaacca agtctcattg acttgccttg tgaagggctt ctacccatcg

1140

gatatcgccg tggaatggga gtccaacggc cagccggaaa acaactacaa gaccacccct

1200

ccggtgctgg actcagacgg atccttcttc ctctactcgc ggctgaccgt ggataagagc

1260

agatggcagg agggaaatgt gttcagctgt tctgtgatgc atgaagccct gcacaaccac

1320

tacactcaga agtccctgtc cctctccctg gga

1353

<210> 136

<211> 1353

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 136

caggtgcagc tggtgcagtc tggcgccgaa gtgaagaaac ctggcgcctc cgtgaaggtg

60

tcctgcaagg cctctggctt caccctgacc aactacggca tgaactgggt gcgacaggcc

120

cctggacagg gcctggaatg gatgggctgg atcaacaccg acaccggcga gcctacctac

180

gccgacgact tcaagggcag attcgtgttc tccctggaca cctccgtgtc caccgcctac

240

ctgcagatct ccagcctgaa ggccgaggat accgccgtgt actactgcgc ccggaacccc

300

ccttactact acggcaccaa caacgccgag gccatggact attggggcca gggcaccacc

360

gtgaccgtgt cctctgcttc taccaagggg cccagcgtgt tccccctggc cccctgctcc

420

agaagcacca gcgagagcac agccgccctg ggctgcctgg tgaaggacta cttccccgag

480

cccgtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc

540

gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc

600

ctgggcacca agacctacac ctgtaacgtg gaccacaagc ccagcaacac caaggtggac

660

aagaggtgg agagcaagta cggcccaccc tgccccccct gcccagcccc cgagttcctg

720

ggcggaccca gcgtgttcct gttccccccc aagcccaagg acaccctgat gatcagcaga

780

acccccgagg tgacctgtgt ggtggtggac gtgtcccagg aggaccccga ggtccagttc

840

aactggtacg tggacggcgt ggaggtgcac aacgccaaga ccaagcccag agaggagcag

900

tttaacagca cctaccgggt ggtgtccgtg ctgaccgtgc tgcaccagga ctggctgaac

960

ggcaaagagt acaagtgtaa ggtctccaac aagggcctgc caagcagcat cgaaaagacc

1020

atcagcaagg ccaagggcca gcctagagag ccccaggtct acaccctgcc acccagccaa

1080

gaggagatga ccaagaacca ggtgtccctg acctgtctgg tgaagggctt ctacccaagc

1140

gacatcgccg tggagtggga gagcaacggc cagcccgaga acaactacaa gaccaccccc

1200

ccagtgctgg acagcgacgg cagcttcttc ctgtacagca ggctgaccgt ggacaagtcc

1260

agatggcagg agggcaacgt ctttagctgc tccgtgatgc acgaggccct gcacaaccac

1320

tacacccaga agagcctgag cctgtccctg ggc

1353

<210> 137

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 137

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ser Ser Gln Asp Ile Ser Asn Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Thr Leu His Leu Gly Ile Pro Pro Arg Phe Ser Gly

50 55 60

Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Asn Ile Glu Ser

65 70 75 80

Glu Asp Ala Ala Tyr Tyr Phe Cys Gln Gln Tyr Tyr Asn Leu Pro Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 138

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 138

gatattcaga tgactcagtc acctagtagc ctgagcgcta gtgtgggcga tagagtgact

60

atcacctgta gctctagtca ggatatctct aactacctga actggtatca gcagaagccc

120

ggtaaagccc ctaagctgct gatctactac actagcaccc tgcacctggg aatcccccct

180

aggtttagcg gtagcggcta cggcaccgac ttcaccctga ctattaacaa tatcgagtca

240

gaggacgccg cctactactt ctgtcagcag tactataacc tgccctggac cttcggtcaa

300

ggcactaagg tcgagattaa g

321

<210> 139

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 139

gacatccaga tgacccagtc cccctccagc ctgtctgctt ccgtgggcga cagagtgacc

60

atcacctgtt cctccagcca ggacatctcc aactacctga actggtatca gcagaagccc

120

ggcaaggccc ccaagctgct gatctactac acctccaccc tgcacctggg catcccccct

180

agattctccg gctctggcta cggcaccgac ttcaccctga ccatcaacaa catcgagtcc

240

gaggacgccg cctactactt ctgccagcag tactacaacc tgccctggac cttcggccag

300

ggcaccaagg tggaaatcaa g

321

<210> 140

<211> 214

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 140

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ser Ser Gln Asp Ile Ser Asn Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Thr Leu His Leu Gly Ile Pro Pro Arg Phe Ser Gly

50 55 60

Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Asn Ile Glu Ser

65 70 75 80

Glu Asp Ala Ala Tyr Tyr Phe Cys Gln Gln Tyr Tyr Asn Leu Pro Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 141

<211> 642

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 141

gatattcaga tgactcagtc acctagtagc ctgagcgcta gtgtgggcga tagagtgact

60

atcacctgta gctctagtca ggatatctct aactacctga actggtatca gcagaagccc

120

ggtaaagccc ctaagctgct gatctactac actagcaccc tgcacctggg aatcccccct

180

aggtttagcg gtagcggcta cggcaccgac ttcaccctga ctattaacaa tatcgagtca

240

gaggacgccg cctactactt ctgtcagcag tactataacc tgccctggac cttcggtcaa

300

ggcactaagg tcgagattaa gcgtacggtg gccgctccca gcgtgttcat cttccccccc

360

agcgacgagc agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac

420

ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag

480

gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc

540

ctgagcaagg ccgactacga gaagcataag gtgtacgcct gcgaggtgac ccaccagggc

600

ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc

642

<210> 142

<211> 642

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 142

gacatccaga tgacccagtc cccctccagc ctgtctgctt ccgtgggcga cagagtgacc

60

atcacctgtt cctccagcca ggacatctcc aactacctga actggtatca gcagaagccc

120

ggcaaggccc ccaagctgct gatctactac acctccaccc tgcacctggg catcccccct

180

agattctccg gctctggcta cggcaccgac ttcaccctga ccatcaacaa catcgagtcc

240

gaggacgccg cctactactt ctgccagcag tactacaacc tgccctggac cttcggccag

300

ggcaccaagg tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttcccccca

360

agcgacgagc agctgaagag cggcaccgcc agcgtggtgt gtctgctgaa caacttctac

420

cccagggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag

480

gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc

540

ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gtgaggtgac ccaccagggc

600

ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc

642

<210> 143

<211> 15

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 143

aattacggga tgaac

15

<210> 144

<211> 15

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic oligonucleotide"

<400> 144

aactacggca tgaac

15

<210> 145

<211> 51

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 145

tggattaaca ccgacaccgg ggagcctacc tacgcggacg atttcaaggg a

51

<210> 146

<211> 51

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 146

tggatcaaca ccgacaccgg cgagcctacc tacgccgacg acttcaaggg c

51

<210> 147

<211> 48

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 147

aacccgccct actactacgg aaccaacaac gccgaagcca tggactac

48

<210> 148

<211> 48

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 148

aacccccctt actactacgg caccaacaac gccgaggcca tggactat

48

<210> 149

<211> 21

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 149

ggattcaccc tcaccaatta c

21

<210> 150

<211> 21

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 150

ggcttcaccc tgaccaacta c

21

<210> 151

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 151

aacaccgaca ccggggag

18

<210> 152

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 152

aacaccgaca ccggcgag

18

<210> 153

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 153

agctctagtc aggatatctc taactacctg aac

33

<210> 154

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 154

tcctccagcc aggacatctc caactacctg aac

33

<210> 155

<211> 21

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 155

tacactagca ccctgcacct g

21

<210> 156

<211> 21

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 156

tacacctcca ccctgcacct g

21

<210> 157

<211> 27

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 157

cagcagtact ataacctgcc ctggacc

27

<210> 158

<211> 27

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 158

cagcagtact acaacctgcc ctggacc

27

<210> 159

<211> 21

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 159

agtcaggata tctctaacta c

21

<210> 160

<211> 21

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 160

agccaggaca tctccaacta c

21

<210> 161

<211> 9

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 161

tacactagc

9

<210> 162

<211> 9

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 162

tacacctcc

9

<210> 163

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 163

tactataacc tgccctgg

18

<210> 164

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 164

tactacaacc tgccctgg

18

<210> 165

<211> 15

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 165

aactacggga tgaac

15

<210> 166

<211> 51

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 166

tggattaaca ccgacaccgg cgagcctacc tacgccgacg actttaaggg c

51

<210> 167

<211> 48

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 167

aaccccccct actactacgg cactaacaac gccgaggcta tggactac

48

<210> 168

<211> 21

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 168

ggcttcaccc tgactaacta c

21

<210> 169

<211> 447

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 169

Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Asp Tyr

20 25 30

Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn His Arg Gly Ser Thr Asn Ser Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Leu Ser Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu

65 70 75 80

Lys Leu Arg Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Phe Gly Tyr Ser Asp Tyr Glu Tyr Asn Trp Phe Asp Pro Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro

210 215 220

Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val

225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu

260 265 270

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

275 280 285

Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser

290 295 300

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile

325 330 335

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

340 345 350

Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

370 375 380

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

385 390 395 400

Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg

405 410 415

Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

420 425 430

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440 445

<210> 170

<211> 214

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 170

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Asn Leu Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 171

<211> 446

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 171

Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln

1 5 10 15

Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ala Tyr

20 25 30

Gly Val Asn Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu

35 40 45

Gly Met Ile Trp Asp Asp Gly Ser Thr Asp Tyr Asn Ser Ala Leu Lys

50 55 60

Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu

65 70 75 80

Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Arg Tyr Tyr Cys Ala

85 90 95

Arg Glu Gly Asp Val Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 172

<211> 220

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 172

Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly

1 5 10 15

Gln Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Gly

20 25 30

Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Ser Pro Lys Leu Leu Val Tyr Phe Ala Ser Thr Arg Asp Ser Gly Val

50 55 60

Pro Asp Arg Phe Ile Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Asp Tyr Phe Cys Leu Gln

85 90 95

His Phe Gly Thr Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile

100 105 110

Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp

115 120 125

Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn

130 135 140

Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu

145 150 155 160

Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp

165 170 175

Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr

180 185 190

Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser

195 200 205

Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215 220

<210> 173

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 173

Gly Phe Thr Leu Thr Asn Tyr Gly Met Asn

1 5 10

<210> 174

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 174

Ser Tyr Asn Met His

15

<210> 175

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 175

Asp Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys

1 5 10 15

Gly

<210> 176

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 176

Val Gly Gly Ala Phe Pro Met Asp Tyr

15

<210> 177

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 177

Gly Tyr Thr Phe Thr Ser Tyr

15

<210> 178

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 178

Tyr Pro Gly Asn Gly Asp

15

<210> 179

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 179

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Asp Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Val Gly Gly Ala Phe Pro Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Thr Val Thr Val Ser Ser

115

<210> 180

<211> 354

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 180

caggtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggctctag cgtgaaagtt

60

tcttgtaaag ctagtggcta caccttcact agctataata tgcactgggt tcgccaggcc

120

ccagggcaag gcctcgagtg gatgggcgat atctaccccg ggaacggcga cactagttat

180

aatcagaagt ttaagggtag agtcactatc accgccgata agtctactag caccgtctat

240

atggaactga gttccctgag gtctgaggac accgccgtct actactgcgc tagagtgggc

300

ggagccttcc ctatggacta ctggggtcaa ggcactaccg tgaccgtgtc tagc

354

<210> 181

<211> 444

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 181

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Asp Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Val Gly Gly Ala Phe Pro Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro

115 120 125

Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly

130 135 140

Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn

145 150 155 160

Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln

165 170 175

Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser

180 185 190

Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser

195 200 205

Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys

210 215 220

Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu

225 230 235 240

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

245 250 255

Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln

260 265 270

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

275 280 285

Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu

290 295 300

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

305 310 315 320

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

325 330 335

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

340 345 350

Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

355 360 365

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

370 375 380

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

385 390 395 400

Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln

405 410 415

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

420 425 430

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly

435 440

<210> 182

<211> 1332

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 182

caggtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggctctag cgtgaaagtt

60

tcttgtaaag ctagtggcta caccttcact agctataata tgcactgggt tcgccaggcc

120

ccagggcaag gcctcgagtg gatgggcgat atctaccccg ggaacggcga cactagttat

180

aatcagaagt ttaagggtag agtcactatc accgccgata agtctactag caccgtctat

240

atggaactga gttccctgag gtctgaggac accgccgtct actactgcgc tagagtgggc

300

ggagccttcc ctatggacta ctggggtcaa ggcactaccg tgaccgtgtc tagcgctagc

360

actaagggcc cgtccgtgtt ccccctggca ccttgtagcc ggagcactag cgaatccacc

420

gctgccctcg gctgcctggt caaggattac ttcccggagc ccgtgaccgt gtcctggaac

480

agcggagccc tgacctccgg agtgcacacc ttccccgctg tgctgcagag ctccgggctg

540

tactcgctgt cgtcggtggt cacggtgcct tcatctagcc tgggtaccaa gacctacact

600

tgcaacgtgg accacaagcc ttccaacact aaggtggaca agcgcgtcga atcgaagtac

660

ggcccaccgt gcccgccttg tcccgcgccg gagttcctcg gcggtccctc ggtctttctg

720

ttcccaccga agcccaagga cactttgatg atttcccgca cccctgaagt gacatgcgtg

780

gtcgtggacg tgtcacagga agatccggag gtgcagttca attggtacgt ggatggcgtc

840

gaggtgcaca acgccaaaac caagccgagg gaggagcagt tcaactccac ttaccgcgtc

900

gtgtccgtgc tgacggtgct gcatcaggac tggctgaacg ggaaggagta caagtgcaaa

960

gtgtccaaca agggacttcc tagctcaatc gaaaagacca tctcgaaagc caagggacag

1020

ccccgggaac cccaagtgta taccctgcca ccgagccagg aagaaatgac taagaaccaa

1080

gtctcattga cttgccttgt gaagggcttc tacccatcgg atatcgccgt ggaatgggag

1140

tccaacggcc agccggaaaa caactacaag accacccctc cggtgctgga ctcagacgga

1200

tccttcttcc tctactcgcg gctgaccgtg gataagagca gatggcagga gggaaatgtg

1260

ttcagctgtt ctgtgatgca tgaagccctg cacaaccact acactcagaa gtccctgtcc

1320

ctctccctggga

1332

<210> 183

<211> 15

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 183

Arg Ala Ser Glu Ser Val Glu Tyr Tyr Gly Thr Ser Leu Met Gln

1 5 10 15

<210> 184

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 184

Ala Ala Ser Asn Val Glu Ser

15

<210> 185

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 185

Gln Gln Ser Arg Lys Asp Pro Ser Thr

15

<210> 186

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 186

Ser Glu Ser Val Glu Tyr Tyr Gly Thr Ser Leu

1 5 10

<210> 187

<211> 3

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 187

Ala Ala Ser

1

<210> 188

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 188

Ser Arg Lys Asp Pro Ser

15

<210> 189

<211> 111

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 189

Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Glu Tyr Tyr

20 25 30

Gly Thr Ser Leu Met Gln Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro

35 40 45

Lys Leu Leu Ile Tyr Ala Ala Ser Asn Val Glu Ser Gly Val Pro Ser

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Ser Arg

85 90 95

Lys Asp Pro Ser Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 190

<211> 333

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 190

gctattcagc tgactcagtc acctagtagc ctgagcgcta gtgtgggcga tagagtgact

60

atcacctgta gagctagtga atcagtcgag tactacggca ctagcctgat gcagtggtat

120

cagcagaagc ccgggaaagc ccctaagctg ctgatctacg ccgcctctaa cgtggaatca

180

ggcgtgccct ctaggtttag cggtagcggt agtggcaccg acttcaccct gactatctct

240

agcctgcagc ccgaggactt cgctacctac ttctgtcagc agtctaggaa ggaccctagc

300

accttcggcg gaggcactaa ggtcgagatt aag

333

<210> 191

<211> 218

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 191

Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Glu Tyr Tyr

20 25 30

Gly Thr Ser Leu Met Gln Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro

35 40 45

Lys Leu Leu Ile Tyr Ala Ala Ser Asn Val Glu Ser Gly Val Pro Ser

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Ser Arg

85 90 95

Lys Asp Pro Ser Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg

100 105 110

Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln

115 120 125

Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr

130 135 140

Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser

145 150 155 160

Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr

165 170 175

Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys

180 185 190

His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro

195 200 205

Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 192

<211> 654

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 192

gctattcagc tgactcagtc acctagtagc ctgagcgcta gtgtgggcga tagagtgact

60

atcacctgta gagctagtga atcagtcgag tactacggca ctagcctgat gcagtggtat

120

cagcagaagc ccgggaaagc ccctaagctg ctgatctacg ccgcctctaa cgtggaatca

180

ggcgtgccct ctaggtttag cggtagcggt agtggcaccg acttcaccct gactatctct

240

agcctgcagc ccgaggactt cgctacctac ttctgtcagc agtctaggaa ggaccctagc

300

accttcggcg gaggcactaa ggtcgagatt aagcgtacgg tggccgctcc cagcgtgttc

360

atcttccccc ccagcgacga gcagctgaag agcggcaccg ccagcgtggt gtgcctgctg

420

aacaacttct acccccggga ggccaaggtg cagtggaagg tggacaacgc cctgcagagc

480

ggcaacagcc aggagagcgt caccgagcag gacagcaagg actccaccta cagcctgagc

540

agcaccctga ccctgagcaa ggccgactac gagaagcata aggtgtacgc ctgcgaggtg

600

acccaccagg gcctgtccag ccccgtgacc aagagcttca acaggggcga gtgc

654

<210> 193

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 193

Asp Ile Tyr Pro Gly Gln Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys

1 5 10 15

Gly

<210> 194

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 194

Tyr Pro Gly Gln Gly Asp

15

<210> 195

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 195

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Asp Ile Tyr Pro Gly Gln Gly Asp Thr Ser Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Arg Ala Thr Met Thr Ala Asp Lys Ser Thr Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Val Gly Gly Ala Phe Pro Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 196

<211> 354

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 196

caggtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggcgctag tgtgaaagtt

60

agctgtaaag ctagtggcta tactttcact tcttataata tgcactgggt ccgccaggcc

120

ccaggtcaag gcctcgagtg gatcggcgat atctaccccg gtcaaggcga cacttcctat

180

aatcagaagt ttaagggtag agctactatg accgccgata agtctacttc taccgtctat

240

atggaactga gttccctgag gtctgaggac accgccgtct actactgcgc tagagtgggc

300

ggagccttcc caatggacta ctggggtcaa ggcaccctgg tcaccgtgtc tagc

354

<210> 197

<211> 444

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 197

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Asp Ile Tyr Pro Gly Gln Gly Asp Thr Ser Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Arg Ala Thr Met Thr Ala Asp Lys Ser Thr Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Val Gly Gly Ala Phe Pro Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro

115 120 125

Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly

130 135 140

Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn

145 150 155 160

Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln

165 170 175

Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser

180 185 190

Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser

195 200 205

Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys

210 215 220

Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu

225 230 235 240

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

245 250 255

Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln

260 265 270

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

275 280 285

Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu

290 295 300

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

305 310 315 320

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

325 330 335

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

340 345 350

Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

355 360 365

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

370 375 380

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

385 390 395 400

Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln

405 410 415

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

420 425 430

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly

435 440

<210> 198

<211> 1332

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 198

caggtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggcgctag tgtgaaagtt

60

agctgtaaag ctagtggcta tactttcact tcttataata tgcactgggt ccgccaggcc

120

ccaggtcaag gcctcgagtg gatcggcgat atctaccccg gtcaaggcga cacttcctat

180

aatcagaagt ttaagggtag agctactatg accgccgata agtctacttc taccgtctat

240

atggaactga gttccctgag gtctgaggac accgccgtct actactgcgc tagagtgggc

300

ggagccttcc caatggacta ctggggtcaa ggcaccctgg tcaccgtgtc tagcgctagc

360

actaagggcc cgtccgtgtt ccccctggca ccttgtagcc ggagcactag cgaatccacc

420

gctgccctcg gctgcctggt caaggattac ttcccggagc ccgtgaccgt gtcctggaac

480

agcggagccc tgacctccgg agtgcacacc ttccccgctg tgctgcagag ctccgggctg

540

tactcgctgt cgtcggtggt cacggtgcct tcatctagcc tgggtaccaa gacctacact

600

tgcaacgtgg accacaagcc ttccaacact aaggtggaca agcgcgtcga atcgaagtac

660

ggcccaccgt gcccgccttg tcccgcgccg gagttcctcg gcggtccctc ggtctttctg

720

ttcccaccga agcccaagga cactttgatg atttcccgca cccctgaagt gacatgcgtg

780

gtcgtggacg tgtcacagga agatccggag gtgcagttca attggtacgt ggatggcgtc

840

gaggtgcaca acgccaaaac caagccgagg gaggagcagt tcaactccac ttaccgcgtc

900

gtgtccgtgc tgacggtgct gcatcaggac tggctgaacg ggaaggagta caagtgcaaa

960

gtgtccaaca agggacttcc tagctcaatc gaaaagacca tctcgaaagc caagggacag

1020

ccccgggaac cccaagtgta taccctgcca ccgagccagg aagaaatgac taagaaccaa

1080

gtctcattga cttgccttgt gaagggcttc tacccatcgg atatcgccgt ggaatgggag

1140

tccaacggcc agccggaaaa caactacaag accacccctc cggtgctgga ctcagacgga

1200

tccttcttcc tctactcgcg gctgaccgtg gataagagca gatggcagga gggaaatgtg

1260

ttcagctgtt ctgtgatgca tgaagccctg cacaaccact acactcagaa gtccctgtcc

1320

ctctccctggga

1332

<210> 199

<211> 111

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 199

Asp Ile Val Leu Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Glu Tyr Tyr

20 25 30

Gly Thr Ser Leu Met Gln Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Ala Ala Ser Asn Val Glu Ser Gly Val Pro Asp

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Ser Arg

85 90 95

Lys Asp Pro Ser Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 200

<211> 333

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 200

gatatcgtcc tgactcagtc acccgatagc ctggccgtca gcctgggcga gcgggctact

60

attaactgta gagctagtga atcagtcgag tactacggca ctagcctgat gcagtggtat

120

cagcagaagc ccggtcaacc ccctaagctg ctgatctacg ccgcctctaa cgtggaatca

180

ggcgtgcccg ataggtttag cggtagcggt agtggcaccg acttcaccct gactattagt

240

agcctgcagg ccgaggacgt ggccgtctac tactgtcagc agtctaggaa ggaccctagc

300

accttcggcg gaggcactaa ggtcgagatt aag

333

<210> 201

<211> 218

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 201

Asp Ile Val Leu Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Glu Tyr Tyr

20 25 30

Gly Thr Ser Leu Met Gln Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Ala Ala Ser Asn Val Glu Ser Gly Val Pro Asp

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Ser Arg

85 90 95

Lys Asp Pro Ser Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg

100 105 110

Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln

115 120 125

Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr

130 135 140

Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser

145 150 155 160

Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr

165 170 175

Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys

180 185 190

His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro

195 200 205

Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 202

<211> 654

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 202

gatatcgtcc tgactcagtc acccgatagc ctggccgtca gcctgggcga gcgggctact

60

attaactgta gagctagtga atcagtcgag tactacggca ctagcctgat gcagtggtat

120

cagcagaagc ccggtcaacc ccctaagctg ctgatctacg ccgcctctaa cgtggaatca

180

ggcgtgcccg ataggtttag cggtagcggt agtggcaccg acttcaccct gactattagt

240

agcctgcagg ccgaggacgt ggccgtctac tactgtcagc agtctaggaa ggaccctagc

300

accttcggcg gaggcactaa ggtcgagatt aagcgtacgg tggccgctcc cagcgtgttc

360

atcttccccc ccagcgacga gcagctgaag agcggcaccg ccagcgtggt gtgcctgctg

420

aacaacttct acccccggga ggccaaggtg cagtggaagg tggacaacgc cctgcagagc

480

ggcaacagcc aggagagcgt caccgagcag gacagcaagg actccaccta cagcctgagc

540

agcaccctga ccctgagcaa ggccgactac gagaagcata aggtgtacgc ctgcgaggtg

600

acccaccagg gcctgtccag ccccgtgacc aagagcttca acaggggcga gtgc

654

<210> 203

<211> 114

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 203

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ala Ser Gly Phe Thr Phe Ser Ser

20 25 30

Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Asp Trp

35 40 45

Val Ser Thr Ile Ser Gly Gly Gly Thr Tyr Thr Tyr Tyr Gln Asp Ser

50 55 60

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu

65 70 75 80

Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Ser Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser

100 105 110

Ser Ala

<210> 204

<211> 108

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 204

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Arg Arg Tyr

20 25 30

Leu Asn Trp Tyr His Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Gly Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser His Ser Ala Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg

100 105

<210> 205

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 205

Glu Val Gln Val Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Tyr Cys Val Ala Ser Gly Phe Thr Phe Ser Gly Ser

20 25 30

Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

35 40 45

Val Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser

50 55 60

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu

65 70 75 80

Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Lys Lys Tyr Tyr Val Gly Pro Ala Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Gly

115 120

<210> 206

<211> 113

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 206

Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser

20 25 30

Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln His Lys Pro Gly Gln

35 40 45

Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln

85 90 95

Tyr Tyr Ser Ser Pro Leu Thr Phe Gly Gly Gly Thr Lys Ile Glu Val

100 105 110

Lys

<210> 207

<211> 114

<212> PROTEIN

<213> Homo sapiens

<400> 207

Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile

1 5 10 15

Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His

20 25 30

Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln

35 40 45

Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu

50 55 60

Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val

65 70 75 80

Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile

85 90 95

Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn

100 105 110

Thr Ser

<210> 208

<211> 170

<212> PROTEIN

<213> Homo sapiens

<400> 208

Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val

1 5 10 15

Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly

20 25 30

Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn

35 40 45

Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile

50 55 60

Arg Asp Pro Ala Leu Val His Gln Arg Pro Ala Pro Pro Ser Thr Val

65 70 75 80

Thr Thr Ala Gly Val Thr Pro Gln Pro Glu Ser Leu Ser Pro Ser Gly

85 90 95

Lys Glu Pro Ala Ala Ser Ser Pro Ser Ser Asn Asn Thr Ala Ala Thr

100 105 110

Thr Ala Ala Ile Val Pro Gly Ser Gln Leu Met Pro Ser Lys Ser Pro

115 120 125

Ser Thr Gly Thr Thr Glu Ile Ser Ser His Glu Ser Ser His Gly Thr

130 135 140

Pro Ser Gln Thr Thr Ala Lys Asn Trp Glu Leu Thr Ala Ser Ala Ser

145 150 155 160

His Gln Pro Pro Gly Val Tyr Pro Gln Gly

165 170

<210> 209

<211> 114

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 209

Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile

1 5 10 15

Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His

20 25 30

Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln

35 40 45

Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu

50 55 60

Asn Leu Ile Ile Leu Ala Asn Asp Ser Leu Ser Ser Asn Gly Asn Val

65 70 75 80

Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile

85 90 95

Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn

100 105 110

Thr Ser

<210> 210

<211> 297

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 210

Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val

1 5 10 15

Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly

20 25 30

Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn

35 40 45

Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile

50 55 60

Arg Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro

65 70 75 80

Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys

85 90 95

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val

100 105 110

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr

115 120 125

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu

130 135 140

Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His

145 150 155 160

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys

165 170 175

Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln

180 185 190

Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu

195 200 205

Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro

210 215 220

Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn

225 230 235 240

Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu

245 250 255

Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val

260 265 270

Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln

275 280 285

Lys Ser Leu Ser Leu Ser Pro Gly Lys

290 295

<210> 211

<211> 114

<212> PROTEIN

<213> Homo sapiens

<220>

<221> OPTION

<222> (93)..(93)

<223> /replace="Lys"

<220>

<221> Website

<222> (1)..(114)

<223> /note="Variant residues indicated in the sequence

have no preference regarding residues in annotations

variant provisions"

<400> 211

Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile

1 5 10 15

Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His

20 25 30

Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln

35 40 45

Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu

50 55 60

Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val

65 70 75 80

Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile

85 90 95

Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn

100 105 110

Thr Ser

<210> 212

<211> 77

<212> PROTEIN

<213> Homo sapiens

<400> 212

Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val

1 5 10 15

Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly

20 25 30

Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn

35 40 45

Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile

50 55 60

Arg Asp Pro Ala Leu Val His Gln Arg Pro Ala Pro Pro

65 70 75

<210> 213

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 213

Gly Tyr Thr Phe Thr Thr Tyr Trp Met His

1 5 10

<210> 214

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 214

Gly Tyr Thr Phe Thr Ser Tyr Trp Met Tyr

1 5 10

<210> 215

<211> 20

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 215

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

1 5 10 15

Gly Gly Gly Ser

20

<210> 216

<211> 15

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 216

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

1 5 10 15

<210> 217

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 217

Gly Gly Gly Gly Ser

15

<210> 218

<211> 242

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 218

Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly

1 5 10 15

Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile

35 40 45

Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln

65 70 75 80

Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr Gly Gly Gly Gly Ser

100 105 110

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Lys Leu Gln Glu

115 120 125

Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys

130 135 140

Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg

145 150 155 160

Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser

165 170 175

Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile

180 185 190

Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln

195 200 205

Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly

210 215 220

Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val

225 230 235 240

Ser Ser

<210> 219

<211> 242

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 219

Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser

100 105 110

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu

115 120 125

Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys

130 135 140

Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg

145 150 155 160

Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly Val Ile Trp Gly Ser

165 170 175

Glu Thr Thr Tyr Tyr Ser Ser Ser Leu Lys Ser Arg Val Thr Ile Ser

180 185 190

Lys Asp Asn Ser Lys Asn Gln Val Ser Leu Lys Leu Ser Ser Val Thr

195 200 205

Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly

210 215 220

Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val

225 230 235 240

Ser Ser

<210> 220

<211> 242

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 220

Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser

100 105 110

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu

115 120 125

Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys

130 135 140

Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg

145 150 155 160

Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly Val Ile Trp Gly Ser

165 170 175

Glu Thr Thr Tyr Tyr Gln Ser Ser Leu Lys Ser Arg Val Thr Ile Ser

180 185 190

Lys Asp Asn Ser Lys Asn Gln Val Ser Leu Lys Leu Ser Ser Val Thr

195 200 205

Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly

210 215 220

Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val

225 230 235 240

Ser Ser

<210> 221

<211> 242

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 221

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr

20 25 30

Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Ser Ser Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Val Ser Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Met Thr Gln Ser Pro Ala

130 135 140

Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala

145 150 155 160

Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly

165 170 175

Gln Ala Pro Arg Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly

180 185 190

Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu

195 200 205

Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln

210 215 220

Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu

225 230 235 240

Ile Lys

<210> 222

<211> 242

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 222

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr

20 25 30

Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Gln Ser Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Val Ser Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Met Thr Gln Ser Pro Ala

130 135 140

Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala

145 150 155 160

Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly

165 170 175

Gln Ala Pro Arg Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly

180 185 190

Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu

195 200 205

Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln

210 215 220

Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu

225 230 235 240

Ile Lys

<210> 223

<211> 247

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 223

Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser

100 105 110

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln

115 120 125

Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr

130 135 140

Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly

145 150 155 160

Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly

165 170 175

Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Ser Ser Ser Leu Lys Ser

180 185 190

Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Val Ser Leu Lys

195 200 205

Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Lys

210 215 220

His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly

225 230 235 240

Thr Leu Val Thr Val Ser Ser

245

<210> 224

<211> 247

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 224

Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser

100 105 110

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln

115 120 125

Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr

130 135 140

Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly

145 150 155 160

Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly

165 170 175

Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Gln Ser Ser Leu Lys Ser

180 185 190

Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Val Ser Leu Lys

195 200 205

Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Lys

210 215 220

His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly

225 230 235 240

Thr Leu Val Thr Val Ser Ser

245

<210> 225

<211> 247

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 225

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr

20 25 30

Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Ser Ser Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Val Ser Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Met

130 135 140

Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr

145 150 155 160

Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr

165 170 175

Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr His Thr Ser

180 185 190

Arg Leu His Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly

195 200 205

Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala

210 215 220

Val Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

225 230 235 240

Gly Thr Lys Leu Glu Ile Lys

245

<210> 226

<211> 247

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 226

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr

20 25 30

Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Gln Ser Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Val Ser Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Met

130 135 140

Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr

145 150 155 160

Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr

165 170 175

Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr His Thr Ser

180 185 190

Arg Leu His Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly

195 200 205

Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala

210 215 220

Val Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

225 230 235 240

Gly Thr Lys Leu Glu Ile Lys

245

<210> 227

<211> 247

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 227

Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser

100 105 110

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln

115 120 125

Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr

130 135 140

Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly

145 150 155 160

Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly

165 170 175

Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ser Leu Lys Ser

180 185 190

Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Val Ser Leu Lys

195 200 205

Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Lys

210 215 220

His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly

225 230 235 240

Thr Leu Val Thr Val Ser Ser

245

<210> 228

<211> 247

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 228

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr

20 25 30

Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Val Ser Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Met

130 135 140

Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr

145 150 155 160

Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr

165 170 175

Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr His Thr Ser

180 185 190

Arg Leu His Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly

195 200 205

Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala

210 215 220

Val Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

225 230 235 240

Gly Thr Lys Leu Glu Ile Lys

245

<210> 229

<211> 242

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 229

Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser

100 105 110

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu

115 120 125

Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys

130 135 140

Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg

145 150 155 160

Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly Val Ile Trp Gly Ser

165 170 175

Glu Thr Thr Tyr Tyr Asn Ser Ser Leu Lys Ser Arg Val Thr Ile Ser

180 185 190

Lys Asp Asn Ser Lys Asn Gln Val Ser Leu Lys Leu Ser Ser Val Thr

195 200 205

Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly

210 215 220

Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val

225 230 235 240

Ser Ser

<210> 230

<211> 242

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 230

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr

20 25 30

Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Val Ser Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Met Thr Gln Ser Pro Ala

130 135 140

Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala

145 150 155 160

Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly

165 170 175

Gln Ala Pro Arg Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly

180 185 190

Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu

195 200 205

Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln

210 215 220

Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu

225 230 235 240

Ile Lys

<210> 231

<211> 12

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 231

His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr

1 5 10

<210> 232

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 232

Gln Gln Gly Asn Thr Leu Pro Tyr Thr

15

<210> 233

<211> 18

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 233

Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr

1 5 10 15

Lys Gly

<210> 234

<211> 119

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 234

Gln Val Gln Leu Leu Glu Ser Gly Ala Glu Leu Val Arg Pro Gly Ser

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr

20 25 30

Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Gln Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe

50 55 60

Lys Gly Gln Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Gly Leu Thr Ser Glu Asp Ser Ala Val Tyr Ser Cys

85 90 95

Ala Arg Lys Thr Ile Ser Ser Val Val Asp Phe Tyr Phe Asp Tyr Trp

100 105 110

Gly Gln Gly Thr Thr Val Thr

115

<210> 235

<211> 111

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 235

Glu Leu Val Leu Thr Gln Ser Pro Lys Phe Met Ser Thr Ser Val Gly

1 5 10 15

Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Pro Leu Ile

35 40 45

Tyr Ser Ala Thr Tyr Arg Asn Ser Gly Val Pro Asp Arg Phe Thr Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Asn Val Gln Ser

65 70 75 80

Lys Asp Leu Ala Asp Tyr Phe Tyr Phe Cys Gln Tyr Asn Arg Tyr Pro

85 90 95

Tyr Thr Ser Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Arg Ser

100 105 110

<210> 236

<211> 248

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 236

Gln Val Gln Leu Leu Glu Ser Gly Ala Glu Leu Val Arg Pro Gly Ser

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr

20 25 30

Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Gln Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe

50 55 60

Lys Gly Gln Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Gly Leu Thr Ser Glu Asp Ser Ala Val Tyr Ser Cys

85 90 95

Ala Arg Lys Thr Ile Ser Ser Val Val Asp Phe Tyr Phe Asp Tyr Trp

100 105 110

Gly Gln Gly Thr Thr Val Thr Gly Ser Thr Ser Gly Ser Gly Lys Pro

115 120 125

Gly Ser Gly Glu Gly Ser Thr Lys Gly Glu Leu Val Leu Thr Gln Ser

130 135 140

Pro Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Val Thr Cys

145 150 155 160

Lys Ala Ser Gln Asn Val Gly Thr Asn Val Ala Trp Tyr Gln Gln Lys

165 170 175

Pro Gly Gln Ser Pro Lys Pro Leu Ile Tyr Ser Ala Thr Tyr Arg Asn

180 185 190

Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe

195 200 205

Thr Leu Thr Ile Thr Asn Val Gln Ser Lys Asp Leu Ala Asp Tyr Phe

210 215 220

Tyr Phe Cys Gln Tyr Asn Arg Tyr Pro Tyr Thr Ser Gly Gly Gly Thr

225 230 235 240

Lys Leu Glu Ile Lys Arg Arg Ser

245

<210> 237

<211> 486

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 237

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu

20 25 30

Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln

35 40 45

Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr

50 55 60

Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val Pro

65 70 75 80

Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile

85 90 95

Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly

100 105 110

Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr

115 120 125

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu

130 135 140

Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser

145 150 155 160

Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly

165 170 175

Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly

180 185 190

Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser

195 200 205

Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys

210 215 220

Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys

225 230 235 240

His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly

245 250 255

Thr Ser Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro

260 265 270

Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu

275 280 285

Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp

290 295 300

Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly

305 310 315 320

Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg

325 330 335

Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln

340 345 350

Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu

355 360 365

Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala

370 375 380

Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu

385 390 395 400

Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp

405 410 415

Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu

420 425 430

Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile

435 440 445

Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr

450 455 460

Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met

465 470 475 480

Gln Ala Leu Pro Pro Arg

485

<210> 238

<211> 486

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 238

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu

20 25 30

Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln

35 40 45

Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala

50 55 60

Pro Arg Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro

65 70 75 80

Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile

85 90 95

Ser Ser Leu Gln Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly

100 105 110

Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

115 120 125

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln

130 135 140

Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr

145 150 155 160

Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly

165 170 175

Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly

180 185 190

Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Ser Ser Ser Leu Lys Ser

195 200 205

Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Val Ser Leu Lys

210 215 220

Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Lys

225 230 235 240

His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly

245 250 255

Thr Leu Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro

260 265 270

Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu

275 280 285

Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp

290 295 300

Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly

305 310 315 320

Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg

325 330 335

Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln

340 345 350

Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu

355 360 365

Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala

370 375 380

Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu

385 390 395 400

Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp

405 410 415

Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu

420 425 430

Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile

435 440 445

Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr

450 455 460

Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met

465 470 475 480

Gln Ala Leu Pro Pro Arg

485

<210> 239

<211> 486

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 239

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu

20 25 30

Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln

35 40 45

Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala

50 55 60

Pro Arg Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro

65 70 75 80

Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile

85 90 95

Ser Ser Leu Gln Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly

100 105 110

Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

115 120 125

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln

130 135 140

Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr

145 150 155 160

Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly

165 170 175

Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly

180 185 190

Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Gln Ser Ser Leu Lys Ser

195 200 205

Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Val Ser Leu Lys

210 215 220

Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Lys

225 230 235 240

His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly

245 250 255

Thr Leu Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro

260 265 270

Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu

275 280 285

Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp

290 295 300

Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly

305 310 315 320

Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg

325 330 335

Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln

340 345 350

Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu

355 360 365

Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala

370 375 380

Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu

385 390 395 400

Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp

405 410 415

Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu

420 425 430

Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile

435 440 445

Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr

450 455 460

Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met

465 470 475 480

Gln Ala Leu Pro Pro Arg

485

<210> 240

<211> 486

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 240

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu

20 25 30

Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val

35 40 45

Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys

50 55 60

Gly Leu Glu Trp Ile Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr

65 70 75 80

Ser Ser Ser Leu Lys Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys

85 90 95

Asn Gln Val Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala

100 105 110

Val Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met

115 120 125

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Met

145 150 155 160

Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr

165 170 175

Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr

180 185 190

Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr His Thr Ser

195 200 205

Arg Leu His Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly

210 215 220

Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala

225 230 235 240

Val Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

245 250 255

Gly Thr Lys Leu Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro

260 265 270

Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu

275 280 285

Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp

290 295 300

Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly

305 310 315 320

Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg

325 330 335

Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln

340 345 350

Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu

355 360 365

Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala

370 375 380

Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu

385 390 395 400

Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp

405 410 415

Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu

420 425 430

Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile

435 440 445

Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr

450 455 460

Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met

465 470 475 480

Gln Ala Leu Pro Pro Arg

485

<210> 241

<211> 486

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 241

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu

20 25 30

Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val

35 40 45

Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys

50 55 60

Gly Leu Glu Trp Ile Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr

65 70 75 80

Gln Ser Ser Leu Lys Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys

85 90 95

Asn Gln Val Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala

100 105 110

Val Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met

115 120 125

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Met

145 150 155 160

Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr

165 170 175

Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr

180 185 190

Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr His Thr Ser

195 200 205

Arg Leu His Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly

210 215 220

Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala

225 230 235 240

Val Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

245 250 255

Gly Thr Lys Leu Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro

260 265 270

Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu

275 280 285

Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp

290 295 300

Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly

305 310 315 320

Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg

325 330 335

Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln

340 345 350

Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu

355 360 365

Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala

370 375 380

Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu

385 390 395 400

Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp

405 410 415

Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu

420 425 430

Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile

435 440 445

Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr

450 455 460

Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met

465 470 475 480

Gln Ala Leu Pro Pro Arg

485

<210> 242

<211> 491

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 242

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu

20 25 30

Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln

35 40 45

Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala

50 55 60

Pro Arg Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro

65 70 75 80

Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile

85 90 95

Ser Ser Leu Gln Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly

100 105 110

Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

115 120 125

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

130 135 140

Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val

145 150 155 160

Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser

165 170 175

Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly

180 185 190

Leu Glu Trp Ile Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Ser

195 200 205

Ser Ser Leu Lys Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn

210 215 220

Gln Val Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val

225 230 235 240

Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp

245 250 255

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Thr Thr Thr Pro

260 265 270

Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu

275 280 285

Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His

290 295 300

Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu

305 310 315 320

Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr

325 330 335

Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe

340 345 350

Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg

355 360 365

Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser

370 375 380

Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr

385 390 395 400

Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys

405 410 415

Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn

420 425 430

Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu

435 440 445

Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly

450 455 460

His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr

465 470 475 480

Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 243

<211> 491

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 243

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu

20 25 30

Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln

35 40 45

Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala

50 55 60

Pro Arg Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro

65 70 75 80

Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile

85 90 95

Ser Ser Leu Gln Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly

100 105 110

Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

115 120 125

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

130 135 140

Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val

145 150 155 160

Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser

165 170 175

Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly

180 185 190

Leu Glu Trp Ile Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Gln

195 200 205

Ser Ser Leu Lys Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn

210 215 220

Gln Val Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val

225 230 235 240

Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp

245 250 255

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Thr Thr Thr Pro

260 265 270

Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu

275 280 285

Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His

290 295 300

Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu

305 310 315 320

Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr

325 330 335

Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe

340 345 350

Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg

355 360 365

Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser

370 375 380

Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr

385 390 395 400

Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys

405 410 415

Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn

420 425 430

Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu

435 440 445

Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly

450 455 460

His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr

465 470 475 480

Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 244

<211> 491

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 244

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu

20 25 30

Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val

35 40 45

Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys

50 55 60

Gly Leu Glu Trp Ile Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr

65 70 75 80

Ser Ser Ser Leu Lys Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys

85 90 95

Asn Gln Val Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala

100 105 110

Val Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met

115 120 125

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

145 150 155 160

Ser Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro

165 170 175

Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys

180 185 190

Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

195 200 205

Ile Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro Ala Arg Phe Ser

210 215 220

Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln

225 230 235 240

Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro

245 250 255

Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Thr Thr Thr Pro

260 265 270

Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu

275 280 285

Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His

290 295 300

Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu

305 310 315 320

Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr

325 330 335

Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe

340 345 350

Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg

355 360 365

Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser

370 375 380

Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr

385 390 395 400

Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys

405 410 415

Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn

420 425 430

Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu

435 440 445

Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly

450 455 460

His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr

465 470 475 480

Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 245

<211> 491

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 245

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu

20 25 30

Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val

35 40 45

Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys

50 55 60

Gly Leu Glu Trp Ile Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr

65 70 75 80

Gln Ser Ser Leu Lys Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys

85 90 95

Asn Gln Val Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala

100 105 110

Val Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met

115 120 125

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

145 150 155 160

Ser Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro

165 170 175

Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys

180 185 190

Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

195 200 205

Ile Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro Ala Arg Phe Ser

210 215 220

Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln

225 230 235 240

Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro

245 250 255

Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Thr Thr Thr Pro

260 265 270

Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu

275 280 285

Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His

290 295 300

Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu

305 310 315 320

Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr

325 330 335

Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe

340 345 350

Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg

355 360 365

Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser

370 375 380

Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr

385 390 395 400

Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys

405 410 415

Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn

420 425 430

Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu

435 440 445

Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly

450 455 460

His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr

465 470 475 480

Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 246

<211> 491

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 246

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu

20 25 30

Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln

35 40 45

Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala

50 55 60

Pro Arg Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro

65 70 75 80

Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile

85 90 95

Ser Ser Leu Gln Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly

100 105 110

Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

115 120 125

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

130 135 140

Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val

145 150 155 160

Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser

165 170 175

Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly

180 185 190

Leu Glu Trp Ile Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn

195 200 205

Ser Ser Leu Lys Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn

210 215 220

Gln Val Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val

225 230 235 240

Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp

245 250 255

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Thr Thr Thr Pro

260 265 270

Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu

275 280 285

Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His

290 295 300

Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu

305 310 315 320

Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr

325 330 335

Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe

340 345 350

Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg

355 360 365

Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser

370 375 380

Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr

385 390 395 400

Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys

405 410 415

Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn

420 425 430

Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu

435 440 445

Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly

450 455 460

His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr

465 470 475 480

Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 247

<211> 491

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 247

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu

20 25 30

Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln

35 40 45

Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala

50 55 60

Pro Arg Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro

65 70 75 80

Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile

85 90 95

Ser Ser Leu Gln Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly

100 105 110

Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

115 120 125

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

130 135 140

Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val

145 150 155 160

Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser

165 170 175

Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly

180 185 190

Leu Glu Trp Ile Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn

195 200 205

Ser Ser Leu Lys Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn

210 215 220

Gln Val Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val

225 230 235 240

Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp

245 250 255

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Thr Thr Thr Pro

260 265 270

Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu

275 280 285

Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His

290 295 300

Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu

305 310 315 320

Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr

325 330 335

Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe

340 345 350

Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg

355 360 365

Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser

370 375 380

Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr

385 390 395 400

Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys

405 410 415

Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn

420 425 430

Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu

435 440 445

Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly

450 455 460

His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr

465 470 475 480

Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 248

<211> 491

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 248

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu

20 25 30

Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val

35 40 45

Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys

50 55 60

Gly Leu Glu Trp Ile Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr

65 70 75 80

Asn Ser Ser Leu Lys Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys

85 90 95

Asn Gln Val Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala

100 105 110

Val Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met

115 120 125

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

145 150 155 160

Ser Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro

165 170 175

Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys

180 185 190

Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

195 200 205

Ile Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro Ala Arg Phe Ser

210 215 220

Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln

225 230 235 240

Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro

245 250 255

Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Thr Thr Thr Pro

260 265 270

Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu

275 280 285

Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His

290 295 300

Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu

305 310 315 320

Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr

325 330 335

Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe

340 345 350

Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg

355 360 365

Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser

370 375 380

Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr

385 390 395 400

Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys

405 410 415

Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn

420 425 430

Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu

435 440 445

Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly

450 455 460

His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr

465 470 475 480

Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 249

<211> 486

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 249

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu

20 25 30

Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln

35 40 45

Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala

50 55 60

Pro Arg Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro

65 70 75 80

Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile

85 90 95

Ser Ser Leu Gln Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly

100 105 110

Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

115 120 125

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln

130 135 140

Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr

145 150 155 160

Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly

165 170 175

Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly

180 185 190

Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ser Leu Lys Ser

195 200 205

Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Val Ser Leu Lys

210 215 220

Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Lys

225 230 235 240

His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly

245 250 255

Thr Leu Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro

260 265 270

Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu

275 280 285

Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp

290 295 300

Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly

305 310 315 320

Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg

325 330 335

Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln

340 345 350

Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu

355 360 365

Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala

370 375 380

Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu

385 390 395 400

Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp

405 410 415

Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu

420 425 430

Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile

435 440 445

Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr

450 455 460

Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met

465 470 475 480

Gln Ala Leu Pro Pro Arg

485

<210> 250

<211> 45

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 250

Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala

1 5 10 15

Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly

20 25 30

Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp

35 40 45

<210> 251

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 251

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

1 5 10 15

Ser Leu Val Ile Thr Leu Tyr Cys

20

<210> 252

<211> 72

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 252

atctacatct gggcgccctt ggccggggact tgtggggtcc ttctcctgtc actggttatc

60

accctttact gc

72

<210> 253

<211> 230

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 253

Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe

1 5 10 15

Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

20 25 30

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

35 40 45

Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val

50 55 60

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser

65 70 75 80

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

85 90 95

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser

100 105 110

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

115 120 125

Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln

130 135 140

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

145 150 155 160

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

165 170 175

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu

180 185 190

Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser

195 200 205

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

210 215 220

Leu Ser Leu Gly Lys Met

225 230

<210> 254

<211> 135

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 254

accacgacgc cagcgccgcg accaccaaca ccggcgccca ccatcgcgtc gcagcccctg

60

tccctgcgcc cagaggcgtg ccggccagcg gcggggggcg cagtgcacac gagggggctg

120

gacttcgcct gtgat

135

<210> 255

<211> 690

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 255

gagagcaagt acggccctcc ctgcccccct tgccctgccc ccgagttcct gggcggaccc

60

agcgtgttcc tgttcccccc caagcccaag gacaccctga tgatcagccg gacccccgag

120

gtgacctgtg tggtggtgga cgtgtcccag gaggaccccg aggtccagtt caactggtac

180

gtggacggcg tggaggtgca caacgccaag accaagcccc gggaggagca gttcaatagc

240

acctaccggg tggtgtccgt gctgaccgtg ctgcaccagg actggctgaa cggcaaggaa

300

tacaagtgta aggtgtccaa caagggcctg cccagcagca tcgagaaaac catcagcaag

360

gccaagggcc agcctcggga gccccaggtg tacaccctgc cccctagcca agaggagatg

420

accaagaacc aggtgtccct gacctgcctg gtgaagggct tctaccccag cgacatcgcc

480

gtggagtggg agagcaacgg ccagcccgag aacaactaca agaccacccc ccctgtgctg

540

gacagcgacg gcagcttctt cctgtacagc cggctgaccg tggacaagag ccggtggcag

600

gagggcaacg tctttagctg ctccgtgatg cacgaggccc tgcacaacca ctacacccag

660

aagagcctga gcctgtccct gggcaagatg

690

<210> 256

<211> 282

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 256

Arg Trp Pro Glu Ser Pro Lys Ala Gln Ala Ser Ser Val Pro Thr Ala

1 5 10 15

Gln Pro Gln Ala Glu Gly Ser Leu Ala Lys Ala Thr Thr Ala Pro Ala

20 25 30

Thr Thr Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Lys Glu Lys

35 40 45

Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro

50 55 60

Ser His Thr Gln Pro Leu Gly Val Tyr Leu Leu Thr Pro Ala Val Gln

65 70 75 80

Asp Leu Trp Leu Arg Asp Lys Ala Thr Phe Thr Cys Phe Val Val Gly

85 90 95

Ser Asp Leu Lys Asp Ala His Leu Thr Trp Glu Val Ala Gly Lys Val

100 105 110

Pro Thr Gly Gly Val Glu Glu Gly Leu Leu Glu Arg His Ser Asn Gly

115 120 125

Ser Gln Ser Gln His Ser Arg Leu Thr Leu Pro Arg Ser Leu Trp Asn

130 135 140

Ala Gly Thr Ser Val Thr Cys Thr Leu Asn His Pro Ser Leu Pro Pro

145 150 155 160

Gln Arg Leu Met Ala Leu Arg Glu Pro Ala Ala Gln Ala Pro Val Lys

165 170 175

Leu Ser Leu Asn Leu Leu Ala Ser Ser Asp Pro Pro Glu Ala Ala Ser

180 185 190

Trp Leu Leu Cys Glu Val Ser Gly Phe Ser Pro Pro Asn Ile Leu Leu

195 200 205

Met Trp Leu Glu Asp Gln Arg Glu Val Asn Thr Ser Gly Phe Ala Pro

210 215 220

Ala Arg Pro Pro Pro Gln Pro Gly Ser Thr Thr Phe Trp Ala Trp Ser

225 230 235 240

Val Leu Arg Val Pro Ala Pro Pro Ser Pro Gln Pro Ala Thr Tyr Thr

245 250 255

Cys Val Val Ser His Glu Asp Ser Arg Thr Leu Leu Asn Ala Ser Arg

260 265 270

Ser Leu Glu Val Ser Tyr Val Thr Asp His

275 280

<210> 257

<211> 847

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 257

aggtggcccg aaagtcccaa ggcccaggca tctagtgttc ctactgcaca gccccaggca

60

gaaggcagcc tagccaaagc tactactgca cctgccacta cgcgcaatac tggccgtggc

120

ggggaggaga agaaaaagga gaaagagaaa gaagaacagg aagagaggga gaccaagacc

180

cctgaatgtc catcccatac ccagccgctg ggcgtctatc tcttgactcc cgcagtacag

240

gacttgtggc ttagagataa ggccaccttt acatgtttcg tcgtgggctc tgacctgaag

300

gatgcccatt tgacttggga ggttgccgga aaggtaccca cagggggggt tgaggaaggg

360

ttgctggagc gccattccaa tggctctcag agccagcact caagactcac ccttccgaga

420

tccctgtgga acgccgggac ctctgtcaca tgtactctaa atcatcctag cctgccccca

480

cagcgtctga tggcccttag agagccagcc gcccaggcac cagttaagct tagcctgaat

540

ctgctcgcca gtagtgatcc cccagaggcc gccagctggc tcttatgcga agtgtccggc

600

tttagcccgc ccaacatctt gctcatgtgg ctggaggacc agcgagaagt gaacaccagc

660

ggcttcgctc cagcccggcc cccaccccag ccgggttcta ccacattctg ggcctggagt

720

gtcttaaggg tcccagcacc acctagcccc cagccagcca catacacctg tgttgtgtcc

780

catgaagata gcaggaccct gctaaatgct tctaggagtc tggaggtttc ctacgtgact

840

gaccatt

847

<210> 258

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 258

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

1 5 10

<210> 259

<211> 30

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 259

ggtggcggag gttctggagg tggaggttcc

thirty

<210> 260

<211> 112

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 260

Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly

1 5 10 15

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

20 25 30

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

35 40 45

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

50 55 60

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

65 70 75 80

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

85 90 95

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

100 105 110

<210> 261

<211> 112

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 261

Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly

1 5 10 15

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

20 25 30

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

35 40 45

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

50 55 60

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

65 70 75 80

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

85 90 95

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

100 105 110

<210> 262

<211> 336

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 262

agagtgaagt tcagcaggag cgcagacgcc cccgcgtaca agcagggcca gaaccagctc

60

tataacgagc tcaatctagg acgaagagg gagtacgatg ttttggacaa gagacgtggc

120

cgggaccctg agatgggggg aaagccgaga aggaagaacc ctcaggaagg cctgtacaat

180

gaactgcaga aagataagat ggcggaggcc tacagtgaga ttgggatgaa aggcgagcgc

240

cggaggggca aggggcacga tggcctttac cagggtctca gtacagccac caaggacacc

300

tacgacgccc ttcacatgca ggccctgccc cctcgc

336

<210> 263

<211> 336

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 263

agagtgaagt tcagcaggag cgcagacgcc cccgcgtacc agcagggcca gaaccagctc

60

tataacgagc tcaatctagg acgaagagg gagtacgatg ttttggacaa gagacgtggc

120

cgggaccctg agatgggggg aaagccgaga aggaagaacc ctcaggaagg cctgtacaat

180

gaactgcaga aagataagat ggcggaggcc tacagtgaga ttgggatgaa aggcgagcgc

240

cggaggggca aggggcacga tggcctttac cagggtctca gtacagccac caaggacacc

300

tacgacgccc ttcacatgca ggccctgccc cctcgc

336

<210> 264

<211> 42

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 264

Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

1 5 10 15

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

20 25 30

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu

35 40

<210> 265

<211> 48

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 265

Gln Arg Arg Lys Tyr Arg Ser Asn Lys Gly Glu Ser Pro Val Glu Pro

1 5 10 15

Ala Glu Pro Cys Arg Tyr Ser Cys Pro Arg Glu Glu Glu Gly Ser Thr

20 25 30

Ile Pro Ile Gln Glu Asp Tyr Arg Lys Pro Glu Pro Ala Cys Ser Pro

35 40 45

<210> 266

<211> 126

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 266

aaacggggca gaaagaaact cctgtatata ttcaaacaac catttatgag accagtacaa

60

actactcaag aggaagatgg ctgtagctgc cgatttccag aagaagaaga aggaggatgt

120

gaactg

126

<210> 267

<211> 144

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 267

caacgaagga aatatagatc aaacaaagga gaaagtcctg tggagcctgc agagccttgt

60

cgttacagct gccccaggga ggagaggagc agcaccatcc ccatccagga ggattaccga

120

aaaccggagc ctgcctgctc cccc

144

<210> 268

<211> 21

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 268

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro

20

<210> 269

<211> 2000

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<220>

<221> other_sign

<222> (1)..(2000)

<223> /note="This sequence can span 50-2000

nucleotides"

<400> 269

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

60

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

120

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

180

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

240

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

300

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

360

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

420

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

480

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

540

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

600

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

660

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

720

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

780

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

840

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

900

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

960

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1020

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1080

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1140

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1200

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1260

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1320

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1380

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1440

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1500

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1560

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1620

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1680

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1740

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1800

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1860

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1920

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1980

aaaaaaaaaa aaaaaaaaaa

2000

<210> 270

<211> 1184

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 270

cgtgaggctc cggtgcccgt cagtgggcag agcgcacatc gcccacagtc cccgagaagt

60

tggggggagg ggtcggcaat tgaaccggtg cctagagaag gtggcgcggg gtaaactggg

120

aaagtgatgt cgtgtactgg ctccgccttt ttcccgaggg tggggggagaa ccgtatataa

180

gtgcagtagt cgccgtgaac gttctttttc gcaacggggtt tgccgccaga acacaggtaa

240

gtgccgtgtg tggttcccgc gggcctggcc tctttacggg ttatggccct tgcgtgcctt

300

gaattacttc cacctggctg cagtacgtga ttcttgatcc cgagcttcgg gttggaagtg

360

ggtggggagag ttcgaggcct tgcgcttaag gagccccttc gcctcgtgct tgagttgagg

420

cctggcctgg gcgctggggc cgccgcgtgc gaatctggtg gcaccttcgc gcctgtctcg

480

ctgctttcga taagtctcta gccatttaaa atttttgatg acctgctgcg acgctttttt

540

tctggcaaga tagtcttgta aatgcgggcc aagatctgca cactggtatt tcggtttttg

600

gggccgcggg cggcgacggg gcccgtgcgt cccagcgcac atgttcggcg aggcggggcc

660

tgcgagcgcg gccaccgaga atcggacggg ggtagtctca agctggccgg cctgctctgg

720

tgcctggcct cgcgccgccg tgtatcgccc cgccctgggc ggcaaggctg gcccggtcgg

780

caccagttgc gtgagcggaa agatggccgc ttcccggccc tgctgcaggg agctcaaaat

840

ggagaggacgcg gcgctcggga gagcgggcgg gtgagtcacc cacacaaagg aaaagggcct

900

ttccgtcctc agccgtcgct tcatgtgact ccacggagta ccgggcgccg tccaggcacc

960

tcgattagtt ctcgagcttt tggagtacgt cgtctttagg ttggggggag gggttttatg

1020

cgatggagtt tccccacact gagtgggtgg agactgaagt taggccagct tggcacttga

1080

tgtaattctc cttggaattt gccctttttg agtttggatc ttggttcatt ctcaagcctc

1140

agacagtggt tcaaagtttt tttcttccat ttcaggtgtc gtga

1184

<210> 271

<211> 448

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 271

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Asp Tyr Ser Ile Thr Ser Asp

20 25 30

Tyr Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Lys Gly Leu Glu Trp

35 40 45

Met Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Ser Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Ile Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Gln Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ser Phe Asp Tyr Ala His Ala Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro

115 120 125

Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly

130 135 140

Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn

145 150 155 160

Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln

165 170 175

Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser

180 185 190

Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser

195 200 205

Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr

210 215 220

His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser

225 230 235 240

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

245 250 255

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro

260 265 270

Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

275 280 285

Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val

290 295 300

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

305 310 315 320

Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr

325 330 335

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

340 345 350

Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

355 360 365

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

370 375 380

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

385 390 395 400

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser

405 410 415

Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

420 425 430

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 272

<211> 214

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 272

Asp Ile Val Leu Thr Gln Ser Pro Ala Phe Leu Ser Val Thr Pro Gly

1 5 10 15

Glu Lys Val Thr Phe Thr Cys Gln Ala Ser Gln Ser Ile Gly Thr Ser

20 25 30

Ile His Trp Tyr Gln Gln Lys Thr Asp Gln Ala Pro Lys Leu Leu Ile

35 40 45

Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Val Glu Ala

65 70 75 80

Glu Asp Ala Ala Asp Tyr Tyr Cys Gln Gln Ile Asn Ser Trp Pro Thr

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 273

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 273

Ser Asp Tyr Ala Trp Asn

15

<210> 274

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 274

Tyr Ile Ser Tyr Ser Gly Ser Thr Ser Tyr Asn Pro Ser Leu Lys Ser

1 5 10 15

<210> 275

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 275

Phe Asp Tyr Ala His Ala Met Asp Tyr

15

<210> 276

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 276

Gln Ala Ser Gln Ser Ile Gly Thr Ser Ile His

1 5 10

<210> 277

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 277

Tyr Ala Ser Glu Ser Ile Ser

15

<210> 278

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 278

Gln Gln Ile Asn Ser Trp Pro Thr Thr

15

<210> 279

<211> 143

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 279

Gly Ala Pro Ala Gly Pro Leu Ile Val Pro Tyr Asn Leu Pro Leu Pro

1 5 10 15

Gly Gly Val Val Pro Arg Met Leu Ile Thr Ile Leu Gly Thr Val Lys

20 25 30

Pro Asn Ala Asn Arg Ile Ala Leu Asp Phe Gln Arg Gly Asn Asp Val

35 40 45

Ala Phe His Phe Asn Pro Arg Phe Asn Glu Asn Asn Arg Arg Val Ile

50 55 60

Val Cys Asn Thr Lys Leu Asp Asn Asn Trp Gly Arg Glu Glu Arg Gln

65 70 75 80

Ser Val Phe Pro Phe Glu Ser Gly Lys Pro Phe Lys Ile Gln Val Leu

85 90 95

Val Glu Pro Asp His Phe Lys Val Ala Val Asn Asp Ala His Leu Leu

100 105 110

Gln Tyr Asn His Arg Val Lys Lys Leu Asn Glu Ile Ser Lys Leu Gly

115 120 125

Ile Ser Gly Asp Ile Asp Ile Thr Ser Ala Ser Tyr Thr Met Ile

130 135 140

<210> 280

<211> 447

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 280

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Ser Asn

20 25 30

Val Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Val Ile Pro Ile Val Asp Ile Ala Asn Tyr Ala Gln Arg Phe

50 55 60

Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Thr Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ser Thr Leu Gly Leu Val Leu Asp Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro

210 215 220

Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val

225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu

260 265 270

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

275 280 285

Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser

290 295 300

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile

325 330 335

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

340 345 350

Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

370 375 380

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

385 390 395 400

Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg

405 410 415

Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

420 425 430

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440 445

<210> 281

<211> 215

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 281

Glu Thr Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Leu Gly Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ala Asp Ser Pro

85 90 95

Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg Thr Val Ala

100 105 110

Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser

115 120 125

Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu

130 135 140

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

145 150 155 160

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

165 170 175

Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val

180 185 190

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

195 200 205

Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 282

<211> 137

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 282

Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly

1 5 10 15

Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln

20 25 30

Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

35 40 45

Ser Val Tyr Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

50 55 60

Glu Trp Val Ala Ile Ile Trp Tyr Asp Gly Asp Asn Gln Tyr Tyr Ala

65 70 75 80

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn

85 90 95

Thr Leu Tyr Leu Gln Met Asn Gly Leu Arg Ala Glu Asp Thr Ala Val

100 105 110

Tyr Tyr Cys Ala Arg Asp Leu Arg Thr Gly Pro Phe Asp Tyr Trp Gly

115 120 125

Gln Gly Thr Leu Val Thr Val Ser Ser

130 135

<210> 283

<211> 126

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 283

Met Leu Pro Ser Gln Leu Ile Gly Phe Leu Leu Leu Trp Val Pro Ala

1 5 10 15

Ser Arg Gly Glu Ile Val Leu Thr Gln Ser Pro Asp Phe Gln Ser Val

20 25 30

Thr Pro Lys Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile

35 40 45

Gly Ser Ser Leu His Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys

50 55 60

Leu Leu Ile Lys Tyr Ala Ser Gln Ser Phe Ser Gly Val Pro Ser Arg

65 70 75 80

Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser

85 90 95

Leu Glu Ala Glu Asp Ala Ala Ala Tyr Tyr Cys His Gln Ser Ser Ser

100 105 110

Leu Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys

115 120 125

<210> 284

<211> 121

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 284

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Leu Trp Glu Val Arg Ala Leu Pro Ser Val Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 285

<211> 109

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 285

Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln

1 5 10 15

Thr Ala Arg Ile Thr Cys Gly Ala Asn Asp Ile Gly Ser Lys Ser Val

20 25 30

His Trp Tyr Gln Gln Lys Ala Gly Gln Ala Pro Val Leu Val Val Ser

35 40 45

Glu Asp Ile Ile Arg Pro Ser Gly Ile Pro Glu Arg Ile Ser Gly Ser

50 55 60

Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Arg Asp Ser Asp Gln

85 90 95

Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly

100 105

<210> 286

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 286

Gln Asn Asp Tyr Ser Tyr Pro Tyr Thr

15

<210> 287

<211> 63

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 287

atggccctgc ctgtgacagc cctgctgctg cctctggctc tgctgctgca tgccgctaga

60

ccc

63

<210> 288

<211> 63

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 288

atggccctcc ctgtcaccgc cctgctgctt ccgctggctc ttctgctcca cgccgctcgg

60

ccc

63

<210> 289

<211> 72

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 289

atctacattt gggcccctct ggctggtact tgcggggtcc tgctgctttc actcgtgatc

60

actctttactt

72

<210> 290

<211> 126

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 290

aagcgcggtc ggaagaagct gctgtacatc tttaagcaac ccttcatgag gcctgtgcag

60

actactcaag aggaggacgg ctgttcatgc cggttcccag aggaggagga aggcggctgc

120

gaactg

126

<210> 291

<211> 336

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 291

cgcgtgaaat tcagccgcag cgcagatgct ccagcctaca agcaggggca gaaccagctc

60

tacaacgaac tcaatcttgg tcggagagag gagtacgacg tgctggacaa gcggagagga

120

cgggacccag aaatgggcgg gaagccgcgc agaaagaatc cccaagaggg cctgtacaac

180

gagctccaaa aggataagat ggcagaagcc tatagcgaga ttggtatgaa aggggaacgc

240

agaagaggca aaggccacga cggactgtac cagggactca gcaccgccac caaggacacc

300

tatgacgctc ttcacatgca ggccctgccg cctcgg

336

<210> 292

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 292

Gly Gly Gly Gly Ser

15

<210> 293

<211> 150

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 293

Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr

1 5 10 15

Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe

20 25 30

Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr

35 40 45

Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu

50 55 60

Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu

65 70 75 80

Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn

85 90 95

Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala

100 105 110

Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg

115 120 125

Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly

130 135 140

Gln Phe Gln Thr Leu Val

145 150

<210> 294

<211> 450

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 294

cccggatggt ttctggactc tccggatcgc ccgtggaatc ccccaacctt ctcaccggca

60

ctcttggttg tgactgaggg cgataatgcg accttcacgt gctcgttctc caacacctcc

120

gaatcattcg tgctgaactg gtaccgcatg agcccgtcaa accagaccga caagctcgcc

180

gcgtttccgg aagatcggtc gcaaccggga caggattgtc ggttccgcgt gactcaactg

240

ccgaatggca gagacttcca catgagcgtg gtccgcgcta ggcgaaacga ctccgggacc

300

tacctgtgcg gagccatctc gctggcgcct aaggcccaaa tcaaagagag cttgagggcc

360

gaactgagag tgaccgagcg cagagctgag gtgccaactg cacatccatc cccatcgcct

420

cggcctgcgg ggcagtttca gaccctggtc

450

<210> 295

<211> 394

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 295

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro

20 25 30

Trp Asn Pro Pro Thr Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly

35 40 45

Asp Asn Ala Thr Phe Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe

50 55 60

Val Leu Asn Trp Tyr Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu

65 70 75 80

Ala Ala Phe Pro Glu Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe

85 90 95

Arg Val Thr Gln Leu Pro Asn Gly Arg Asp Phe His Met Ser Val Val

100 105 110

Arg Ala Arg Arg Asn Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser

115 120 125

Leu Ala Pro Lys Ala Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg

130 135 140

Val Thr Glu Arg Arg Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser

145 150 155 160

Pro Arg Pro Ala Gly Gln Phe Gln Thr Leu Val Thr Thr Thr Pro Ala

165 170 175

Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser

180 185 190

Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr

195 200 205

Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala

210 215 220

Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys

225 230 235 240

Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

245 250 255

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

260 265 270

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg

275 280 285

Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn

290 295 300

Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg

305 310 315 320

Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro

325 330 335

Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala

340 345 350

Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His

355 360 365

Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp

370 375 380

Ala Leu His Met Gln Ala Leu Pro Pro Arg

385 390

<210> 296

<211> 1182

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 296

atggccctcc ctgtcactgc cctgcttctc cccctcgcac tcctgctcca cgccgctaga

60

ccacccggat ggtttctgga ctctccggat cgcccgtgga atcccccaac cttctcaccg

120

gcactcttgg ttgtgactga gggcgataat gcgaccttca cgtgctcgtt ctccaacacc

180

tccgaatcat tcgtgctgaa ctggtaccgc atgagcccgt caaaccagac cgacaagctc

240

gccgcgtttc cggaagatcg gtcgcaaccg ggacaggatt gtcggttccg cgtgactcaa

300

ctgccgaatg gcagagactt ccacatgagc gtggtccgcg ctaggcgaaa cgactccggg

360

acctacctgt gcggagccat ctcgctggcg cctaaggccc aaatcaaaga gagcttgagg

420

gccgaactga gagtgaccga gcgcagagct gaggtgccaa ctgcacatcc atccccatcg

480

cctcggcctg cggggcagtt tcagaccctg gtcacgacca ctccggcgcc gcgcccaccg

540

actccggccc caactatcgc gagccagccc ctgtcgctga ggccggaagc atgccgccct

600

gccgccggag gtgctgtgca tacccgggga ttggacttcg catgcgacat ctacatttgg

660

gctcctctcg ccggaacttg tggcgtgctc cttctgtccc tggtcatcac cctgtactgc

720

aagcggggtc ggaaaaagct tctgtacatt ttcaagcagc ccttcatgag gcccgtgcaa

780

accacccagg aggaggacgg ttgctcctgc cggttccccg aagaggaaga aggaggttgc

840

gagctgcgcg tgaagttctc ccggagcgcc gacgcccccg cctataagca gggccagaac

900

cagctgtaca acgaactgaa cctgggacgg cgggaagagt acgatgtgct ggacaagcgg

960

cgcggccggg accccgaaat gggcgggaag cctagaagaa agaaccctca ggaaggcctg

1020

tataacgagc tgcagaagga caagatggcc gaggcctact ccgaaattgg gatgaaggga

1080

gagcggcgga ggggaaaggg gcacgacggc ctgtaccaag gactgtccac cgccaccaag

1140

gacacatacg atgccctgca catgcaggcc cttccccctc gc

1182

<210> 297

<211> 4

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 297

Gly Gly Gly Ser

1

<210> 298

<211> 5000

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<220>

<221> other_sign

<222> (1)..(5000)

<223> /note="This sequence can cover 50-5000

nucleotides"

<400> 298

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

60

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

120

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

180

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

240

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

300

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

360

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

420

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

480

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

540

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

600

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

660

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

720

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

780

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

840

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

900

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

960

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1020

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1080

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1140

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1200

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1260

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1320

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1380

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1440

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1500

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1560

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1620

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1680

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1740

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1800

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1860

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1920

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

1980

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

2040

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

2100

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

2160

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

2220

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

2280

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

2340

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

2400

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

2460

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

2520

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

2580

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

2640

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

2700

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

2760

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

2820

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

2880

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

2940

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

3000

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

3060

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

3120

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

3180

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

3240

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

3300

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

3360

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

3420

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

3480

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

3540

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

3600

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

3660

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

3720

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

3780

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

3840

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

3900

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

3960

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

4020

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

4080

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

4140

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

4200

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

4260

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

4320

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

4380

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

4440

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

4500

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

4560

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

4620

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

4680

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

4740

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

4800

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

4860

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

4920

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

4980

aaaaaaaaaa aaaaaaaaaa

5000

<210> 299

<211> 373

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 299

Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr

1 5 10 15

Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe

20 25 30

Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr

35 40 45

Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu

50 55 60

Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu

65 70 75 80

Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn

85 90 95

Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala

100 105 110

Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg

115 120 125

Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly

130 135 140

Gln Phe Gln Thr Leu Val Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr

145 150 155 160

Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala

165 170 175

Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe

180 185 190

Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val

195 200 205

Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys

210 215 220

Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr

225 230 235 240

Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu

245 250 255

Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro

260 265 270

Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly

275 280 285

Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro

290 295 300

Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr

305 310 315 320

Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly

325 330 335

Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln

340 345 350

Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln

355 360 365

Ala Leu Pro Pro Arg

370

<210> 300

<211> 35

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 300

Thr Lys Lys Lys Tyr Ser Ser Ser Val His Asp Pro Asn Gly Glu Tyr

1 5 10 15

Met Phe Met Arg Ala Val Asn Thr Ala Lys Lys Ser Arg Leu Thr Asp

20 25 30

Val Thr Leu

35

<210> 301

<211> 105

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 301

acaaaaaaga agtattcatc cagtgtgcac gaccctaacg gtgaatacat gttcatgaga

60

gcagtgaaca cagccaaaaa atccagactc acagatgtga cccta

105

<210> 302

<211> 69

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 302

Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala

1 5 10 15

Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly

20 25 30

Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Phe Trp Leu

35 40 45

Pro Ile Gly Cys Ala Ala Phe Val Val Val Cys Ile Leu Gly Cys Ile

50 55 60

Leu Ile Cys Trp Leu

65

<210> 303

<211> 207

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 303

accacgacgc cagcgccgcg accaccaaca ccggcgccca ccatcgcgtc gcagcccctg

60

tccctgcgcc cagaggcgtg ccggccagcg gcggggggcg cagtgcacac gagggggctg

120

gacttcgcct gtgatttctg gttacccata ggatgtgcag cctttgttgt agtctgcatt

180

ttgggatgca tacttatttg ttggctt

207

<210> 304

<211> 41

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 304

Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr

1 5 10 15

Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro

20 25 30

Pro Arg Asp Phe Ala Ala Tyr Arg Ser

35 40

<210> 305

<211> 123

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polynucleotide"

<400> 305

aggagtaaga ggagcaggct cctgcacagt gactacatga acatgactcc ccgccgcccc

60

gggcccaccc gcaagcatta ccagccctat gccccaccac gcgacttcgc agcctatcgc

120

tcc

123

<210> 306

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 306

Gly Val Ser Leu Pro Asp Tyr Gly Val Ser

1 5 10

<210> 307

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 307

Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser

1 5 10 15

<210> 308

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 308

Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Ser Ser Ser Leu Lys Ser

1 5 10 15

<210> 309

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 309

Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Gln Ser Ser Leu Lys Ser

1 5 10 15

<210> 310

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 310

Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ser Leu Lys Ser

1 5 10 15

<210> 311

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 311

Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn

1 5 10

<210> 312

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 312

His Thr Ser Arg Leu His Ser

15

<210> 313

<211> 40

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<220>

<221> Website

<222> (1)..(40)

<223> /note="This sequence may span 1-10

repeating links "Gly Gly Gly Ser"

<400> 313

Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser

1 5 10 15

Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser

20 25 30

Gly Gly Gly Ser Gly Gly Gly Ser

35 40

<210> 314

<211> 4

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 314

Arg Gly Asp Ser

1

<---

Claims (67)

1. Compound of formula (I'): Where: each of X ₁ and X ₂ independently represents H or halogen; R _x represents H; R _a and R _b are each independently H, or R _a and R _b together with the atom to which they are attached form =(O); R ₁ represents or R ₂ represents H or (C ₁ -C ₆ )alkyl; or R ₅ is -OR ₆ or -NR ₇ R _7' ; R ₆ represents H, (C ₁ -C ₆ )alkyl, wherein the alkyl is optionally substituted with one substituent independently selected from phenyl; each of R ₇ and R _7' independently represents H, (C ₁ -C ₆ )alkyl, wherein the alkyl is optionally substituted with one to three R ₈ ; or R ₇ and R _7' , together with the nitrogen atom to which they are attached, form a 5-membered heterocycloalkyl ring; each R ₈ is -C(O)OH, (C ₃ -C ₇ )cycloalkyl, phenyl or 6-membered heteroaryl containing 1 heteroatom selected from N, wherein the cycloalkyl is optionally substituted with one to four R ₁₀ ; each R ₁₀ is independently in each case (C ₁ -C ₆ )alkyl; n1 is 1, 2 or 3; each of n2 and n3 is independently equal to 1; or pharmaceutically acceptable salts thereof. 2. A compound according to claim 1, characterized by formula (I): Where: R _x represents H; R ₁ represents R ₂ represents H, (C ₁ -C ₆ )alkyl; or R ₅ is -OR ₆ or -NR ₇ R _7' ; R ₆ represents H, (C ₁ -C ₆ )alkyl, wherein the alkyl is optionally substituted with one substituent, each independently selected from phenyl; each of R ₇ and R _7' independently represents H, (C ₁ -C ₆ )alkyl, wherein the alkyl is optionally substituted with one to three R ₈ ; or R ₇ and R _7' , together with the nitrogen atom to which they are attached, form a 5-membered heterocycloalkyl ring; each R ₈ is a (C ₃ -C ₇ )cycloalkyl or a 6-membered heterocycloalkyl ring containing 1 heteroatom selected from N, wherein the cycloalkyl is optionally substituted by one to four R ₁₀ ; each R ₁₀ is independently in each case (C ₁ -C ₆ )alkyl; n1 is 1, 2 or 3; or pharmaceutically acceptable salts thereof. 3. The connection according to claim 1 or 2, where R ₁ represents 4. A connection according to any one of claims 1-3, where n1 is 1 or 2. 5. A compound according to claim 1 or 2, characterized by formula (Ia), formula (Ia-1): or or pharmaceutically acceptable salts thereof. 6. A compound according to claim 1 or 2, characterized by formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ic-1), formula (Id-1), formula (Ie-1 ), formula (If-1): or pharmaceutically acceptable salts thereof. 7. A compound according to claim 1 or 2, characterized by formula (Ik), formula (Il), formula (Io), formula (Ip), formula (Ik-1), formula (Il-1), formula (Io-1 ) or formula (Ip-1): or pharmaceutically acceptable salts thereof. 8. A compound according to any one of claims 1 to 7, where R ₅ represents -OR ₆ . 9. A compound according to any one of claims 1 to 7, where R ₅ represents -NR ₇ R _7' . 10. A compound according to claim 1 or 2, characterized by formula (Iq), formula (Ir), formula (Is), formula (It), formula (Iq-1), formula (Ir-1), formula (Is-1 ) or formula (It-1): or pharmaceutically acceptable salts thereof. 11. A compound according to any one of claims 1 to 10, where R ₂ represents H or methyl. 12. Connection selected from No. Connection Chemical structure I-1 I-3 I-4 I-9 I-6 I-7 I-8 I-40 I-45 I-55 I-12 I-14 I-15 mixture of I-16 and I-17
I-114 I-99 I-104 I-109 mixture
I-119 and
I-121
I-133 I-143 I-138 I-163 I-128 I-10 I-96 I-153 I-148 or pharmaceutically acceptable salts thereof. 13. A pharmaceutical composition for the treatment of a disease or disorder affected by reduction of IKZF2 protein levels, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. 14. The pharmaceutical composition according to claim 13, further containing at least one additional pharmaceutical agent. 15. The pharmaceutical composition according to claim 13 or 14 for use in the treatment of a disease or disorder that is affected by a decrease in the levels of IKZF2 protein. 16. A method for destroying IKZF2, comprising administering to a patient in need thereof a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof. 17. A method of treating a disease or disorder affected by modulation of IKZF2 protein levels, comprising administering to a patient in need thereof a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof. 18. A method of modulating IKZF2 protein levels, comprising administering to a patient in need thereof a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof. 19. A method of reducing IKZF2 protein levels in a subject, comprising the step of administering to the subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof. 20. The method according to any one of claims 16 to 19, where the administration is carried out orally, parenterally, subcutaneously, by injection or infusion. 21. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder affected by reduction in IKZF2 protein levels. 22. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease or disorder affected by reduction in IKZF2 protein levels. 23. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a disease or disorder associated with decreased levels of IKZF2 protein. 24. The compound of claim 23, wherein the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid , acute myelogenous leukemia and gastrointestinal stromal tumor (GIST). 25. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof in the treatment of a disease or disorder associated with a decrease in IKZF2 protein levels.