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  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
  • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
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  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

• MLL mixed-lineage leukemia
• MEN Multiple Endocrine Neoplasia
• HOX genes Aberrant expression of HOX genes has been implicated in many diseases, including hematological malignancies such as acute myeloid leukemia (AML), and Ewing's sarcoma. Certain hematological malignancies are characterized by the presence of a specific genetic abnormality or mutation, including a nucleoporin 98 (NUP98) gene fusion (Xu et al.; Cancer Cell. 2016 Dec 12;30(6):863-878.), mutation in the nucleophosmin (NPM1) gene (Kiihn et al.; Cancer Discov.
• NUP98 nucleoporin 98
• Ewing's sarcoma tumors and cell lines express high levels of menin and MLL1, which are required for tumor maintenance and progression, and HOXD 13 is a downstream target of MLL1 (Svoboda et al.; Oncotarget. 2017 Jan 3;8(1):458-471.).
• the present disclosure addresses a need in the art by providing compositions and methods for treating hematological malignancies, such as acute myeloid leukemia, or Ewing's sarcoma using a menin inhibitor.
• the menin inhibitor can inhibit the protein-protein interaction of menin with an MLL protein (e.g., MLL1, MLL2, or MLL fusion protein).
• MLL protein e.g., MLL1, MLL2, or MLL fusion protein.
• the compositions and methods herein may be useful for treating diseases dependent on the activity of menin, MLL1, and/or MLL2, such as a hematological malignancy or Ewing's sarcoma.
• the present disclosure provides a method of treating acute myeloid leukemia in a subject exhibiting a nucleoporin 98 (NUP98) gene fusion, mutation in the DNA (cytosine-5)-methyltransferase 3A (D MT3 A) gene, or mixed lineage leukemia (MLL) gene amplification, the method comprising administering to a subject in need thereof a menin inhibitor.
• the subject exhibits a nucleoporin 98 (NUP98) gene fusion.
• the nucleoporin 98 (NUP98) gene fusion is a gene fusion of NUP98 and a homeodomain partner gene.
• the nucleoporin 98 (NUP98) gene fusion is a gene fusion of NUP98 and a non-homeodomain partner gene.
• the nucleoporin 98 (NUP98) gene fusion is a gene fusion of NUP98 and a partner gene selected from HOXA9, HOXA11, HOXA13, HOXC11, HOXC13, HOXD11, HOXD13, PMX1, PMX2, HHEX, PHF23, JARIDl A, NSDl, NSD3, MLL, SETBPl, LEDGF, CCDC28, HMGB3, IQCG, RAPIGDSI, ADD3, DDX10, TOPI, TOP2B, LNPl, RARG, ANKRD28, and POUIFI .
• the subject exhibits a mutation in the DNA (cytosine-5)-methyltransferase 3 A (DNMT3 A) gene.
• the mutation in the DNA (cytosine-5)- methyltransf erase 3 A (DNMT3A) gene is a mutation of R882.
• the mutation in the DNA (cytosine-5)-methyltransferase 3A (DNMT3 A) gene is not a mutation of R882.
• the mutation in the DNA (cytosine-5)-methyltransferase 3 A (DNMT3A) gene is a frameshift deletion, missense mutation, nonsense mutation, splice-site substitution, splice-site deletion, or whole-gene deletion.
• the subject exhibits a mixed lineage leukemia (MLL) gene amplification.
• MLL mixed lineage leukemia
• the present disclosure provides a method of treating a subject having acute myeloid leukemia or acute lymphoblastic leukemia, comprising: (a) screening the subject for the presence of an MLL rearrangement, a partial tandem duplication of MLL, or elevated MEISl expression levels; and (b) administering a menin inhibitor to the subject if one or more of the MLL rearrangement, partial tandem duplication of MLL, or elevated MEISl expression levels are determined to be present.
• the menin inhibitor is a compound of Formula (I- A):
• H is selected from C5-12 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R 50 ;
• A is selected from bond, C 3 . 12 carbocycle and 3- to 12-membered heterocycle;
• B is selected from C 3 . 12 carbocycle and 3- to 12-membered heterocycle
• C is 3- to 12-membered heterocycle
• L 1 , L 2 and L 3 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 - , -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, - C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)-, -N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)N(R 51 )-, - C( R 51 )-, -N(R 51 )C( R 51 )-, -C( R 51 )N(R 51 )-, -N(R 51 )C(0)N(R 51 )-, -S(0) 2- , -OS(O)-, -
• R A , R B and R c are each independently selected at each occurrence from R 50 , or two R
• n and p are each independently an integer from 0 to 6;
• R 50 is independently selected at each occurrence from:
• Ci-io alkyl C 2- io alkenyl, and C 2- io alkynyl, each of which is
• R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 ;
• R 57 is selected from:
• Ci-io alkyl C 2- i 0 alkenyl, and C 2- i 0 alkynyl, each of which is
• p is an integer from 1 to 6;
• L 3 is substituted with one or more R 50 , wherein L 3 is not -CH 2 CH(OH)-.
• the menin inhibitor is a compound of Formula (I-B):
• H is selected from C 5 . 12 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R 50 ;
• A, B and C are each independently selected from C 3 . 12 carbocycle and 3- to 12-membered heterocycle;
• L 1 and L 2 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, - C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, - C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)-, -N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)N(R 51 )-, - C( R 51 )-, -N(R 51 )C( R 51 )-, -C( R 51 )N(R 51 )-, -N(R 51 )C(0)N(R 51 )-, -S(0) 2- , -OS(O)-, - S(0)
• L 3 is selected from alkylene, alkenylene, and alkynylene, each of which is substituted with one or more R 56 and optionally further substituted with one or more R 50 ;
• R A , R B and R c are each independently selected at each occurrence from R 50 , or two R
• n and p are each independently an integer from 0 to 6;
• R 50 is independently selected at each occurrence from:
• Ci-io alkyl C 2- i 0 alkenyl, and C 2- i 0 alkynyl, each of which is
• R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 ;
• R 56 is independently selected at each occurrence from:
• R 56 optionally forms a bond to ring C
• the menin inhibitor is a com ound of Formula (II):
• H is selected from C 5 . 12 carbocycle and 5- to 12-membered heterocycle, each of which i optionally substituted with one or more R 50 ;
• A is selected from bond, C 3 . 12 carbocycle and 3- to 12-membered heterocycle;
• B is selected from C 3 . 12 carbocycle and 3- to 12-membered heterocycle
• L 1 , L 2 and L 3 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH , -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, - C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)-, -N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)N(R 51 )-, - C( R 51 )-, -N(R 51 )C( R 51 )-, -C( R 51 )N(R 51 )-, -N(R 51 )C( R 51 )N(R 51 )-, -S(0) 2- , -OS(O)-,
• R A , R B and R c are each independently selected at each occurrence from R 50 , or two R groups or two R B groups attached to the same atom or different atoms can together optionally form a bridge or ring;
• n are each independently an integer from 0 to 6;
• W 1 is Ci-4 alkylene, optionally substituted with one or more R 50 ;
• W 2 is selected from a bond; and Ci -4 alkylene, optionally substituted with one or more
• W 3 is selected from absent; and Ci -4 alkylene, optionally substituted with one or more
• R 50 is independently selected at each occurrence from:
• Ci-io alkyl C 2- io alkenyl, and C 2- io alkynyl, each of which is
• R 51 is independently selected at each occurrence from:
• R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 , wherein for a compound or salt of Formula (II), when W 3 is absent:
• W 1 is Ci alkylene, W 2 is a bond, and L 3 is not a bond;
• W 1 is C 2 -4 alkylene and W 2 is a bond
• W 1 and W 2 are each Ci alkylene and L 3 is not a bond, wherein each Ci alkylene is independently optionally substituted with one or more R .
• the menin inhibitor is a compound of Formula
• H is selected from C 3 . 12 carbocycle and 3- to 12-membered heterocycle, each of which is optionall substituted with one or more R 50 ;
• each of Z 1 , Z 2 , Z 3 , and Z 4 is independently selected from -C(R A1 )(R A2 )-, -C(R A1 )(R A2 )- C(R A1 )(R A2 )-, -C(O)-, and -C(R A1 )(R A2 )-C(0)-, wherein no more than one of Z 1 , Z 2 , Z 3 , and Z 4 is -C(O)- or -C(R A1 )(R A2 )-C(0)-;
• B is selected from bond, C 3 . 12 carbocycle and 3- to 12-membered heterocycle
• C is selected from bond, C 3 . 12 carbocycle and 3- to 12-membered heterocycle
• L 1 , L 2 and L 3 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 - , -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, - C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)-, -N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)N(R 51 )-, - C( R 51 )-, -N(R 51 )C( R 51 )-, -C( R 51 )N(R 51 )-, -N(R 51 )C(0)N(R 51 )-, -S(0) 2- , -OS(O)-, -
• R B is independently selected at each occurrence from R 50 , or two R B groups attached to the same atom or different atoms can together optionally form a bridge or ring;
• R is independently selected at each occurrence from hydrogen and R , or two R groups attached to the same atom or different atoms can together optionally form a bridge or ring;
• R A1 and R ⁇ are each independently selected at each occurrence from hydrogen and R ;
• n is an integer from 0 to 6;
• p is an integer from 1 to 6;
• R 50 is independently selected at each occurrence from:
• R 51 is independently selected at each occurrence from:
• R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 .
• the menin inhibitor is a compound of Formula (IV):
• harmaceutically acceptable salt or prodrug thereof wherein: fused thienyl or fused phenyl group;
• R 2a is selected from hydrogen, alkyl, alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, and aralkyl;
• R 3a and R 3b are each independently selected from hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, and haloalkoxy;
• X a is selected from hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, and haloalkoxy;
• Y a is selected from cyano, hydroxy, and -CH 2 R 50 ;
• R 4a is selected from hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, aralkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl;
• R 14a is selected from hydrogen and alkyl
• R 50 is independently selected at each occurrence from:
• Ci-io alkyl C 2- i 0 alkenyl, and C 2- i 0 alkynyl, each of which is
• R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 .
• he menin inhibitor is a compound of Formula (VI):
• H 2 is selected from C 3 . 12 carbocycle and 3- to 12-membered heterocycle
• H is selected from C 3 . 12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more R 50 ;
• Z 5 and Z 6 are independently selected from -C(R A3 )- and -N-;
• B is selected from bond, C 3 . 12 carbocycle and 3- to 12-membered heterocycle;
• L 1 , L 2 and L 4 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 - , -C(0)-, -C(0)0-, -0C(0)-, -0C(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, - C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)-, -N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)N(R 51 )-, - C( R 51 )-, -N(R 51 )C( R 51 )-, -C( R 51 )N(R 51 )-, -N(R 51 )C( R
• R B is independently selected at each occurrence from hydrogen and R 50 , or two R B groups attached to the same atom or different atoms can together optionally form a bridge or ring;
• R H2 is independently selected at each occurrence from R 50 , or two R H2 groups attached to the same atom or different atoms can together optionally form a bridge or ring;
• R A1 , R A2 and R A3 are each independently selected at each occurrence from hydrogen and
• n is an integer from 0 to 6;
• r is an integer from 1 to 6;
• R 50 is independently selected at each occurrence from:
• Ci-io alkyl C 2- io alkenyl, and C 2- io alkynyl, each of which is
• R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 .
• the present disclosure provides a method of treating acute myeloid leukemia in a subject exhibiting a mutation in the nucleophosmin ( PM1) gene, the method comprising administering to a sub ect in need thereof a compound of Formula (I- A):
• H is selected from C 5 . 12 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R 50 ;
• A is selected from bond, C 3 . 12 carbocycle and 3- to 12-membered heterocycle;
• B is selected from C 3 . 12 carbocycle and 3- to 12-membered heterocycle
• C is 3- to 12-membered heterocycle
• L 1 , L 2 and L 3 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -
• R 50 wherein two R 50 groups attached to the same atom or different atoms of any one of L 1 , L 2 or L 3 can together optionally form a bridge or ring;
• R A , R B and R c are each independently selected at each occurrence from R 50 , or two R
• n and p are each independently an integer from 0 to 6;
• Ci-io alkyl C 2- i 0 alkenyl, and C 2- i 0 alkynyl, each of which is
• R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 ;
• R 57 is selected from:
• Ci-io alkyl C 2- io alkenyl, and C 2- io alkynyl, each of which is
• p is an integer from 1 to 6;
• L 3 is substituted with one or more R 50 , wherein L 3 is not -CH 2 CH(OH)-.
• the present disclosure provides a method of treating a hemtological malignancy in a subject exhibiting a mutation in the nucleophosmin (NPMl) gene, DNA
• cytosine-5)-methyltransferase 3A (DNMT3 A) gene, FMS-like tyrosine kinase-3 (FLT3) gene, isocitrate dehydrogenase 1 (IDH1) gene, isocitrate dehydrogenase 2 (IDH2) gene, or a combination thereof, the method comprising administering to a subject in need thereof a compound of Formula (I-A).
• DNMT3 A FMS-like tyrosine kinase-3
• IDH1 isocitrate dehydrogenase 1
• IDH2 isocitrate dehydrogenase 2
• the present disclosure provides a method of treating acute myeloid leukemia in a subject exhibiting a mutation in the nucleophosmin (NPMl) gene, the method comprising administering t ormula (I-B):
• H is selected from C 5- i 2 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R 50 ;
• A, B and C are each independently selected from C 3- i 2 carbocycle and 3- to 12-membered heterocycle;
• L 1 and L 2 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, - C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, - C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)-, -N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)N(R 51 )-, - C(NR 51 )-, -N(R 51 )C(NR 51 )-, -C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(0) 2- , -OS(O)-, - S
• L 3 is selected from alkylene, alkenylene, and alkynylene, each of which is substituted with one or more R 56 and optionally further substituted with one or more R 50 ;
• R A , R B and R c are each independently selected at each occurrence from R 50 , or two R
• n and p are each independently an integer from 0 to 6;
• R 50 is independently selected at each occurrence from:
• Ci-io alkyl C 2- io alkenyl, and C 2- io alkynyl, each of which is
• R 51 is independently selected at each occurrence from:
• R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 ;
• R 56 is independently selected at each occurrence from:
• R optionally forms a bond to ring C
• the present disclosure provides a method of treating a hemtologic malignancy in a subject exhibiting a mutation in the nucleophosmin ( PM1) gene, DNA
• cytosine-5)-methyltransferase 3A D MT3 A gene
• FMS-like tyrosine kinase-3 FLT3 gene
• Isocitrate dehydrogenase 1 IDH1 gene
• Isocitrate dehydrogenase 2 IDH2 gene
• the present disclosure provides a method of treating acute myeloid leukemia in a subject exhibiting a mutation in the nucleophosmin ( PM1) gene, the method comprising administering to a subject in need thereof a compound of Formula (II):
• H is selected from C5-0 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R 50 ;
• A is selected from bond, C 3- i 2 carbocycle and 3- to 12-membered heterocycle;
• B is selected from C 3- i 2 carbocycle and 3- to 12-membered heterocycle
• L 1 , L 2 and L 3 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 - , -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, - C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)-, -N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)N(R 51 )-, - C( R 51 )-, -N(R 51 )C( R 51 )-, -C( R 51 )N(R 51 )-, -N(R 51 )C(0)N(R 51 )-, -S(0) 2- , -OS(O)-, -
• R A , R B and R c are each independently selected at each occurrence from R 50 , or two R groups or two R B groups attached to the same atom or different atoms can together optionally form a bridge or ring;
• n are each independently an integer from 0 to 6;
• W 1 is Ci-4 alkylene, optionally substituted with one or more R 50 ;
• W 2 is selected from a bond; and Ci -4 alkylene, optionally substituted with one or more W 3 is selected from absent; and C 1-4 alkylene, optionally substituted with one or more
• R is independently selected at each occurrence from:
• R 51 is independently selected at each occurrence from:
• R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 ,
• W 1 is Ci alkylene, W 2 is a bond, and L 3 is not a bond;
• W 1 is C 2- 4 alkylene and W 2 is a bond
• W 1 and W 2 are each Ci alkylene and L 3 is not a bond, wherein each Ci alkylene is independently optionally substituted with one or more R 50 .
• the present disclosure provides a method of treating a hemtological malignancy in a subject exhibiting a mutation in the nucleophosmin (NPMl) gene, DNA
• DNMT3 A cytosine-5)-methyltransferase 3A
• FLT3 A FMS-like tyrosine kinase-3
• IDH1 isocitrate dehydrogenase 1
• IDH2 isocitrate dehydrogenase 2
• the present disclosure provides a method of treating a hematological malignancy in a subject exhibiting a mutation in the nucleophosmin (NPMl) gene, DNA (cytosine-5)-methyltransferase 3A (D MT3 A) gene, FMS-like tyrosine kinase-3 (FLT3) gene, isocitrate dehydrogenase 1 (IDH1) gene, isocitrate dehydrogenase 2 (IDH2) gene, or
• H is selected from C 3 . 12 carbocycle and 3- to 12-membered heterocycle, each of which is optionall substituted with one or more R 50 ;
• each of Z 1 , Z 2 , Z 3 , and Z 4 is independently selected from -C(R A1 )(R A2 )-, -C(R A1 )(R A2 )- C(R A1 )(R A2 )-, -C(O)-, and -C(R A1 )(R A2 )-C(0)-, wherein no more than one of Z 1 , Z 2 , Z 3 , and Z 4 is -C(O)- or -C(R A1 )(R A2 )-C(0)-;
• B is selected from bond, C 3 . 12 carbocycle and 3- to 12-membered heterocycle
• C is selected from bond, C 3 . 12 carbocycle and 3- to 12-membered heterocycle
• L 1 , L 2 and L 3 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 - , -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, - C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)-, -N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)N(R 51 )-, - C( R 51 )-, -N(R 51 )C( R 51 )-, -C( R 51 )N(R 51 )-, -N(R 51 )C(0)N(R 51 )-, -S(0) 2- , -OS(O)-, -
• R B is independently selected at each occurrence from R 50 , or two R B groups attached to the same atom or different atoms can together optionally form a bridge or ring;
• R is independently selected at each occurrence from hydrogen and R , or two R groups attached to the same atom or different atoms can together optionally form a bridge or ring;
• R and R are each independently selected at each occurrence from hydrogen and R ; n is an integer from 0 to 6; p is an integer from 1 to 6;
• R 50 is independently selected at each occurrence from:
• R 51 is independently selected at each occurrence from:
• R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 .
• the present disclosure provides a method of treating a hematological malignancy in a subject exhibiting a mutation in the nucleophosmin (NPMl) gene, DNA
• DNMT3 A cytosine-5)-methyltransferase 3A
• FMT3 A FMS-like tyrosine kinase-3
• IDH1 isocitrate dehydrogenase 1
• IDH2 isocitrate dehydrogenase 2
• G a is selected from C 3 . 12 carbocycle and 3- to 12-membered heterocycle, each of which is substituted with -E ⁇ R 43 and optionally further substituted with one or more R 50 ;
• R 2a is selected from hydrogen, alkyl, alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, and aralkyl;
• R 3a and R 3b are each independently selected from hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, and haloalkoxy;
• X a is selected from hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, and haloalkoxy;
• Y a is selected from cyano, hydroxy, and -CH 2 R 50 ;
• R 4a is selected from hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, aralkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl;
• R 14a is selected from hydrogen and alkyl
• R 50 is independently selected at each occurrence from:
• Ci-io alkyl C 2- i 0 alkenyl, and C 2- i 0 alkynyl, each of which is
• R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 .
• the present disclosure provides a method of treating a hematological malignancy in a subject exhibiting a mutation in the nucleophosmin (NPMl) gene, DNA
• DNMT3 A cytosine-5)-methyltransferase 3A
• FMT3 A FMS-like tyrosine kinase-3
• IDH1 isocitrate dehydrogenase 1
• IDH2 isocitrate dehydrogenase 2
• H 2 is selected from C 3 . 12 carbocycle and 3- to 12-membered heterocycle
• H is selected from C 3- i 2 carbocycle and 3- to 12-membered heterocycle, each of which is optionall substituted with one or more R 50 ;
• Z 5 and Z 6 are independently selected from -C(R A3 )- and -N-;
• B is selected from bond, C 3 . 12 carbocycle and 3- to 12-membered heterocycle
• L 1 , L 2 and L 4 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 - , -C(0)-, -C(0)0-, -0C(0)-, -0C(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, - C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)-, -N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)N(R 51 )-, - C( R 51 )-, -N(R 51 )C( R 51 )-, -C( R 51 )N(R 51 )-, -N(R 51 )C( R 51 )N(R 51 )-, -S(0) 2- , -0S(0)-,
• R B is independently selected at each occurrence from hydrogen and R 50 , or two R B groups attached to the same atom or different atoms can together optionally form a bridge or ring;
• R H2 is independently selected at each occurrence from R 50 , or two R H2 groups attached to the same atom or different atoms can together optionally form a bridge or ring;
• R A1 , R A2 and R A3 are each independently selected at each occurrence from hydrogen and
• n is an integer from 0 to 6;
• r is an integer from 1 to 6;
• R 50 is independently selected at each occurrence from:
• R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 .
• the hematological malignancy is selected from a malignant lymphoma, a leukemia, a mature B cell neoplasm, a mature T cell and natural killer (NK) cell neoplasm, a precursor lymphoid neoplasm, Hodgkin lymphoma (HL), a plasma cell tumor, a mast cell tumor, a neoplasm of histiocytes and accessory lymphoid cells, an immunoproliferative disease, a myeloid leukemia, and a myelodysplastic syndrome (MDS).
• a malignant lymphoma a malignant lymphoma
• a leukemia a mature B cell neoplasm
• NK natural killer
• a precursor lymphoid neoplasm a precursor lymphoid neoplasm
• HL Hodgkin lymphoma
• HL Hodgkin lymphoma
• plasma cell tumor a mast cell tumor
• the hematoligical malignancy is selected from acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, non-Hodgkin's lymphoma, multiple myeloma, mixed lineage leukemia and myelodysplastic syndromes.
• the hematological malignancy is aceute myeloid leukemia. In some embodiments, a relapse of the hematological malignancy is prevented.
• the mutation in the nucleophosmin (NPMl) gene is a mutation in exon 12 of the NPMl gene. In some embodiments, the mutation in the nucleophosmin (NPMl) gene is a frameshift mutation. In some embodiments, the mutation in the nucleophosmin (NPMl) gene comprises an insertion of two to nine bases, such as the insertion is of four bases. In some embodiments, the insertion of four bases is selected from TCTG, CATG, CCTG, CGTG, CAGA, CTTG, and TATG. In some embodiments, the insertion is of nine bases. In some embodiments, the insertion of nine bases is selected from CTCTTGCCC and CCCTGGAGA.
• the mutation in the nucleophosmin (NPMl) gene comprises a deletion of nucleotides 965 through 969 (GGAGG).
• the subject further exhibits a mutation in the FLT3 gene.
• the mutation in the FLT3 gene is an internal tandem duplication.
• the subject further exhibits a mutation in the DNA (cytosine-5)-methyltransferase 3A (DNMT3 A) gene.
• the mutation in the FLT3 gene is in the tyrosine kinase domain.
• the mutation is in the nucleophosmin (NPMl) gene and FMS-like tyrosine kinase-3 (FLT3) gene.
• the mutation is in the nucleophosmin (NPMl) gene, DNA (cytosine-5)-methyl transferase 3 A (DNMT3A) gene, isocitrate dehydrogenase 2 (IDH2) gene, and FMS-like tyrosine kinase-3 (FLT3) gene.
• the subject exhibits a mutation in the DNA (cytosine-5)-methyltransferase 3 A (DNMT3 A) gene.
• the present disclosure provides a method of treating Ewing's sarcoma, the method comprising administerin to a subject in need thereof a compound of Formula (I- A):
• H is selected from C 5 . 12 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R 50 ;
• A is selected from bond, C 3 . 12 carbocycle and 3- to 12-membered heterocycle;
• B is selected from C 3 . 12 carbocycle and 3- to 12-membered heterocycle
• C is 3- to 12-membered heterocycle
• L 1 , L 2 and L 3 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -
• R 50 wherein two R 50 groups attached to the same atom or different atoms of any one of L 1 , L 2 or L 3 can together optionally form a bridge or ring;
• R A , R B and R c are each independently selected at each occurrence from R 50 , or two R
• n, n and p are each independently an integer from 0 to 6; R 50 is independently selected at each occurrence from:
• R 51 is independently selected at each occurrence from:
• R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 ;
• R 57 is selected from:
• Ci-io alkyl C 2- io alkenyl, and C 2- io alkynyl, each of which is
• p is an integer from 1 to 6;
• L 3 is substituted with one or more R 50 , wherein L 3 is not -CH 2 CH(OH)-.
• the present disclosure provides a method of treating Ewing's sarcoma, the method comprising administering to a subject in need thereof a compound of Formula (I-B):
• H is selected from C5-0 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R 50 ;
• A, B and C are each independently selected from C 3- i 2 carbocycle and 3- to 12-membered heterocycle;
• L 1 and L 2 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -
• L 3 is selected from alkylene, alkenylene, and alkynylene, each of which is substituted with one or more R 56 and optionally further substituted with one or more R 50 ;
• R A , R B and R c are each independently selected at each occurrence from R 50 , or two R
• n and p are each independently an integer from 0 to 6;
• R 50 is independently selected at each occurrence from:
• Ci-io alkyl C 2- i 0 alkenyl, and C 2- i 0 alkynyl, each of which is
• R 51 is independently selected at each occurrence from:
• R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 ;
• R 56 is independently selected at each occurrence from:
• R optionally forms a bond to ring C
• the present disclosure provides a method of treating Ewing' s sarcoma, the method comprising administering to a subject in need thereof a compound of Formula (II):
• H is selected from C 5- i 2 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R 50 ;
• A is selected from bond, C3-12 carbocycle and 3- to 12-membered heterocycle
• B is selected from C 3- i 2 carbocycle and 3- to 12-membered heterocycle
• L 1 , L 2 and L 3 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 - , -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, - C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)-, -N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)N(R 51 )-, - C( R 51 )-, -N(R 51 )C( R 51 )-, -C( R 51 )N(R 51 )-, -N(R 51 )C(0)N(R 51 )-, -S(0) 2- , -OS(O)-, -
• R A , R B and R c are each independently selected at each occurrence from R 50 , or two R groups or two R B groups attached to the same atom or different atoms can together optionally form a bridge or ring;
• n are each independently an integer from 0 to 6;
• W 1 is Ci-4 alkylene, optionally substituted with one or more R 50 ;
• W 2 is selected from a bond; and Ci -4 alkylene, optionally substituted with one or more
• W 3 is selected from absent; and Ci -4 alkylene, optionally substituted with one or more
• R 50 is independently selected at each occurrence from:
• R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 ,
• W 1 is Ci alkylene, W 2 is a bond, and L 3 is not a bond;
• W 1 is C 2- 4 alkylene and W 2 is a bond
• W 1 and W 2 are each Ci alkylene and L 3 is not a bond, wherein each Ci alkylene is independently optionally substituted with one or more R .
• the present disclosure provides a method of treating Ewing's sarcoma, method comprising administering to a subject in need thereof a compound of Formula (III):
• H is selected from C 3- i 2 carbocycle and 3- to 12-membered heterocycle, each of which is optionall substituted with one or more R 50 ;
• each of Z 1 , Z 2 , Z 3 , and Z 4 is independently selected from -C(R A1 )(R A2 )-, -C(R A1 )(R A2 )- C(R A1 )(R A2 )-, -C(O)-, and -C(R A1 )(R A2 )-C(0)-, wherein no more than one of Z 1 , Z 2 , Z 3 , and Z 4 is -C(O)- or -C(R A1 )(R A2 )-C(0)-;
• B is selected from bond, C 3- i 2 carbocycle and 3- to 12-membered heterocycle
• C is selected from bond, C 3- i 2 carbocycle and 3- to 12-membered heterocycle
• L 1 , L 2 and L 3 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 - , -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, - C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)-, -N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)N(R 51 )-, - C( R 51 )-, -N(R 51 )C( R 51 )-, -C( R 51 )N(R 51 )-, -N(R 51 )C(0)N(R 51 )-, -S(0) 2- , -OS(0)-,
• R B is independently selected at each occurrence from R 50 , or two R B groups attached to the same atom or different atoms can together optionally form a bridge or ring;
• R is independently selected at each occurrence from hydrogen and R , or two R groups attached to the same atom or different atoms can together optionally form a bridge or ring;
• R A1 and R ⁇ are each independently selected at each occurrence from hydrogen and R ; n is an integer from 0 to 6;
• p is an integer from 1 to 6;
• R 50 is independently selected at each occurrence from:
• Ci-io alkyl C 2- io alkenyl, and C 2- io alkynyl, each of which is
• R 51 is independently selected at each occurrence from:
• R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 .
• the present disclosure provides a method of treating Ewing' s sarcoma, the method comprising administering to a sub ect in need thereof a compound of Formula (IV):
• harmaceutically acceptable salt or prodrug thereof wherein: fused thienyl or fused phenyl group;
• G a is selected from C 3 . 12 carbocycle and 3- to 12-membered heterocycle, each of which is substituted with -E ⁇ R 43 and optionally further substituted with one or more R 50 ;
• R 2a is selected from hydrogen, alkyl, alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, and aralkyl;
• R 3a and R 3b are each independently selected from hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, and haloalkoxy;
• X a is selected from hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, and haloalkoxy;
• Y a is selected from cyano, hydroxy, and -CH 2 R 50 ;
• R a is selected from hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, aralkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl;
• R 14a is selected from hydrogen and alkyl
• R 50 is independently selected at each occurrence from:
• Ci-io alkyl C 2- i 0 alkenyl, and C 2- i 0 alkynyl, each of which is
• R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 .
• the present disclosure provides a method of treating Ewing's sarcoma, the method comprising administering to a subject in need thereof a compound of Formula (VI):
• H 2 is selected from C 3 . 12 carbocycle and 3- to 12-membered heterocycle
• H is selected from C 3 . 12 carbocycle and 3- to 12-membered heterocycle, each of which is optionall substituted with one or more R 50 ;
• Z 5 and Z 6 are independently selected from -C(R A3 )- and -N-;
• B is selected from bond, C 3 . 12 carbocycle and 3- to 12-membered heterocycle
• L 1 , L 2 and L 4 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 - , -C(0)-, -C(0)0-, -0C(0)-, -0C(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, - C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)-, -N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)N(R 51 )-, - C( R 51 )-, -N(R 51 )C( R 51 )-, -C( R 51 )N(R 51 )-, -N(R 51 )C( R 51 )N(R 51 )-, -S(0) 2- , -0S(0)-,
• R B is independently selected at each occurrence from hydrogen and R 50 , or two R B groups attached to the same atom or different atoms can together optionally form a bridge or ring;
• R H2 is independently selected at each occurrence from R 50 , or two R H2 groups attached to the same atom or different atoms can together optionally form a bridge or ring;
• R A1 , R A2 and R A3 are each independently selected at each occurrence from hydrogen and
• n is an integer from 0 to 6;
• r is an integer from 1 to 6;
• Ci-io alkyl C 2- i 0 alkenyl, and C 2- i 0 alkynyl, each of which is
• R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 .
• the subject exhibits an EWSR1-FLI1 gene fusion, EWSR1-ERG gene fusion, or EWSR1-FEV gene fusion.
• the subject exhibits a FUS- NCATc2 gene fusion, CIC-FOX04 gene fusion, or ETV6-NTRK3 gene fusion.
• the subject exhibits a mutation in a STAG2 gene, mutation in a TP53 gene, or CDKN2A deletion.
• C is 5- to 12- membered heterocycle, wherein the heterocycle comprises at least one nitrogen atom.
• the heterocycle is saturated.
• C is selected from: In some embodiments, R is selected from -
• C is
• R is selected from Ci -3 alkyl and Ci -3 haloalkyl.
• H is 5- to 12-membered heterocycle, optionally substituted with one or more R 50 ;
• A is 3- to 12-membered heterocycle; and B is 3- to 12-membered heterocycle.
• H is 6- to 12-membered bicyclic heterocycle, optionally substituted with one or more R 50 .
• H is thienopyrimidinyl, optionally substituted with one or more
• H is ;
• X 1 and X 2 are each independently selected from CR 2 and
• X 3 and X 4 are each independently selected from C and N; Y 1 and Y 2 are each independently selected from CR 3 , N, R 4 , O, and S; R 1 , R 2 and R 3 are each independently selected at each occurrence from hydrogen and R 50 ; and R 4 is selected from R 51 .
• X 3 and X 4 are each C.
• X 1 is CR 2
• R 2 is selected from hydrogen, halogen, - OH, -OR 52 , - H 2 , -N(R 52 ) 2 , -CN, Ci -3 alkyl, -CH 2 OH, -CH 2 OR 52 , -CH 2 H 2 , -CH 2 N(R 52 ) 2 , Ci -3 alkyl-N(R 52 ) 2 , Ci -3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl.
• X 1 is CR 2
• R 2 is selected from hydrogen, halogen, -OH, -OR 52 , - H 2 , -N(R 52 ) 2 , -CN, Ci -3 alkyl, Ci -3 alkyl-N(R 52 ) 2 , Ci -3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl.
• X 2 is N.
• Y 2 is CR 3 , and R 3 is selected from hydrogen, halogen, -OH, -N(R 52 ) 2 , -CN, - C(0)OR 52 , Ci-3 alkyl, and Ci -3 haloalkyl.
• R 1 is C 1-3 haloalkyl.
• A is 5- to 8-membered heterocycle.
• A is 6-membered monocyclic heterocycle.
• the heterocycle comprises at least one nitrogen atom.
• A is selected from piperidinylene and piperazinylene.
• A is 7- to 12-membered spirocyclic heterocycle or C 7 . 12 spirocyclic carbocycle. In some embodiments, A is 7- to 12-membered spirocyclic heterocycle, such as 7- to 10-membered spirocyclic heterocycle. In some embodiments, A is ?
• each of Z 1 , Z2 , Z3 , and Z 4 is independently selected from - C(R A1 )(RA2)-, .c ⁇ XR ⁇ CiR ⁇ XR 2 )-, -C(O)-, and -C(R A1 )(R A2 )-C(0)-, wherein no more than one of Z 1 , Z 2 , Z 3 , and Z 4 is -C(O)- or -C(R A1 )(R A2 )-C(0)-; and R A1 and R ⁇ are each independently selected at each occurrence from hydrogen and R 50 .
• R A1 and R ⁇ are each independently selected at each occurrence from hydrogen, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, -CN, -N0 2 , and -OH.
• A is
• B is 6- to 12-membered bicyclic heterocycle.
• the heterocycle comprise one nitrogen atom.
• B is
• B is ? optionally substituted with one or more
• H is thienopyrimidinyl substituted with one or more R 50 ;
• A is selected from piperidinylene and piperazinylene; and B is indolylene.
• H is substituted with -CH 2 CF 3 .
• n is an integer from 1 to 3.
• L 1 comprises less than 10 atoms. In some embodiments, L 1 is - N(R 51 )-.
• L 2 comprises less than 10 atoms.
• L 2 is Ci. 4 alkylene, optionally substituted with one or more R 50 .
• L 2 is selected from -CH 2 -, -N(R 51 )-, -N(R 51 )CH 2 -, -N(R 51 )C(0)-, and -N(R 51 )S(0) 2 -.
• L 3 comprises less than 20 atoms.
• L 3 is Ci -6 alkylene, optionally substituted with one or more R 50 .
• L 3 is Ci -4 alkylene, optionally substituted with one or more R 50 .
• L 3 is -CH 2 -.
• L 3 is C 2 alkylene substituted with at least one Ci -3 alkyl or Ci -3 haloalkyl, and optionally further substituted with one or more R 50 .
• R 50 is methyl.
• L 3 is selected from and .
• R 56 is methyl.
• H is thienopyrimidinyl, optionally substituted with one or more R 50 ;
• A is 3- to 12-membered heterocycle;
• B is 6- to 12-membered bicyclic heterocycle;
• m is an integer from 0 to 3; and
• n is an integer from 1 to 3.
• H is thienopyrimidinyl, optionally substituted with one or more R 50 ;
• A is selected from piperidinylene and piperazinylene
• L 1 and L 2 are each independently selected from -0-, -S-, -NH-, and -CH 2 -;
• L 3 is selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(0)0-, -OC(O)-, - OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, -C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)-, - N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)N(R 51 )-, -C( R 51 )-, -N(R 51 )C( R 51 )-, - C( R 51 )N(R 51 )-, -N(R 51 )C( R 51 )N(R 51 )-, -S(0) 2- , -OS(O)-, -S(0)0-,
• R A , R B and R c are each independently selected at each occurrence from R 50 , or two R
• n is an integer from 0 to 3;
• n is an integer from 1 to 3;
• p is an integer from 0 to 6;
• R 57 is selected from:
• Ci-io alkyl C 2 . 10 alkenyl, and C 2 . 10 alkynyl, each of which is
• H is thienopyrimidinyl, optionally substituted with one or more R 50 ;
• A is selected from piperidinylene and piperazinylene
• L 1 and L 2 are each independently selected from -0-, -S-, -NH-, and -CH 2 -;
• L 3 is selected from Ci -6 alkylene, C 2- 6 alkenylene, and C 2-6 alkynylene, each of which is substituted with one or more R 56 and optionally further substituted with one or more R 50 ;
• R A , R B and R c are each independently selected at each occurrence from R 50 , or two R
• n is an integer from 0 to 3;
• n is an integer from 1 to 3;
• p is an integer from 0 to 6;
• R 56 is independently selected at each occurrence from:
• R 56 optionally forms a bond to ring C
• R 57 is selected from -
• R 2 is selected from hydrogen, halogen, -OH, -OR 52 , - H 2 , -N(R 52 ) 2 , -CN, Ci-3 alkyl, Ci -3 alkyl-OR 52 , Ci -3 alkyl-N(R 52 ) 2 , Ci -3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl.
• R 2 is selected from -NH 2 , -CH 3 , and - HCH 3 .
• the compound for a compound of Formula (I- A), Formula (I-B), Formula (II), Formula (III), Formula (IV), or Formula (VI), is provided as a substantially pure stereoisomer. In some embodiments, the stereoisomer is provided in at least 90% enantiomeric excess. In some embodiments, for a compound of Formula (I- A), Formula (I-B), Formula (II), Formula (III), Formula (IV), or Formula (VI), the compound is isotopically enriched. In some embodiments, for a compound of Formula (I- A) or Formula (I-B), the compound is selected from Table 1. In some embodiments, for a compound of Formula (II), the compound is selected from Table 2.
• the compound for a compound of Formula (III), the compound is selected from Table 3, Table 5 or Table 7. In some embodiments, for a compound of Formula (IV), the compound is selected from Table 4. In some embodiments, for a compound of Formula (VI), the compound is selected from Table 6.
• W 1 , W 2 and W 3 are each independently selected from C 1-4 alkylene, wherein each C 1-4 alkylene is optionally substituted with one or more R 50 .
• W 1 , W 2 and W 3 are each Ci alkylene.
• W 1 and W 2 are each Ci alkylene and W 3 is absent.
• a method described herein further comprises reducing an expression of a target gene.
• the target gene is selected from Hoxa5, Hoxa7, Hoxa9, HoxalO, Hoxb2, Hoxb3, Hoxb4, Hoxb5, Hoxb8, HoxdlO, HoxdlL Hoxdl3, DLX2, PBX3, Meisl, Mir 196b, Flt3, and Bahccl.
• the target gene is Hoxa9, DLX2, PBX3, or Meisl.
• a method described herein further comprises administering a second therapeutic agent.
• the second therapeutic agent is a DOT1L inhibitor.
• the second therapeutic agent is a FLT3 inhibitor.
• the FLT3 inhibitor is quizartinib.
• the FLT3 inhibitor is midostaurin.
• the subject is human.
• a method described herein further comprises obtaining a nucleic acid sample from the subject.
• the nucleic acid sample comprises a nucleic acid selected from genomic DNA, cDNA, circulating tumor DNA, cell-free DNA, RNA, and mRNA.
• a method described herein further comprises obtaining a biological sample from the subject.
• the biological sample is a tissue sample.
• the tissue sample is fixed, paraffin-embedded, fresh, or frozen.
• the tissue sample is derived from fine needle, core, or other types of biopsy.
• the biological sample is whole blood or plasma.
• a method described herein further comprises conducting a nucleic acid analysis on the nucleic acid sample.
• the nucleic acid analysis comprises PCR, sequencing, hybridization, microarray, S P, cell-free nucleic acid analysis, or whole genome sequencing.
• the subject has been tested for the presence of a nucleoporin 98 (NUP98) gene fusion, mutation in the nucleophosmin (NPM1) gene, mutation in the DNA (cytosine-5)- methyltransferase 3 A (DNMT3 A) gene, or mixed lineage leukemia (MLL) gene amplification.
• a method described herein further comprises testing the subject for the presence of a nucleoporin 98 (NUP98) gene fusion, mutation in the nucleophosmin (NPM1) gene, mutation in the DNA (cytosine-5)-methyltransferase 3 A (DNMT3 A) gene, or mixed lineage leukemia (MLL) gene amplification.
• the subject has been tested for the presence of a nucleoporin 98 (NUP98) gene fusion, mutation in the nucleophosmin (NPM1) gene, mutation in the DNA (cytosine-5)-methyltransferase 3A (DNMT3 A) gene, mutation in the FMS-like tyrosine kinase-3 (FLT3) gene, mutation in the isocitrate dehydrogenase 1 (IDHl) gene, mutation in the isocitrate dehydrogenase 2 (IDH2) gene, or mixed lineage leukemia (MLL) gene amplification.
• NUP98 nucleoporin 98
• a method described herein further comprises testing the subject for the presence of a nucleoporin 98 (NUP98) gene fusion, mutation in the nucleophosmin (NPM1) gene, mutation in the DNA (cytosine-5)-methyltransferase 3 A (DNMT3A) gene, mutation in the FMS-like tyrosine kinase-3 (FLT3) gene, mutation in the isocitrate dehydrogenase 1 (IDHl) gene, mutation in the isocitrate dehydrogenase 2 (IDH2) gene, or mixed lineage leukemia (MLL) gene amplification.
• NUP98 nucleoporin 98
• the subject has been tested for the presence of an MLL rearrangement, a partial tandem duplication of MLL, or elevated MEIS1 expression levels.
• a method described herein further comprises testing the subject for the presence of an MLL rearrangement, a partial tandem duplication of MLL, or elevated MEIS1 expression levels.
• FIG. 1 is an amino acid sequence of human menin, isoform 1 (SEQ ID NO: 1).
• FIG. 2 is an amino acid sequence of human menin, isoform 2 (SEQ ID NO: 2).
• FIG. 3 is an amino acid sequence of human menin, isoform 3 (SEQ ID NO: 3).
• FIG. 4 depicts cdl lb cell surface expression in compound treated OCI-AML3 cells.
• FIG. 5 depicts the change in volume of OCI-AML3 tumors in vehicle and compound treated mice.
• FIGS. 6A, 6B and 6C depict percentages of CD45+/CD38+ blasts, CD45+/CD1 lb+ monocytes, and CD45+/CD14+ monocytes in vehicle and compound treated AM7577 models.
• FIGS. 7A, 7B and 7C depict overall survival, bone marrow phenotype at sacrifice, and spleen weight at sacrifice in vehicle and compound treated AM7577 models.
• FIGS. 8A and 8B depict percentages of CD45+/CD38+ blasts and CD45+/CDl lb+ monocytes in vehicle, compound and quizartinib treated AM7577 models.
• FIGS. 9A, 9B, 9C, 9D and 9E depict overall survival, bone marrow phenotype after seven and 21 days, bone marrow AML blasts at sacrifice, and spleen weight at sacrifice in vehicle, compound and quizartinib treated AM7577 models.
• FIG. 10 depicts percentages of CD45+/CD33+ blasts in vehicle, compound and quizartinib treated LXFE 2734 models.
• FIG. 11 depicts overall survival in vehicle, compound and quizartinib treated LXFE 2734 models.
• FIG. 12 depicts dose-response curves for acute myeloid leukemia cells treated with Compound A.
• FIG. 13 depicts dose-response curves for B-cell acute lymphoblastic leukemia cells treated with Compound A.
• the present invention provides compositions and methods useful for treating
• the present invention provides a method of treating a hematological malignancy, such as acute myeloid leukemia, in a subject exhibiting a nucleoporin 98 (NUP98) gene fusion, mutation in the nucleophosmin ( PM1) gene, mutation in the DNA (cytosine-5)-methyltransferase 3A (D MT3 A) gene, mutation in the FMS- like tyrosine kinase-3 (FLT3) gene, mutation in the isocitrate dehydrogenase 1 (IDH1) gene, mutation in the isocitrate dehydrogenase 2 (IDH2) gene, or mixed lineage leukemia (MLL) gene amplification.
• NUP98 nucleoporin 98
• the present invention provides a method of treating a hematological malignancy, such as acute myeloid leukemia or acute lymphoblastic leukemia, in a subject exhibiting an MLL rearrangement, optionally wherein the subject further exhibits elevated MEIS1 expression levels.
• a hematological malignancy such as acute myeloid leukemia or acute lymphoblastic leukemia
• the subject exhibits elevated MEIS1 expression levels.
• the subject exhibits a partial tandem
• a subject method typically involves administering to a subject in need thereof a menin inhibitor.
• the menin inhibitor administered for treating the hematological malignancy is a compound of Formula (I- A) or a compound of Formula (I-B).
• the menin inhibitor administered for treating the hematological malignancy is a compound of Formula (II).
• the menin inhibitor administered for treating the hematological malignancy is a compound of Formula (III).
• the menin inhibitor administered for treating the hematological malignancy is a compound of Formula (IV).
• the menin inhibitor administered for treating the hematological malignancy is a compound of Formula (VI).
• the present invention provides a method of treating Ewing's sarcoma, by administering to a subject in need thereof a menin inhibitor.
• the menin inhibitor administered for treating Ewing's sarcoma is a compound of Formula (I-A) or a compound of Formula (I-B).
• the menin inhibitor administered for treating Ewing's sarcoma is a compound of Formula (II).
• the menin inhibitor administered for treating Ewing's sarcoma is a compound of Formula (III).
• the menin inhibitor administered for treating Ewing's sarcoma is a compound of Formula (IV).
• the menin inhibitor administered for treating Ewing's sarcoma is a compound of Formula (VI).
• the subject being treated has been tested for the presence of a genetic abnormality or mutation.
• the subject has been tested for the presence of a nucleoporin 98 (NUP98) gene fusion, mutation in the nucleophosmin ( PM1) gene, mutation in the DNA (cytosine-5)-methyltransferase 3 A (DNMT3 A) gene, mutation in the FMS-like tyrosine kinase-3 (FLT3) gene, mutation in the isocitrate dehydrogenase 1 (IDH1) gene, mutation in the isocitrate dehydrogenase 2 (IDH2) gene, or mixed lineage leukemia (MLL) gene amplification.
• NUP98 nucleoporin 98
• a nucleic acid sample may be obtained from the subject.
• the nucleic acid sample comprises a nucleic acid selected from genomic DNA, cDNA, circulating tumor DNA, cell-free DNA, RNA, and mRNA.
• a biological sample may be obtained from the subject.
• the biological sample is a tissue sample (e.g., fixed, paraffin- embedded, fresh, or frozen tissue sample). The tissue sample may be derived from fine needle, core, or other types of biopsy.
• the biological sample is whole blood or plasma.
• a nucleic acid analysis may be conducted on the biological sample containing nucleic acid.
• a nucleic acid analysis include PCR, sequencing, hybridization, microarray, SNP, cell-free nucleic acid analysis, and whole genome sequencing.
• the subject may exhibit a nucleoporin 98 (NUP98) gene fusion.
• the nucleoporin 98 (NUP98) gene fusion is a gene fusion of NUP98 and a homeodomain partner gene.
• the nucleoporin 98 (NUP98) gene fusion is a gene fusion of NUP98 and a non-homeodomain partner gene.
• the nucleoporin 98 (NUP98) gene fusion is a gene fusion of NUP98 and a partner gene selected from HOXA9, HOXA11, HOXA13,
• the subject may exhibit a mutation in the nucleophosmin (NPMl) gene.
• the mutation in the nucleophosmin (NPMl) gene is a mutation in exon 12 of the NPMl gene.
• the mutation in the nucleophosmin (NPMl) gene is a frameshift mutation.
• the mutation in the nucleophosmin (NPMl) gene comprises an insertion of two to nine bases, such as the insertion is of four bases (e.g., TCTG, CATG, CCTG, CGTG, CAGA, CTTG, and TATG). In some cases, the insertion is of nine bases (e.g., CTCTTGCCC and
• the mutation in the nucleophosmin (NPMl) gene comprises a deletion of nucleotides 965 through 969 (GGAGG).
• the subject may exhibit a mutation in the FLT3 gene.
• the mutation in the FLT3 gene is an internal tandem duplication (FLT3-ITD).
• the mutation in the FLT3 gene is an in-frame, internal tandem duplication mutation of a nucleotide sequence within exon 14.
• the size of the FLT3-ITD mutation may range from 3 to over 400 bp.
• the FLT3-ITD mutation is near residues 590-600 of the FLT3 amino acid sequence.
• the FLT3- ITD mutation may be located in exon 14, exon 15 and/or in the intron between exons 14 and 15.
• the subject may comprise both partial tandem duplication of the MLL gene and a FLT3-ITD mutation.
• the subject may exhibit a FLT3 activating mutation.
• the mutation in the FLT3 gene is a point mutation involving the tyrosine kinase domain.
• the mutation of the FLT3 gene is a point mutation at aspartate 835 or isoleucine 836.
• the subject may exhibit a mutation in the DNA (cytosine-5)-methyl transferase 3 A (DNMT3A) gene.
• the mutation in the DNMT3A gene is a mutation of R882.
• the mutation in the DNMT3A gene is not a mutation of R882.
• the mutation in the DNMT3A gene is a frameshift deletion, missense mutation, nonsense mutation, splice-site substitution, splice-site deletion, or whole-gene deletion.
• the subject may exhibit a mutation in the isocitrate dehydrogenase 1 (IDHl) gene or isocitrate dehydrogenase 2 (IDH2) gene.
• IDHl isocitrate dehydrogenase 1
• IDH2 isocitrate dehydrogenase 2
• dehydrogenase 1 (IDHl) gene is a heterozygous somatic point mutation in codon 132.
• the mutation in the isocitrate dehydrogenase 2 (IDH2) gene is a heterozygous somatic point mutation in codons 172 or 140.
• the mutation in the isocitrate dehydrogenase 2 (IDH2) gene is R140Q.
• the subject may exhibit one or more of an NPMl mutation, FLT3 mutation, IDHl mutation, IDH2 mutation, and DNMT3A mutation.
• the subject exhibits an NPMl mutation, a FLT3 mutation, an IDH2 mutation and a DNMT3 A mutation.
• the subject exhibits an NPMl mutation, an IDHl mutation, a FLT3 mutation and a DNMT3A mutation.
• the subject exhibits an NPMl mutation, a FLT3 mutation and a DNMT3A mutation.
• the subject exhibits an NPMl mutation, a FLT3 mutation and an IDHl mutation.
• the subject exhibits an NPMl mutation, a FLT3 mutation and an IDH2 mutation. In some cases, the subject exhibits an NPMl mutation, a DNMT3A mutation and an IDHl mutation. In some cases, the subject exhibits an NPMl mutation, a DNMT3A mutation and an IDH2 mutation. In some cases, the subject exhibits an NPMl mutation and a FLT3 mutation.
• the subject may exhibit a mixed lineage leukemia (MLL) gene amplification.
• the subject may exhibit a mixed lineage leukemia (MLL) gene rearrangement.
• the subject may exhibit an 1 lq23 rearragement.
• the subject may exhibit MLL partial tandem duplications.
• the subject may exhibit an EWSR1-FLI1 gene fusion, EWSR1-ERG gene fusion, or EWSR1-FEV gene fusion.
• the subject may exhibit a FUS-NCATc2 gene fusion, CIC-FOX04 gene fusion, or ETV6-NTRK3 gene fusion.
• the subject may exhibit a mutation in a STAG2 gene, mutation in a TP53 gene, or CDKN2A deletion.
• the subject may exhibit elevated myeloid ecotropic viral integration site 1 homolog (MEIS1) expression levels (MEIS l ⁇ 11 ).
• MEIS1 myeloid ecotropic viral integration site 1 homolog
• expression refers to the process by which a polynucleotide is transcribed into mRNA and/or the process by which the transcribed mRNA (also referred to as a "transcript") is subsequently translated into peptides, polypeptides, or proteins.
• the transcripts and the encoded polypeptides are collectedly referred to as "gene product.” If the polynucleotide is derived from genomic DNA, expression may include splicing of the mRNA in a eukaryotic cell.
• the level of expression (or alternatively, the "expression level") of a MEIS 1 gene can be determined, for example, by determining the level of MEIS1 polynucleotides, polypeptides, and/or gene products.
• “Differentially expressed” or “differential expression” as applied to a nucleotide sequence (e.g., a gene) or polypeptide sequence in a subject refers to the differential production of the mRNA transcribed and/or translated from the nucleotide sequence or the protein product encoded by the nucleotide sequence.
• a differentially expressed sequence may be overexpressed or underexpressed as compared to the expression level of a reference sample (i.e., a reference level).
• elevated expression levels refer to an increase in expression, generally at least 1.25 fold, or alternatively, at least 1.5 fold, or alternatively, at least 2 fold, or alternatively, at least 3 fold, or alternatively, at least 4 fold, or alternatively, at least 10 fold expression over that detected in a reference sample.
• underexpression is a reduction in expression and generally is at least 1.25 fold, or alternatively, at least 1.5 fold, or alternatively, at least 2 fold, or alternatively, at least 3 fold, or alternatively, at least 4 fold, or alternatively, at least 10 fold expression under that detected in a reference sample. Underexpression also encompasses absence of expression of a particular sequence as evidenced by the absence of detectable expression in a test subject when compared to a reference sample.
• the present disclosure provides compounds for modulating the interaction of menin with proteins such as MLL1 and MLL2 and MLL-fusion oncoproteins.
• the disclosure provides compounds and methods for inhibiting the interaction of menin with its upstream or downstream signaling molecules including but not limited to MLLl, MLL2 and MLL-fusion oncoproteins.
• Compounds of the disclosure may be used in methods for the treatment of a wide variety of cancers and other diseases associated with one or more of MLLl, MLL2, MLL fusion proteins, and menin, such as hematological malignancies and Ewing' s sarcoma.
• the hematological maligancy comprises a nucleoporin 98 (NUP98) gene fusion, mutation in the nucleophosmin (NPM1) gene, mutation in the DNA (cytosine-5)- methyltransferase 3 A (DNMT3 A) gene, mutation in the FMS-like tyrosine kinase-3 (FLT3) gene, mutation in the isocitrate dehydrogenase 1 (IDHl) gene, mutation in the isocitrate dehydrogenase 2 (IDH2) gene, and/or mixed lineage leukemia (MLL) gene amplification.
• NUP98 nucleoporin 98
• a compound of the disclosure interacts non-covalently with menin and inhibits the interaction of menin with MLL. In certain embodiments, a compound of the disclosure covalently binds menin and inhibits the interaction of menin with MLL.
• the present disclosure provides a compound or salt thereof that selectively binds to the menin protein and/or modulates the interaction of menin with an MLL protein (e.g., MLL1, MLL2, or an MLL fusion protein).
• the compound modulates the menin protein by binding to or interacting with one or more amino acids and/or one or more metal ions.
• Certain compounds may occupy the F9 and/or PI 3 pocket of menin.
• the binding of a compound disclosed herein may disrupt menin or MLL (e.g., MLL1, MLL2, or an MLL fusion protein) downstream signaling.
• Nucleoporin 98 (NUP98) gene fusion refers to a gene which encodes a protein with an N-terminal fragment of NUP98 fused with a partner protein.
• Nucleoporin 98 (NUP98) fusion protein refers to a protein with an N-terminal fragment of NUP98 fused with a partner protein.
• Non-limiting examples of a partner protein include HOXA9, HOXA11, HOXA13, HOXC11, HOXC13, HOXDl l, HOXD13, PMXl, PMX2, HHEX, PHF23, JARIDl A, NSDl, NSD3, MLL, SETBP1, LEDGF, CCDC28, HMGB3, IQCG, RAPIGDSI, ADD3, DDX10, TOPI, TOP2B, LNPl, RARG, ANKRD28, and POU1F1.
• NUP98 fusion proteins may be created through the joining of a gene that codes for NUP98 and a gene that codes for a partner protein creating a fusion gene. Translation of this fusion gene may result in a single or multiple polypeptides with functional properties derived from each of the original proteins.
• MLL fusion protein refers to a protein with an N-terminal fragment of MLL fused with a partner protein.
• a partner protein include 1 lq23, 1 lq23.3, l lq24, lpl3.1, lp32 (EPS 15), 21q22, 9pl3.3, 9p22 (MLLT3/AF9), ABIl, ABI2, ACACA, ACTN4, AFF1/AF4, AFF3/LAF4, AFF4/AF5, AKAP13, AP2A2, ARHGEF12, ARHGEF17, BCL9L, BTBD18, BUD13, C2CD3, CASC5, CASP8AP2, CBL, CEP164, CEP170B, CREBBP, DCP1A, DCPS, EEFSEC/SELB, ELL, EPS 15, FLNA, FNBP1, FOX03, GAS7, GMPS,
• MLL fusion proteins may be created through the joining of a gene that codes for an MLL protein and a gene that codes for a partner protein creating a fusion gene. Translation of this fusion gene may result in a single or multiple polypeptides with functional properties derived from each of the original proteins.
• C x-y or "C x -C y " when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain.
• C x-y alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain.
• C x-y alkenyl and C x-y alkynyl refer to substituted or unsubstituted straight-chain or branched-chain unsaturated hydrocarbon groups that contain at least one double or triple bond respectively. Unless stated otherwise specifically in the specification, a C x-y alkyl, C x-y alkenyl, or C x-y alkynyl is optionally substituted by one or more substituents such as those substituents described herein.
• Carbocycle refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is a carbon atom.
• Carbocycle may include 3- to 10-membered monocyclic rings, 6- to 12- membered bicyclic rings, and 6- to 12-membered bridged rings.
• Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings.
• the carbocycle is an aryl. In some embodiments, the carbocycle is a cycloalkyl. In some embodiments, the carbocycle is a cycloalkenyl. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane,
• cyclopentane or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic.
• Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Unless stated otherwise specifically in the specification, a carbocycle is optionally substituted by one or more substituents such as those substituents described herein.
• Heterocycle refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms.
• exemplary heteroatoms include N, O, Si, P, B, and S atoms.
• Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings.
• the heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the
• heterocycle In some embodiments, the heterocycle is a heteroaryl. In some embodiments, the heterocycle is a heterocycloalkyl. In an exemplary embodiment, a heterocycle, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene.
• Heteroaryl refers to a 3- to 12-membered aromatic ring that comprises at least one heteroatom wherein each heteroatom may be independently selected from N, O, and S.
• the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems rings wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hiickel theory.
• the heteroatom(s) in the heteroaryl may be optionally oxidized.
• One or more nitrogen atoms, if present, are optionally quatemized.
• heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl.
• heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl,
• Compounds of the present disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
• the compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
• hydrogen has three naturally occurring isotopes, denoted X H (protium), 2 H (deuterium), and 3 H (tritium). Protium is the most abundant isotope of hydrogen in nature.
• Enriching for deuterium may afford certain therapeutic advantages, such as increased in vivo half-life and/or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism.
• Isotopically-enriched compounds may be prepared by conventional techniques well known to those skilled in the art.
• Steps are isomers that differ only in the way the atoms are arranged in space.
• Enantiomers are a pair of stereoisomers that are non superimposable mirror images of each other.
• a 1 : 1 mixture of a pair of enantiomers is a “racemic” mixture.
• the term “( ⁇ )” is used to designate a racemic mixture where appropriate.
• “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other.
• the absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S.
• Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line.
• Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
• Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
• the optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.
• Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, chemical entities described herein are intended to include all Z-, E- and tautomeric forms as well.
• substituted refers to moieties having substituents replacing a hydrogen on one or more carbons or heteroatoms of the structure.
• substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
• substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
• substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
• substituted is
• the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
• the permissible substituents can be one or more and the same or different for appropriate organic compounds.
• the heteroatoms such as nitrogen may have hydrogen
• Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a
• substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH 2 0- is equivalent to -OCH 2 -.
• salt or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art.
• Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
• Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
• Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
• Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
• Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
• Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
• the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
• the term "effective amount” or “therapeutically effective amount” refers to that amount of a compound described herein that is sufficient to affect the intended application, including but not limited to disease treatment, as defined below.
• the therapeutically effective amount may vary depending upon the intended treatment application (in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
• the term also applies to a dose that will induce a particular response in target cells, e.g., reduction of platelet adhesion and/or cell migration.
• the specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
• treatment refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including but not limited to a therapeutic benefit and/or a prophylactic benefit.
• therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
• a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject,
• compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
• a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
• co-administration encompass administration of two or more agents to an animal, including humans, so that both agents and/or their metabolites are present in the subject at the same time.
• Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.
• antagonists are used interchangeably, and they refer to a compound having the ability to inhibit a biological function (e.g., activity, expression, binding, protein-protein interaction) of a target protein (e.g., menin, MLL1, MLL2, and/or an MLL fusion protein). Accordingly, the terms “antagonist” and “inhibitor” are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition. A preferred biological activity inhibited by an antagonist is associated with the development, growth, or spread of a tumor.
• agonist refers to a compound having the ability to initiate or enhance a biological function of a target protein, whether by inhibiting the activity or expression of the target protein. Accordingly, the term “agonist” is defined in the context of the biological role of the target polypeptide. While preferred agonists herein specifically interact with (e.g., bind to) the target, compounds that initiate or enhance a biological activity of the target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition.
• Signal transduction is a process during which stimulatory or inhibitory signals are transmitted into and within a cell to elicit an intracellular response.
• a modulator of a signal transduction pathway refers to a compound which modulates the activity of one or more cellular proteins mapped to the same specific signal transduction pathway.
• a modulator may augment (agonist) or suppress (antagonist) the activity of a signaling molecule.
• an "anti-cancer agent”, “anti -tumor agent” or “chemotherapeutic agent” refers to any agent useful in the treatment of a neoplastic condition.
• One class of anti-cancer agents comprises chemotherapeutic agents.
• “Chemotherapy” means the administration of one or more
• chemotherapeutic drugs and/or other agents to a subject by various methods, including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal, or inhalation or in the form of a suppository.
• Subject refers to an animal, such as a mammal, for example a human.
• the methods described herein can be useful in both human therapeutics and veterinary applications.
• the subject is a mammal, and in some embodiments, the subject is human.
• “Mammal” includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.
• Prodrug is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein (e.g., compound of Formula (I- A), Formula (I-B), Formula (II), Formula (III), Formula (IV), or Formula (VI)).
• a biologically active compound described herein e.g., compound of Formula (I- A), Formula (I-B), Formula (II), Formula (III), Formula (IV), or Formula (VI)
• prodrug refers to a precursor of a biologically active compound that is pharmaceutically acceptable.
• a prodrug is inactive when administered to a subject but is converted in vivo to an active compound, for example, by hydrolysis.
• the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam); Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems,” (1987)
• prodrug is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject.
• Prodrugs of an active compound, as described herein are typically prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
• Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
• prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of a hydroxy functional group, or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.
• in vivo refers to an event that takes place in a subject's body.
• in vitro refers to an event that takes places outside of a subject's body.
• an in vitro assay encompasses any assay run outside of a subject.
• in vitro assays encompass cell-based assays in which cells alive or dead are employed.
• In vitro assays also encompass a cell-free assay in which no intact cells are employed.
• optionally substituted aryl means that the aryl group may or may not be substituted and that the description includes both substituted aryl groups and aryl groups having no substitution.
• “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
• the present disclosure provides compounds for modulating the interaction of menin with proteins such as MLL1, MLL2 and MLL-fusion oncoproteins.
• the disclosure provides compounds and methods for inhibiting the interaction of menin with its upstream or downstream signaling molecules including, but not limited to, MLL1, MLL2 and MLL-fusion oncoproteins.
• Compounds of the disclosure may be used in methods for the treatment of a wide variety of cancers and other diseases associated with one or more of MLL1, MLL2, MLL fusion proteins, and menin, such as hematological maligancies or Ewing's sarcoma.
• a compound of the disclosure covalently binds menin and inhibits the interaction of menin with MLL.
• a compound of the disclosure interacts non-covalently with menin and inhibits the interaction of menin with MLL.
• the present disclosure provides a compound or salt that selectively binds to the menin protein and/or modulates the interaction of menin with an MLL protein (e.g., MLLl, MLL2, or an MLL fusion protein).
• an MLL protein e.g., MLLl, MLL2, or an MLL fusion protein.
• the compound modulates the menin protein by binding to or interacting with one or more amino acids and/or one or more metal ions.
• Certain compounds may occupy the F9 and/or P13 pocket of menin.
• the binding of a compound disclosed herein may disrupt menin or MLL (e.g., MLLl, MLL2, or an MLL fusion protein) downstream signaling.
• the resent disclosure provides a compound of Formula (I- A):
• H is selected from C 5 . 12 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R 50 ;
• A is selected from bond, C 3 . 12 carbocycle and 3- to 12-membered heterocycle;
• B is selected from C 3 . 12 carbocycle and 3- to 12-membered heterocycle
• C is 3- to 12-membered heterocycle
• L 1 , L 2 and L 3 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -
• R 50 wherein two R 50 groups attached to the same atom or different atoms of any one of L 1 , L 2 or L 3 can together optionally form a bridge or ring;
• R A , R B and R c are each independently selected at each occurrence from R 50 , or two R
• R 50 is independently selected at each occurrence from:
• R 51 is independently selected at each occurrence from:
• R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 ;
• R 57 is selected from:
• Ci-io alkyl C 2- i 0 alkenyl, and C 2- i 0 alkynyl, each of which is
• p is an integer from 1 to 6;
• L 3 is ssuubbssttiittuutteedd wwiitthh oonnee oorr mmoorree R 50 , wherein L 3 is not -CH 2 CH(OH)- [0124]
• a compound of Formula (I-A) may be represented by
• R 1 , R 2 and R 3 are each independently selected at each occurrence from hydrogen and R 50 .
• R 1 is selected from R 50 .
• R 1 is Ci -3 haloalkyl, such as - CH 2 CF 3 .
• R 2 is selected from R 50 .
• R 2 is selected from hydrogen, halogen, -OH, -OR 52 , - H 2 , -N(R 52 ) 2 , -CN, Ci -3 alkyl, Ci -3 alkyl-OR 52 , Ci -3 alkyl-N(R 52 ) 2 , Ci -3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl.
• R 2 is selected from halogen, -OH, -OR 52 , -NH 2 , -N(R 52 ) 2 , -CN, Ci -3 alkyl, -CH 2 OH, -CH 2 OR 52 , -CH 2 NH 2 , - CH 2 N(R 52 ) 2 , Ci-3 alkyl-N(R 52 ) 2 , Ci -3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl, such as R 2 is selected from -OH, -OR 52 , -NH 2 , -N(R 52 ) 2 , -CN, and Ci -2 alkyl.
• R 2 is selected from - NH 2 , -CH 3 , -OCH 3 , -CH 2 OH, and -NHCH 3 .
• R 3 is selected from hydrogen, halogen, -OH, -N(R 52 ) 2 , -CN, -C(0)OR 52 , Ci -3 alkyl, and Ci -3 haloalkyl.
• R 51 is selected from selected from hydrogen and alkyl, such as R 51 is hydrogen.
• m is 0.
• L 2 is selected from -0-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(0)N(R 51 )-, -N(R 51 )C(0)-, -N(R 51 )S(0) 2 -, - S(0) 2 N(R 51 )-, Ci-4 alkylene and C 1-4 heteroalkylene.
• L 2 is C 1-4 alkylene, optionally substituted with one or more R 50 .
• L 2 is C 1-2 alkylene, optionally substituted with one or more R 50 .
• L 2 is selected from -CH 2 -, - N(R 51 )-, -N(R 51 )CH 2 -, -N(R 51 )C(0)-, and -N(R 51 )S(0) 2 -.
• L 2 is -CH 2 -.
• R B is present at one or more positions of the indole, such as at position 2, 3, 4, or 6 of the indole.
• R B is selected from halogen, -CN, -OR 52 , -N(R 52 ) 2 , -NR 53 R 54 , Ci -3 alkyl, and optionally substituted Ci -3 alkyl, such as R B is selected from halogen, -CN, -OR 52 , -N(R 52 ) 2 , -NR 53 R 54 , and Ci -2 alkyl.
• n is an integer from 1 to 4, such as an integer from 2 to 3.
• n is 2.
• L 3 is selected from Ci -6 alkylene, C 2-6 alkenylene, and C 2 . 6 alkynylene, each of which is substituted with one or more R 50 .
• L 3 is Ci -6 alkylene, optionally substituted with one or more R 50 .
• L 3 is C 2 alkylene substituted with at least one C 1-3 alkyl or C 1-3 haloalkyl, and optionally further substituted with one or more R 50 .
• L is substituted with -CH 3 .
• L 3 is selected from where R 50 is optionally methyl.
• C is 3- to 12-membered heterocycle, such as 5- to 12- membered heterocycle. In some embodiments, the heterocycle is saturated. In some
• C is selected from 5- to 7-membered monocyclic heterocycle, 8- to 10-membered fused bicyclic heterocycle, and 7- to 12-membered spirocyclic heterocycle.
• the heterocycle comprises at least one nitrogen atom, such as one or two nitrogen atoms.
• C comprises at least one ring nitrogen. In some embodiments, C is
• C is selected from .
• R is selected from -C(0)R , -
• R is selected from C 1-3 alkyl and C 1-3 haloalkyl, such as -CH 3 .
• p is selected from an integer 0 to 4, such as p is selected from an integer 0 to 2. In some embodiments, p is 0.
• a compound of Formula (I- A) may be represented by:
• R 2 is selected from R 50 .
• R 2 is selected from hydrogen, halogen, -OH, -OR 52 , - H 2 , -N(R 52 ) 2 , -CN, C1.3 alkyl, C1.3 alkyl-OR 52 , C1.3 alkyl-N(R 52 ) 2 , C1.3 haloalkyl, C 2- 3 alkenyl, and C 2- 3 alkynyl.
• R 2 is selected from halogen, - OH, -OR 52 , - H 2 , -N(R 52 ) 2 , -CN, C1.3 alkyl, -CH 2 OH, -CH 2 OR 52 , -CH 2 NH 2 , -CH 2 N(R 52 ) 2 , C1.3 alkyl-N(R 52 ) 2 , Ci -3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl, such as R 2 is selected from -OH, - OR 52 , - H 2 , -N(R 52 ) 2 , -CN, and Ci -2 alkyl.
• R 2 is selected from - H 2 , -CH 3 , -OCH 3 , - CH 2 OH, and - HCH 3 .
• Ci-io alkyl C 2 . 10 alkenyl, C 2 . 10 alkynyl, optionally substituted Ci. w alkyl, optionally
• R B is selected from halogen, -CN, -OR 52 , -N(R 52 ) 2 , -NR 53 R 54 , Ci -3 alkyl, and optionally substituted C 1-3 alkyl, such as R B is selected from halogen, -CN, -OR 52 , -N(R 52 ) 2 , - NR 53 R 54 , and Ci -2 alkyl.
• L 3 is selected from Ci -6 alkylene, C 2-6 alkenyl ene, and C 2-6 alkynylene, each of which is substituted with one or more R 50 .
• L 3 is Ci -6 alkylene, optionally substituted with one or more R 50 .
• L 3 is C 2 alkylene substituted with at least one C 1-3 alkyl or C 1-3 haloalkyl, and optionally further substituted with one or more R 50 .
• L 3 is substituted with
• Ci.6 alkyl Ci -6 haloalkyl
• Ci -3 alkyl(cyclopropyl) Ci -3 alkyl(NR 32 C(0)R 32 ) or -0(Ci -6 alkyl).
• L 3 is substituted with -CH 3 . In some embodiments, L 3 is selected from where R is optionally methyl. In some embodiments, C is 3- to 12-membered heterocycle, such as 5- to 12-membered heterocycle. In some embodiments, the heterocycle is saturated. In some embodiments, C is selected from 5- to 7-membered monocyclic heterocycle, 8- to 10-membered fused bicyclic heterocycle, and 7- to 12-membered spirocyclic heterocycle. In some embodiments, the heterocycle comprises at least one nitrogen atom, such as one or two nitrogen atoms. In some embodiments, C comprises at least one ring nitrogen. In some
• C is selected from
• C is selected from
• R is selected from C 1-3 alkyl and C 1-3 haloalkyl, such as -CH 3 .
• p is selected from an integer 0 to 4, such as p is selected from an integer 0 to 2. In some embodiments, p is 0.
• a compound of Formula (I- A) may be represented by:
• C is selected from 5- to 7-membered monocyclic heterocycle, such as piperidinyl and piperazinyl.
• R 50 is selected from deuterium, C 1-4 alkyl, C 1-4 haloalkyl,
• R 2 is selected from hydrogen, halogen, -OH, -OR 52 , - H 2 , -N(R 52 ) 2 , -CN, Ci -3 alkyl, -CH 2 OH, - CH 2 OR 52 , -CH 2 NH 2 , -CH 2 N(R 52 ) 2 , Ci -3 alkyl-N(R 52 ) 2 , Ci -3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl, such as R 2 is selected from -OH, -OR 52 , -NH 2 , -N(R 52 ) 2 , -CN, and Ci -2 alkyl.
• R 2 is methyl or -NHCH 3 .
• R 2 is H.
• a compound of Formula (I- A) may be represented by: (I-A-7), such as (I-A-8).
• C is selected from 5- to 7-membered monocyclic heterocycle, such as piperidinyl and piperazinyl.
• R 50 is selected from deuterium, C 1-4 alkyl, C 1-4 haloalkyl,
• R 2 is selected from hydrogen, halogen, -OH, -OR 52 , - H 2 , -N(R 52 ) 2 , -CN, Ci -3 alkyl, -CH 2 OH, - CH 2 OR 52 , -CH 2 NH 2 , -CH 2 N(R 52 ) 2 , Ci -3 alkyl-N(R 52 ) 2 , Ci -3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl, such as R 2 is selected from -OH, -OR 52 , -NH 2 , -N(R 52 ) 2 , -CN, and Ci -2 alkyl.
• R 2 is methyl or -NHCH 3 .
• R 2 is H.
• the present disclosure provides a compound of Formula (I-B):
• H is selected from C 5 . 12 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R 50 ;
• A, B and C are each independently selected from C 3 . 12 carbocycle and 3- to 12-membered heterocycle;
• L 1 and L 2 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -
• L 3 is selected from alkylene, alkenylene, and alkynylene, each of which is substituted with one or more R 56 and optionally further substituted with one or more R 50 ;
• R A , R B and R c are each independently selected at each occurrence from R 50 , or two R
• n and p are each independently an integer from 0 to 6;
• R 50 is independently selected at each occurrence from:
• Ci-io alkyl C 2- i 0 alkenyl, and C 2- i 0 alkynyl, each of which is
• R 51 is independently selected at each occurrence from: hydrogen, -C(0)R 52 , -C(0)OR 52 , -C(0)N(R 52 ) 2 , -C(0) R 53 R 54 ;
• R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 ;
• R 56 is independently selected at each occurrence from:
• R optionally forms a bond to ring C
• a compound of Formula (I-B) may be represented by:
• R 1 , R 2 and R 3 are each independently selected at each occurrence from hydrogen and R 50 .
• R 1 is selected from R 50 .
• R 1 is C 1-3 haloalkyl, such as - CH 2 CF 3 .
• R 2 is selected from R 50 .
• R 2 is selected from hydrogen, halogen, -OH, -OR 52 , - H 2 , -N(R 52 ) 2 , -CN, C1.3 alkyl, C1.3 alkyl-OR 52 , C1.3 alkyl-N(R 52 ) 2 , Ci -3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl.
• R 2 is selected from halogen, -OH, -OR 52 , - H 2 , -N(R 52 ) 2 , -CN, C1.3 alkyl, -CH 2 OH, -CH 2 OR 52 , -CH 2 NH 2 , - CH 2 N(R 52 ) 2 , C1.3 alkyl-N(R 52 ) 2 , C1.3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl, such as R 2 is selected from -OH, -OR 52 , -NH 2 , -N(R 52 ) 2 , -CN, and Ci -2 alkyl.
• R 2 is selected from - NH 2 , -CH 3 , -OCH 3 , -CH 2 OH, and -NHCH 3 .
• R 3 is selected from hydrogen, halogen, -OH, -N(R 52 ) 2 , -CN, -C(0)OR 52 , C1.3 alkyl, and C1.3 haloalkyl.
• R 51 is selected from selected from hydrogen and alkyl, such as R 51 is hydrogen.
• m is 0.
• L 2 is selected from -0-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(0)N(R 51 )-, -N(R 51 )C(0)-, -N(R 51 )S(0) 2 -, - S(0) 2 N(R 51 )-, Ci-4 alkylene and C 1-4 heteroalkylene.
• L 2 is C 1-4 alkylene, optionally substituted with one or more R 50 .
• L 2 is C 1-2 alkylene, optionally substituted with one or more R 50 .
• L 2 is selected from -CH 2 -, - N(R 51 )-, -N(R 51 )CH 2 -, -N(R 51 )C(0)-, and -N(R 51 )S(0) 2 -.
• L 2 is -CH 2 -.
• R B is present at one or more positions of the indole, such as at position 2, 3, 4, or 6 of the indole.
• R B is selected from halogen, -CN, -OR 52 , -N(R 52 ) 2 , -NR 53 R 54 , C1.3 alkyl, and optionally substituted C1.3 alkyl, such as R B is selected from halogen, -CN, -OR 52 , -N(R 52 ) 2 , -NR 53 R 54 , and Ci -2 alkyl.
• n is an integer from 1 to 4, such as an integer from 2 to 3.
• n is 2.
• L 3 is selected from alkylene, alkenylene, and alkynylene, each of which is substituted with one or more R 56 and optionally further substituted with one or more R 50 .
• L 3 is selected from Ci -6 alkylene, C 2-6 alkenylene, and C 2-6 alkynylene, each of which is substituted with one or more R 56 and optionally further substituted with one or more R 50 .
• L 3 is selected from Ci -6 alkylene, which is substituted with one or more R 56 and optionally further substituted with one or more R 50 .
• L 3 is C 2 alkylene substituted with at least one Ci -3 alkyl or C i -3 haloalkyl, and optionally further substituted with one or more R 50 .
• C is selected from C
• the heterocycle is saturated.
• C is selected from 5- to 7-membered monocyclic heterocycle, 8- to 10-membered fused bicyclic heterocycle, and 7- to 12-membered spirocyclic heterocycle.
• the heterocycle comprises at least one nitrogen atom, such as one or two nitrogen atoms.
• C comprises at least one ring nitrogen.
• C is selected from piperidinyl and piperazinyl, is selected from
• C is selected from hydrogen and R 50 . In some embodiments, C is selected from hydrogen and R 50 .
• R 57 is selected from hydrogen and R 50
• C is selected from wherein
• C is selected from .R 57
• R is selected from C 1-3 alkyl and Ci ⁇ 3 haloalkyl, such as -CH 3 .
• a compound of Formula I-B may be represented by:
• R 2 is selected from R 50 .
• R 2 is selected from hydrogen, halogen, -OH, -OR 52 , - H 2 , -N(R 52 ) 2 , -CN, C 1 alkyl, Ci -3 alkyl-OR 52 , Ci -3 alkyl-N(R 52 ) 2 , Ci -3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl.
• R 2 is selected from halogen, - OH, -OR 52 , - H 2 , -N(R 52 ) 2 , -CN, Ci -3 alkyl, -CH 2 OH, -CH 2 OR 52 , -CH 2 NH 2 , -CH 2 N(R 52 ) 2 , Ci -3 alkyl-N(R 52 ) 2 , Ci -3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl, such as R 2 is selected from -OH, - OR 52 , -NH 2 , -N(R 52 ) 2 , -CN, and Ci -2 alkyl.
• R 2 is selected from -NH 2 , -CH 3 , -OCH 3 , - CH 2 OH, and -NHCH 3 .
• Ci-io alkyl C 2 . 10 alkenyl, C 2 . 10 alkynyl, optionally substituted Ci. w alkyl,
• R B is selected from halogen, -CN, -OR 52 , -N(R 52 ) 2 , -NR 53 R 54 , Ci -3 alkyl, and optionally substituted Ci -3 alkyl, such as R B is selected from halogen, -CN, -OR 52 , -N(R 52 ) 2 , - NR 53 R 54 , and Ci -2 alkyl.
• L 3 is selected from alkylene, alkenyl ene, and alkynylene, each of which is substituted with one or more R 56 and optionally further substituted with one or more R 50 .
• L 3 is selected from Ci -6 alkylene, C 2-6 alkenylene, and C alkynylene, each of which is substituted with one or more R 56 and optionally further substituted with one or more R 50 .
• L 3 is selected from Ci -6 alkylene, which is substituted with one or more R 56 and optionally further substituted with one or more R 50 .
• L 3 is C 2 alkylene substituted with at least one Ci -3 alkyl or Ci -3 haloalkyl, and optionally further substituted with one or more R 50 .
• C is selected from C 3 . 12 carbocycle and 3- to 12-membered heterocycle, such as 5- to 12-membered heterocycle.
• the heterocycle is saturated.
• C is selected from 5- to 7-membered monocyclic heterocycle, 8- to 10-membered fused bicyclic heterocycle, and 7- to 12-membered spirocyclic heterocycle.
• the heterocycle comprises at least one nitrogen atom, such as one or two nitrogen atoms.
• C comprises at least one ring nitrogen.
• C is selected from r A ⁇ rr rr rAr RC WHEREIN piperidinyl and piperazinyl, such as
• C is selected from , and R , wherein R 57 is selected from hydrogen and R 50 .
• C is selected from and , wherein R 57 is selected from
• C is selected from , optionally substituted with one or more R c , wherein R 57 is selected
• R C from hydrogen and R 50
• C is selected from 1 ⁇ 4 C N -/ xR C , 1 ⁇ 2 N N / R C ? and 1 ⁇ 4 ⁇ O N V - / R C
• C is selected from
• R is selected from C 1-3 alkyl and Ci ⁇ 3 haloalkyl, such as -CH 3 .
• C is selected from 5- to 7-membered monocyclic heterocycle, such as pipendinyl and piperazinyl.
• R 56 is selected from deuterium, C alkyl, Ci- 4 haloalkyl,
• p is an integer from 1 to 3, such as p is 1.
• R 2 is selected from hydrogen, halogen, -OH, -OR 52 , - H 2 , -N(R 52 ) 2 , -CN, Ci -3 alkyl, -CH 2 OH, -CH 2 OR 52 , -CH 2 H 2 , -CH 2 N(R 52 ) 2 , Ci- 3 alkyl-N(R 52 ) 2 , Ci -3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl, such as R 2 is selected from -OH, -OR 52 , - H 2 , -N(R 52 ) 2 , -CN, and Ci -2 alkyl.
• R 2 is methyl or -NHCH 3 .
• R 2 is H.
• a compound of Formula (I-B) may be represented by: (I-B-7), such as (I-B-8).
• C is selected from 5- to 7-membered monocyclic heterocycle, such as piperidinyl and piperazinyl.
• R 56 is selected from deuterium, C 1-4 alkyl, C 1-4 haloalkyl,
• p is an integer from 1 to 3, such as p is 1.
• R 2 is selected from hydrogen, halogen, -OH, -OR 52 , - H 2 , -N(R 52 ) 2 , -CN, Ci -3 alkyl, -CH 2 OH, -CH 2 OR 52 , -CH 2 H 2 , -CH 2 N(R 52 ) 2 , Ci-3 alkyl-N(R 52 ) 2 , Ci -3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl, such as R 2 is selected from -OH, -OR 52 , - H 2 , -N(R 52 ) 2 , -CN, and Ci -2 alkyl.
• R 2 is methyl or -NHCH 3 .
• R 2 is H.
• the resent disclosure provides a compound of Formula (II):
• H is selected from C 5 . 12 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R 50 ;
• A is selected from bond, C 3 . 12 carbocycle and 3- to 12-membered heterocycle;
• B is selected from C 3 . 12 carbocycle and 3- to 12-membered heterocycle
• L 1 , L 2 and L 3 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -
• R R A , R B and R c are each independently selected at each occurrence from R 50 , or two R groups or two R B groups attached to the same atom or different atoms can together optionally form a bridge or ring;
• n are each independently an integer from 0 to 6;
• W 1 is Ci-4 alkylene, optionally substituted with one or more R 50 ;
• W 2 is selected from a bond; and C 1-4 alkylene, optionally substituted with one or more
• W 3 is selected from absent; and C 1-4 alkylene, optionally substituted with one or more
• R 50 is independently selected at each occurrence from:
• Ci-io alkyl C 2 . 10 alkenyl, and C 2 . 10 alkynyl, each of which is
• R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 ,
• W 1 is Ci alkylene, W 2 is a bond, and L 3 is not a bond;
• W 1 is C 2- 4 alkylene and W 2 is a bond
• W 1 and W 2 are each Ci alkylene and L 3 is not a bond, wherein each Ci alkylene is independently optionally substituted with one or more R 50 .
• a compound of Formula (II) may be represented by:
• R 1 , R 2 and R 3 are each independently selected at each occurrence from hydrogen and R 50 .
• R 1 is selected from R 50 .
• R 1 is C 1-3 haloalkyl, such as -CH 2 CF 3 .
• R 2 is selected from R 50 .
• R 2 is selected from hydrogen, halogen, -OH, -OR 52 , - H 2 , -N(R 52 ) 2 , -CN, C 1 .3 alkyl, C 1 .3 alkyl-OR 52 , Ci-3 alkyl-N(R 52 ) 2 , C 1-3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl.
• R 2 is selected from halogen, -OH, -OR 52 , -NH 2 , -N(R 52 ) 2 , -CN, C 1 .3 alkyl, -CH 2 OH, -CH 2 OR 52 , - CH 2 NH 2 , -CH 2 N(R 52 ) 2 , C 1 .3 alkyl-N(R 52 ) 2 , C 1 .3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl, such as R 2 is selected from -OH, -OR 52 , -NH 2 , -N(R 52 ) 2 , -CN, and Ci -2 alkyl.
• R 2 is selected from -NH 2 , -CH 3 , -OCH 3 , -CH 2 OH, and -NHCH 3 .
• R 3 is selected from hydrogen, halogen, -OH, -N(R 52 ) 2 , -CN, -C(0)OR 52 , C 1 .3 alkyl, and C 1 .3 haloalkyl.
• R 51 is selected from selected from hydrogen and alkyl, such as R 51 is hydrogen.
• m is an integer from 0 to 3.
• L 2 is selected from -0-, -N(R 51 )-, -N(R 51 )CH 2 -, - C(0)N(R 51 )-, -N(R 51 )C(0)-, -N(R 51 )S(0) 2 -, -S(0) 2 N(R 51 )-, d -4 alkylene and C M heteroalkylene.
• L 2 is C 1-4 alkylene, optionally substituted with one or more R 50 .
• L 2 is C 1-2 alkylene, optionally substituted with one or more R 50 .
• L 2 is selected from -CH 2 -, -N(R 51 )-, -N(R 51 )CH 2 -, -N(R 51 )C(0)-, and - N(R 51 )S(0) 2 -.
• L 2 is -CH 2 -.
• R B is present at one or more positions of the indole, such as at position 2, 3, 4, or 6 of the indole.
• R B is selected from halogen, -CN, -OR 52 , -N(R 52 ) 2 , - NR 53 R 54 , Ci -3 alkyl, and optionally substituted C 1-3 alkyl, such as R B is selected from halogen, - CN, -OR 52 , -N(R 52 ) 2 , -NR 53 R 54 , and Ci -2 alkyl.
• n is an integer from 1 to 4, such as an integer from 2 to 3.
• n is 2.
• L 3 is C 1-4 alkylene, optionally substituted with one or more R 50 .
• L 3 is C 1-2 alkylene, optionally substituted with one or more R 50 . In some embodiments, L 3 is -CH 2 -. In some embodiments, W 1 is C 1-4 alkylene, optionally substituted with one or more R 50 . In some embodiments, W 1 is C 1-2 alkylene, optionally substituted with one or more R 50 . In some embodiments, W 1 is C 1-2 alkylene, such as Ci alkylene or -CH 2 -. In some embodiments, W 2 is Ci-4 alkylene, optionally substituted with one or more R 50 . In some embodiments, W 2 is C 1-2 alkylene, optionally substituted with one or more R 50 .
• W 2 is C 1-2 alkylene, such as Ci alkylene or -CH 2 -. In some embodiments, W 3 is absent. In some embodiments, W 3 is Ci-4 alkylene, optionally substituted with one or more R 50 . In some embodiments, W 3 is C 1-2 alkylene, optionally substituted with one or more R 50 . In some embodiments, W 3 is C 1-2 alkylene,
• R c is selected from
• a compound of Formula II may be represented by:
• R 2 is selected from R 50 .
• R 2 is selected from hydrogen, halogen, -OH, -OR 52 , - H 2 , -N(R 52 ) 2 , -CN, Ci -3 alkyl, Ci -3 alkyl-OR 52 , Ci -3 alkyl-N(R 52 ) 2 , Ci -3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl.
• R 2 is selected from halogen, - OH, -OR 52 , - H 2 , -N(R 52 ) 2 , -CN, Ci -3 alkyl, -CH 2 OH, -CH 2 OR 52 , -CH 2 NH 2 , -CH 2 N(R 52 ) 2 , Ci -3 alkyl-N(R 52 ) 2 , C 1-3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl, such as R 2 is selected from -OH, - OR 52 , -NH 2 , -N(R 52 ) 2 , -CN, and Ci -2 alkyl.
• R 2 is selected from -NH 2 , -CH 3 , -OCH 3 , - CH 2 OH, and -NHCH 3 .
• R B is selected from halogen, -CN, -OR 52 , -N(R 52 ) 2 , - R 53 R 54 , Ci -3 alkyl, and optionally substituted C 1-3 alkyl, such as R B is selected from halogen, -CN, -OR 52 , -N(R 52 ) 2 , - NR 53 R 54 , and Ci. 2 alkyl.
• L 3 is C M alkylene, optionally substituted with one or more R 50 . In some embodiments, L 3 is C 1-2 alkylene, optionally substituted with one or more R 50 .
• L 3 is -CH 2 -.
• W 1 is C 1-4 alkylene, optionally substituted with one or more R 50 .
• W 1 is C 1-2 alkylene, optionally substituted with one or more R 50 .
• W 1 is C 1-2 alkylene, such as Ci alkylene or -CH 2 -.
• W 2 is C 1-4 alkylene, optionally substituted with one or more R 50 .
• W 2 is C 1-2 alkylene, optionally substituted with one or more R 50 .
• W 2 is C 1-2 alkylene, such as Ci alkylene or -CH 2 -.
• W 3 is absent.
• W 3 is C 1-4 alkylene, optionally substituted with one or more R 50 . In some embodiments, W 3 is C 1-2 alkylene, optionally substituted with one or more R 50 . In some embodiments, W 3 is C 1-2 alkylene, such as C 1 alkylene or -CH 2 -.
• R c is selected from o o , o o
• a compound of Formula (II) may be represented by
• R 2 is selected from R 50 .
• R 2 is selected from hydrogen, halogen, -OH, -OR 52 , -NH 2 , -N(R 52 ) 2 , -CN, Ci -3 alkyl, Ci -3 alkyl-OR 52 , Ci -3 alkyl-N(R 52 ) 2 , Ci -3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl.
• R 2 is selected from halogen, -OH, -OR 52 , -NH 2 , -N(R 52 ) 2 , -CN, Ci -3 alkyl, - CH 2 OH, -CH 2 OR 52 , -CH 2 NH 2 , -CH 2 N(R 52 ) 2 , Ci -3 alkyl-N(R 52 ) 2 , Ci -3 haloalkyl, C 2-3 alkenyl, and C 2 -3 alkynyl, such as R 2 is selected from -OH, -OR 52 , - H 2 , -N(R 52 ) 2 , -CN, and Ci -2 alkyl.
• R 2 is selected from - H 2 , -CH 3 , -OCH 3 , -CH 2 OH, and - HCH 3 .
• H is selected from C 3 . 12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more R 50 ;
• each of Z 1 , Z 2 , Z 3 , and Z 4 is independently selected from -C(R A1 )(R A2 )-, -C(R A1 )(R A2 )- C(R A1 )(R A2 )-, -C(O)-, and -C(R A1 )(R A2 )-C(0)-, wherein no more than one of Z 1 , Z 2 , Z 3 , and Z 4 is -C(O)- or -C(R A1 )(R A2 )-C(0)-;
• B is selected from bond, C 3 . 12 carbocycle and 3- to 12-membered heterocycle
• C is selected from bond, C 3 . 12 carbocycle and 3- to 12-membered heterocycle
• L 1 , L 2 and L 3 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -
• R B is independently selected at each occurrence from R 50 , or two R B groups attached to the same atom or different atoms can together optionally form a bridge or ring;
• R is independently selected at each occurrence from hydrogen and R , or two R groups attached to the same atom or different atoms can together optionally form a bridge or ring;
• R A1 and R ⁇ are each independently selected at each occurrence from hydrogen and R ; n is an integer from 0 to 6;
• p is an integer from 1 to 6;
• R 50 is independently selected at each occurrence from:
• Ci-io alkyl C 2- io alkenyl, and C 2- io alkynyl, each of which is
• R 51 is independently selected at each occurrence from:
• R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 .
• a compound of Formula (III) may be represented by: (Ill- A), such as (III-B), wherein R 1 , R 2 and R 3 are each independently selected at each occurrence from hydrogen and R 50 .
• R 1 is selected from R 50 .
• R 1 is C 1-3 haloalkyl, such as - CH 2 CF 3 .
• R 2 is selected from hydrogen and R 50 .
• R 2 is selected from hydrogen, halogen, -OH, -OR 52 , - H 2 , -N(R 52 ) 2 , -CN, C 1 .3 alkyl, C 1 .3 alkyl- OR 52 , C 1 .3 alkyl-N(R 52 ) 2 , C 1 .3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl.
• R 2 is selected from halogen, -OH, -OR 52 , - H 2 , -N(R 52 ) 2 , -CN, C 1 .3 alkyl, -CH 2 OH, -CH 2 OR 52 , - CH 2 NH 2 , -CH 2 N(R 52 ) 2 , C 1 .3 alkyl-N(R 52 ) 2 , C 1 .3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl, such as R 2 is selected from -OH, -OR 52 , -NH 2 , -N(R 52 ) 2 , -CN, and Ci -2 alkyl.
• R 2 is selected from -NH 2 , -CH 3 , -OCH 3 , -CH 2 OH, and -NHCH 3 .
• R 3 is selected from hydrogen, halogen, -OH, -N(R 52 ) 2 , -CN, -C(0)OR 52 , C 1 .3 alkyl, and C 1 .3 haloalkyl.
• R 52 is selected from selected from hydrogen and alkyl, such as R 52 is hydrogen.
• A is selected from
• the present disclosure provides a compound of Formula (IV):
• G a is selected from C 3- i 2 carbocycle and 3- to 12-membered heterocycle, each of which is substituted with -E x -R 4a and optionally further substituted with one or more R 50 ;
• R 2a is selected from hydrogen, alkyl, alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, and aralkyl;
• R 3a and R 3b are each independently selected from hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, and haloalkoxy;
• X a is selected from hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, and haloalkoxy;
• Y a is selected from cyano, hydroxy, and -CH 2 R 50 ;
• R 4a is selected from hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, aralkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl;
• R 14a is selected from hydrogen and alkyl
• R 50 is independently selected at each occurrence from:
• Ci-io alkyl C 2- i 0 alkenyl, and C 2- i 0 alkynyl, each of which is
• R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 .
• G a is piperidinyl.
• a compound of Formula (IV) is represented by:
• R a and R a is independently selected from hydrogen and R ;
• R 24a is selected from hydrogen and fluoro.
• R 3a and R 3b are independently selected from hydrogen and halo.
• X a and Y a do not form a chemical bond, and X a is hydrogen.
• R 4a is selected from hydrogen; and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclo, heteroaryl, aralkyl, (heterocyclo)alkyl, and
• R 4a is R 50 -substituted heterocyclo.
• the present disclosure rovides a compound of Formula (VI):
• H 2 is selected from C 3- i 2 carbocycle and 3- to 12-membered heterocycle
• H is selected from C 3 . 12 carbocycle and 3- to 12-membered heterocycle, each of which is optionall substituted with one or more R 50 ;
• Z 5 and Z 6 are independently selected from -C(R A3 )- and -N-;
• B is selected from bond, C 3 . 12 carbocycle and 3- to 12-membered heterocycle
• L 1 , L 2 and L 4 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 - , -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, - C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)-, -N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)N(R 51 )-, - C( R 51 )-, -N(R 51 )C( R 51 )-, -C( R 51 )N(R 51 )-, -N(R 51 )C(0)N(R 51 )-, -S(0) 2- , -OS(O)-, -
• R B is independently selected at each occurrence from hydrogen and R 50 , or two R B groups attached to the same atom or different atoms can together optionally form a bridge or ring;
• R H2 is independently selected at each occurrence from R 50 , or two R H2 groups attached to the same atom or different atoms can together optionally form a bridge or ring;
• R A1 , R A2 and R A3 are each independently selected at each occurrence from hydrogen and n is an integer from 0 to 6;
• r is an integer from 1 to 6;
• R 50 is independently selected at each occurrence from:
• R 51 is independently selected at each occurrence from:

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