EA038388B1 - Substituted inhibitors of menin-mll and methods of use - Google Patents

Abstract

The invention relates to compounds of formula II-A and the use thereof in methods of inhibiting the interaction of menin with MLL1, MLL2 and MLL-fusion oncoproteins. The methods are useful for the treatment of leukemia, solid cancers, diabetes and other diseases dependent on activity of MLL1, MLL2, MLL fusion proteins, and/or menin. The invention also relates to compositions for the treatment of cancer.

Description

Cross reference

The application for this invention claims the advantage of US Provisional Application No. 62/309372, filed March 16, 2016; US Provisional Application No. 62/334369, filed May 10, 2016; US Provisional Application No. 62/431389, filed December 7, 2016; and US Provisional Application No. 62/446640, filed January 16, 2017, and applications are incorporated herein by reference.

State of the art of the invention

Mixed-lineage leukemia (MIX) protein is a histone methyltransferase critical for epigenetic regulation of gene transcription. Many acute leukemias, including acute myeloblastic leukemia (AML), acute lymphoblastic leukemia (ALL), and mixed-lineage leukemia (MLL), are characterized by the presence of chimeric MLL fusion proteins that are a consequence of chromosomal translocations of the MLL gene located on chromosome 11, band q23 (11q23). Chimeric MLL fusion proteins retain approximately 1400 amino acids from the N-terminus of MLL, but are fused to one of about 80 partner proteins (eg, AF4, AF9, ENL, AF10, ELL, AF6, AF1p, GAS7). MLL fusion proteins do not possess the initial histone methyltransferase activity associated with the C-terminus of MLL and acquire the ability to regulate the transcription of numerous oncogenes, including HOX and MEIS1, which leads to an increase in cell proliferation and a decrease in cell differentiation, which ultimately leads to leucogenesis ... The protein menin, encoded by the Multiple Endocrine Neoplasia (MEN) gene, is a ubiquitous nuclear protein that interacts with DNA processing and repair proteins, chromatin modification proteins, and numerous transcription factors (Agarwal et al., Horm Metab Res , 2005, 37 (6): 369-374). The association of menin with the N-terminus of the MLL fusion proteins is required for the observed oncogenic activity of the MLL fusion proteins. It was shown that this association constitutively activates the expression of the HOX and MEIS1 oncogenes and disrupts the proliferation and differentiation of hematopoietic cells, which leads to the development of leukemia. Because menin acts as a common oncogenic cofactor in MLL-associated leukemias, the interaction between menin and MLL and MLL fusion proteins has been shown to represent a potential chemotherapeutic target.

Patients, especially newborns, with leukemias carrying chromosomal translocations of the MLL gene have a poor prognosis with less than 40% survival within five years (Slany, Haematologica, 2009, 94 (7): 984-993). A new therapeutic strategy is urgently needed to treat such leukemias. Thus, small molecule inhibitors that block the menin-MLL interaction are valuable targets for the treatment of diseases associated with MLL fusion proteins.

The essence of the invention

The present disclosure addresses the need that exists in the art to provide compositions and methods for inhibiting the protein-protein interaction of menin with MLL1, MLL2, and MLL-fusion oncoproteins. The compositions and methods of the present invention may be useful in the treatment of diseases dependent on the activity of MLL1, MLL2, MLL and / or menin fusion proteins, such as leukemia, solid cancers, and diabetes. In some embodiments, a compound of the present invention interacts non-covalently with menin and inhibits the interaction of menin with MLL. In some embodiments, a compound of the present invention covalently binds meenine and inhibits the interaction of meenine with MLL.

In some embodiments of a compound provided in the present invention, said compound non-covalently or covalently binds to any one or more isoforms of menin, for example, isoform 1 (SEQ ID NO: 1), isoform 2 (SEQ ID NO: 2), or isoform 3 (SEQ ID NO: 3) Menina. In certain embodiments of the invention, the meinine protein has 60% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or 99% or more sequence identity with isoform 1 (SEQ ID NO: 1), isoform 2 (SEQ ID NO: 2) or isoform 3 (SEQ ID NO: 3). In one aspect, the present invention relates to a compound of formula (I)

or a pharmaceutically acceptable salt, isotopic form or prodrug thereof, wherein H is selected from a C _5-12 carbocycle and a 5-12 membered heterocycle, each of which is optionally substituted with one or more R ⁵⁰ ;

A is selected from a bond, a C _3-12 carbocycle, and a 3-12 membered heterocycle;

- 1 038388

B is selected from C _3-12 carbocycle and 3-12 membered heterocycle;

C is a 3-12 membered heterocycle;

L ¹ , L ² and L ³ are each independently selected from a bond, -O-, -S-, -N (R ⁵¹ ) -, -N (R ⁵¹ ) CH ₂ -, -C (O) -, - C (O) -,

-OC (O) -, -OC (O) -, -C (O) N (R ⁵¹ ) -, -C (O) N (R ⁵¹ ) C (O) -, -C (O) N (R ⁵¹ ) C (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) -,

-N (R ⁵¹ ) C (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) O-, -OC (O) 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 (O) 2 -, -OS (O) -, -S (O) O-, -S (O) -, -OS (O) 2-, -S (O) 2O-, -N (R ⁵¹ ) S (O) 2-, -S (O) 2N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) -, -S (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) ₂ N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) N (R ⁵¹ ) -; alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene and heteroalkynylene, each of which is optionally substituted with one or more R ⁵⁰ , with two R ⁵⁰ groups attached to the same atom or different atoms of any of L ¹ , L ² or L ³ , together can 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 ^A groups, two R ^B groups or two R ^C groups attached to the same atom or different atoms, together can optionally form a bridge or ring;

m, n and p are each independently an integer from 0 to 6;

R ^{50 is} independently selected at each occurrence from:

halogen, -NO2, -CN, -OR ⁵² , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N ( R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, - NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) ( R ⁵² ) ₂ , = O, = S, = N (R ⁵² );

C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO2, —CN, —OR ⁵² , —SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O ) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² ,

-NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C _3-12 carbocycle and 3-12 membered heterocycle; and a C _3-12 carbocycle and a 3-12 membered heterocycle, each C _3-12 carbocycle and 3-12 membered heterocycle in R ⁵⁰ independently optionally substituted with one or more substituents selected from halogen, —NO2, —CN, - OR ⁵² , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O ) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C1-6alkyl, C.ιaloιenalkyl. C _2-6 alkenyl and C _2-6 alkynyl;

R ^{51 is} independently selected at each occurrence from:

hydrogen, —C (O) R ⁵² , —C (O) OR ⁵² , —C (O) N (R ⁵² ) 2, —C (O) NR ⁵³ R ⁵⁴ ; Cl-6alkyl, C _2-6 alkenyl and C _2-6 alkynyl, each independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO2, —CN, —OR ⁵² , —SR ⁵² , —N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N ( R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), A C3-12 carbocycle and a 3-12 membered heterocycle; and a C3-l2 carbocycle and a 3-12 membered heterocycle, each C3-l2 carbocycle and 3-12 membered heterocycle in R ^{51 is} independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR ⁵² , - SR ⁵² , -N (R ⁵² ) ₂ , -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, and C _2-6 alkynyl;

R ^{52 is} independently selected at each occurrence from hydrogen and C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, 1-6 membered heteroalkyl, C _3-12 carbocycle, and 3-12 membered heterocycle, each of which is optionally substituted with halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, = O, —OH, —OCH3, —OCH2CH3, C _3-12 carbocycle or 3-6 membered heterocycle;

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 selected from:

halogen, -NO2, -CN, -SR ⁵² , -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵⁸ , -S (AF '), -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ ,

-C (O) NH (C1-6alkyl), -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = S, = N ( R ⁵² ); and

C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl, each of which is independently substituted at each occurrence with one or more substituents selected from —NO2, —CN, —SR ⁵² , —N (R ⁵² ) 2 , -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , - NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2,

-NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2 , -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) R ⁵² ) 2, = S and

- 2 038388 = N (R ⁵² ); and

R ^{58 is} selected from hydrogen and C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, 1-6 membered heteroalkyl, C _3-12 carbocycle, and 3-12 membered heterocycle, each of which is optionally substituted with halogen , -CN, -NO ₂ , -NH ₂ , -NHCH ₃ , -NHCH ₂ CH ₃ , = O, -OH, -OCH ₃ , -OCH ₂ CH ₃ , C _3-12 carbocycle or 3-6 membered heterocycle wherein for a compound or salt of formula (I), when C is azetidinylene, piperidinylene or piperazinylene and R ⁵⁷ is —S (= O) 2R ⁵⁸ , —S (= O) 2N (R ⁵² ) 2 or —NR ⁵² S (= O) 2R ⁵² :

p is an integer from 1 to 6; and / or

L ^{3 is} substituted with one or more R ⁵⁰ , where L ^{3 is} not —CH ₂ CH (OH) -.

In one aspect, the present invention relates to a compound of formula (II)

or a pharmaceutically acceptable salt thereof, wherein H is selected from a C _5-12 carbocycle and a 5-12 membered heterocycle, each of which is optionally substituted with one or more R ⁵⁰ ;

A, B and C are each independently selected from a C _3-12 carbocycle and a 3-12 membered heterocycle;

L ¹ and L ² are each independently selected from a bond, -O-, -S-, -N (R ⁵¹ ) -, -N (R ⁵¹ ) CH ₂ -, -C (O) -, -C (O ) O-, -OC (O) -, -OC (O) O-, -C (O) N (R ⁵¹ ) -, -C (O) N (R ⁵¹ ) C (O) -, -C ( O) N (R ⁵¹ ) C (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) -,

-N (R ⁵¹ ) C (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) -, -OC (O) 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 (O) 2- , -OS (O) -, -S (O) O-, -S (O) -, -OS (O) 2-, -S (O) 2O-, -N (R ⁵¹ ) S (O) 2 -, -S (O) 2N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) -, -S (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) 2N ( R ⁵¹ ) -, -N (R ⁵¹ ) S (O) N (R ⁵¹ ) -; alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more R ⁵⁰ ;

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 ^A groups, two R ^B groups, or two R ^C groups attached to the same atom or different atoms, together may optionally form bridge or ring;

m, n and p are each independently an integer from 0 to 6;

R ^{50 is} independently selected at each occurrence from:

halogen, -NO ₂ , -CN, -OR ⁵² , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , - S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, - NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) ₂ , = O, = S, = N (R ⁵² );

C _1-10 αalkyl α, C ₂ _ ₁₀ alkenyl and C _2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO ₂ , —CN, —OR ⁵² , —SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² ,

-NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C ₃ . ₁₂ carbocycle and 3-12 membered heterocycle; and a C _3-12 carbocycle and a 3-12 membered heterocycle, each C _3-12 carbocycle and 3-12 membered heterocycle in R ⁵⁰ independently optionally substituted with one or more substituents selected from halogen, —NO2, —CN, - OR ⁵² , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O ) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C1-6 alkyl, C ₁ . ₆ haloalkyl, C2-6 alkenyl and C2-6 alkynyl;

R ^{51 is} independently selected at each occurrence from:

hydrogen, —C (O) R ⁵² , —C (O) OR ⁵² , —C (O) N (R ⁵² ) 2, —C (O) NR ⁵³ R ⁵⁴ ; C1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO2, —CN, —OR ⁵² , —SR ⁵² , —N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N ( R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C3.12kαrbocycleα and a 3-12 membered heterocycle; and a C3.12 carbocycle and a 3-12 membered heterocycle, each C3.12 carbocycle and 3-12 membered heterocycle in R ^{51 is} independently optionally substituted with one or more substituents selected from halogen, —NO2, —CN, —OR ⁵² , - SR ⁵² , -N (R ⁵² ) ₂ , -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2,

- 3 038388

-NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ ,

-NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O ) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ ,

-P (O) (OR ⁵² ) ₂ , -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C1-6 alkyl, _C1-6 haloalkyl, C _2-6 alkenyl and C _2-6 alkynyl;

R ^{52 is} independently selected at each occurrence from hydrogen; and C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, 1-6 membered heteroalkyl, C _3-12 carbocycle and 3-12 membered heterocycle, each of which is optionally substituted with halogen, -CN, - NO ₂ , -NH ₂ , -NHCH ₃ , -NHCH ₂ CH ₃ , = O, -OH, -OCH ₃ , -OCH ₂ CH ₃ ,

C _3-12 carbocycle or 3-6 membered heterocycle;

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:

-NO2, -OR ⁵⁹ , -SR ⁵² , -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= ObR ⁵² , -S (= ObN (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ) , C1-1oalkyl, C2-1oalkenyl and C2-1oalkynyl,

A C _3-12 carbocycle and a 3-12 membered heterocycle, each C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl in R ⁵⁶ independently optionally substituted at each occurrence with one or more substituents selected from halogen, -NO2, -CN, -OR ⁵⁹ , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² ,

-NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C _3-12 carbocycle and 3-12 membered heterocycle;

wherein each C _3-12 carbocycle and 3-12 membered heterocycle in R ^{56 is} independently optionally substituted with one or more substituents selected from halogen, —NO2, —CN, —OR ⁵² , —SR ⁵² , —N (R ⁵² ) 2 , -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , - NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O ) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, and C _2-6 alkynyl; and additionally, wherein R ⁵⁶ optionally forms a bond with ring C; and

R ^{59 is} independently selected at each occurrence from C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, 1-6 membered heteroalkyl, C _3-12 carbocycle, and 3-12 membered heterocycle, each of which is optionally substituted with halogen, -CN, -NO ₂ , -NH ₂ , -NHCH ₃ , -NHCH ₂ CH ₃ , = O, -OH, -OCH ₃ , -OCH ₂ CH ₃ , C _3-12 carbocycle or 36-membered heterocycle where, for a compound or salt of formula (II), when R ⁵⁶ is —CH ₃ , L ^{3 is} not further substituted with —OH, —NH _2, or —CN.

In some embodiments, for a compound of formula (II), R ^{C is} selected from -C (O) R ⁵² , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , = O, C1-alkyl and C1-3 haloalkyl or two R ^C groups attached to different atoms can together form C1-3 bridge. For a compound of formula (I) or (II), C may be a 5-12 membered heterocycle, the heterocycle containing at least one nitrogen atom. In some embodiments, the heterocycle is saturated. In some embodiments, the heterocycle is selected from piperidinyl and piperazinyl. In some embodiments of the invention for coR ^c R ^c

X xR ⁵⁷ 'R ⁵⁷ J \ / R ⁵⁷ / R ⁵⁷ f N [n IIII unity of formula (I) C is selected from ^rC,, r ^c and% ^N r ^c

In some embodiments, R ^{57 is} selected from —S (= O) R ⁵² , —S (= O) 2R ⁵⁸ , —S (= O) 2N (R ⁵² ) 2, and —NR ⁵² S (= O) 2R ⁵² ...

In some embodiments, for a compound of formula (II), C is selected from

R ^c R ^c

Λ xR ⁵⁷ _X R ⁵⁷ А / R ⁵⁷ / R ⁵⁷

I 7 I ^N IIII. _and wherein R ^{57 is} selected from -S (= O) R ⁵² , -S (= O) ₂ R ⁵² , -S (= O) 2N (R ⁵² ) 2,

-S (= O) ₂ NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² ; and C1-10 alkyl substituted with one or more substituents selected from -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ and -NR ⁵² S (= O) 2R ⁵² . In some embodiments, R ^{57 is} selected from —S (= O) R ⁵² , —S (= O) 2R ⁵² , —S (= O) 2N (R ⁵² ) 2, and —NR ⁵² S (= O) 2R ⁵² ...

In some embodiments, R ^{57 is} selected from —S (= O) CH ₃ , —S (= O) ₂ CH ₃ , —S (= O) ₂ NH ₂ , —NHS (= O) ₂ CH _3, and —S (= O) ₂ NHCH ₃ . For a compound of formula (I) or (II), R ^C may be selected from C _1-3 alkyl and C _1-3 haloalkyl.

In some embodiments, for a compound of formula (I) or (II), H is a 5-12 membered heterocycle optionally substituted with one or more R ⁵⁰ ; A represents a 3-12 membered heterocycle; and B is a 3-12 membered heterocycle. For a compound of formula (I) or (II), H may be a 6-12 membered bicyclic heterocycle optionally substituted with one or more R ⁵⁰ . In some embodiments, H is thienopyrimidinyl optionally substituted with one or more R ⁵⁰ .

- 4 038388

In some embodiments of the invention

H is;

X ¹ and X ² are each independently selected from CR ² and N;

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, NR ⁴ , O and S;

R ¹ , R ² and R ³ are each independently selected at each occurrence from hydrogen and R ⁵⁰ ;

R ^{4 is} selected from R ⁵¹ .

In some embodiments, X ³ and X ⁴ are each C. In some embodiments, X ¹ is CR ² and R ^{2 is} selected from hydrogen, halogen, —OH, —OR ⁵² , —NH2, —N ( R ⁵² ) 2, —CN, C _1-3 alkyl, C _1-3 alkyl-N (R ⁵² ) 2, C1-3 haloalkyl, C2-3 alkenyl and C2-3 alkynyl. In some embodiments, X ¹ is CR ² and R ^{2 is} selected from hydrogen, halogen, —OH, —OR ⁵² , —NH2, —N (R ⁵² ) 2, —CN, C1-3 alkyl, —CH2OH, —CH2OR ⁵² , —CH2NH ₂ , —CH ₂ N (R ⁵² ) 2, C1-3 alkyl-N (R ⁵² ) 2, C _1-3 haloalkyl, C _2-3 alkenyl and C _2-3 alkynyl. In some embodiments, X ² is N. In some embodiments, Y ² is CR ³ and R ^{3 is} selected from hydrogen, halogen, —OH, —N (R ⁵² ) 2, —CN, —C (O) OR ⁵² , C1-3 alkyl and C _1-3 haloalkyl. In some embodiments, R ¹ is C _1-3 haloalkyl.

For a compound of formula (I) or (II), A may be a 5 to 8 membered heterocycle, such as a 6 membered monocyclic heterocycle. In some embodiments, the heterocycle contains at least one nitrogen atom. In some embodiments, A is selected from piperidinylene and piperazinylene such as ^{lR, t}

For a compound of formula (I) or (II), B may be a 6-12 membered bicyclic heterocycle. In some embodiments, the heterocycle contains at least one nitrogen atom. In some embodiments, B is indolylene, such as> optionally substituted with one or more R ^B.

In some embodiments, for a compound of formula (I) or (II), H is thienopyrimidinyl substituted with one or more R ⁵⁰ ; A is selected from piperidinylene and piperazinylene; and B is indolylene. For a compound of formula (I) or (II), H may be substituted with —CH2CF3. In some embodiments, m is 0. In some embodiments, n is an integer from 1 to 3. In some embodiments, L ¹ contains less than 10 atoms. In some embodiments, L ¹ is —N (R ⁵¹ ) -. In some embodiments, L ² contains less than 10 atoms. In some embodiments, L ² is C1-4 alkylene optionally substituted with one or more R ⁵⁰ . In some embodiments, L ^{2 is} selected from —CH2—, —N (R ⁵¹ ) -, —N (R ⁵¹ ) CH2—, —N (R ⁵¹ ) C (O) -, and —N (R ⁵¹ ) S ( O) 2-. In some embodiments, L ³ contains less than 20 atoms. In some embodiments, L ³ is C1-6 alkylene optionally substituted with one or more R ⁵⁰ . In some embodiments, 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 . In some embodiments, L ^{3 is} substituted with = O, C1-6 alkyl, C _1-6 haloalkyl, C _1-3 alkyl (cyclopropyl), C _1-3 alkyl (NR ⁵² C (O) R ⁵² ), or —O (C1 -6alkul). In some embodiments, L ^{3 is} substituted with —CH 3. In some embodiments of the invention, the compound of formula (I) or (II) is selected from table. 1.

For a compound of formula (I), L ³ can be selected from and X.

Optionally, R ⁵⁰ is methyl. In some embodiments of the invention

J ^R) for a compound of formula (II) L ^{3 is} selected from and

Optionally, R ⁵⁶ is methyl. In certain aspects, the present disclosure provides a substantially pure stereoisomer of a compound of formula (I) or (II).

Optionally, the stereoisomer is provided in at least 90% ee.

In some embodiments, for a compound of formula (I) or (II):

H is thienopyrimidinyl optionally substituted with one or more R ⁵⁰ ;

A represents a 3-12 membered heterocycle;

B represents a 6-12 membered bicyclic heterocycle;

- 5,038388 m represents an integer from 0 to 3;

n is an integer from 1 to 3.

In some embodiments, for a compound of formula (I):

H is thienopyrimidinyl optionally substituted with one or more R ⁵⁰ ;

A is selected from piperidinylene and piperazinylene;

B represents indolylene;

L ¹ and L ² are each independently selected from —O—, —S—, —NH— and —CH ₂ -;

L ^{3 is} selected from a bond, -O-, -S-, -N (R ⁵¹ ) -, -N (R ⁵¹ ) CH2-, -C (O) -, -C (O) -, -OC (O) -, -OC (O) -, -C (O) N (R ⁵¹ ) -, -C (O) N (R ⁵¹ ) C (O) -, -C (O) N (R ⁵¹ ) C (O ) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) -, -N (R ⁵¹ ) C (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) O-, -OC (O) 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 (O) 2-, -OS (O) -, -S (O) O-, -S (O) -, -OS (O) 2 -, -S (O) 2O-, -N (R ⁵¹ ) S (O) 2-, -S (O) 2N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) -, -S ( O) N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) 2N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) N (R ⁵¹ ) -; alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each optionally substituted with one or more R ⁵⁰ , where two R ⁵⁰ groups attached to the same or different L ³ atoms may optionally form a ring together;

R ^a , R ^b and R ^C are each independently selected in each occurrence from R ⁵⁰ or two R ^A groups, two R ^B groups or two R ^C groups attached to the same atom or different atoms can together form a ring ;

m 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 selected from:

-S (= O) R ⁵² , -S (= O) 2R ⁵⁸ , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C ( O) NR ⁵³ R ⁵⁴ , -C (O) NH (C1-6alkyl), -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2 ; and

C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl, each of which is independently substituted at each occurrence with one or more substituents selected from —NO ₂ , —CN, —SR ⁵² , —N (R ⁵² ) ₂ , -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2,

-NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2 , -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) R ⁵² ) 2, = S and = N (R ⁵² ); and

R ^{58 is} selected from hydrogen and C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, 1-6 membered heteroalkyl, C _3-12 carbocycle, and 3-12 membered heterocycle, each of which is optionally substituted with halogen , —CN, —NO ₂ , —NH ₂ , —NHCH3, —NHCH2CH3, = O, —OH, —OCH ₃ , —OCH ₂ CH ₃ , C _3-12 carbocycle or 3-6 membered heterocycle.

In some embodiments, for a compound of formula (II):

H is thienopyrimidinyl optionally substituted with one or more R ⁵⁰ ;

A is selected from piperidinylene and piperazinylene; B represents indolylene;

L ¹ and L ² are each independently selected from —O—, —S—, —NH— and —CH2—; L ^{3 is} selected from C1-6 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 ^A groups, two R ^B groups, or two R ^C groups attached to the same atom or different atoms, together can optionally form a bridge or ring;

m 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:

-OR ⁵⁹ , = O, C1-10alkyl, C2-10 alkenyl and C2-10 alkynyl, each C1-10 alkyl, C2-10 alkenyl and C2-10 alkynyl in R ⁵⁶ independently optionally substituted at each occurrence with one or more substituents selected from halogen, -NO2, -CN, -OR ⁵⁹ , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C3-1 ₂ carbocycle and 3-12 membered heterocycle;

wherein each C _3- l ₂ carbocycle and 3-12 membered heterocycle in R ^{56 is} independently optionally substituted with one or more substituents selected from halogen, —NO2, —CN, —OR ⁵² , —SR ⁵² , —N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C ( O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2 , -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), Cl _-6 alkyl , ^^ haloalkyl, C _2-6 alkenyl and C _2-6 alkynyl; and additionally, where R ⁵⁶ optionally forms a bond with ring C; and

- 6 038388

R ^{59 is} independently selected at each occurrence from C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, 1-6 membered heteroalkyl, C _3-12 carbocycle, and 3-12 membered heterocycle, each of which is optionally substituted with halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, = O, -OH, -OCH ₃ , -OCH2CH3, C _3-12 carbocycle or

3-6 membered heterocycle.

For a compound of formula (I), R ⁵⁷ may be selected from —S (= O) 2R ⁵⁸ , —S (= O) 2N (R ⁵² ) 2, and —S (= O) 2NR ⁵³ R ⁵⁴ such as —S ( = O) 2CH ₃ and -S (= O) ₂ NHCH ₃ . For a compound of formula (II), C may be substituted with —S (= O) ₂ R ⁵⁸ , —S (= O) 2N (R ⁵² ) 2, or —S (= O) ₂ NR ⁵³ R ⁵⁴ . In some embodiments, for compound ^R Ws CF _{3 of} formula (I) or (II), H is and R ^{2 is} selected from hydrogen, halogen, —OH, —OR ⁵² ,

-NH ₂ , -N (R ⁵² ) 2, -CN, C1-3 alkyl, C1-3 alkyl-N (R ⁵² ) 2, C _1-3 haloalkyl, C _2-3 alkenyl and C _2-3 alkynyl.

Optionally, R ^{2 is} selected from —NH2, —CH3, and —NHCH3. In some embodiments, for a compound of formula (I) or (II), H is and R ^{2 is} selected from hydrogen, halogen, —OH, —OR ⁵² , —NH2, —N (R ⁵² ) 2, —CN, C _{1 -3} alkyl, C _1-3 alkyl-OR ⁵² , C1-3 alkyl-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.

Optionally, R ^{2 is} selected from —NH ₂ , —CH ₃ , —OCH ₃ , —CH2 OH, and —NHCH3. For a compound of formula (I) or (II) L ³ can be selected from% and X.

In some aspects, the present invention provides a pharmaceutical composition comprising a compound or salt of formula (I) or (II) and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for injection.

In certain aspects, the present disclosure provides a method of inhibiting the interaction of menin with one or more MLL1, MLL2, MLL and MLL partial tandem duplication fusion protein (MLL Partial Tandem Duplication), comprising contacting menin with an effective amount of a compound or salt of formula (I) or (II ). In certain aspects, the present disclosure provides a method of inhibiting the interaction of menin with MLL, comprising contacting the menin with an effective amount of a compound or salt of formula (I) or (II), wherein the inhibition of the interaction is evidenced by decreasing expression of the MLL fusion protein gene of interest. In certain aspects, the present disclosure provides a method for stabilizing menine comprising contacting the menine with a compound or salt of formula (I) or (II).

In any of the contemplated methods of the invention, the MLL fusion protein gene of interest may be HOXA9, DLX2, or MEIS1. Contacting can involve contact with a cell that expresses menin. In some embodiments, the method comprises administering a second therapeutic agent. In some embodiments, the contacting occurs in vivo. In some embodiments, the contacting occurs in vitro.

In certain aspects, the present disclosure provides a method of treating a disease or condition associated with MLL fusion proteins, comprising administering to a subject in need thereof an effective amount of a compound or salt of formula (I) or (II). In certain aspects, the present disclosure provides a method of treating a disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of a compound or salt of formula (I) or (II). In some embodiments, the disease or condition includes leukemia, hematologic cancer, solid tumor cancer, prostate cancer, breast cancer, liver cancer, brain tumor, or diabetes. In some embodiments, the leukemia includes AML, ALL, Mixed Lineage Leukemia, or Partial Tandem Duplications of MLL (MLL) protein leukemia.

In certain aspects, the present disclosure provides a method of treating a disorder mediated by a chromosomal rearrangement on chromosome 11q23 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a salt of a compound of formula (I) or (II). In certain aspects, the present disclosure provides a method of treating a disorder mediated by an interaction between menin and another protein, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound or salt of formula (I) or (II). In some embodiments, the subject is human.

In certain aspects, the present disclosure provides a kit comprising a pharmaceutical composition as described herein and instructions for using the composition to treat a subject suffering from a disease or condition mediated by the interaction between menin and another protein.

- 7 038388

Incorporation by link

All publications, patents and patent applications mentioned in this description are incorporated herein by reference to the same extent as if each individual publication, patent or patent application were specifically and individually indicated for inclusion by reference.

Brief Description of Drawings

The novel features of the invention are set forth in detail in the appended claims. A more complete understanding of the features and advantages of the present invention will be obtained with reference to the following detailed description, which presents illustrative embodiments of the invention that employ the principles of the invention and the accompanying drawings.

FIG. 1 is the amino acid sequence of human menin isoform 1 (SEQ ID NO: 1).

FIG. 2 is the amino acid sequence of human menin isoform 2 (SEQ ID NO: 2).

FIG. 3 is the amino acid sequence of human menin isoform 3 (SEQ ID NO: 3).

FIG. 4 depicts the volume change of MV4; 11 tumors in vehicle and compound treated mice.

FIG. 5 depicts the luminescence of MV4; 11-luc tumors in xenotransplant mouse models of MLL leukemia after 6 days of treatment.

FIG. 6 depicts changes in the expression of genes DLX2, HOXA9, MEIS1 and CD11B in bone marrow samples taken from vehicle and compound treated mice shown in FIG. 5.

FIG. 7 depicts the survival curve of vehicle and compound treated mice with MV4; 11-luc tumors.

FIG. 8 depicts the volume change of MV4; 11 tumors in vehicle and compound treated mice.

FIG. 9 depicts changes in the expression of the HOXA9, MEIS1 and CD11B genes in bone marrow samples taken from mice treated with vehicle and compound.

FIG. 10 depicts the survival curve of mice treated with vehicle and compound with MOLM13 tumors.

FIG. 11 depicts the luminescence of MV4; 11-luc tumors in xenotransplant mouse models of MLL leukemia treated with vehicle and compound after 6 days of treatment.

FIG. 12 depicts changes in the expression of the HOXA9, MEIS1 and CD11B genes in bone marrow samples from vehicle and compound treated mice shown in FIG. eleven.

FIG. 13 depicts the survival curve of mice treated with vehicle and compound with MOLM13 tumors.

Detailed description of the invention

Unless otherwise indicated, all technical and scientific terms used in the present invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

MIX fusion protein refers to a protein with an N-terminal fragment of the MLL protein fused to a partner protein. Non-limiting examples of a partner protein include 11q23, 11q23.3, 11q24, 1p13.1, 1p32 (EPS15), 21q22, 9p13.3, 9p22 (MLLT3 / AF9), ABI1, ABI2, ACACA, ACTN4, AFF1 / AF4, AFF3 / LAF4, AFF4 / AF5, AKAP13, AP2A2, ARHGEF12, ARHGEF17, BCL9L, BTBD18, BUD13, C2CD3, CASC5, CASP8AP2, CBL, CEP164, SERPOV, CREBBP, DCP1A, DCPS, EEFSEC, EPS15 FOXO3, GAS7, GMPS, KIAA1524, LAMC3, LOC100131626, MAML2, ME2, MLLT1 / ENL, MLLT10 / AF10, MLLT11 / AF1Q, MLLT3 / AF9, MLLT4 / AF6, MLLT6 / AF17, MYH11, MYBO1F, NR PDS5A, PICALM, PRPF19, PTD, RUNDC3B, SEPT11, SEPT2, SEPT5, SEPT6, SEPT9, SMAP1, TET1, TNRC18, TOP3A, VAV1 and Xq26.3 (CT45A2). MLL fusion proteins can be created by combining a gene that encodes an MLL protein and a gene that encodes a partner protein, resulting in a fusion gene. Translation of a given fusion gene can result in one or more polypeptides with functional properties derived from each of the parent proteins.

The term C _xy or C _x -C _y , when used in combination with a chemical moiety such as alkyl, alkenyl or alkynyl, includes groups that contain from x to y carbon atoms in the chain. For example, the term C _xy- alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight chain and branched chain alkyl groups, which contain from x to y carbon atoms in the chain. The terms C _xy- alkenyl and Cxy-alkynyl refer to substituted or unsubstituted unsaturated straight chain or branched hydrocarbon groups that contain at least one double or triple bond, respectively. Unless otherwise specifically indicated in the specification, Cxy-alkyl, Cxy-alkenyl or Cxy-alkynyl is optionally substituted with one or more substituents, such as the aforementioned substituents.

A carbocycle refers to a saturated, unsaturated, or aromatic ring in which each ring atom is a carbon atom. The carbocycle may include 3-10 membered monocyclic rings, 6-12 membered bicyclic rings, and 6-12 membered bridging rings. Each ring of the bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. In some embodiments, the carbocycle is aryl. In some embodiments, the carbocycle is cycloalkyl. In some embodiments, the carbocycle is cycloalkenyl. In an illustrative embodiment, an aromatic ring such as phenyl can be fused to a saturated or unsaturated ring such as cyclohexane, cyclopentane or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings with regard to valency is included in the definition of carbocyclic. Examples of carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Unless otherwise specifically indicated in the description, the carbocycle is optionally substituted with one or more substituents, such as the aforementioned substituents.

Heterocycle refers to a saturated, unsaturated, or aromatic ring containing one or more heteroatoms. Typical heteroatoms include N, O, Si, P, B, and S. Heterocycles include 3-10 membered monocyclic rings, 6-12 membered bicyclic rings, and 6-12 membered bridging rings. Each ring of the bicyclic heterocycle can be selected from saturated, unsaturated and aromatic rings. The heterocycle can be attached to the rest of the molecule through any atom of the heterocycle, taking into account the valency, such as a carbon or nitrogen atom of the heterocycle. In some embodiments, the heterocycle is heteroaryl. In some embodiments, the heterocycle is heterocycloalkyl. In an illustrative embodiment of the invention, a heterocycle, for example, pyridyl, can be fused with a saturated or unsaturated ring, for example, cyclohexane, cyclopentane, or cyclohexene.

Heteroaryl refers to a 3-12 membered aromatic ring that contains at least one heteroatom, each heteroatom can be independently selected from N, O, and S. As used herein, the heteroaryl ring can be selected from monocyclic or bicyclic and fused or bridged ring systems, where at least one of the rings in the ring system is aromatic, i. e. contains a cyclic, delocalized (4n + 2) π-electron system in accordance with the Hückel theory. The heteroatom (s) in the heteroaryl can optionally be oxidized. One or more nitrogen atoms, if any, are optionally quaternized. Heteroaryl can be attached to the remainder of the molecule through any heteroaryl atom with regard to valency, such as a carbon or nitrogen atom of the heteroaryl. Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo [d] thiazolyl, benzothiadiazolyl, benzo [b] [1,4] dioxepinyl, benzo [b] [ 1,4] oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolil, benzodioxynil, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno [3,2-d] pyrimidinyl, benzotriazolidinyl, benzotriazolidin ] imidazo [1,2a] pyridinyl, carbazolyl, cinnolinyl, cyclopenta [d] pyrimidinyl, 6,7-dihydro-5H-cyclopenta [4,5] thieno [2,3-d] pyrimidinyl, 5,6-benzo [h ] quinolyl, 5,6-benzo [h] cinolinyl, 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo [3,2с ] pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta [d] pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta [d] pyridazinyl, 5,6,7,8,9,10 -hexahydrocyclooct [d] pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyls, indazolyl, isoindolyl, indolinyl, isoindoline yl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6а, 7, 8,9,10,10а-octahydrobenzo [h] quinazolinyl, 1-phenyl-1Hpyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazol [3,4-d] pyrimidinyl, pyridinyl, pyridinyl 3,2-d] pyrimidinyl, pyrido [3,4d] pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta [4,5] thieno [2,3-d] pyrimidinyl, 5.6, 7,8-tetrahydropyrido [4,5-c] pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno [2,3-d] pyrimidinyl, thieno [3,2-d] pyrimidinyl, thieno [2,3- c] pridinyl and thiophenyl (i.e. thienyl). Unless otherwise specifically indicated in the description, the term heteroaryl means heteroaryls as defined above, which are optionally substituted with one or more substituents, such as the aforementioned substituents.

The compounds of the present invention also include crystalline and amorphous forms of these 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 compounds, and mixtures thereof.

The compounds described in the present invention may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched with a particular isotope having the same atomic number, but an atomic mass or mass number other than atomic mass, or

- 9 038388 mass number, mainly found in nature. All isotopic variations of the compounds of the present invention, whether they are radioactive or not, are included within the scope of the present disclosure. For example, hydrogen has three natural isotope denoted 1H (protium) ² H (deuterium) and ³ H (tritium). Protium is the most abundant hydrogen isotope in nature. Deuterium enrichment can provide certain therapeutic benefits, such as an increase in in vivo half-life and / or radiation, or can be a compound useful for studying in vivo pathways of elimination and metabolism. Isotopically enriched compounds can be prepared by conventional methods well known to those skilled in the art.

Isomers are different compounds having the same molecular formula. Stereoisomers are isomers that differ only in how the atoms are arranged in space. Enantiomers are a pair of stereoisomers that are not superimposed mirror images. A 1: 1 mixture of a pair of enantiomers is a racemic mixture. The term (±) is used to refer to a racemic mixture where appropriate. Diastereoisomers or diastereomers are stereoisomers that have at least two asymmetric atoms, but are not mirror images of one another. The absolute stereochemistry is determined according to the RS-system Cahn-Ingold-Prelog. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be defined as R or S. Permitted compounds, the absolute configuration of which is unknown, can be designated (+) or (-) depending on the direction (right- or levogyrate), in where they rotate plane polarized light at the sodium D line wavelength. Some of the compounds described in the present invention contain one or more asymmetric centers and, thus, can form enantiomers, diastereomers and other stereoisomeric forms, the asymmetric centers of which can be defined from the point of view of absolute stereochemistry as (R) - or (S) -. The chemicals, pharmaceutical compositions and methods present are intended to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers, and intermediate mixtures. Optically active (R) - and (S) -isomers can be prepared using chiral synthons or chiral reagents, or separated using standard methods. The optical activity of a compound can be analyzed using any suitable method, including, but not limited to, chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over another isomer can be determined.

Chemical structural units having carbon-carbon double bonds or carbon-nitrogen double bonds can exist in Z- or E-form (or cis- or trans-form). In addition, some chemical structural units can exist in various tautomeric forms. Unless otherwise indicated, the chemical structural units described in the present invention are intended to include all Z-, E- and tautomeric forms.

The term substituted refers to residues having substituents replacing hydrogen with one or more carbon atoms or heteroatoms of the structure. It is understood that a substitution or substituted includes the implicit condition that such a substitution corresponds to the allowed valence of the substituted atom and substituent and that this substitution results in a stable compound, for example, which does not undergo spontaneous transformation, such as rearrangement, cyclization, elimination, etc. ... Used in the present invention, the term substituted includes all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic, organic substituents. Permissible substituents can be one or more and the same or different for the corresponding organic compounds. For the purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described in the present invention that satisfy the valence of the heteroatoms. Substituents can include any substituents described in the present invention, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyl (such as thioether, thioacetate or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, carbocycle, heterocycle, cycloalkyl, heterocycloalkyl, aromatic and heteroaromatic fragment.

In some embodiments, the substituents may include any substituents described in the present invention, for example, halogen, hydroxy, oxo (= O), thioxo (= S), cyano (-CN), nitro (-NO2), imino (= NH) , oximo (= N-OH), hydrazino (= N-NH ₂ ), -R ^b -OR ^a , -R ^b -OC (O) -R ^a , -R ^b -OC (O) -OR ^a , - R ^b -OC (O) -N (R ^a ) 2, -R ^b -N (R ^a ) 2, -R ^b -C (O) R ^a , -R ^b -C (O) OR ^a , -R ^b -C (O) N (R ^a ) 2, -R ^b -OR ^c C (O) N (R ^a ) 2, -R ^b -N (R ^a ) ^c (°) 0R ^a , -R ^b - N (R ^a ) C (O) R ^a , -R ^b -N (R ^a ) S (O) tR ^a (where t is 1 or 2), -R ^b -S (O) tR ^a (where t is 1 or 2), -R ^b -S (O) tOR ^a (where t is 1 or 2) and -R ^b -S (O) tN (R ^a ) ₂ (where t is 1 or 2); alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may optionally be substituted

- 10 038388 alkyl, alkenyl, alkynyl, halogen, hydroxy, haloalkyl, haloalkenyl, haloalkynyl, oxo (= O), thioxo (= S), cyano (-CN), nitro (-NO2), imino (= NH), oximo (= N-OH), hydrazino (= N-NH ₂ ), -R ^b -OR ^a , -R ^b -OC (O) -R ^a , -R ^b -OC (O) -OR ^a , -R ^b -OC (O) -N (R ^a ) 2, -R ^b -N (R ^a b, -R ^b -C (O) R ^a , -R ^b -C (O) OR ^a , -R ^b -C (O) N (R ^a ) 2, -R ^b -OR ^c -C (O) N (R ^a ) 2, -R ^b -N (R ^a ) C (O) OR ^a , -R ^b -N ( R ^a ) C (O) R ^a , -R ^b -N (R ^a ) S (O) tR ^a (where t is 1 or 2), -R ^b -S (O) tR ^a (where t is 1 or 2), -R ^b -S (O) tOR ^a (where t is 1 or 2) and -R ^b -S (O) tN (R ^a ) 2 (where t is 1 or 2); wherein each R ^{a is} independently is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each R ^a , taking into account its valence, may be optionally substituted by alkyl, alkenyl, alkynyl, halogenoalkyl, halogeno, halogeno (= O), thioxo (= S), cyano (-CN), nitro (-NO2), and mino (= NH), oximo (= N-OH), hydrazino (= N-NH2), -R ^b -OR ^a , -R ^b -OC (O) -R ^a , -R ^b -OC (O) - OR ^a , -R ^b -OC (O) -N (R ^a ) 2, -R ^b -N (R ^a ) 2, -R ^b -C (O) R ^a , -R ^b -C (O) OR ^a , -R ^b -C (O) N (R ^a ) 2, -R ^b -OR ^c -C (O) N (R ^a ) 2, -R ^b -N (R ^a ) C (O) OR ^a , -R ^b -N (R ^a ) C (O) R ^a , -R ^b -N (R ^a ) S (O) tR ^a (where t is 1 or 2), -R ^b -S (O) tR ^a (where t is 1 or 2), -R ^b -S (O) tOR ^a (where t is 1 or 2) and -R ^b -S (O) tN (R ^a ) 2 (where t is 1 or 2 ); and wherein each R ^{b is} independently selected from a direct bond or a straight or branched alkylene, alkenylene or alkynylene chain, and each R ^c is a straight or branched alkylene, alkenylene or alkynylene chain.

Those of skill in the art will understand that the substituents themselves may be substituted if necessary. Unless specifically indicated as unsubstituted, references to chemical moieties in the present invention are understood to include substituted variants. For example, reference to a heteroaryl group or moiety implicitly includes both substituted and unsubstituted variants.

When substituent groups are defined by their conventional left-to-right chemical formulas, they equally encompass chemically identical substituents that would result from right-to-left writing of the structure, eg —CH2O—, equivalent to —OCH2—.

The term salt or pharmaceutically acceptable salt refers to salts prepared from various organic and inorganic counterions 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, such as in particular isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts.

An effective amount or a therapeutically effective amount refers to a given amount of a compound described herein that is sufficient to affect the intended use, including, but not limited to, treatment of diseases as defined below. The therapeutically effective amount may vary depending on the intended use in treatment (in vivo) or the subject and the condition of the disease being treated, for example, the weight and age of the subject, the severity of the disease, the route of administration, and the like, which can be readily determined by one of ordinary skill in the art. the field of technology. This term also refers to a dose that will elicit a specific response in target cells, for example, decreased platelet adhesion and / or cell migration. The particular dose will vary depending on the particular compounds selected, the dosage regimen to be followed, whether it is administered in combination with other compounds, the time of administration, the tissue into which it is administered, and the physical delivery system in which it is transferred. ...

As used herein, the term “treat or treat” refers to an approach for obtaining positive or desired results for a disease, disorder, or health condition, including, but not limited to, therapeutic benefit and / or prophylactic benefit. By therapeutic benefit is meant curing or ameliorating the underlying disease to be treated. In addition, therapeutic benefit is obtained by curing or ameliorating one or more physiological symptoms associated with the underlying disorder, such that improvement is observed in the subject, although the subject may still be suffering from the underlying disorder. In certain embodiments, the compositions are administered to a subject at risk of developing a particular disease or to a subject reporting one or more physiological symptoms of a disease to achieve prophylactic benefit, although the disease may not have been diagnosed.

Therapeutic effect, as this term is used in the present invention, encompasses the therapeutic benefit and / or prophylactic benefit as described above. Preventive effect includes delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing down, stopping or canceling the progression of a disease or condition, or any combination thereof.

The terms co-administration, administered in combination with and their grammatical equivalents, as used in the present invention, encompass the administration of two or more agents to an animal, including humans, such that both agents and / or their metabolites are present in the subject simultaneously. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in compositions in which both agents are present.

The terms antagonist and inhibitor are used interchangeably and refer to a compound that has the ability to inhibit a biological function (eg, activity, expression, binding, protein-protein interaction) of a target protein (eg, menin, MLL1, MLL2 and / or 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 in the present invention specifically interact (e.g., bind) to a target, compounds that inhibit the biological activity of a 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 the scope of this definition. The preferred biological activity inhibited by the antagonist is related to the development, growth or spread of a tumor.

As used herein, the term “agonist” refers to a compound having the ability to initiate or enhance the biological function of a target protein, whether by inhibiting the activity or inhibiting the 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 in the present invention specifically interact (e.g., bind) to a target, compounds that initiate or enhance the biological activity of a 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 the scope of this definition.

Signal transduction is the process during which stimulating or inhibitory signals are transmitted into and within a cell to induce an intracellular response. Signal transduction pathway modulator refers to a compound that modulates the activity of one or more cellular proteins associated with the same specific signaling pathway. The modulator can increase (agonist) or suppress (antagonist) the activity of the signaling molecule.

An anticancer agent, anticancer agent, or chemotherapeutic agent refers to any agent useful in the treatment of a neoplastic condition. One class of anti-cancer agents includes chemotherapeutic agents. Chemotherapy means the administration of one or more chemotherapeutic drugs and / or other agents to a cancer patient by various means, including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal or inhalation, or as a suppository.

A subject refers to an animal, such as a mammal, such as a human. The methods described in the present invention can be used in both therapeutic and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is human. Mammals include humans and domestic animals such as laboratory animals and domestic animals (eg, cats, dogs, pigs, cattle, sheep, goats, horses, rabbits) and non-domestic animals such as wild animals, and the like. A prodrug is intended to mean a compound that can be converted under physiological conditions or by solvolysis to a biologically active compound described in the present invention (eg, a compound of formula (I) or (II)). Thus, the term prodrug refers to a precursor of a biologically active compound that is pharmaceutically acceptable. In certain aspects, the prodrug is inactive when administered to a subject, but is converted in vivo to the active compound, for example, by hydrolysis. A prodrug often confers the advantages of solubility, tissue compatibility, or sustained release in a mammal (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam); Higuchi, T. ., et al., Pro-drugs as Novel Delivery Systems, (1987), ACS Symposium Series, Vol. 14; and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press), each which is fully incorporated in the present invention by reference. The term prodrug also includes

- 12 038388 the inclusion of any covalently linked carriers that release the active compound in vivo when such a prodrug is administered to a mammalian subject. Prodrugs of an active compound as described herein are typically prepared by modifying the functional groups present in the active compound such that the modifications are cleaved, either in routine manipulation or in vivo, into the parent active compound. Prodrugs include compounds in which a hydroxyl group, amino group, or mercapto group is bonded to any group that, when a prodrug of an active compound is administered to a mammalian subject, cleaves to form a free hydroxyl group, a free amino group, or a free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of the hydroxyl functional group or acetamide, formamide and benzamide derivatives of the amino functional group in the active compound, and the like. The term in vivo refers to an event that occurs in the body of a subject. The term in vitro refers to an event that occurs outside the body of a subject. For example, an in vitro assay encompasses any assay performed outside the subject. In vitro assays encompass cellular assays that use live or dead cells. In vitro assays also encompass a cell-free assay that does not use intact cells.

Optional or optional means that the subsequently described circumstance may or may not occur, and that the description includes when an event or circumstance occurs and when it does not. For example, optionally substituted aryl means that the aryl group may or may not be substituted and that the disclosure includes both substituted aryl groups and aryl groups not having substitution. A pharmaceutically acceptable carrier, diluent, or excipient includes, without limitation, an adjuvant, carrier, excipient, flow regulator, sweetening agent, diluent, preservative, coloring agent, coloring agent, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, a stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the United States Food and Drug Administration as acceptable for use in humans or pets.

The present disclosure contains compounds for modulating the interaction of menin with proteins such as MLL1, MLL2, and MLL-fusion oncoproteins. In certain embodiments, the disclosure provides compounds and methods for inhibiting the interaction of menin with its signaling molecules, upstream and downstream of the signaling pathway, including but not limited to MLL1, MLL2, and MLL fusion oncoproteins. The compounds of the present invention can be used in methods of treating a wide variety of cancers and other diseases associated with one or more MLL1, MLL2, MLL fusion proteins and menin. In certain embodiments of the invention, a compound of the present invention covalently binds meenine and inhibits the interaction of mesenine with MLL. In certain embodiments of the invention, a compound of the present invention interacts non-covalently with menin and inhibits the interaction of menin with MLL.

The compounds of the present invention can be used in methods of treating a wide variety of diseases associated with MLL1, MLL2, MLL fusion proteins and menin. In certain embodiments of the invention, a compound of the present invention interacts non-covalently with menin and inhibits the interaction of menin with MLL. In certain embodiments of the invention, a compound of the present invention covalently binds meenine and inhibits the interaction of mesenine with MLL.

In certain aspects, the present invention relates to a compound or salt that selectively binds to the menin protein and / or modulates the interaction of the menin with the MLL protein (eg, MLL1, MLL2, or MLL fusion protein). In certain embodiments of the invention, the compound modulates the mening protein by binding or interacting with one or more amino acids and / or one or more metal ions. Certain compounds may occupy the F9 and / or P13 meninge pocket. Binding of a compound disclosed in the present invention can interfere with the downstream signaling of menin or MLL (eg, MLL1, MLL2, or MLL fusion protein) in the signaling pathway. In certain aspects, the present invention relates to a compound of formula (I)

or a pharmaceutically acceptable salt, isotopic form or prodrug thereof, wherein H is selected from a C _5-12 carbocycle and a 5-12 membered heterocycle, each of which is optionally substituted with one or more R ⁵⁰ ;

- 13 038388

A is selected from a bond, a C _3-12 carbocycle, and a 3-12 membered heterocycle;

B is selected from C _3-12 carbocycle and 3-12 membered heterocycle;

C is a 3-12 membered heterocycle;

L ¹ , L ² and L ³ are each independently selected from a bond, -O-, -S-, -N (R ⁵¹ ) -, -N (R ⁵¹ ) CH ₂ -, -C (O) -, - C (O) -,

-OC (O) -, -OC (O) -, -C (O) N (R ⁵¹ ) -, -C (O) N (R ⁵¹ ) C (O) -, -C (O) N (R ⁵¹ ) C (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) -,

-N (R ⁵¹ ) C (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) O-, -OC (O) 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 (O) 2 -, -OS (O) -, -S (O) O-, -S (O) -, -OS (O) 2-, -S (O) 2O-, -N (R ⁵¹ ) S (O) 2-, -S (O) 2N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) -, -S (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) ₂ N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) N (R ⁵¹ ) -; alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene and heteroalkynylene, each of which is optionally substituted with one or more R ⁵⁰ , with two R ⁵⁰ groups attached to the same atom or different atoms of any of L ¹ , L ² or L ³ , together can 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 ^A groups, two R ^B groups or two R ^C groups attached to the same atom or different atoms, together may optionally form bridge or ring;

m, n and p are each independently an integer from 0 to 6;

R ^{50 is} independently selected at each occurrence from:

halogen, -NO2, -CN, -OR ⁵² , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N ( R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, - NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) ( R ⁵² ) ₂ , = O, = S, = N (R ⁵² );

C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO2, —CN, —OR ⁵² , —SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O ) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² ,

-NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C _3-12 carbocycle and 3-12 membered heterocycle; and

C _3-12 carbocycle and 3-12 membered heterocycle, each C _3-12 carbocycle and 3-12 membered heterocycle in R ⁵⁰ independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR ⁵² , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2 , -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S , = N (R ⁵² ), C1-6 alkyl, Cl _-6 haloalkyl, C _2-6 alkenyl and C _2-6 alkynyl;

R ^{51 is} independently selected at each occurrence from:

hydrogen, —C (O) R ⁵² , —C (O) OR ⁵² , —C (O) N (R ⁵² ) 2, —C (O) NR ⁵³ R ⁵⁴ ; Cl-6alkyl, C _2-6 alkenyl and C _2-6 alkynyl, each independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO2, —CN, —OR ⁵² , —SR ⁵² , —N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N ( R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C3-1 ₂ carbocycle and 3-12 membered heterocycle; and

C _3- l ₂ carbocycle and 3-12 membered heterocycle, each C _3- l ₂ carbocycle and 3-12 membered heterocycle in R ^{51 is} independently optionally substituted with one or more substituents selected from halogen, —NO2, —CN, -OR ⁵² , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC ( O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C1-6 alkyl, Cl _-6 haloalkyl, C _2-6 alkenyl and C _2-6 alkynyl;

R ^{52 is} independently selected at each occurrence from hydrogen; and C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, 1-6 membered heteroalkyl, C _{3-1 2} carbocycle and 3-12 membered heterocycle, each of which is optionally substituted with halogen, —CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, = O, -OH, -OCH3, -OCH2CH3, C 3- l ₂ carbocycle or a 3-6-membered heterocycle;

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 selected from:

halogen, -NO2, -CN, -SR ⁵² , -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵⁸ , -S (= O) 2N (R ⁵² ) 2, - S (= O) 2NR ⁵³ R ⁵⁴ , NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O ) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ ,

-C (O) NH (C1-6alkyl), -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = S, = N ( R ⁵² ); and

Cl _is l ₀ alkyl, C _2- l ₀ alkenyl and C _2- l ₀ alkynyl, each of which is independently substituted at each occurrence with one or more substituents selected from -NO ₂ , -CN, -SR ⁵² , -N (R ⁵² ) ₂ , -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2,

- 14 038388

-NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ ,

-NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -P (O ) (OR ⁵² ) 2, -P (O) R ⁵² ) 2, = S and = N (R ⁵² ); and

R ^{58 is} selected from hydrogen; and C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, 1-6 membered heteroalkyl, C _3-12 carbocycle and 3-12 membered heterocycle, each of which is optionally substituted with halogen, -CN, - NO2, -NH ₂ , -NHCH3, -NHCH2CH3, = O, -OH, -OCH3, -OCH2CH3, C3-12 carbocycle or 3-6 membered heterocycle, where for a compound or salt of formula (I) when C is azetidinylene , piperidinylene or piperazinylene and R ⁵⁷ is —S (= O) 2R ⁵⁸ , —S (= O) 2N (R ⁵² ) 2 or —NR ⁵² S (= O) 2R ⁵² :

p is an integer from 1 to 6; and / or

L ^{3 is} substituted with one or more R ⁵⁰ , where L ^{3 is} not —CH ₂ CH (OH) -.

In certain aspects, the present invention relates to a compound of formula (II)

or a pharmaceutically acceptable salt thereof, wherein H is selected from a C _5-12 carbocycle and a 5-12 membered heterocycle, each of which is optionally substituted with one or more R ⁵⁰ ;

A, B and C are each independently selected from a C _3-12 carbocycle and a 3-12 membered heterocycle;

L ¹ and L ² are each independently selected from a bond, -0-, -S-, -N (R ⁵¹ ) -, -N (R ⁵¹ ) CH ₂ -, -C (O) -, -C (O ) О-, -0С (0) -, -0С (0) 0-, -C (O) N (R ⁵¹ ) -, -C (O) N (R ⁵¹ ) C (O) -, -C ( O) N (R ⁵¹ ) C (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) -,

-N (R ⁵¹ ) C (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) -, -OC (O) 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 (O) 2- , -OS (O) -, -S (O) O-, -S (O) -, -OS (O) 2-, -S (O) 2O-, -N (R ⁵¹ ) S (O) 2 -, -S (O) 2N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) -, -S (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) 2N ( R ⁵¹ ) -, -N (R ⁵¹ ) S (O) N (R ⁵¹ ) -; alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more R ⁵⁰ ;

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 ^A groups, two R ^B groups or two R ^C groups attached to the same atom or different atoms, together may optionally form bridge or ring;

m, n and p are each independently an integer from 0 to 6;

R ^{50 is} independently selected at each occurrence from:

halogen, -NO2, -CN, -OR ⁵² , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N ( R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, - NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) ( R ⁵² ) 2, = O, = S, = N (R ⁵² );

C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO2, —CN, —OR ⁵² , —SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O ) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² ,

-NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C ₃ . ₁₂ carbocycle and 3-12 membered heterocycle; and C _3-12 carbocycle and 3-12 membered heterocycle, each C _3-12 carbocycle and 3-12 membered heterocycle in R ⁵⁰ independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, - OR ⁵² , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O ) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) ₂ , = O, = S, = N (R ⁵² ), C _1-6 alkyl, C ₁ . ₆ haloalkyl, C _2-6 alkenyl and C _2-6 alkynyl;

R ^{51 is} independently selected at each occurrence from:

hydrogen, —C (O) R ⁵² , —C (O) OR ⁵² , —C (O) N (R ⁵² ) 2, —C (O) NR ⁵³ R ⁵⁴ ; C 1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -NO2, -CN, -OR ^52, -SR ^52, -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N ( R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), A C3 _-12 carbocycle and a 3-12 membered heterocycle; and

C _3-12 carbocycle and 3-12 membered heterocycle, each C _3-12 carbocycle and 3-12 membered heterocycle in R ^{51 is} independently optionally substituted with one or more substituents selected from

- 15 038388 halogen, -NO, -CN, -OR ⁵² , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -SiOtR ⁵ ', -Si Oi -Nilfi,

-S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² ,

-OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2,

-NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) ₂ , -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C ₁ . ₆ alkyl,

C _1-6 haloalkyl, C _2-6 alkenyl and C ₂ . ₆ alkynyl;

R ^{52 is} independently selected at each occurrence from hydrogen; and C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, 1-6 membered heteroalkyl, C ₃ . ₁₂ carbocycle and 3-12 membered heterocycle, each of which is optionally substituted with halogen, -CN, -NO ₂ , -NH ₂ , -NHCH ₃ , -NHCH ₂ CH ₃ , = O, -OH, -OCH ₃ , -OCH ₂ CH ₃ , C _3-12 carbocycle or 3-6 membered heterocycle;

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:

-NO ₂ , -OR ⁵⁹ , -SR ⁵² , -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) ₂ R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) ₂ NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) ₂ R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O ) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl, C _3-12 carbocycle and 3-12 membered heterocycle, each C _1-10 alkyl, C _{2 -10} alkenyl and C _2-10 alkynyl in R ^{56 are} independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO ₂ , —CN, —OR ⁵⁹ , —SR ⁵² , —N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² ,

-NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C _3-12 carbocycle and 3-12 membered heterocycle;

wherein each C _3-12 carbocycle and 3-12 membered heterocycle in R ^{56 is} independently optionally substituted with one or more substituents selected from halogen, —NO2, —CN, —OR ⁵² , —SR ⁵² , —N (R ⁵² ) 2 , -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , - NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O ) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl and C _2-6 alkynyl; and additionally, where R ⁵⁶ optionally forms a bond with ring C; and R ^{59 is} independently selected at each occurrence from C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, 1-6 membered heteroalkyl, C _3-12 carbocycle, and 3-12 membered heterocycle, each of which optionally substituted with halogen, -CN, -NO ₂ , -NH ₂ , -NHCH ₃ , -NHCH ₂ CH ₃ , = O, -OH, -OCH ₃ , -OCH ₂ CH ₃ , C _3-12 carbocycle or 3-6 -membered heterocycle, where for a compound or salt of formula (II), when R ⁵⁶ is —CH3, L ^{3 is} not further substituted with —OH, —NH2, or —CN.

In certain aspects, the present invention relates to a compound of formula (I)

or a pharmaceutically acceptable salt, isotopic form or prodrug thereof, wherein H is selected from a C _5-12 carbocycle and a 5-12 membered heterocycle, each of which is optionally substituted with one or more R ⁵⁰ ;

A is selected from a bond, a C _3-12 carbocycle, and a 3-12 membered heterocycle;

B is selected from C _3-12 carbocycle and 3-12 membered heterocycle;

C is a 3-12 membered heterocycle;

L ¹ , L ² and L ³ are each independently selected from a bond, -O-, -S-, -N (R ⁵¹ ) -, -N (R ⁵¹ ) CH2-, -C (O) -, -C (O) -, -OC (O) -, -OC (O) -, -C (O) N (R ⁵¹ ) -, -C (O) N (R ⁵¹ ) C (O) -, -C ( O) N (R ⁵¹ ) C (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) -, -N (R ⁵¹ ) C (O) N (R ⁵¹ ) -, -N ( R ⁵¹ ) C (O) O-, -OC (O) 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 (O) 2-, -OS (O) -, -S (O) O-, -S ( O) -, -OS (O) 2-, -S (O) 2O-, -N (R ⁵¹ ) S (O) 2-, -S (O) 2N (R ⁵¹ ) -, -n (r ⁵¹ ) s (O) -, -S (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) 2N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) N (R ⁵¹ ) -; alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene and heteroalkynylene, each of which is optionally substituted with one or more R ⁵⁰ , with two R ⁵⁰ groups attached to the same atom or different atoms of any of L ¹ , L ² or L ³ , together can optionally form a bridge or ring;

R ^a , R ^b and RC are each independently selected at each occurrence from R ⁵⁰ , or two R ^A groups, two R ^B groups or two RC groups attached to the same atom or different atoms, together can optionally form a bridge or a ring;

m, n and p are each independently an integer from 0 to 6;

R ^{50 is} independently selected at each occurrence from:

halogen, -NO2, -CN, -OR ⁵² , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2,

- 16 038388

-S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² ,

-OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2,

-NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² );

C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO ₂ , —CN, —OR ⁵² , —SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² ,

-NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) ₂ NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) ₂ , -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C _3-12 carbocycle and 3-12 membered heterocycle; and

C _3-12 carbocycle and 3-12 membered heterocycle, each C _3-12 carbocycle and 3-12 membered heterocycle in R ⁵⁰ independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR ⁵² , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2 , -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S , = N (R ⁵² ), C1. ₆ alkyl, C _1-6 haloalkyl, C _2-6 alkenyl and C _2-6 alkynyl;

R ^{51 is} independently selected at each occurrence from:

hydrogen, —C (O) R ⁵² , —C (O) OR ⁵² , —C (O) N (R ⁵² ) 2, —C (O) NR ⁵³ R ⁵⁴ ;

C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO2, —CN, —OR ⁵² , —SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O ) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , - NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C ₃ .12 carbocycle and 3-12 membered heterocycle; and a C _3-12 carbocycle and a 3-12 membered heterocycle, each C _3-12 carbocycle and 3-12 membered heterocycle in R ⁵¹ independently optionally substituted with one or more substituents selected from halogen, —NO2, —CN, - OR ⁵² , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O ) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S = N (R ⁵² ), C1-6αalkyl, N-haloalkyl, C2-6alkenyl and C2-6alkynyl;

R ^{52 is} independently selected at each occurrence from hydrogen; and C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, 1-6 membered heteroalkyl, C _3-12 carbocycle and 3-12 membered heterocycle, each of which is optionally substituted with halogen, -CN, - NO2, -NH2, -NHCH3, -NHCH2CH3, = O, -OH, -OCH3, -OCH2CH3, C _3-12 carbocycle or 3-6 membered heterocycle;

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 selected from:

halogen, -NO2, -CN, -SR ⁵² , -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵⁸ , -S (= O) 2N (R ⁵² ) 2, - S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , - C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C ( O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ ,

-C (O) NH (C _1-6 alkyl), -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = S, = N (R ⁵² ); and

C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl, each of which is independently substituted at each occurrence with one or more substituents selected from —NO ₂ , —CN, —SR ⁵² , —N (R ⁵² ) ₂ , -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² ,

-NR ⁵² S (= O) 2N (R ⁵² ) 2, NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) R ⁵² ) 2, = S and = N (R ⁵² ); and

R ^{58 is} selected from hydrogen; and C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, 1-6 membered heteroalkyl, C _3-12 carbocycle and 3-12 membered heterocycle, each of which is optionally substituted with halogen, CN, -NO2 , -NH ₂ , -NHCH3, -NHCH2CH3, = O, -OH, -OCH3, -OCH2CH3, C3-12 carbocycle or 3-6 membered heterocycle, moreover, for a compound or salt of formula (I), when C is azetidinylene, piperidinylene or piperazinylene and R ⁵⁷ is —S (= O) 2R ⁵⁸ , —S (= O) 2N (R ⁵² ) 2 or —NR ⁵² S (= O) 2R ⁵² :

p is an integer from 1 to 6; and / or

L ^{3 is} substituted with one or more R ⁵⁰ , where L ^{3 is} not —CH ₂ CH (OH) -.

In certain aspects, the present invention relates to a compound of formula (II)

17 038388 or a pharmaceutically acceptable salt thereof, where H is selected from a C _5-12 carbocycle and a 5-12 membered heterocycle, each of which is optionally substituted with one or more R ⁵⁰ ;

A, B and C are each independently selected from a C _3-12 carbocycle and a 3-12 membered heterocycle;

L ¹ and L ² are each independently selected from a bond, -O-, -S-, -N (R ⁵¹ ) -, -N (R ⁵¹ ) CH ₂ -, -C (O) -, -C (O ) O-, -OC (O) -, -OC (O) O-, -C (O) N (R ⁵¹ ) -, -C (O) N (R ⁵¹ ) C (O) -, -C ( O) N (R ⁵¹ ) C (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) -,

-N (R ⁵¹ ) C (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) -, -OC (O) 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 (O) 2- , -OS (O) -, -S (O) O-, -S (O) -, -OS (O) 2-, -S (O) 2O-, -N (R ⁵¹ ) S (O) 2 -, -S (O) 2N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) -, -S (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) 2N ( R ⁵¹ ) -, -N (R ⁵¹ ) S (O) N (R ⁵¹ ) -; alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more R ⁵⁰ ;

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 ^A groups, two R ^B groups or two R ^C groups attached to the same atom or different atoms, together may optionally form bridge or ring;

m, n and p are each independently an integer from 0 to 6;

R ^{50 is} independently selected at each occurrence from:

halogen, -NO2, -CN, -OR ⁵² , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N ( R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, - NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) ( R ⁵² ) 2, = O, = S, = N (R ⁵² );

C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO2, —CN, —OR ⁵² , —SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O ) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² ,

-NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C _3-12 carbocycle and 3-12 membered heterocycle; and a C _3-12 carbocycle and a 3-12 membered heterocycle, each C _3-12 carbocycle and 3-12 membered heterocycle in R ⁵⁰ independently optionally substituted with one or more substituents selected from halogen, —NO2, —CN, - OR ⁵² , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O ) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl and C2-6alkynyl;

R ^{51 is} independently selected at each occurrence from:

hydrogen, —C (O) R ⁵² , —C (O) OR ⁵² , —C (O) N (R ⁵² ) 2, —C (O) NR ⁵³ R ⁵⁴ ; C 1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -NO =, -CN, -OR ^52, -SR ^52, - N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ) , C3 _-12 carbocycle and 3-12 membered heterocycle; and a C _3-12 carbocycle and a 3-12 membered heterocycle, each C _3-12 carbocycle and 3-12 membered heterocycle in R ⁵¹ independently optionally substituted with one or more substituents selected from halogen, —NO2, —CN, - OR ⁵² , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O ) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl and C _2-6 alkynyl;

R ^{52 is} independently selected at each occurrence from hydrogen; and C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, 1-6 membered heteroalkyl, C _3-12 carbocycle and 3-12 membered heterocycle, each of which is optionally substituted with halogen, -CN, - NO2, -NH2, -NHCH3, -NHCH2CH3, = O, -OH, -OCH3, -OCH2CH3, C _3-12 carbocycle or 3-6 membered heterocycle;

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:

-NO2, -OR ⁵⁹ , -SR ⁵² , -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl, C _3-12 carbocycle and 3-12 membered heterocycle, each C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl in R ^{56 is} independently optionally substituted in

- 18 038388 each occurrence with one or more substituents selected from halogen, —NO ₂ , —CN, —OR ⁵⁹ , —SR ⁵² ,

-N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O ) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² ,

-NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2,

-OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O ) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2,

-C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C _3-12 carbocycle and a 3-12 membered heterocycle;

wherein each C _3-12 carbocycle and 3-12 membered heterocycle in R ^{56 is} independently optionally substituted with one or more substituents selected from halogen, —NO2, —CN, —OR ⁵² , —SR ⁵² , —N (R ⁵² ) 2 , -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , - NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O ) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C _1-6 alkyl , C _1-6 halogenoalkyl, C _2-6 alkenyl and C _2-6 alkynyl; and additionally, where R ⁵⁶ optionally forms a bond with ring C; and R ^{59 is} independently selected at each occurrence from C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, 1-6 membered heteroalkyl, C _3-12 carbocycle, and 3-12 membered heterocycle, each of which optionally substituted with halogen, -CN, -NO ₂ , -NH ₂ , -NHCH ₃ , -NHCH ₂ CH ₃ , = O, -OH, -OCH ₃ , -OCH ₂ CH ₃ , C _3-12 carbocycle or 3-6 -membered heterocycle, where for a compound or salt of formula (II), when R ⁵⁶ is —CH3, L ^{3 is} not further substituted with —OH, —NH2, or —CN.

In some embodiments, for a compound of formula (I) or (II), H is a 5-12 membered heterocycle, such as a 6-12 membered bicyclic heterocycle, optionally substituted with one or more R ⁵⁰ . In some embodiments, H contains one or more heteroatoms, such as 1, 2, 3, 4, 5, or 6 ring heteroatoms. In some embodiments, H contains at least 1, 2, 3, 4, or 5 ring nitrogen atoms. In some embodiments, H is thienopyrimidinyl optionally substituted with one or more R ⁵⁰ . In some embodiments, H is substituted with Cl _-4 haloalkyl, such as —CH ₂ CF ₃ . In some embodiments, H is substituted with one or more R ⁵⁰ (eg, by replacing the hydrogen bound to a ring atom with a bond to R ⁵⁰ ). H may be substituted with 0, 1, 2, 3, 4, 5, 6 or more R ⁵⁰ groups. H may be substituted with 1, 2, 3, 4, 5 or 6 R ⁵⁰ groups, for example H substituted with 1 or 2 R ⁵⁰ groups. In some embodiments, H is substituted with at least 1, 2, 3, 4, 5, or 6 R ⁵⁰ groups. In some embodiments, H is substituted with up to 6, 5, 4, 3, 2, or 1 R ⁵⁰ groups. In some embodiments, for a compound of formula (I) or (II), H is x * is'

R ¹

- where X ¹ and X ² are each independently selected from:

CR ² and N;

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, NR ⁴ , O and S;

R ¹ , R ² and R ³ are each independently selected at each occurrence from hydrogen and R ⁵⁰ ;

R ^{4 is} selected from R ⁵¹ .

In some embodiments, X ³ and X ⁴ are each C. In some embodiments, X ¹ is CR ² and R ^{2 is} selected from hydrogen, halogen, —OH, —OR ⁵² , —NH2, —N ( R ⁵² ) 2, -CN, C _1-3 alkyl, C _1-3 alkyl-N (R ⁵² ) ₂ , C _1-3 haloalkyl, C _2-3 alkenyl and C _2-3 alkynyl, for example R ^{2 is} selected from -OH, -OR ^52, -NH2, -N (R ⁵²⁾ 2, -CN and _C1-C2 alkyl. In some embodiments, R ² is methyl or —NHCH3. In some embodiments, R ² is H. In some embodiments, X ² is N. In some embodiments, Y ² is CR ³ and R ^{3 is} selected from hydrogen, halogen, —OH, —N (R ⁵² ) ₂ , —CN, —C (O) OR ⁵² , C1-3alkyl and C1-3haloalkyl. In some embodiments, Y ¹ is S. In some embodiments, at least one of Y ¹ and Y ^{2 is} selected from N, NR ⁴ , O, and S. In some embodiments, R ¹ is C1-3 haloalkyl, such as -CH ₂ CF ₃ . In some embodiments, X ¹ is CR ² , X ² is N, X ³ and X ⁴ are each C, Y ¹ is S, Y ² is CR ^3, and R ^{1 is} selected from R ⁵⁰ . In some embodiments, X ¹ is CR ² ; X ² represents N; X ³ and X ⁴ each represent C; Y ¹ represents S; Y ² represents CH; R ¹ is C1-3 haloalkyl and R ^{2 is} selected from hydrogen, halogen, —OH, —OR ⁵² , —NH2, —N (R ⁵² ) 2, —CN, C1-3 alkyl, —CH2OH, —CH2OR ⁵² , —CH2NH ₂ , —CH ₂ N (R ⁵² ) 2, C1-3 alkyl-N (R ⁵² ) 2, C _1-3 haloalkyl, C _2-3 alkenyl and C _2-3 alkynyl.

In some embodiments, H is

- 19 038388

Tl I —R ¹

Ν.

In some embodiments, H is n for example

In some embodiments, H is and R ^{2 is} selected from hydrogen, halogen, —OH, —OR ⁵² , —NH2, —N (R ⁵² ) 2, —CN, ^ alkyl, —CH2OH, —CH2OR ⁵² , —CH2NH2 , -CH2N (R ⁵² ) 2, C _1-3 αalkyl-N (R ⁵² ) 2, C1-3 haloalkyl, C2-3 alkenyl and C2-3 alkynyl. In some embodiments, R ^{2 is} selected from hydrogen, halogen, —OH, alkoxy (eg —OR ⁵² , —OCH3, —OCH2CH3), aminoalkyl, alkylamino, —N (R ⁵² ) 2 (eg, NH ₂ , —NHCH3 , -NHCH2CH3), -N (CH ₃ ) ₂ , -CN, C _1-3 alkyl (for example, -CH3), cyclopropyl, C _1-3 alkyl-OR ⁵² (for example, -CH2OH, -CH2OC (O) CH3 ), C1-3alkyl-N (R ⁵² ) 2, C _1-3 haloalkyl, C _2-3 alkenyl and C _2-3 alkynyl.

In some embodiments, for a compound of formula (I) or (II), H is N is

R ¹ 'wherein R ^{1 is} selected from H, halogen, hydroxyl, amino, cyano, dialkyl phosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, and haloalkyl such as alkyl and haloalkyl; R ^{2 is} selected from H, halogen, hydroxyl, amino, cyano, dialkyl phosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, and alkylamino such as H, halogen, hydroxyl, and amino; and Y ¹ and Y ^{2 are} each independently selected from S, CR ³ , N, NR ^4, and O. In some embodiments, up to one of Y ¹ and Y ² is O or S.

In some embodiments, for a compound of formula (I) or (II), L ¹ contains less than 20 atoms, eg, less than 10 atoms. In some embodiments, L ¹ contains less than 20, 15, 10, 9, 8, 7, 6, 5, 4, or less than 3 atoms. In some embodiments, L ¹ contains at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or at least 20 atoms. In some embodiments, L ¹ contains at least one heteroatom, eg, L ¹ contains at least one nitrogen. In some embodiments, L ^{1 is} substituted with one or more R ⁵⁰ . In some embodiments, L ¹ is unsubstituted. In some embodiments, L ^{1 is} selected from a bond, -O-, -S-, -N (R ⁵¹ ) -, -N (R ⁵¹ ) CH2-, -C (O) -, -C (O) O- , -OC (O) -, -C (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) -, -N (R ⁵¹ ) C (O) N (R ⁵¹ ) -, - S (O) 2-, -S (O) -, -N (R ⁵¹ ) S (O) 2-, -S (O) 2N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) 2N (R ⁵¹ ) -, alkylene, alkenylene, heteroalkylene and heteroalkenylene. In some embodiments, L ^{1 is} selected from a bond, -O-, -S-, -N (R ⁵¹ ) -, -N (R ⁵¹ ) CH2-, -C (O) -, -C (O) O- , -OC (O) -, -C (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) -, -N (R ⁵¹ ) C (O) N (R ⁵¹ ) -, - S (O) 2-, -S (O) -, -n (r ⁵¹ ) s (O) 2-, -S (O) 2N (R ⁵¹ ) -, -N (R ⁵¹ ) s (O) 2N (R ⁵¹ ) -, C1-6 alkylene and C2-6 alkenylene, each C1-6alkylene and C2-6 alkenylene optionally substituted with one or more R ⁵⁰ . In some embodiments, L ¹ is —N (R ⁵¹ ) - such as —NH—. In some embodiments, L ^{1 is} selected from —O—, —N (R ⁵¹ ) -, —N (R ⁵¹ ) CH2—, —C (O) -, —C (O) N (R ⁵¹ ) -, - N (R ⁵¹ ) C (O) -, -N (R ⁵¹ ) S (O) 2-, -S (O) 2N (R ⁵¹ ) -, C1-4alkylene, C _2-4 alkenylene and C _1-4 heteroalkylene. In some embodiments, L ¹ is —N (R ⁵¹ ) -, wherein R ^{51 is} selected from hydrogen and alkyl. In some embodiments, for a compound of formula (I) or (II), A is a 3-12 membered heterocycle, such as a 5-8 membered heterocycle. In some embodiments, A is a 6-membered monocyclic heterocycle. In some embodiments, the heterocycle contains at least one nitrogen atom. In some embodiments, A contains at least one ring nitrogen. In some embodiments, A is selected from piperidinylene and piperazinylene such as

In some embodiments, A is

In some embodiments, A is an aromatic, non-aromatic, saturated, or unsaturated ring. In some embodiments, A is selected from arylene, cycloalkylene, heterocycloalkylene, N-heterocycloalkylene, heteroarylene, and N-heteroarylene. In some embodiments, A is a 5-8 membered heterocycle, wherein the heterocycle contains at least 1, 2, 3, or 4 ring heteroatoms selected from N, O, and S.

- 20 038388

In some embodiments, A is selected from

In some embodiments, A is substituted with one or more R ^A (eg, by replacing the hydrogen attached to the ring atom with a bond to R ^A ). A may be substituted with 0, 1, 2, 3, 4, 5, 6 or more R ^A A may be substituted with 1, 2, 3, 4, 5 or 6 R ^A groups, for example A substituted with 1 or 2 R groups ^A In some embodiments, A is substituted with at least 1, 2, 3, 4, 5, or 6 R groups. ^A In some embodiments, A is unsubstituted. In some embodiments, A is substituted with m groups R ^A , where m is an integer from 0 to 6. In some embodiments, m is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, m is at least 1, 2, 3, 4, 5, or 6. In some embodiments, m is up to 6, 5, 4, 3, 2, or 1. In some embodiments, m is 0.

In some embodiments, R ^{A is} independently selected at each occurrence from halogen, hydroxyl, amino, cyano, dialkyl phosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkylalkyl, cycloalkylalkyl , tsikloalkilalkiloksi, cycloalkylamino, tsikloalkilalkilamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamine, geterotsiklilalkilamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, and heteroarylamino heteroarylalkylamino. In some embodiments, two R ^A groups attached to the same atom or different atoms may together form a ring.

In some embodiments of the invention for a compound of formula (I) or (II), L ² contains less than 20 atoms, for example, less than 10 atoms. In some embodiments, L ² contains less than 20, 15, 10, 9, 8, 7, 6, 5, 4, or less than 3 atoms. In some embodiments, L ² contains at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or at least 20 atoms. In some embodiments, L ² contains at least one heteroatom, eg, L ² , contains at least one nitrogen. In some embodiments, L ² is C1.10 alkylene, such as C1.4 alkylene, optionally substituted with one or more R ⁵⁰ . In some embodiments, L ^{2 is} substituted with one or more R ⁵⁰ . In some embodiments, L ² is unsubstituted. In some embodiments, L ^{2 is} selected from a bond, —O—, —S—, —N (R ⁵¹ ), —N (R ⁵¹ ) CH2—, —C (O), —C (O) O, —OC (O), -C (O) N (R ⁵¹ ), -N (R ⁵¹ ) C (O), -N (R ⁵¹ ) C (O) N (R ⁵¹ ), -S (O) 2, - S (O), -N (R ⁵¹ ) S (O) 2, -S (O) 2N (R ⁵¹ ), -N (R ⁵¹ ) S (O) 2N (R ⁵¹ ) -, alkylene, alkenylene, heteroalkylene and heteroalkenylene. In some embodiments, L ^{2 is} selected from a bond, —O—, —S—, —N (R ⁵¹ ), —N (R ⁵¹ ) CH ₂ -, —C (O), —C (O) O, - OC (O),

- 21 038388

-C (O) N (R ⁵¹ ), -N (R ⁵¹ ) C (O), -N (R ⁵¹ ) C (O) N (R ⁵¹ ), -S (O) 2, -S (O) , -N (R ⁵¹ ) S (O) 2, -S (O) 2N (R ⁵¹ ), -N (R ⁵¹ ) S (O) 2N (R ⁵¹ ) -, C1-6 alkylene and C _2-6 alkenylene wherein each C _1-6 alkylene and each C _2-6 alkenylene are optionally substituted with one or more R ⁵⁰ . In some embodiments, L ^{2 is} selected from —O—, —N (R ⁵¹ ), —N (R ⁵¹ ) CH2—, —C (O) N (R ⁵¹ ), —N (R ⁵¹ ) C (O) , -N (R ⁵¹ ) S (O) 2, -S (O) 2N (R ⁵¹ ), C1-4 alkylene and C1.4 heteroalkylene. In some embodiments, L ^{2 is} selected from —CH2—, —N (R ⁵¹ ) -, —N (R ⁵¹ ) CH2—, —N (R ⁵¹ ) C (O) -, and —N (R ⁵¹ ) S ( O) 2-. In some embodiments, L ² is —CH2—.

In some embodiments, for a compound of formula (I) or (II), B is a 3-12 membered heterocycle, eg, a 6-12 membered bicyclic heterocycle. In some embodiments, the heterocycle contains at least one nitrogen atom. In some embodiments, B is a 6-12 membered heterocycle, where the heterocycle contains at least 1, 2, 3, or 4 ring heteroatoms selected from N, O, and S. In some embodiments, B is 6.5 - or 6,6-bicyclic heterocycle. In some embodiments, B contains at least one ring nitrogen. In some embodiments, B is indolylene, such as' optionally optionally substituted with one or more R ^B. In some embodiments, “A r ⁵ ° ni ^{cn of the} invention B is ^r5 ° 'for example ^CH3 ·

In some embodiments, B is selected from

where Z ¹ , Z ² , Z ³ and Z ⁴ are each independently selected from CR ⁷ , N and NR ⁹ ;

Z ^{5 is} selected from C and N;

Z ⁶ , Z ⁷ and Z ⁸ are each independently selected from CR ⁸ , N, NR ⁹ , O and S;

Z ⁹ , Z ¹⁰ and Z ¹¹ are each independently selected from CR ¹⁰ , CR ⁿ R ¹² , NR ¹³ , O and S;

R ⁷ , R ⁸ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected from hydrogen and R ⁵⁰ ;

R ⁹ and R ¹³ are each independently selected from R ⁵¹ , where B may be bonded to any ring atom with L ² or L ³ (eg, by replacing the hydrogen bonded to the ring atom with a bond with L ² or L ³ ).

In some embodiments, B is selected from

- 22 038388

In some embodiments, B is substituted with one or more R ^B (eg, by replacing the hydrogen attached to the ring atom with a bond to R ^B ). B can be replaced

- 23 038388

0, 1, 2, 3, 4, 5, 6 or more R ^B groups. B may be substituted with 1, 2, 3, 4, 5 or 6 R ^B groups, for example B substituted with 1 or 2 R ^B groups. In some embodiments, B is substituted with at least 1, 2, 3, 4, 5, or 6 R ^B groups. In some embodiments, B is substituted with n R ^B groups, where n is an integer from 0 to 6. In some embodiments, n is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, n is at least 1, 2, 3, 4, 5, or 6. In some embodiments, n is up to 6, 5, 4, 3, 2, or 1. In some embodiments, n is an integer from 1 to 3 ...

In some embodiments, R ^{B is} independently selected at each occurrence from halogen, hydroxyl, amino, cyano, dialkyl phosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkylalkyl, cycloalkylalkyl , tsikloalkilalkiloksi, cycloalkylamine, tsikloalkilalkilamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamine, geterotsiklilalkilamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, and heteroarylamino heteroarylalkylamino. In some embodiments, R ^{B is} independently selected at each occurrence from halogen, hydroxyl, amino, cyano, dialkyl phosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, heterocyclyeroylalkyl, and ... In some embodiments, two R ^B groups attached to the same atom or different atoms may together form a ring.

In some embodiments, for a compound of formula (I), L ³ contains less than 30 atoms, eg, less than 20 atoms. In some embodiments, L ³ contains less than 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, or less than 3 atoms. In some embodiments, L ³ contains at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or at least 20 atoms. In some embodiments, L ³ contains at least one heteroatom, for example L ³ contains at least one nitrogen. In some embodiments, L ³ is C1-1oαalkylene, such as C1-4alkylene, optionally substituted with one or more R ⁵⁰ . In some embodiments, L ^{3 is} substituted with one or more R ⁵⁰ . In some embodiments, L ³ is unsubstituted. In some embodiments, L ^{3 is} selected from a bond, —O—, —S—, —N (R ⁵¹ ), —N (R ⁵¹ ) CH2—, —C (O), —C (O) O, —OC (O), -C (O) N (R ⁵¹ ), -N (R ⁵¹ ) C (O), -N (R ⁵¹ ) C (O) N (R ⁵¹ ), -S (O) 2, - S (O), -N (R ⁵¹ ) S (O) 2, -S (O) 2N (R ⁵¹ ), -N (R ⁵¹ ) S (O) 2N (R ⁵¹ ) -, alkylene, alkenylene, heteroalkylene and heteroalkenylene. In some embodiments, L ³ is C 1-6alkylene optionally substituted with one or more R ⁵⁰ , wherein R ^{50 is} selected from deuterium, C 1-4 alkyl, C 1-4 halogenalkyl, and —OR ⁵² . In some embodiments, L ³ is —CH2CH (R ⁵⁰ ) - such as —CH2CH (CH3) -. In some embodiments, two R ⁵⁰ groups attached to the same or different L ³ atoms optionally form a bridge or ring, such as a cyclopropyl ring. In some embodiments, L ^{3 is} substituted with R ⁵⁰ , with R ⁵⁰ bonding to ring C. In some embodiments, L ^{3 is} substituted with one or more groups selected from deuterium, C1-4alkyl, C _1-4 halogenalkyl, and —OR ⁵² ... In some embodiments, L ^{3 is} substituted with —CH 3. In some embodiments, 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 . In some embodiments, L ^{3 is} substituted with = O, C1-6alkyl, C1-6haloalkyl, C1-3alkyl (cyclopropyl), C13alkyl (NR ⁵² C (O) R ⁵² ), or —O (C1-6 alkyl).

In some embodiments, for a compound of formula (I), L ^{3 is} selected from R ^5C + X R'Q, X \ (R) \ (S)

X and X.

IMe ^ X \ (R) \ (S)

Optionally R is methyl; L can be selected from Chi X.

| Me * ^ X | Me * 0X Λ (R). ... , -. ....

In some embodiments, L ³ comprises a stereocenter. In some embodiments, the stereocenter is in the R configuration. In some embodiments, the stereocenter is in the S-configuration. In some embodiments, the R isomer of L ^{3 is} provided in at least 20, 30, 40, 50, 55, 60, 65, 70, 75, 80, 85, 88, 90, 91, 92, 93, 94, 95 , 96, 97, 98, 99, 99.5 or 99.9% excess over the S isomer.

In some embodiments, the S isomer of L ^{3 is} provided in at least 20,

- 24 038388

30, 40, 50, 55, 60, 65, 70, 75, 80, 85, 88, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5 or 99.9% excess over the R-isomer.

In some embodiments, for a compound of formula (I), C is azetidinylene, piperidinylene, or piperazinylene; R ⁵⁷ is —S (= O) 2R ⁵⁸ , —S (= O) 2N (R ⁵² ) 2 or —NR ⁵² S (= O) 2R ⁵² and L ^{3 is} substituted with one or more R ⁵⁰ , where L ^{3 is} not is an

-CH ₂ CH (OH) -.

In some embodiments, C is azetidinylene, piperidinylene, or piperazinylene; R ⁵⁷ is -S (= O) 2R ⁵⁸ , -S (= O) 2N (R ⁵² ) 2, or -NR ⁵² S (= O) 2R ⁵² and L ^{3 is} substituted with C ₁ _ ₄ α-alkyl α-alkyl or C ₁ _ ₄ alkylhaloalkyl.

In some embodiments, for a compound of formula (I), L ^{3 is} selected from

and any combination of them.

In some embodiments, for a compound of formula (I), L ^{3 is} selected from

Μ 'Ά

And X-.

In some embodiments of the invention for a compound of formula (II), L ³ contains less than 30 atoms, for example, less than 20 atoms. In some embodiments, L ³ contains less than 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, or less than 3 atoms. In some embodiments, L ³ contains at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or at least 20 atoms. In some embodiments, L ³ is C1.10alkylene, such as C1.4alkylene, substituted with one or more R ^56, and optionally further substituted with one or more R ⁵⁰ . In some embodiments, L ^{3 is} substituted with one or more R ⁵⁰ . In some embodiments, L ^{3 is} substituted with R ⁵⁶ . In some embodiments, L ^{3 is} selected from alkylene and alkenylene. In some embodiments, L ³ is C1. ₆ alkyl substituted with one or more R ⁵⁶ , wherein R ^{56 is} selected from deuterium, C1.4 alkyl, C1.4 halogenalkyl, and —OR ⁵⁹ . In some embodiments, L ³ is C1. _{4 is} alkylylene substituted with R ⁵⁶ , wherein R ⁵⁶ forms a bond to ring C. In some embodiments, L ³ is —CH2CH (R ⁵⁶ ) -, eg, CH2CH (CH ₃ ) -. In some embodiments, two R ⁵⁶ groups attached to the same or different L ³ atoms optionally form a bridge or ring, eg, a cyclopropyl ring. In some embodiments, L ^{3 is} substituted with R ⁵⁶ , with R ⁵⁶ forming a bond to ring C. In some embodiments, L ^{3 is} substituted with one or more groups selected from C1.4alkyl, C1.4halogenoalkyl, and —OR ⁵⁹ . In some embodiments, L ^{3 is} substituted with —CH 3. In some embodiments, L ³ is C1.4αalkylene substituted with —CH3 and optionally further substituted with R ⁵⁰ , wherein R ^{50 is} not —OH, —NH2, or —CN. In some embodiments, L ³ represents a C2-Alkyl substituted by at least one or C1.3alkilom C1.3galogenalkilom and optionally further substituted by one or more R ^50. In some embodiments, L ^{3 is} substituted with = O, C1. ₆ alkyl, C ₁ . ₆ haloalkyl, C ₁ . ₃ alkyl (cyclopropyl), C ₁ . ₃ alkyl (NR ⁵² C (O) R ⁵² ) or —O (C1. ₆ alkyl).

In some embodiments, for a compound of formula (II), L ^{3 is} selected from

R ^5s ., X

J ”’ Y

X and X.

| Me * 2X MvchX

X (R) \ (S)

Optionally, r is methyl. l can be selected from X- and X.

\ (R). ... ... ... ... ... ... %.

Me -, X \ (S)

In some embodiments, L ³ is

In some embodiments, L ³ comprises a stereocenter. In some embodiments, the stereocenter is in the R configuration. In some embodiments, the stereocenter is in the S-configuration. In some embodiments, the R isomer of L ^{3 is} provided in at least 20, 30, 40, 50, 55, 60, 65, 70, 75, 80, 85, 88, 90, 91, 92, 93, 94, 95 , 96, 97, 98, 99, 99.5 or 99.9% excess over the S isomer. In some embodiments, the S isomer of L ^{3 is} provided in at least 20, 30, 40, 50, 55, 60, 65, 70,

- 25 038388

75, 80, 85, 88, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5 or 99.9% excess over the R isomer.

In some embodiments, for a compound of formula (II), L ^{3 is} selected from

combinations.

In some embodiments, for a compound of formula (II), L ^{3 is} selected from

In some embodiments, for a compound of formula (I), C is a 3-12 membered heterocycle, such as a 5-12 membered heterocycle. In some embodiments, the heterocycle is saturated. In some embodiments, C is selected from a 5-7 membered monocyclic heterocycle, an 8 to 10 membered fused bicyclic heterocycle, and a 7 to 12 membered spirocyclic heterocycle. In some embodiments, the heterocycle contains at least one nitrogen atom, such as one or two nitrogen atoms. In some embodiments, C contains at least one ring nitrogen. In some embodiments, C is selected from piperidinyl and piperazinyl such as

optionally substituted with one or more R ^c .

In some embodiments, C is selected from

In some embodiments, C is selected from

In some embodiments, C is selected from

B / h xR ⁵⁷

I ^N some

R ^c R ⁵⁷

embodiments of the invention C is selected

R ⁵⁷ of

R ^c AND

R ^c and R ^{57 is} selected from -S (= O) R ⁵² , -S (= O) 2R ⁵² ,

-S (= O) 2N (R ⁵² ) 2,

-S (= O) ₂ NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² and C1-10αalkyl substituted with one or more substituents selected from -S (= O) R ⁵² , -S (= O) ₂ R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) ₂ NR ⁵³ R ⁵⁴ and -NR ⁵² S (= O) ₂ R ⁵² . In some embodiments, R ^{57 is} selected from —S (= O) R ⁵² , —S (= O) ₂ R ⁵⁸ , —S (= O) 2N (R ⁵² ) 2, and —NR ⁵² S (= O) ₂ R ⁵² , for example R ^{57 is} selected from -S (= O) CH3, -S (= O ^ CH3, -S (= ObNH2, -NHS (= O) 2CH and -S (= O ^ NHCH3.

In some embodiments, for a compound of formula (I), C is selected from

R ^c

O ' ^R "

R ^c

Λ. xR ⁵⁷ \ nA _rC

R ^c R ^c

X xR ⁵⁷ Jx „R ⁵⁷

О I У

In some embodiments

R ^c

X xR ^{57 of the} invention for a compound of formula (I) R ^{57 is} selected from

- 26 038388

-S (= O) 2R ⁵⁸ , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ ,

-C (O) NH (C _1-6 alkyl), -C (O) NR ⁵³ R ⁵⁴ and C _1-6 alkylene and C _2-6 alkenylene, each of which is independently substituted in each occurrence with one or more substituents, selected from -S (= O) 2R,

-S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ ,

-C (O) NH (C _1-6 alkyl), -C (O) NR ⁵³ R ⁵⁴ . In some embodiments, R ^{57 is} selected from -S (= O) 2R ⁵⁸ , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ and C1-6 alkyl substituted with one or more substituents selected from -S (= O) 2R ⁵⁸ , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2 and -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ . In some embodiments, R ^{57 is} selected from —S (= O) R ⁵² , —S (= O) 2R ⁵⁸ , —S (= O) 2N (R ⁵² ) 2, and —NR ⁵² S (= O) 2R ⁵² ... In some embodiments, R ^{57 is} selected from —S (= O) CH3, —S (= O) 2CH3, —S (= O) 2NH2, —NHS (= O) 2CH3, and —S (= O) 2NHCH3.

In some embodiments, for a compound of formula (I) or (II), C is substituted with one or more RCs (eg, by replacing a hydrogen atom attached to a ring atom with a bond to RC). C may be substituted with 0, 1, 2, 3, 4, 5, 6 or more RC groups. C may be substituted with 1, 2, 3, 4, 5 or 6 RC groups, for example C substituted with 1 or 2 RC groups. In some embodiments, C is substituted with at least 1, 2, 3, 4, 5, or 6 RC groups. In some embodiments, C is unsubstituted. In some embodiments, C is substituted with p RC groups, where p is an integer from 0 to 6. In some embodiments, p is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, p is at least 1, 2, 3, 4, 5, or 6. In some embodiments, p is up to 6, 5, 4, 3, 2, or 1. In some embodiments, p is 0. In some embodiments, p is is 1 or 2. In some embodiments, for a compound of formula (I), C is azetidinylene, piperidinylene, or piperazinylene; R ⁵⁷ is —S (= O) 2R ⁵⁸ , —S (= O) ₂ N (R ⁵² ) 2, or —NR ⁵² S (= O) 2R ^52, and p is an integer from 1 to 6.

In some embodiments, RC is selected from -C (O) R ⁵² , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S ( = O) ₂ NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , = O, C1-3 alkyl and C _1-3 haloalkyl or two RC groups attached to different atoms can together form a C _{1-3 bridge} ... In some embodiments, RC is selected from C _1-3 alkyl and C _1-3 haloalkyl such as —CH ₃ .

In some embodiments, for a compound of formula (II), C is selected from a C _3-12 carbocycle and a 3-12 membered heterocycle, such as a 5-12 membered heterocycle. In some embodiments, the heterocycle is saturated. In some embodiments, C is selected from a 5-7 membered monocyclic heterocycle, an 8-10 membered fused bicyclic heterocycle, and a 7-12 membered spirocyclic heterocycle. In some embodiments, the heterocycle contains at least one nitrogen atom, such as one or two nitrogen atoms. In some embodiments, C contains at least one ring nitrogen.

In some embodiments, C is selected from piperidinyl and piperazinyl, taR ^c

A, R ⁵⁷

I ^N whom as ^R

R ^c and

_r 57 ^rC , wherein R ^{57 is} selected from hydrogen and R ⁵⁰ .

In some embodiments, C is selected from wherein R ^{57 is} selected from hydrogen and R ⁵⁰ .

R ^c A zR ⁵⁷ g

C

In some embodiments, C is selected from ^R selected from hydrogen and R ⁵⁰ .

^ _n , r ⁵⁷ _and n and R ⁵⁷

In some embodiments, C is selected from

- 27 038388 optionally substituted with one or more R ^C , wherein R ^{57 is} selected from

hydrogen and R ⁵⁰ .

In some variants

implementation of the invention

C is selected from wherein R ^{57 is} selected from -S (= O) R ⁵² , -S (= ObR ⁵² , -S (= O) 2N (R ⁵² ) 2,

-S (= O) ₂ NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² and C1-10 alkyl substituted with one or more substituents selected from -S (= O) R ⁵² , -S (= O ) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ and -NR ⁵² S (= O) 2R ⁵²

In some embodiments, R ^{57 is} selected from —S (= O) R ⁵² , —S (= O) 2R ⁵² , —S (= O) 2N (R ⁵² ) 2, and —NR ⁵² S (= O) 2R ⁵² , for example, R ^{57 is} selected from -S (= O) CH3, -S (= O) ₂ CH ₃ , -S (= O) 2NH2,

-NHS (= O) 2CH3 and -S (= O) 2NHCH3.

In some embodiments, for a compound of formula (II), C is selected from

In some embodiments, for a compound of formula (I) or (II), R ^{C is} selected from:

halogen, -OR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2 , -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2; and

C ₁ . ₁₀ αalkyl α, C ₂ . ₁₀ alkenyl, C ₁ . ₂₀ alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO ₂ , —CN, —OR ⁵² , —SR ⁵² , —N (R ⁵² ) 2, —NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² ,

-NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C ₃ . ₁₂ carbocycle and 3-12 membered heterocycle;

and each C ₃ . ₁₂ carbocycle and 3-12 membered heterocycle in R ^{C are} independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR ⁵² , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² ,

-NR ⁵² S (= O) 2N (R ⁵² ) 2, NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , - P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C ₁ . ₆ alkyl, C ₁ . ₆ halogenalkyl, C ₂ . ₆ alkenyl and C ₂ . ₆ alkynyl.

In some embodiments, R ^{c is} selected from —N (R ⁵² ) 2, —NR ⁵³ R ⁵⁴ , —NR ⁵² S (= O) 2R ⁵² , —C (O) R ⁵² , —C (O) OR ⁵² , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O ) N (R ⁵² ) 2 and -C (O) NR ⁵³ R ⁵⁴ . In some embodiments, R ^{c is} selected from —N (R ⁵² ) 2, —NR ⁵³ R ⁵⁴ , —NR ⁵² S (= O) 2R ⁵² , —C (O) R ⁵² , —C (O) OR ⁵² , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O ) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , C1-6alkyl and C ^ alkyl substituted with N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -C (O) R ⁵² , -C (O) OR ⁵² , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2 , -NR ⁵² c (o) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) ₂ or -C (O) NR ⁵³ R ⁵⁴ f N

In some embodiments, C is selected from,

- 28 038388

In some embodiments, for a compound of formula (I) or (II), H is a 5-12 membered heterocycle optionally substituted with one or more R ⁵⁰ ; A is a 3-12 membered heterocycle and B is a 3-12 membered heterocycle. In some embodiments, H is a 6-12 membered bicyclic heterocycle optionally substituted with one or more R ⁵⁰ ; A is a 3-12 membered heterocycle and B is a 3-12 membered heterocycle. In some embodiments, H is a 6-12 membered bicyclic heterocycle optionally substituted with one or more R ⁵⁰ ; A is a 3-12 membered heterocycle and B is a 612 membered bicyclic heterocycle. In some embodiments, H is a 5-12 membered heterocycle optionally substituted with one or more R ⁵⁰ ; A is a 3-12 membered heterocycle and B is a 6-12 membered bicyclic heterocycle. In some embodiments, H is thienopyrimidinyl optionally substituted with one or more R ⁵⁰ ; A is a 3-12 membered heterocycle and B is a 3-12 membered heterocycle. In some embodiments, H is a 5-12 membered heterocycle optionally substituted with one or more R ⁵⁰ ; A is selected from piperidinylene and piperazinylene; and B is a 3-12 membered heterocycle. In some embodiments, H is a 5-12 membered heterocycle optionally substituted with one or more R ⁵⁰ ; A is a 3-12 membered heterocycle and B is indolylene. In some embodiments, H is thienopyrimidinyl substituted with one or more R ⁵⁰ ; A is selected from piperidinylene and piperazinylene; and B is indolylene.

In some embodiments, for a compound of formula (I) or (II), H is a 5-12 membered heterocycle optionally substituted with one or more R ⁵⁰ ; A represents a 3-12 membered heterocycle; B represents a 3-12 membered heterocycle; C is a 3-12 membered heterocycle; m is an integer from 0 to 3 and n is an integer from 1 to 3. In some embodiments, H is a 6-12 membered bicyclic heterocycle optionally substituted with one or more R ⁵⁰ ; A represents a 3-12 membered heterocycle; B represents a 6-12 membered bicyclic heterocycle; C is a 3-12 membered heterocycle; m is an integer from 0 to 3 and n is an integer from 1 to 3. In some embodiments, H is a 5-12 membered heterocycle optionally substituted with one or more R ⁵⁰ ; A represents a 3-12 membered heterocycle; B is a 3-12 membered heterocycle and C is a 3-12 membered heterocycle. In some embodiments, H is a 6-12 membered bicyclic heterocycle optionally substituted with one or more R ⁵⁰ ; A represents a 3-12 membered heterocycle; B is a 6-12 membered bicyclic heterocycle and C is a 3-12 membered heterocycle. In some embodiments, H is a 6-12 membered bicyclic heterocycle optionally substituted with one or more R ⁵⁰ ; A is selected from piperidinylene and piperazinylene; B is a 6-12 membered bicyclic heterocycle and C is a 3-12 membered heterocycle. In some embodiments, H is a 6-12 membered bicyclic heterocycle optionally substituted with one or more R ⁵⁰ ; A is selected from piperidinylene and piperazinylene; B represents a 6-12 membered bicyclic heterocycle; m is an integer from 0 to 3 and n is an integer from 1 to 3. In some embodiments, H is thienopyrimidinyl optionally substituted with one or more R ⁵⁰ ; A is a 3-12 membered heterocycle and B is a 6-12 membered bicyclic heterocycle. In some embodiments, H is thienopyrimidinyl optionally substituted with one or more R ⁵⁰ ; A represents 3-12

- 29 038388 membered heterocycle; B represents a 6-12 membered bicyclic heterocycle; m is an integer from 0 to 3 and n is an integer from 1 to 3. In some embodiments, H is a 9-10 membered bicyclic heterocycle optionally substituted with one or more R ⁵⁰ ; A is a 5 to 7 membered heterocycle; and B is a 9 membered bicyclic heterocycle, each of said heterocycles containing at least one nitrogen atom. In some embodiments, H is a 9-10 membered bicyclic heterocycle optionally substituted with one or more R ⁵⁰ ; represents a 5-7 membered heterocycle; B is a 9-membered bicyclic heterocycle and n is an integer from 1 to 3, each of said heterocycles containing at least one nitrogen atom.

In some embodiments, for a compound of formula (I), L ¹ contains less than 10 atoms, L ² contains less than 10 atoms, and L ³ contains less than 20 atoms. In some embodiments, L ¹ , L ^2, and L ³ each contain at least 1 atom, such as at least 2 atoms. In some embodiments, L ¹ , L ² and L ³ are each independently selected from a bond, -O-, -S-, -N (R ⁵¹ ), -N (R ⁵¹ ) CH2-, -C (O ), -C (O) O, -OC (O), -C (O) N (R ⁵¹ ), -N (R ⁵¹ ) C (O), -N (R ⁵¹ ) C (O) N (R ⁵¹ ), -S (O) 2, -S (O), -N (R ⁵¹ ) S (O) 2, -S (O) 2N (R ⁵¹ ), -N (R ⁵¹ ) S (O) 2N (R ⁵¹ ) -, alkylene, alkenylene, heteroalkylene and heteroalkenylene. In some embodiments, L ¹ , L ^2, and L ³ are each independently selected from —CH2—, —CH ₂ CH ₂ -, —CH ₂ CH (CH ₃ ) -, —N (R ⁵¹ ) -, —N (R ⁵¹ ) CH2-, -N (R ⁵¹ ) C (O) - and -N (R ⁵¹ ) S (O) 2-. In some embodiments, L ^{1 is} selected from —O—, —S—, —N (R ⁵¹ ) -, —N (R ⁵¹ ) CH2—, —C (O) -, —C (O) O—, - OC (O) -, -C (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) -, -N (R ⁵¹ ) C (O) N (R ⁵¹ ) -, -S ( O) 2, -S (O) -, -N (R ⁵¹ ) S (O) 2-, -S (O) 2N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) 2N (R ⁵¹ ) -, alkylene, alkenylene, heteroalkylene and heteroalkenylene and L ² and L ^{3 are} independently selected from C1-4 alkylene optionally substituted with one or more R ⁵⁰ . In some embodiments, L ¹ , L ^2, and L ³ are each independently selected from —O—, —S—, —N (R ⁵¹ ) -; C1-4 alkylene and 1-4 membered heteroalkylene, each of which is optionally substituted with one or more R ⁵⁰ . In some embodiments, L ¹ is —NH—, L ² is —CH2—, and L ³ is C _1-4 alkylene optionally substituted with one or more R ⁵⁰ .

In some embodiments, for a compound of formula (II), L ¹ contains less than 10 atoms, L ² contains less than 10 atoms, and L ³ contains less than 20 atoms. In some embodiments, L ¹ , L ^2, and L ³ each contain at least 1 atom, such as at least 2 atoms. In some embodiments, L ¹ and L ² are each independently selected from a bond, -O-, -S-, -N (R ⁵¹ ) -, -N (R ⁵¹ ) CH2-, -C (O) - , -C (O) -, -OC (O) -, -C (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) -, -N (R ⁵¹ ) C (O) N (R ⁵¹ ) -, -S (O) 2-, -S (O) -, -N (R ⁵¹ ) S (O) 2-, -S (O) 2N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) 2N (R ⁵¹ ) -, alkylene, alkenylene, heteroalkylene and heteroalkenylene, and L ^{3 is} selected from C1-10 alkylene and C _2-10 alkenylene substituted with one or more R ⁵⁶ and optionally further substituted with one or more R ⁵⁰ . In some embodiments, L ¹ and L ² are each independently selected from —CH ₂ -, —N (R ⁵¹ ) -, —N (R ⁵¹ ) CH2-, —N (R ⁵¹ ) C (O) -, and —N (R ⁵¹ ) S (O) 2 - and L ^{3 is} selected from C _1-10 alkylene and C _2-10 alkenylene substituted with one or more R ⁵⁶ and optionally further substituted with one or more R ⁵⁰ . In some embodiments, L ^{1 is} selected from —O—, —S—, —N (R ⁵¹ ) -, —N (R ⁵¹ ) CH2—, —C (O) -, —C (O) -, —OC (O) -, -C (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) -, -N (R ⁵¹ ) C (O) N (R ⁵¹ ) -, -S (O ) 2-, -S (O) -, -N (R ⁵¹ ) S (O) 2-, -S (O) 2N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) 2N (R ⁵¹ ) -, alkylene, alkenylene, heteroalkylene and heteroalkenylene and L ² is C 1-4 alkylene optionally substituted with one or more R ⁵⁰ and L ³ is C 1-4 alkylene substituted with one or more R ⁵⁶ and optionally further substituted with one or more R ⁵⁰ . In some embodiments, L ¹ and L ² are each independently selected from O-, -S-, -N (R ⁵¹ ) -; C1-4 alkylene and 1-4 membered heteroalkylene, each of which is optionally substituted with one or more R ⁵⁰ , and L ³ is C1-4 alkylene substituted with one or more R ⁵⁶ and optionally further substituted with one or more R ⁵⁰ . In some embodiments, L ¹ is —NH—, L ² is —CH 2—, and L ³ is C _1-4 alkylene substituted with one or more R ⁵⁶ and optionally further substituted with one or more R ⁵⁰ .

In certain aspects, for a compound of formula (I):

H is a 5-12 membered heterocycle optionally substituted with one or more R ⁵⁰ ;

A, B and C are each independently selected from a 3-12 membered heterocycle;

L ¹ , L ² and L ³ are each independently selected from a bond, -O-, -S-, -N (R ⁵¹ ) -, -N (R ⁵¹ ) CH ₂ -, -C (O) -, - C (O) -, -OC (O) -, -OC (O) -, -C (O) N (R ⁵¹ ) -, -C (O) N (R ⁵¹ ) C (O) -, -C (O) N (R ⁵¹ ) C (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) -,

-N (R ⁵¹ ) C (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) O-, -OC (O) 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 (O) 2 -, -OS (O) -, -S (O) O-, -S (O) -, -OS (O) 2-, -S (O) 2O-, -N (R ⁵¹ ) S (O) 2-, -S (O) 2N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) -, -S (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) ₂ N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) N (R ⁵¹ ) -; alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene and heteroalkynylene, each of which is optionally substituted with one or more R ⁵⁰ , with two R ⁵⁰ groups attached to the same atom or different atoms of any of L ¹ , L ² or L ³ , can optionally form a ring together;

- 30 038388

R ^a , R ^b and R ^C are each independently selected in each occurrence from R ⁵⁰ or two groups R ^A , two groups

R ^B or two R ^C groups attached to the same atom or different atoms may optionally form a ring together;

m is an integer from 0 to 3;

n is an integer from 1 to 3;

p is an integer from 0 to 6;

R ^{50 is} independently selected at each occurrence from:

halogen, -NO2, -CN, -OR ⁵² , -SR ⁵² , -N (R ⁵² ) ₂ , -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N ( R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, - NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) ( R ⁵² ) 2, = O, = S, = N (R ⁵² );

C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO2, —CN, —OR ⁵² , —SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O ) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² ,

-NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C _3-12 carbocycle and 3-12 membered heterocycle; and

C _3-12 carbocycle and 3-12 membered heterocycle, each C _{3-1 2} carbocycle and 3-12 membered heterocycle in R ^{50 is} independently optionally substituted with one or more substituents selected from halogen, —NO2, —CN, - OR ⁵² , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O ) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S = N (R ⁵² ), Cl _-6 alkyl, ^^ haloalkyl, C _2-6 alkenyl and C _2-6 alkynyl;

R ^{51 is} independently selected at each occurrence from:

hydrogen, —C (O) R ⁵² , —C (O) OR ⁵² , —C (O) N (R ⁵² ) 2, —C (O) NR ⁵³ R ⁵⁴ ;

Cl _-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO ₂ , —CN, —OR ⁵² , —SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O ) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² ,

-NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C _{3-1 2} carbocycle and 3-12 membered heterocycle; and

C _3- l ₂ carbocycle and 3-12 membered heterocycle, each C _3- l ₂ carbocycle and 3-12 membered heterocycle in R ^{51 is} independently optionally substituted with one or more substituents selected from halogen, —NO2, —CN, -OR ⁵² , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC ( O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl and C _2-6 alkynyl;

R ^{52 is} independently selected at each occurrence from hydrogen; and

C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, 1-6 membered heteroalkyl, C _3-12 carbocycle and 3-12 membered heterocycle, each of which is optionally substituted with halogen, —CN, —NO ₂ , -NH2, -NHCH _3, -NHCH2CH3, = O, -OH, -OCH _3, -OCH2CH3, C _3-12 carbocycle or a 3-6-membered heterocycle;

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 selected from:

halogen, -NO2, -CN, -SR ⁵² , -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵⁸ , -S ((WV -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) OR ⁵² , - OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ ,

-C (O) NH (C _1-6 alkyl), -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = S, = N (R ⁵² ); and

C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl, each of which is independently substituted at each occurrence with one or more substituents selected from —NO ₂ , —CN, —SR ⁵² , —N (R ⁵² ) ₂ , -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2,

-NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2 , -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) R ⁵² ) 2, = S and = N (R ⁵² ); and

R ^{58 is} selected from hydrogen and C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, 1-6 membered heteroalkyl, C _3-12 carbocycle, and 3-12 membered heterocycle, each of which is optionally substituted with halogen , -CN, -NO ₂ , -NH2, -NHCH3, -NHCH2CH3, = O, -OH, -OCH ₃ , -OCH2CH3, C _3-12 carbocycle or 3-6-membered heterocycle, and for a compound or salt of formula ( I) when C is azetidinylene, piperidinylene or piperazinylene and R ⁵⁷ is —S (= O) 2R ⁵⁸ , —S (= O) 2N (R ⁵² ) 2 or —NR ⁵² S (= O) 2R ⁵² :

- 31,038388 p is an integer from 1 to 6; and / or

L ^{3 is} substituted with one or more R ⁵⁰ , and L ^{3 is} not —CH2CH (OH) -.

In certain aspects, for a compound of formula (II):

H is a 5-12 membered heterocycle optionally substituted with one or more R ⁵⁰ ;

A, B and C are each independently selected from a 3-12 membered heterocycle;

L ¹ and L ² are each independently selected from a bond, -O-, -S-, -N (R ⁵¹ ) -, -N (R ⁵¹ ) CH ₂ -, -C (O) -, -C (O ) O-, -OC (O) -, -OC (O) O-, -C (O) N (R ⁵¹ ) -, -C (O) N (R ⁵¹ ) C (O) -, -C ( O) N (R ⁵¹ ) C (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) -,

-N (R ⁵¹ ) C (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) -, -OC (O) 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 (O) 2- , -OS (O) -, -S (O) O-, -S (O) -, -OS (O) 2-, -S (O) 2O-, -N (R ⁵¹ ) S (O) 2 -, -S (O) 2N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) -, -S (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) 2N ( R ⁵¹ ) -, -N (R ⁵¹ ) S (O) N (R ⁵¹ ) -; alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene and heteroalkynylene, each of which is optionally substituted with one or more R ⁵⁰ , wherein two R ⁵⁰ groups attached to the same atom or different atoms of any of L ¹ or L ² can together optionally form a ring;

L ^{3 is} selected from C _1-6 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 ^A groups, two R ^B groups, or two R ^C groups attached to the same atom or different atoms, m is an integer from 0 to 3;

n is an integer from 1 to 3;

p is an integer from 0 to 6;

R ^{50 is} independently selected at each occurrence from:

halogen, -NO2, -CN, -OR ⁵² , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) ₂ , -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² );

C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO ₂ , —CN, —OR ⁵² , —SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² ,

-NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C _3-12 carbocycle and 3-12 membered heterocycle; and

C _3-12 carbocycle and 3-12 membered heterocycle, each C _3-12 carbocycle and 3-12 membered heterocycle in R ⁵⁰ independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR ⁵² , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2 , -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S , = N (R ⁵² ), C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl and C _2-6 alkynyl;

R ^{51 is} independently selected at each occurrence from:

hydrogen, —C (O) R ⁵² , —C (O) OR ⁵² , —C (O) N (R ⁵² ) 2, —C (O) NR ⁵³ R ⁵⁴ ;

C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO2, —CN, —OR ⁵² , —SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O ) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² ,

-NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C _3-12 carbocycle and 3-12 membered heterocycle; and a C _3-12 carbocycle and a 3-12 membered heterocycle, each C _3-12 carbocycle and 3-12 membered heterocycle in R ⁵¹ independently optionally substituted with one or more substituents selected from halogen, —NO2, —CN, - OR ⁵² , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O ) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl and C _2-6 alkynyl;

R ^{52 is} independently selected at each occurrence from hydrogen; and C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, 1-6 membered heteroalkyl, C _3-12 carbocycle and 3-12 membered heterocycle, each of which is optionally substituted with halogen, -CN, - NO2, -NH2, -NHCH3, -NHCH2CH3, = O, -OH, -OCH3, -OCH2CH3, C _3-12 carbocycle or 3-6 membered heterocycle;

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:

-NO2, -OR ⁵⁹ , -SR ⁵² , -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² ,

- 32 038388

-NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2,

-OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O ) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2,

-C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C _1-10 alkyl , C _2-10 alkenyl and C _2-10 alkynyl,

A C _3-12 carbocycle and a 3-12 membered heterocycle, each C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl in R ⁵⁶ independently optionally substituted at each occurrence with one or more substituents selected from halogen, -NO ₂ , -CN, -OR ⁵⁹ , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S ( = O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² ,

-NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C _3-12 carbocycle and 3-12 membered heterocycle;

wherein each C _3-12 carbocycle and 3-12 membered heterocycle in R ^{56 is} independently optionally substituted with one or more substituents selected from halogen, —NO2, —CN, —OR ⁵² , —SR ⁵² , —N (R ⁵² ) 2 , -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , - NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O ) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C _1-6 alkyl , C _1-6 haloalkyl, C _2-6 alkenyl and C _2-6 alkynyl; and additionally, wherein R ⁵⁶ optionally forms a bond to ring C and R ^{59 is} independently selected at each occurrence from C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, 1-6 membered heteroalkyl, C _3-12 carbocycle and 312 membered heterocycle, each of which is optionally substituted with halogen, -CN, -NO ₂ , -NH ₂ , -NHCH ₃ , -NHCH ₂ CH ₃ , = O, -OH, -OCH ₃ , -OCH ₂ CH ₃ , C _3-12 carbocycle or 3-6 membered heterocycle, where for a compound or salt of formula (II) when R ⁵⁶ is —CH3, L ^{3 is} not further substituted with —OH, —NH2, or —CN.

In certain aspects, for a compound of formula (I):

H is thienopyrimidinyl optionally substituted with one or more R ⁵⁰ ;

A is selected from piperidinylene and piperazinylene;

B represents indolylene;

L ¹ and L ² are each independently selected from —O—, —S—, —NH— and —CH ₂ -;

L ^{3 is} selected from a bond, -O-, -S-, -N (R ⁵¹ ) -, -N (R ⁵¹ ) CH2-, -CB) -, -C (O) -, -OC (O) -, -OC (O) -, -C (O) N (R ⁵¹ ) -, -C (O) N (R ⁵¹ ) C (O) -, -C (O) N (R ⁵¹ ) C (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) -, -N (R ⁵¹ ) C (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) O-, -OC (O) 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 (O) 2-, -OS (O) -, -S (O) O-, -S (O) -, -OS (O) 2-, -S (O) 2O-, -N (R ⁵¹ ) S (O) 2-, -S (O) 2N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) -, -S (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) 2N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) N (R ⁵¹ ) -; alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene and heteroalkynylene, each of which is optionally substituted with one or more R ⁵⁰ , with two R ⁵⁰ groups attached to the same atom or different atoms of any of L ¹ , L ² or L ³ , together can 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 ^A groups, two R ^B groups, or two R ^C groups attached to the same atom or different atoms may optionally form together ring;

m 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 selected from:

-S (= O) R ⁵² , -S (= O) 2R ⁵⁸ , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C ( O) NR ⁵³ R ⁵⁴ , -C (O) NH (C1-6 alkyl), -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2 ; and

C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl, each of which is independently substituted at each occurrence with one or more substituents selected from —NO2, —CN, —SR ⁵² , —N (R ⁵² ) 2 , -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , - NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2,

-NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2 , -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) R ⁵² ) 2, = S and = N (R ⁵² ); and

R ^{58 is} selected from hydrogen; and C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, 1-6 membered heteroalkyl, C _3-12 carbocycle and 3-12 membered heterocycle, each of which is optionally substituted with halogen, -CN, - NO ₂ , -NH ₂ , -NHCH ₃ , -NHCH ₂ CH ₃ , = O, -OH, -OCH ₃ , -OCH ₂ CH ₃ , C _3-12 carbocycle or 3-6-membered heterocycle, and for the connection or salts of formula (I) when C is azetidinylene, piperidinylene or piperazinylene and R ⁵⁷ is —S (= O) 2R ⁵⁸ , —S (= O) 2N (R ⁵² ) 2 or —NR ⁵² S (= O) 2R ⁵² :

p is an integer from 1 to 6; and / or

L ^{3 is} substituted with one or more R ⁵⁰ , and L ^{3 is} not —CH2CH (OH) -.

In certain aspects, for a compound of formula (II):

H is thienopyrimidinyl optionally substituted with one or more R ⁵⁰ ;

A is selected from piperidinylene and piperazinylene;

- 33 038388

B represents indolylene;

L ¹ and L ² are each independently selected from —O—, —S—, —NH— and —CH ₂ -;

L ^{3 is} selected from C _1-6 α-alkyl, 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 ^A groups, two R ^B groups, or two R ^C groups attached to the same atom or different atoms, together may optionally form bridge or ring;

m 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:

-OR ⁵⁹ , = O, C1-10αalkyl, C2-10αalkenyl and C2-10αalkynyl, each C1-10αalkyl, C2-10alkenyl and C2-10alkynyl in R ⁵⁶ independently optionally substituted at each occurrence with one or more substituents selected from halogen, -NO2, -CN, -OR ⁵⁹ , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = o, = s, = N (R ⁵² ), C _3-12 carbocycle and 3-12 membered heterocycle;

wherein each C _3-12 carbocycle and 3-12 membered heterocycle in R ^{51 is} independently optionally substituted with one or more substituents selected from halogen, —NO2, —CN, —OR ⁵² , —SR ⁵² , —N (R ⁵² ) 2 , -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , - NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O ) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C _1-6 α alkyl , C _1-6 halogenaalkyl, C _2-6 alkenyl and C _2-6 alkynyl; and further wherein R ⁵⁶ optionally forms a bond to a ring C and R ⁵⁹ is independently selected at each occurrence from C _1-20 alkyl, C _2-20 αlkenila, C _2-20 alkynyl, 1-6 membered heteroalkyl, C _3-12 carbocycle and 3-12 membered heterocycle, each of which is optionally substituted with halogen, -CN, -NO ₂ , -NH ₂ , -NHCH ₃ , -NHCH ₂ CH ₃ , = O, -OH, -OCH ₃ , -OCH ₂ CH ₃ , a C _3-12 carbocycle and a 3-6 membered heterocycle, wherein for a compound or salt of formula (II) when R ⁵⁶ is —CH3, L ^{3 is} not further substituted with —OH, —NH2, or —CN.

In certain aspects, a compound of formula (I) can be represented by the following formula:

In some embodiments, R ^{1 is} selected from R ⁵⁰ . In some embodiments, R ¹ is C _1-3 haloalkyl, such as —CH ₂ CF ₃ . In some embodiments, R ^{2 is} selected from R ⁵⁰ . In some embodiments, R ^{2 is} selected from hydrogen, halogen, —OH, —OR ⁵² , —NH2, —N (R ⁵² ) 2, —CN, C _1-3 alkyl, C _1-3 alkyl — OR ⁵² , C _1-3 alkylN (R ⁵² ) 2, C1-3 haloalkyl, C2-3 alkenyl and C2-3 alkynyl. In some embodiments, R ^{2 is} selected from halogen, —OH, —OR ⁵² , —NH2, —N (R ⁵² ) 2, —CN, C1-3 alkyl, —CH2OH, —CH2OR ⁵² , —CH2NH ₂ , —CH ₂ N (R ⁵² ) 2, C1-3alkyl-N (R ⁵² ) 2 C _1-3 gαlogenoalkyl, C _2-3 alkenyl and C _2-3 alkynyl, for example, R ^{2 is} selected from -OH, -OR ⁵² , -NH2 , —N (R ⁵² ) 2, —CN, and C1-2αalkyl. Optionally, R ^{2 is} selected from —NH2, —CH3, —OCH3, —CH2OH, and —NHCH3. In some embodiments, R ^{3 is} selected from hydrogen, halogen, —OH, —N (R ⁵² ) 2, —CN, —C (O) OR ⁵² , C1-3αalkyl, and C1-Zrαlogenαalkyl. In some embodiments, R ^{51 is} selected from hydrogen and alkyl, for example, R ⁵¹ is hydrogen. In some embodiments, R ^{A is} selected from halogen, CN-, -OR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -NR ⁵² C (O) R ⁵² , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , = O, C1-10 alkyl, C _2-10 α-alkenyl and C _2-10 α-alkyl, optionally substituted C _1-10 α-alkyl, optionally substituted C _2-10 α-alkenyl, and optionally substituted C _2-10 α-alkyl. In some embodiments, m is 0. In some embodiments, L ^{2 is} selected from —O—, —N (R ⁵¹ ) -, —N (R ⁵¹ ) CH ₂ -, —C (O) N (R ⁵¹ ) -, -N (R ⁵¹⁾ C (O) -, -N (R ⁵¹⁾ S (O) 2-, -S (O) 2N (R ⁵¹⁾ -, and C _1-4 C1-4αlkilena geteroαlkilena. In some embodiments, L ² is C _1-4 α-alkyl, optionally substituted with one or more R ⁵⁰ . In some embodiments, L ² is C _1-2 alkyl, optionally substituted with one or more R ⁵⁰ . In some embodiments, L ^{2 is} selected from —CH2—, —N (R ⁵¹ ) -, —N (R ⁵¹ ) CH2—, —N (R ⁵¹ ) C (O) -, and —N (R ⁵¹ ) S ( O) ₂ -. In some embodiments, L ² is —CH2—. In some embodiments, R ^{B is} present at one or more positions of the indole, for example, at the 2, 3, 4, or 6 position of the indole. In some embodiments, R ^{B is} selected from halogen, CN-, -OR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -NR ⁵² C (O) R ⁵² , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , = O, C1-1oalkyl,

- 34 038388

C _2-10 alkenyl; and C _2-10 alkynyl, optionally substituted C _1-10 alkyl, optionally substituted C _2-10 alkenyl, and optionally substituted C _2-10 alkynyl. In some embodiments, R ^{B is} selected from halogen, —CN, —OR ⁵² , —N (R ⁵² ) 2, —NR ⁵³ R ⁵⁴ , C1-3αalkyl, and optionally substituted C _1-3 alkyl, for example, R ^{B is} selected from halogen , —CN, —OR ⁵² , —N (R ⁵² ) 2, —NR ⁵³ R ⁵⁴ and C1-2 alkyl. In some embodiments, n is an integer from 1 to 4, such as an integer from 2 to 3. In some embodiments, n is 2. In some embodiments, L ^{3 is} selected from C1-6 alkylene, C2-6 alkenylene, and C2 -6 alkynylene, each of which is substituted with one or more R ⁵⁰ . In some embodiments, L ³ is C1-6 alkylene optionally substituted with one or more R ⁵⁰ . In some embodiments, L ³ is C2 alkylene substituted with at least one C1-3 alkyl or C1-3 haloalkyl, and optionally further substituted with one or more R ⁵⁰ . In some embodiments, L ^{3 is} substituted with = O, C1-6 alkyl, C _1-6 haloalkyl, C _1-3 alkyl (cyclopropyl), C _1-3 alkyl (NR ⁵² C (O) R ⁵² ), or —O (C1 -6alkyl). In some embodiments, L ^{3 is} substituted with —CH 3. In some embodiments, _R 60X of the invention L ^{3 is} selected from ^and , wherein R ⁵⁰ is optionally methyl. In some embodiments, C is a 3-12 membered heterocycle, such as a 5-12 membered heterocycle. In some embodiments, the heterocycle is saturated. In some embodiments, C is selected from a 5-7 membered monocyclic heterocycle, an 8-10 membered fused bicyclic heterocycle, and a 7-12 membered spirocyclic heterocycle. In some embodiments, the heterocycle contains at least one nitrogen atom, such as one or two nitrogen atoms. In some embodiments, C contains at least one ring nitrogen. In some embodiments, C is selected from piperidinyl and piperazinyl, such as the invention

In some embodiments, C is selected from

In some embodiments, C is selected from

In some embodiments, C is selected from

optionally substituted with one or more R ^C.

some

R ^c R ⁵⁷

In xR ⁵⁷

I ^N embodiments of the invention C is selected

R ⁵⁷

R ^c and

wherein R ^{57 is} selected from -S (= O) R ⁵² , -S (= ObR ⁵² , -S (= O) 2N (R ⁵² ) 2, ⁵² ; and C _1-10 alkyl substituted with one or more substituents, you

-S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R selected from -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ and -NR ⁵² S (= O) 2R ⁵² .

In some embodiments, R ^{57 is} selected from —S (= O) R ⁵² , —S (= O) 2R ⁵⁸ , —S (= O) 2N (R ⁵² ) 2, and —NR ⁵² S (= O) 2R ⁵² for example R ^{57 is} selected from -S (= O) CH3, -S (= O) 2CH3, -S (= O) 2NH2, -NHS (= O) ₂ CH ₃ and -S (= O) ₂ NHCH ₃ . In some embodiments, C is selected from

35 038388 embodiment of the invention RC is selected from -N (R ⁵² ) ₂ , -NR ⁵³ R ⁵⁴ ,

-C (O) OR ⁵² , -NR ⁵² c (o) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) ₂ ,

options

-C (O) R ⁵² ,

In some -NR ⁵² S (= O) 2R ⁵² ,

-NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2 and -C (O) NR ⁵³ R ⁵⁴ . In some embodiments, R ^{c is} selected from —N (R ⁵² ) 2, —NR ⁵³ R ⁵⁴ , —NR ⁵² S (= O) 2R ⁵² , —C (O) R ⁵² , —C (O) OR ⁵² , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O ) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , C1-6αalkyl and C _1-6 αalkyl substituted with N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -C (O) R ⁵² , -C (O) OR ⁵² , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) ₂ or -C (O) NR ⁵³ R ⁵⁴ . In some embodiments, C is selected from

e

Λ

Me

In some embodiments, RC is selected from -C (O) R ⁵² , -S (= O) R ⁵² , -S (= O) ₂ R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) ₂ NR ⁵³ R ^54, -NR ⁵² S (= O) 2R ^52, = O, C1-3αlkila, c _1-W gαlogenαlkila or two groups R ^c, attached to different atoms together may form a bridge c _{1 -3} . In some embodiments, R ^{c is} selected from C1-3alkyl and C1-Zhalogenalkyl such as —CH3. In some embodiments, p is selected from an integer from 0 to 4, for example, p is selected from an integer from 0 to 2. In some embodiments, p is 0. In some embodiments, R ^{57 is} selected from -S (= O) 2R ⁵⁸ , -S (= O) 2N (R ⁵² ) 2, -S (= O) ₂ NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) ₂ R ⁵² , -NR ⁵² S (= O) 2N ( R ⁵² ) 2, -NR ⁵² S (= O) ₂ NR ⁵³ R ⁵⁴ , -C (o) NH (C1-6alkyl), -C (O) NR ⁵³ R ⁵⁴ ; and C1-6alkila and _C2-6 alkenyl, each of which is independently substituted at each occurrence with one or more substituents selected from -S (= O) ₂ R ^58, -S (= O) 2N (R ⁵²⁾ 2, - S (= O) ₂ NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) ₂ R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) ₂ NR ⁵³ R ⁵⁴ , -C (O) NH (C1-6alkyl), -C (O) NR ⁵³ R ⁵⁴ . In some embodiments, R ^{57 is} selected from -S (= O) 2R ⁵⁸ , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ and C1-6alkyl substituted with one or more substituents selected from -S (= O) 2R ⁵⁸ , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2 and -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ . In some embodiments, R ^{57 is} selected from —S (= O) R ⁵² , —S (= O) 2R ⁵⁸ , —S (= O) 2N (R ⁵² ) 2, and —NR ⁵² S (= O) 2R ⁵² ... In some embodiments, R ^{57 is} selected from —S (= O) CH3,

-S (= O) 2CH3, -S (= O) 2NH2, -NHS (= O) 2CH3 and -S (= ObNHCH ₃ .

In certain aspects, a compound of formula (I) can be represented by the following formula:

In some embodiments, R ^{2 is} selected from R ⁵⁰ . In some embodiments, R ^{2 is} selected from hydrogen, halogen, —OH, —OR ⁵² , —NH2, —N (R ⁵² ) 2, —CN, C _1-3 alkyl, C _1-3 alkyl — OR ⁵² , C1 -3alkyl-N (R ⁵² ) 2, C _1-3 haloalkyl, C _2-3 alkenyl and C _2-3 alkynyl. In some embodiments, R ^{2 is} selected from halogen, —OH, —OR ⁵² , —NH2, —N (R ⁵² ) 2, —CN, C _1-3 alkyl, —CH ₂ OH, —CH2OR ⁵² , —CH2NH2, -CH2n (r ⁵² ) 2, C _1-3 alkyl-N (R ⁵² ) ₂ , C _1-3 haloalkyl, C _2-3 alkenyl and C _2-3 alkynyl, for example, R ^{2 is} selected from -OH, -OR ⁵² , —NH2, —N (R ⁵² ) 2, —CN and C _1-2 alkyl. Optionally, R ^{2 is} selected from —NH ₂ , —CH ₃ , —OCH ₃ , —CH ₂ OH, and —NHCH ₃ . In some embodiments, R ^B

- 36 038388 selected from halogen, CN-, -OR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -NR ⁵² C (O) R ⁵² ,

-C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , = O, C1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl optionally substituted

C _1-10 α-alkyl, optionally substituted C _2-10 alkenyl and optionally substituted C _2-10 alkynyl.

In some embodiments, R ^{B is} selected from halogen, —CN, —OR ⁵² , —N (R ⁵² ) 2, —NR ⁵³ R ⁵⁴ , C1-3 alkyl, and optionally substituted C _1-3 alkyl, for example, R ^{B is} selected from halogen, —CN, —OR ⁵² , —N (R ⁵² ) 2, —NR ⁵³ R ⁵⁴ and C1-2αalkyl. In some embodiments, L ^{3 is} selected from C1-6 alkylene and C2-6 alkenylene and C2-6 alkynylene, each of which is substituted with one or more R ⁵⁰ . In some embodiments, L ³ is C1-6 alkylene optionally substituted with one or more R ⁵⁰ . In some embodiments, L ³ is C _2-6 αalkylene substituted with at least one C _1-3 alkyl or C _1-3 haloalkyl, and optionally further substituted with one or more R ⁵⁰ . In some embodiments, L ^{3 is} substituted with = O, C1-6 alkyl, C1-6 rαloalkyl, C1-3 alkyl (cyclopropyl), C1-3 alkyl (NR ⁵² C (O) R ⁵² ), or —O (C1-6 alkyl). In some embodiments, L ^{3 is} substituted with —CH 3. In some embodiments, L ³ youIR50j < _R 50., X _x n and n, and R is optionally methyl. In some embodiments, C is a 3-12 membered heterocycle, such as a 5-12 membered heterocycle. In some embodiments, the heterocycle is saturated. In some embodiments, C is selected from a 5-7 membered monocyclic heterocycle, an 8-10 membered fused bicyclic heterocycle, and a 7-12 membered spirocyclic heterocycle. In some embodiments, the heterocycle contains at least one nitrogen atom, such as one or two nitrogen atoms. In some embodiments, C contains at least one ring nitrogen.

In some embodiments, C is selected from piperidinyl and piperazinyl, ta-

who like

In some embodiments, C is selected from

In some embodiments, C is selected from

In some embodiments, C is selected from

but substituted with one or more R ^C.

optional

In some variants

implementation of the invention C is selected from

wherein R ^{57 is} selected from -S (= O) R ⁵² , -S (= O) ₂ R ⁵² , -S (= O) 2N (R ⁵² ) 2,

-S (= O) ₂ NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² ; and C1-10 alkyl substituted with one or more substituents selected from -S (= O) R ⁵² , -S (= O) ₂ R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O ) ₂ NR ⁵³ R ⁵⁴ and -NR ⁵² S (= O) ₂ R ⁵² . In some embodiments, R ^{57 is} selected from —S (= O) R ⁵² , —S (= O) ₂ R ⁵⁸ , —S (= O) 2N (R ⁵² ) 2, and —NR ⁵² S (= O) ₂ R ⁵² , for example R ^{57 is} selected from -S (= O) CH3, -S (= O) 2CH3, -S (= O) 2NH2, -NHS (= O) 2CH3 and -S (= O) 2NHCH3. Some 37 038388

In other embodiments, C is selected from

R ^c R ^c

X -R ⁵⁷ A. xR ⁵⁷ p Ν p Ν

In some embodiments, R ^{C is} selected from —N (R ⁵² ) ₂ ,

-nr ⁵³ r ⁵⁴ ,

-NR ⁵² S (= O) 2R ⁵² , -C (O) R ⁵² , -C (O) OR ⁵² , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) ₂ and -C (O) NR ⁵³ R ⁵⁴ . In some embodiments, R ^{C is} selected from —N (R ⁵² ) 2, —NR ⁵³ R ⁵⁴ , —NR ⁵² S (= O) 2R ⁵² , —C (O) R ⁵² , —C (O) OR ⁵² , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O ) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , C1-6alkyl and C1-6αalkyl substituted with -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -C (O) R ⁵² , -C (O) OR ⁵² , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2 or -C (O) NR ⁵³ R ⁵⁴ .

In some embodiments, C is selected from

In some embodiments, R ^{C is} selected from —C (O) R ⁵² , —S (= O) R ⁵² , —S (= O) ₂ R ⁵² , —S (= O) 2N (R ⁵² ) 2, - S (= O) ₂ NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) ₂ R ⁵² , = O, C1-Zαalkyl and C1-3-haloalkyl or two R ^C groups attached to different atoms can together form a C1- 3. In some embodiments, R ^{C is} selected from C1-Zαalkyl and C1-3-haloαalkyl such as -CH3. In some embodiments, p is selected from an integer from 0 to 4, for example, p is selected from an integer from 0 to 2. In some embodiments, p is 0. In some embodiments, R ^{57 is} selected from -S (= O ) 2R ⁵⁸ , -S (= O) 2N (R ⁵² ) 2, -S (= O) ₂ NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) ₂ R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) NH (C1-6αalkyl), -C (O) NR ⁵³ R ⁵⁴ ; and C1-6αalkylene and

C _2-6 alkenylene, each of which is independently substituted in each occurrence with one or more substituents selected from -S (= O) ₂ R ⁵⁸ , -S (= O) 2N (R ⁵² ) 2, -S (= O) ₂ NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) ₂ R ⁵² ,

-NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) NH (C1-6αalkyl), -C (O) NR ⁵³ R ⁵⁴ . In some embodiments, R ^{57 is} selected from -S (= O) 2R ⁵⁸ , -S (= o) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ and C1-6 alkyl substituted with one or more substituents selected from -S (= ObR ⁵⁸ , -S (= ObN (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2 and -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ In some embodiments, R ^{57 is} selected from —S (= O) R ⁵² , —S (= O) 2R ⁵⁸ , —S (= O) 2N (R ⁵² ) 2, and -NR ⁵² S (= O) ₂ R ⁵² In some embodiments, R ⁵⁷ is selected from -S (= O) CH3, -S (= O) 2CH3, -S (= O) 2NH2, -NHS (= O) 2CH3 and -S (= O) 2NHCH ₃ .

In certain aspects, a compound of formula (I) can be represented by the following formula:

In some embodiments, C is selected from a 5-7 membered monocyclic heterocycle such as piperidinyl and piperazinyl. In some embodiments, R ^{50 is} selected from deuterium, C1-4 alkyl, C1-4 haloalkyl, and —OR ⁵² , for example, R ⁵⁰ is methyl. In some embodiments, R ^{57 is} selected from —S (= O) R ⁵² , —S (= O) 2R ⁵⁸ , —S (= O) 2N (R ⁵² ) 2, and —NR ⁵² S (= O) 2R ⁵² for example, R ^{57 is} selected from -S (= O) CH3, -S (= O ^ CH3, -S (= O ^ NH2, -NHS (= O) 2CH3 and -S (= O) 2NHCH3. In some embodiments R ⁵⁷ is —S (= O) 2CH _3. In some embodiments, R ⁵⁰ is methyl and R ⁵⁷ is —S (= O) ₂ CH _3. In some embodiments, R ^{2 is} selected from hydrogen , halogen, -OH, -OR ⁵² , -NH2, -N (R ⁵² ) 2, -CN, C1-zalkyl, -CH2OH, -CH2OR ⁵² , -CH2NH2,

- 38 038388

-CH2N (R ⁵² ) 2, C1.3 alkyl-N (R ⁵² ) 2, C1. ₃ haloalkyl, C ₂ . ₃ alkenyl and C ₂ . ₃ alkynyl, for example R ^{2 is} selected from

-OH, -OR ⁵² , -NH2, -N (R ⁵² ) 2, -CN and C1. ₂ alkyl. In some embodiments, R ² is methyl or —NHCH3. In some embodiments, R ² is H.

In certain aspects, a compound of formula (I) can be represented by the following formula:

In some embodiments, C is selected from a 5-7 membered monocyclic heterocycle such as piperidinyl and piperazinyl. In some embodiments, R ^{50 is} selected from deuterium, C1.4 alkyl, C1.4 haloalkyl, and —OR ⁵² , for example, R ⁵⁰ is methyl. In some embodiments, R ^{57 is} selected from —S (= O) R ⁵² , —S (= O) 2R ⁵⁸ , —S (= O) 2N (R ⁵² ) 2, and —NR ⁵² S (= O) 2R ⁵² e.g. R ^{57 is} selected from -S (= O) CH3, -S (= O) ₂ CH ₃ , -S (= O) ₂ NH ₂ , -NHS (= O) 2CH3 and -S (= O) 2NHCH3 ... In some embodiments, R ⁵⁷ is —S (= O) 2CH3. In some embodiments, R ⁵⁰ is methyl and R ⁵⁷ is —S (= O) 2CH3. In some embodiments, R ^{2 is} selected from hydrogen, halogen, —OH, —OR ⁵² , —NH2, —n (r ⁵² ) 2, —CN, ^^ alkyl, —CH2OH, —CH2OR ⁵² , —CH2NH2, —CH2N (R ⁵² ) 2, C ₁ . ₃ alkyl-N (R ⁵² ) ₂ , C ₁ . ₃ haloalkyl, C ₂ . ₃ alkenyl and C ₂ . ₃ alkynyl, for example R ^{2 is} selected from —OH, —OR ⁵² , —NH2, —N (R ⁵² ) 2, —CN, and C ₁ . ₂ alkyl. In some embodiments, R ² is methyl or —NHCH ₃ . In some embodiments, R ² is H.

In certain aspects, a compound of formula (II) can be represented by the following formula:

In some embodiments, R ^{1 is} selected from R ⁵⁰ . In some embodiments, R ¹ is C ₁ . ₃ haloalkyl such as —CH2CF3. In some embodiments, R ^{2 is} selected from R ⁵⁰ . In some embodiments, R ^{2 is} selected from hydrogen, halogen, —OH, —OR ⁵² , —NH2, —N (R ⁵² ) 2, —CN, C ₁ . ₃ alkyl, C ₁ . ₃ alkyl-OR ⁵² , C1.3 alkyl-N (R ⁵² ) 2, C ₁ . ₃ haloalkyl, C ₂ . ₃ alkenyl and C ₂ . ₃ alkynyl. In some embodiments, R ^{2 is} selected from halogen, —OH, —OR ⁵² , —NH2, —N (R ⁵² ) 2, —CN, C ₁ . ₃ alkyl, -CH2OH, -CH2OR ^52, -CH2NH2, -CH ₂ N (R ⁵²⁾ 2, C1.3alkil-N (R ⁵²⁾ 2, C _{1. 3} haloalkyl, C ₂ . ₃ alkenyl and C ₂ . ₃ alkynyl, for example R ^{2 is} selected from —OH, —OR ⁵² , —NH2, —N (R ⁵² ) 2, —Cn, and C ₁ . ₂ alkyl. Optionally, R ^{2 is} selected from —NH2, —CH3, —OCH3, —CH2OH, and —NHCH3. In some embodiments, R ^{3 is} selected from hydrogen, halogen, —OH, —N (R ⁵² ) 2, —CN, —C (O) OR ⁵² , C1.3 alkyl, and C1.3 haloalkyl. In some embodiments, R ^{51 is} selected from hydrogen and alkyl, for example, R ⁵¹ is hydrogen. In some embodiments, R ^{A is} selected from halogen, —CN—, —OR ⁵² , —N (R ⁵² ) 2, —NR ⁵³ R ⁵⁴ , —C (O) R ⁵² , —C (O) OR ⁵² , - OC (O) R ⁵² , -NR ⁵² C (O) R ⁵² , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , = O, C1.1oalkyl, C2.1oαalkenyl and

C ₂ . ₁₀ alkynyl optionally substituted with C ₁ . ₁₀ alkyl optionally substituted with C ₂ . ₁₀ alkenyl and optionally substituted C ₂ . ₁₀ alkynyl. In some embodiments, m is 0. In some embodiments, L ^{2 is} selected from —O—, —N (R ⁵¹ ) -, —N (R ⁵¹ ) CH2—, —C (O) N (R ⁵¹ ) - , -N (R ⁵¹ ) C (O) -, -N (R ⁵¹ ) S (O) 2-, -S (O) ₂ N (R ⁵¹ ) -, C1.4 alkylene and C1.4 heteroalkylene. In some embodiments, L ² is C1. ₄ alkylene optionally substituted with one or more R ⁵⁰ . In some embodiments, L ² is C ₁ . ₂ alkylene optionally substituted with one or more R ⁵⁰ . In some embodiments, L ^{2 is} selected from —CH2—, —N (R ⁵¹ ) -, —N (R ⁵¹ ) CH2—, —N (R ⁵¹ ) C (O) -, and —N (R ⁵¹ ) S ( O) 2-. In some embodiments, L ² is —CH ₂ -. In some embodiments, R ^{B is} present at one or more positions of the indole, for example, at the 2, 3, 4, or 6 position of the indole. In some embodiments, R ^{B is} selected from halogen, CN-, -OR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -NR ⁵² C (O) R ⁵² , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , = O, C1-1oalkyl, C2. ₁₀ alkenyl and C ₂ . ₁₀ alkynyl optionally substituted with C ₁ . ₁₀ alkyl optionally substituted with C ₂ . ₁₀ alkenyl and optionally substituted C ₂ . ₁₀ alkynyl. In some embodiments, R ^{B is} selected from halogen, —CN, —OR ⁵² , —N (R ⁵² ) 2, —NR ⁵³ R ⁵⁴ , C1. ₃ alkyl and optionally substituted C ₁ . ₃ alkyl, for example R ^{B is} selected from halogen, —CN, —OR ⁵² , —N (R ⁵² ) 2, —NR ⁵³ R ⁵⁴ and C1. ₂ alkyl. In some embodiments, n is an integer from 1 to 4, such as an integer

- 39 038388 from 2 to 3. In some embodiments, n is 2. In some embodiments, 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 ... In some embodiments, L ^{3 is} selected from C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, each of which is substituted with one or more R ⁵⁶ and optionally further substituted with one or more R ⁵⁰ . In some embodiments, L ^{3 is} selected from C1-6αalkylene which is substituted with one or more R ⁵⁶ and optionally further substituted with one or more R ⁵⁰ . In some embodiments, L ³ is C2 alkylene substituted with at least one C1-3αalkyl or C1-3haloalkyl, and optionally further substituted with one or more R ⁵⁰ . In some embodiments, L ^{3 is} substituted with = O, C1-6αalkyl, C _1-6 haloalkyl, C _1-3 alkyl (cyclopropyl), C _1-3 alkyl (NR ⁵² C (O) R ⁵² ), or —O (C1 -6 alkyl). In some embodiments, L ^{3 is} substituted with —CH 3. In some _R 56 X _R 66, X \ (R) \ (S) embodiments, L ^{3 is} selected from ^and > wherein R ^{56 is} optionally methyl. In some embodiments, C is selected from a C _3-12 carbocycle and a 3-12 membered heterocycle, such as a 5-12 membered heterocycle. In some embodiments, the heterocycle is saturated. In some embodiments, C is selected from a 5-7 membered monocyclic heterocycle, an 8-10 membered fused bicyclic heterocycle, and a 7-12 membered spirocyclic heterocycle. In some embodiments, the heterocycle contains at least one nitrogen atom, such as one or two nitrogen atoms.

In some embodiments, C contains at least one ring nitrogen.

In some embodiments, C is selected from piperidinyl and piperazinyl, taR ^c 57

Λ R ⁵⁷ / X xR ⁵⁷ XR ⁵⁷

Λ ^ν rt> ^Ν χΑ = ^ Nx ^ rC k ^N x ^ _R c π as ^R - ^{4 H} - ^{ς R} and

R ^{57 rC} , wherein R ^{57 is} selected from hydrogen and R ⁵⁰ .

/ x xR ⁵⁷ vQ (r ^c )

In some embodiments, C is selected from ^p wherein R ^{57 is} selected from hydrogen and R ⁵⁰ .

VN.

In some embodiments, C is selected from ^Λ

R ^c

Λ xR ⁵⁷

N

And is selected from hydrogen and R ⁵⁰ . In some embodiments, C is selected from

optionally substituted with one or more RCs, wherein R ^{57 is} selected from hydrogen and R ⁵⁰ .

V

- ^R g

Г ^N Г \ N ^ _rC ^ N.

some embodiments of the invention pC xR ⁵⁷ A R ⁵⁷ / x / R ⁵⁷ , R ⁵⁷ N .R ⁵⁷ (r ^c ) [/ x xR ⁵⁷

X ^N ^ _R c _n 57 n ^R , and R

C selected from

-S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² ;

^rC 'wherein R ^{57 is} selected from -S (= O) R ⁵² , -S (= O) ₂ R ⁵² , -S (= O) 2N (R ⁵² ) 2, and C _1-10 alkyl substituted with one or more substituents selected from -S (= O) R ⁵² , -S (= ObR ⁵² , -S (= ObN (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ and -NR ⁵² S (= O ) 2R ⁵² In some embodiments, R ^{57 is} selected from —S (= O) R ⁵² , —S (= O) ₂ R ⁵² , —S (= O) 2N (R ⁵² ) 2, and —NR ⁵² S ( = O) 2R ⁵² , for example, R ^{57 is} selected from -S (= O) CH3, -S (= O) 2CH ₃ , -S (= O ^ NH2, -NHS (= O) 2CH ₃ and -S (= O) 2NHCH3.

In some embodiments, C is selected from

- 40 038388

In some embodiments, R ^{C is} selected from —C (O) R ⁵² , —S (= O) R ⁵² , —S (= O) ₂ R ⁵² ,

-S (= O) ₂ N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , = O, C ₁ . ₃ α-alkyl and C ₁ . ₃ halogenoalkyl or two groups R ^C ,

attached to different atoms, can together form a C _1-3 bridge. In some embodiments, R ^{C is} selected from C1.3αalkyl, C1.3gαlogenαalkyl, such as —CH3. In some embodiments, p is selected from an integer from 0 to 4, for example, p is selected from an integer from 0 to 2. In some embodiments, p is 0. In some embodiments, R ^{C is} selected from -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -C (O) R ⁵² , -C (O) OR ⁵² , -NR ⁵² C (O) R ⁵² , -NR ⁵² C ( O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2 and -C (O) NR ⁵³ R ⁵⁴ . In some embodiments, R ^{c is} selected from —N (R ⁵² ) 2, —NR ⁵³ R ⁵⁴ , —NR ⁵² S (= O) ₂ R ⁵² , —C (O) R ⁵² , —C (O) OR ⁵² , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C ( O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , C1-6alkyl and ^ alkyl substituted with -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -C (O) R ⁵² , -C (O) OR ⁵² , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2 or -C (O) NR ⁵³ R ⁵⁴ .

selected from

In the invention of some embodiments

In certain aspects, a compound of formula (II) can be represented by the following formula:

D).

In some embodiments, R ^{2 is} selected from R ⁵⁰ . In some embodiments, R ^{2 is} selected from hydrogen, halogen, —OH, —OR ⁵² , —NH2, —N (R ⁵² ) 2, —CN, C ₁ . ₃ alkyl, C ₁ . ₃ alkyl-OR ⁵² , C1.3 alkyl-N (R ⁵² ) 2, C ₁ . ₃ halogenoalkyl, C _2-3 alkenyl and C ₂ . ₃ alkynyl. In some embodiments, R ^{2 is} selected from halogen, —OH, —OR ⁵² , —NH2, —N (R ⁵² ) 2, —CN, C ₁ . ₃ αalkyl, -CH2OH, -CH2OR ⁵² , -CH2NH2, -CH2N (R ⁵² ) 2, C1.zαalkyl-N (R ⁵² ) 2, C1.zalkyl-N (R ⁵² ) 2, C1- ₃ haloalkyl, C ₂ ... ₃ α-alkenyl and C ₂ . ₃ α-alkyl, for example R ^{2 is} selected from —OH, —OR ⁵² , —NH2, —N (R ⁵² ) 2, —CN, and C ₁ . ₂ alkyl. Optionally, R ^{2 is} selected from —NH2, —CH3, —OCH3, —CH2OH, and —NHCH3. In some embodiments, R ^{B is} selected from halogen, CN-, -OR ⁵² , -N (R ⁵² ) ₂ , -NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -NR ⁵² C (O) R ⁵² , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , = O, C1. ₁₀ α-alkyl, C ₂ . ₁₀ alkenyl and C ₂ . ₁₀ α-alkyl, optionally substituted with C ₁ . ₁₀ α alkyl optionally substituted with C ₂ . ₁₀ α-alkenyl and optionally substituted C ₂ . ₁₀ α-alkyl. In some embodiments, R ^{B is} selected from halogen, —CN, —OR ⁵² , —N (R ⁵² ) 2, —NR ⁵³ R ⁵⁴ , C1. ₃ α alkyl and optionally substituted C ₁ . ₃ α-alkyl, for example R ^{B is} selected from halogen, —CN, —OR ⁵² , —N (R ⁵² ) 2, —NR ⁵³ R ⁵⁴ and C1. ₂ α-alkyl. In some embodiments, 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 . In some embodiments, L ^{3 is} selected from C1.6αalkylene, C2.6αalkenylene, and C2.6αalkynylene, each of which is substituted with one or more R ⁵⁶ and optionally further substituted with one or more R ⁵⁰ . In some embodiments, L ^{3 is} selected from C1. ₆ α-alkyl which is substituted with one or more R ⁵⁶ and optionally further substituted with one or more R ⁵⁰ . In some embodiments, L ³ is C ₂ -αalkylene substituted by at least

- 41 038388 with one C _1-3 alkyl or C ₁ . ₃ haloalkyl, and optionally further substituted with one or more R ⁵⁰ . In some embodiments, L ^{3 is} substituted with = O, C ₁ . _{6 by} alkyl,

C ₁ . ₆ haloalkyl, C1. ₃ alkyl (cyclopropyl), C _1-3 alkyl (NR ⁵² C (O) R ⁵² ) or —O (C _1-6 alkyl). In some embodiments, L ^{3 is} substituted with —CH 3. In some embodiments

IR ^S J <R ⁵⁶ -, X \ (R) \ (S) of the invention L "is selected from X and X, and R ⁵⁶ is optionally methyl. In some embodiments, C is selected from a C _3-12 carbocycle and a 3-12 membered heterocycle, such as a 5-12 membered heterocycle. In some embodiments, the heterocycle is saturated. In some embodiments, C is selected from a 5-7 membered monocyclic heterocycle, an 8-10 membered fused bicyclic heterocycle, and a 7-12 membered spirocyclic heterocycle. In some embodiments, the hetero ring contains at least one nitrogen atom, such as one or two nitrogen atoms. In some embodiments, C contains at least one ring nitrogen. In some embodiments, C is selected from piperidinyl and piperazinyl such as

R ^c

X xR ⁵⁷

I ^N ^ ^N ^ _r c рС xR ⁵⁷ 1

N

R ⁵⁷

R ^c and ^rC 'wherein R ^{57 is} selected from hydrogen and R ⁵⁰ .

In some _x Щ ⁵⁷ , R ⁵⁷

N

embodiments of the invention

R ⁵⁷ selected from

n wherein R ^{57 is} selected from hydrogen and R ⁵⁰ .

In some embodiments, C is selected from

invention selected

C from wherein R ^{57 is} selected from hydrogen and R ⁵⁰ .

In some embodiments

optionally substituted with one or more R ^C , wherein R ^{57 is} selected from hydrogen and R ⁵⁰ .

V

R ^c

X xR ⁵⁷

I ^{N in} some embodiments, C is selected from &quot; R ^c &quot; pZ ⁵⁷ _ν &quot; and

R ^{57 rC} , wherein R ^{57 is} selected from -S (= O) R ⁵² , -S (= ObR ⁵² , -S (= ObN (R ⁵² ) 2,

-S (= O) ₂ NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² ; and C1. ₁₀ alkyl substituted with one or more substituents selected from -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ and -NR ⁵² S (= O) 2R ⁵² .

In some embodiments, R ^{57 is} selected from —S (= O) R ⁵² , —S (= O) 2N (R ⁵² ) 2, and —NR ⁵² S (= O) 2R ⁵² , for example, R ^{57 is} selected from —S ( = O) CH3, -S (= O) ₂ CH ₃ , -NHS (= O) 2CH3 and -S (= O) 2NHCH3.

-S (= O) 2R ⁵² ,

-S (= O) 2NH2,

In some embodiments, C is selected from

In some embodiments, RC is selected from -C (O) R ⁵² , -S (= O) R ⁵² , -S (= O) ₂ R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) ₂ NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) ₂ R ⁵² , = O, C1.3 alkyl, C1.3 haloalkyl or two R ^C groups attached to different atoms can together form a C1-3 bridge ... In some embodiments, R ^{C is} selected from C ₁ . ₃ alkyl, C ₁ . ₃ haloalkyl such as -CH3. In some

42,038388 embodiments of the invention p is selected from an integer from 0 to 4, for example, p is selected from an integer from 0 to 2. In some embodiments, p is 0. In some embodiments, R ^{C is} selected from -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -C (O) R ⁵² , -C (O) OR ⁵² , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2 and -C (O) NR ⁵³ R ⁵⁴ . In some embodiments, R ^{c is} selected from —N (R ⁵² ) 2, —NR ⁵³ R ⁵⁴ , —NR ⁵² S (= O) 2R ⁵² , —C (O) R ⁵² , —C (O) OR ⁵² , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O ) N (R ⁵² ) 2, -c (o) nR ⁵³ R ⁵⁴ , C1-6 alkyl and C1-6 alkyl substituted with -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) ₂ R ⁵² , -C (O) R ⁵² , -C (O) OR ⁵² , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2 or -c (o) nr ⁵³ r ⁵⁴ .

In some embodiments, C is selected from

loy:

In certain aspects, the compound of formula (II) can be represented by the following form-

In some embodiments, C is selected from a 5-7 membered monocyclic heterocycle such as piperidinyl and piperazinyl. In some embodiments, R ^{56 is} selected from deuterium, C1-4 alkyl, C1-4 haloalkyl, and —OR ⁵⁹ , for example R ⁵⁶ is methyl. In some embodiments, R ^{C is} selected from -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, and -NR ⁵² S (= O) 2R ⁵² , for example R ^{C is} selected from -S (= O) CH3, -S (= O) 2CH3, -S (= O) 2NH2, -NHS (= O) 2CH3 and -S (= O) 2NHCH3. In some embodiments, p is an integer from 1 to 3, for example p is 1. In some embodiments, R ^C is —S (= O) 2CH ₃ . In some embodiments, R ⁵⁶ is methyl and R ^C is —S (= O) 2CH3. In some embodiments, R ^{2 is} selected from hydrogen, halogen, —OH, —OR ⁵² , —NH2, —N (R ⁵² ) 2, —CN, C _1-3 alkyl, —CH2OH, —CH2OR ⁵² , —CH2NH2, -CH2N (R ⁵² ) 2, C _1-3 αalkyl-N (R ⁵² ) ₂ , C _1-3 haloalkyl, C _2-3 alkenyl and C _2-3 alkynyl, for example, R ^{2 is} selected from -OH, -OR ⁵² , —NH2, —N (R ⁵² ) 2, —CN, and C _1-2 alkyl. In some embodiments, R ² is methyl or —NHCH ₃ . In some embodiments, R ² is H.

In certain aspects, a compound of formula (II) can be represented by the following formula:

In some embodiments, C is selected from a 5-7 membered monocyclic heterocycle such as piperidinyl and piperazinyl. In some embodiments, R ^{56 is} selected from deuterium, C1-4 alkyl, C1-4 haloalkyl, and —OR ⁵⁹ , for example R ⁵⁶ is methyl. In some embodiments, RC is selected from -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, and -NR ⁵² S (= O) 2R ⁵² , e.g. R ^{C is} selected from -S (= O) CH3, -S (= O) ₂ CH ₃ , -S (= O) ₂ NH ₂ , -NHS (= O) ₂ CH ₃ and -S (= O) ₂ NHCH ₃ . In some embodiments, p is an integer from 1 to 3, such as p is 1. In some embodiments, R ^C is —S (= O) 2CH3. In some embodiments, R ⁵⁶ is methyl and R ^C is —S (= O) 2CH ₃ . In some embodiments, R ^{2 is} selected from hydrogen, halogen, —OH, —OR ⁵² , —NH2, —N (R ⁵² ) 2, —CN, C _1-3 alkyl, —Ch ₂ OH, —CH2OR ⁵² , - CH ₂ NH ₂ , -CH ₂ N (R ⁵² ) 2, C1-3alkyl-N (R ⁵² ) 2, C _1-3 ralogenoalkyl, C _2-3 alkenyl and C _2-3 alkynyl, for example, R ^{2 is} selected from —OH, —OR ⁵² , —NH2, —N (R ⁵² ) 2, —CN, and C _1-2 alkyl. In some embodiments, R ² is methyl or —NHCH3. In some embodiments, R ² is H. In certain embodiments, the present disclosure provides a stereoisomer of a compound of formula (I) or (II). In some embodiments, the stereoisomer is in enantiomeric excess. In some embodiments, the stereoisomer is provided at at least 20, 30, 40, 50, 55, 6θ, 65, 70, 75, 80, 85, 88, 90, 91, 92, 93, 94, 95, 96, 97 , 98, 99, 99.5 or 99.9% ee. In some embodiments, the stereoisomer is provided in more than 20, 30, 40, 50, 55, 60, 65, 70, 75, 80, 85, 88, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5, or 99.9% ee. In some embodiments, the enantiomeric excess of a given stereoisomer is greater than 95%, for example, the enantiomeric excess of a given stereoisomer is greater than 99%.

In certain embodiments of the invention, the present disclosure provides a stereoisomer of a compound of formula (I) or (II). In some embodiments, the stereoisomer is in diastereomeric excess. In some embodiments, the stereoisomer is provided in at least 20, 30, 40, 50, 55, 60, 65, 70, 75, 80, 85, 88, 90, 91, 92, 93, 94, 95, 96, 97 , 98, 99, 99.5 or 99.9% diastereomeric excess. In some embodiments, the stereoisomer is provided in more than 20, 30, 40, 50, 55, 6θ, 65, 70, 75, 80, 85, 88, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5 or 99.9% diastereomeric excess. In some embodiments, the diastereomeric excess of a given stereoisomer is greater than 95%, for example, the diastereomeric excess of a given stereoisomer is greater than 99%. In certain certain embodiments of the invention, a compound of formula (I) or (II) is preferably used as a non-racemic mixture, wherein one enantiomer is present in excess relative to its corresponding enantiomer. Typically, such a mixture will contain a mixture of the two isomers in a ratio of at least about 9: 1, preferably at least 19: 1. In some embodiments, the compound is provided in at least 96% ee, i. E. the compound has less than 2% of the corresponding enantiomer. In some embodiments, the compound is provided in at least 96% diastereomeric excess, i. E. the compound has less than 2% of the corresponding diastereomer. In certain embodiments of the invention, the compound of formula (I) or (II) is preferably used in the form of a non-racemic mixture, where the (+) - isomer is the main component of the mixture. Typically, such a mixture will contain no more than about 10% of the (-) - isomer, i.e. the ratio of the (+) - isomer to (-) - isomer is at least about 9: 1 and preferably less than 5% of the (-) - isomer, i. e. the ratio of the (+) - isomer to (-) - isomer is at least about 19: 1. In some embodiments, the compound used has less than 2% of the (-) - isomer, i. E. has an enantiomeric excess of at least about 96%. In some embodiments, the compound has an enantiomeric excess of at least 98%. In some embodiments, the compound has an enantiomeric excess of at least 99%.

In some embodiments of the invention, the compound of formula (I) or (II) is preferably used as a non-racemic mixture, where the (-) - isomer is the main component of the mixture. Typically, such a mixture will contain no more than 10% of the (+) - isomer, i.e. the ratio of the (+) - isomer to (-) - isomer is at least about 9: 1 and preferably less than 5% of the (+) - isomer, i. e. the ratio of the (+) - isomer to (-) - isomer is at least about 19: 1. In some embodiments, the compound used has less than 2% of the (+) - isomer, i. E. has an enantiomeric excess of at least about 96%. In some embodiments, the compound has an enantiomeric excess of at least 98%. In some embodiments, the compound has an enantiomeric excess of at least 99%.

In certain aspects, the present disclosure provides a stereoisomer of a compound of formula (I)

- 44 038388

or a pharmaceutically acceptable salt, isotopic form or prodrug thereof, wherein H is selected from a C _5-12 carbocycle and a 5-12 membered heterocycle, each of which is optionally substituted with one or more R ⁵⁰ ;

A is selected from a bond, a C _3-12 carbocycle, and a 3-12 membered heterocycle;

B is selected from C _3-12 carbocycle and 3-12 membered heterocycle;

C is a 3-12 membered heterocycle;

L ¹ , L ² and L ³ are each independently selected from a bond, -O-, -S-, -N (R ⁵¹ ) -, -N (R ⁵¹ ) CH ₂ -, -C (O) -, - C (O) -, -OC (O) -, -OC (O) -, -c (O) N (R ⁵¹ ) -, -C (O) N (R ⁵¹ ) C (O) -, -C (O) N (R ⁵¹ ) C (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) -,

-N (R ⁵¹ ) C (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) O-, -OC (O) 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 (O) 2 -, -OS (O) -, -S (O) O-, -S (O) -, -OS (O) 2-, -S (O) 2O-, -N (R ⁵¹ ) S (O) 2-, -S (O) 2N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) -, -S (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) 2N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) N (R ⁵¹ ) -; alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene and heteroalkynylene, each of which is optionally substituted with one or more R ⁵⁰ , with two R ⁵⁰ groups attached to the same atom or different atoms of any of L ¹ , L ² or L ³ , together can form a bridge or ring;

R ^a , R ^b and RC are each independently selected at each occurrence from R ⁵⁰ , or two R ^A groups, two R ^B groups, or two RC groups attached to the same atom or different atoms, together can optionally form a bridge or a ring; m, n and p are each independently an integer from 0 to 6;

R ^{50 is} independently selected at each occurrence from:

halogen, -NO ₂ , -CN, -OR ⁵² , -SR ⁵² , -N (R ⁵² ) ₂ , -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , - S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, - NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² c (O) NR ⁵³ R ⁵⁴ , -c (O) N (R ⁵² ) 2, -c (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² );

C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO ₂ , —CN, —OR ⁵² , —SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² ,

-NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -c (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C3-12 carbocycle and 3-12 membered heterocycle; and a C3-12 carbocycle and a 3-12 membered heterocycle, each C3-12 carbocycle and 3-12 membered heterocycle in R ^{50 is} independently optionally substituted with one or more substituents selected from halogen, —NO2, —CN, —OR ⁵² , - SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -c (O) N (R ⁵² ) 2, -c (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), N-alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C _2-6 alkynyl;

R ^{51 is} independently selected at each occurrence from:

hydrogen, -c (O) R ⁵² , -c (O) OR ⁵² , -c (O) N (R ⁵² ) 2, -c (O) NR ⁵³ R ⁵⁴ ; C1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO ₂ , —CN, —OR ⁵² , —SR ⁵² , - N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) ₂ NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) ₂ R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) ₂ NR ⁵³ R ⁵⁴ , -c ( O) R ⁵² , -c (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -0c (0) N (R ⁵² ) 2, -0c (0) NR ⁵³ R ⁵⁴ , -NR ⁵² c (O) R ⁵² , -NR ⁵² c (O) OR ⁵² , -NR ⁵² c (O) N (R ⁵² ) 2, -NR ⁵² c (O) NR ⁵³ R ⁵⁴ , -c ( O) N (R ⁵² ) 2, -c (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = o, = s, = N ( R ⁵² ), C _3-12 carbocycle and 3-12 membered heterocycle; and a C _3-12 carbocycle and a 3-12 membered heterocycle, each C _3-12 carbocycle and 3-12 membered heterocycle in R ⁵¹ independently optionally substituted with one or more substituents selected from halogen, —NO2, —CN, - OR ⁵² , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) ₂ NR ⁵³ R ⁵⁴ , -c (O) R ⁵² , -c (O) OR ⁵² , -0c (0) R ⁵² , -0c (0) 0R ⁵² , -0c (0) N (R ⁵² ) 2, -0c ( 0) NR ⁵³ R ⁵⁴ , -NR ⁵² c (O) R ⁵² , -NR ⁵² c (O) OR ⁵² , -NR ⁵² c (O) N (R ⁵² ) 2, -NR ⁵² c (O) NR ⁵³ R ⁵⁴ , -c (O) N (R ⁵² ) ₂ , -c (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl and C _2-6 alkynyl;

R ^{52 is} independently selected at each occurrence from hydrogen; and C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, 1-6 membered heteroalkyl, C _3-12 carbocycle and 3-12 membered heterocycle, each of which is optionally substituted with halogen, -CN, - NO ₂ , —NH ₂ , —NHCH3, —NHCH2CH3, = O, —OH, —OCH ₃ , —OCH2CH3, C _3-12 carbocycle or 3-6 membered heterocycle;

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 ;

- 45 038388

R ⁵⁷ selected from:

halogen, -NO2, -CN, -SR ⁵² , -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵⁸ , -S (= O) 2N (R ⁵² ) 2, - S (= O) 2NR ⁵³ R ⁵⁴ ,

-NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) OR ⁵² , -OC ( O) R ⁵² , -OC (O) OR ⁵² ,

-OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ ,

-C (O) NH (C1-6alkyl), -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = S, = N ( R ⁵² ); and

C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl, each of which is independently substituted at each occurrence with one or more substituents selected from —NO ₂ , —CN, —SR ⁵² , —N (R ⁵² ) ₂ , -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2,

-NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2 , -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) R ⁵² ) 2, = S and = N (R ⁵² ); and

R ^{58 is} selected from hydrogen; and C ₁ .2 ₀ alkyl, C _2- 2 ₀ alkenyl, C ₂ .2 ₀ alkynyl, 1-6 membered heteroalkyl, C _3-12 carbocycle and a 3-12 membered heterocycle, each of which is optionally substituted by halogen, - CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, = O, -OH, -OCH3, -OCH2CH3, C3-12 carbocycle or 3-6 membered heterocycle. In some embodiments, the stereoisomer of a compound of formula (I) is provided in at least 20, 30, 40, 50, 55, 60, 65, 70, 75, 80, 85, 88, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5 or 99.9% ee. In some embodiments, the stereoisomer is provided in more than 20, 30, 40, 50, 55, 60, 65, 70, 75, 80, 85, 88, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5, or 99.9% ee. In some embodiments, the enantiomeric excess of a given stereoisomer is greater than 95%, for example, the enantiomeric excess of a given stereoisomer is greater than 99%. In some embodiments, for a stereoisomer of a compound of formula (I), L ^{3 is} selected from and X.

Optionally, R ⁵⁰ is methyl. In some embodiments of the invention

L ³ represents

In some embodiments, L ³ is an embodiment of the invention C is selected from

In some variants

In some embodiments, L ^{3 is} selected from ^and C a C

selected from

Any combination of groups described above for various embodiments of a compound of formula (I) is contemplated in the present invention for a stereoisomer of a compound of formula (I).

In certain aspects, the present invention provides a stereoisomer of a compound of formula (II)

or a pharmaceutically acceptable salt thereof, wherein H is selected from a C _5-12 carbocycle and a 5-12 membered heterocycle, each of which is optionally substituted with one or more R ⁵⁰ ;

A, B and C are each independently selected from a C _3-12 carbocycle and a 3-12 membered heterocycle;

L ¹ and L ² are each independently selected from a bond, -O-, -S-, -N (R ⁵¹ ) -, -N (R ⁵¹ ) CH ₂ -, -C (O) -, -C (O ) -,

-OC (O) -, -OC (O) -, -C (O) N (R ⁵¹ ) -, -C (O) N (R ⁵¹ ) C (O) -, -C (O) N (R ^5I ) C (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) -,

-N (R ⁵¹ ) C (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) O-, -OC (O) 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 (O) 2 -, -OS (O) -, -S (O) O-, -S (O) -, -OS (O) 2-, -S (O) 2O-, -N (R ⁵¹ ) S (O) 2-, -S (O) 2N (R ⁵¹ ) -, -n (r ⁵¹ ) s (O) -, -S (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) ₂ N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) N (R ⁵¹ ) -; alkylene, alkenylene, alkynylene,

- 46 038388 heteroalkylene, heteroalkenylene and heteroalkynylene, each of which is optionally substituted with one or more R ⁵⁰ , wherein two R ⁵⁰ groups attached to the same atom or different atoms of any of L ¹ , L ² or L ³ may together form bridge or ring;

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 ^A groups, two R ^B groups or two R ^C groups attached to the same atom or different atoms, together may optionally form bridge or ring;

m, n and p are each independently an integer from 0 to 6;

R ^{50 is} independently selected at each occurrence from:

halogen, —NO2, —CN, —OR ⁵² , —SR ⁵² , —N (R ⁵² ) 2, —NR ⁵³ R ⁵⁴ , —S (= O) R ⁵² , —S (O) _; R \ -S (= O) 2N (R ⁵² ) 2,

-S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² );

C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO ₂ , —CN, —OR ⁵² , —SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² ,

-NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C _3-12 carbocycle and 3-12 membered heterocycle; and

C _3-12 carbocycle and 3-12 membered heterocycle, each C _3-12 carbocycle and 3-12 membered heterocycle in R ⁵⁰ independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR ⁵² , -SR ⁵² , -N (R ⁵² ) 2, NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , - C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , P (O) (OR ⁵² ) ₂ , -P (O) (R ⁵² ) 2, = O, = S, = N ( R ⁵² ), C1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl and C _2-6 alkynyl;

R ^{51 is} independently selected at each occurrence from:

hydrogen, —C (O) R ⁵² , —C (O) OR ⁵² , —C (O) N (R ⁵² ) 2, —C (O) NR ⁵³ R ⁵⁴ ;

C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO ₂ , —CN, —OR ⁵² , —SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² ,

-NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C _3-12 carbocycle and 3-12 membered heterocycle; and

C _3-12 carbocycle and 3-12 membered heterocycle, each C _3-12 carbocycle and 3-12 membered heterocycle in R ⁵¹ independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR ⁵² , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2 , -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S , = N (R ⁵² ), C1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl and C _2-6 alkynyl;

R ^{52 is} independently selected at each occurrence from hydrogen; and C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, 1-6 membered heteroalkyl, C _3-12 carbocycle and 3-12 membered heterocycle, each of which is optionally substituted with halogen, -CN, - NO2, —NH2, —NHCH3, —NHCH2CH ₃ , = O, —OH, —OCH ₃ , —OCH2CH ₃ , C _3-12 carbocycle or 3-6 membered heterocycle;

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:

-NO2, -OR ⁵⁹ , -SR ⁵² , -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl, C _3-12 carbocycle and 3-12 membered heterocycle, each C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl in R ^{56 is} independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO2, —CN, —OR ⁵⁹ , —SR ⁵² , —N (R ⁵² ) 2, —NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O ) 2R ⁵² ,

-NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C _3-12 carbocycle and 3-12 membered heterocycle;

wherein each C _3-12 carbocycle and 3-12 membered heterocycle in R ^{56 is} independently optionally substituted with one or more substituents selected from halogen, —NO2, —CN, —OR ⁵² , —SR ⁵² , —N (R ⁵² ) 2 ,

- 47 038388

-NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= ObR ⁵² , -NR ⁵² S (= ObN (R ⁵² ) 2,

-NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ ,

-NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O ) N (R ⁵² ) 2, -c (o) nr ⁵³ r ⁵⁴ ,

-P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² C1.6 alkyl, C1.6 haloalkyl, C _{2. 6} alkenyl and C ₂ . ₆ alkynyl; and additionally, wherein R ⁵⁶ optionally forms a bond with ring C; and

R ^{59 is} independently selected at each occurrence from C ₁ . ₂₀ alkyl, C ₂ . ₂₀ alkenyl, C ₂ . ₂₀ alkynyl, 1-6 membered heteroalkyl, C ₃ . ₁₂ carbocycle and 3-12 membered heterocycle, each of which is optionally substituted with halogen, -CN, -NO ₂ , -NH2, -NHCH3, -NHCH2CH3, = O, -OH, -OCH3, -OCH2CH3, C3.12 carbocycle or - 6-membered heterocycle.

In some embodiments, the stereoisomer of a compound of formula (II) is provided in at least 20, 30, 40, 50, 55, 60, 65, 70, 75, 80, 85, 88, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5 or 99.9% ee. In some embodiments, the stereoisomer is provided in more than 20, 30, 40, 50, 55, 60, 65, 70, 75, 80, 85, 88, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5, or 99.9% ee. In some embodiments, the stereoisomer is in greater than 95% ee, eg, greater than 99% ee.

In some embodiments, for the stereoisomer of a compound of formula (II)

L ^{3 is} selected from and%.

Optionally, R ⁵⁶ is methyl. In some embodiments of the invention

L ³ represents

In some embodiments, L ³ is

implementation of the invention C is selected from

options

In some

in some embodiments, l is selected from% and%, and C is selected from

Any combination of groups described above for various variants of a compound of formula (II) is contemplated in the present invention for a stereoisomer of a compound of formula (II).

In certain aspects, a compound of the present invention covalently binds to menin and inhibits the interaction of menin with MLL. Such binding can lead to an increase in the affinity of the compound for menin, which is an advantageous property in many applications, including therapeutic and diagnostic applications. In some embodiments, the compounds of the present invention include electrophilic groups capable of reacting with a nucleophilic group present in the meenine protein. Suitable electrophilic groups are described throughout this specification, while suitable nucleophilic groups include, for example, the cysteine moieties present in the binding domain of the menin protein. Without wishing to be bound by theory, a cysteine residue in the menin-binding domain can react with an electrophilic group of a compound of the invention to form a conjugate. In some embodiments, the compounds of the invention are capable of covalently binding to a cysteine residue at position 329 of Menin Isoform 2 (SEQ ID NO: 2) or a Cysteine 334 residue in Menin Isoform 1 (SEQ ID NO: 1). In some embodiments, the present disclosure provides a menin protein conjugate of a compound of the present invention. For example, the present disclosure provides a conjugate of a compound of the present invention with menin coupled to cysteine residue 329 of meminine isoform 2 (SEQ ID NO: 2) or cysteine residue 334 in isoform 1 of menin (SEQ ID NO:

In some embodiments of the invention for a compound of formula (I) or (II), one or more of R ^A , R ^B and R ^C , when present, contains a functional group that reacts to form a covalent bond with one or more residues on the meneine ... In some embodiments, a functional group is reacted to form a covalent bond with one or more cysteine residues in the menin. In some embodiments of the invention, a functional group reacts to form a covalent bond with a cysteine residue in meenine at position corresponding to position 329 in SEQ ID NO: 2 when it is optimally aligned, or at position corresponding to position 334 in SEQ ID NO: 1 when its optimal alignment. In some embodiments of the invention, a functional group interacts to form a covalent bond with one or more residues in the menin selected from cysteine residue 329, cysteine residue 241 and / or cysteine residue 230 in menin relative to SEQ ID NO: 2 when optimally aligned. In some embodiments, a functional group interacts to form a covalent bond with a cysteine residue at position 329 in SEQ ID NO: 2 when optimally aligned.

In some embodiments of the invention for a compound of formula (I) or (II), one or more of R ^A , R ^B and R ^C , when present, contains a moiety that reacts to form a covalent bond with one or more residues in the menine. In some embodiments, one or more of R ^A , R ^B, and R ^C , when present, contains a moiety that reacts to form a covalent bond with one or more isoforms of menin, for example, isoform 1 (SEQ ID NO: 1), isoform 2 (SEQ ID NO: 2) or isoform 3 (SEQ ID NO: 3) of menin. In some embodiments, one or more of R ^A , R ^B, and R ^C , when present, contains a moiety that interacts to form a covalent bond with menin, wherein the menin protein has 60% or more, 70% or more, 75%, or more, 80% or more, 85% or more, 90% or more, 95% or more, or 99% or more sequence identity with isoform 1 (SEQ ID NO: 1), isoform 2 (SEQ ID NO: 2) or isoform 3 (SEQ ID NO: 3).

In some embodiments of the invention, for a compound of formula (I) or (II), one or more of R ^A , R ^B and R ^C , when present, contains an electrophilic group that is susceptible to nucleophilic attack of a residue in the menin. The present invention contemplates any suitable electrophilic group known to one of ordinary skill in the art to bind to nucleophilic residues, for example, any electrophilic group known to bind to cysteine residues. In some embodiments, one or more of R ^A , R ^B and R ^C , when present, contains a group other than an electrophilic group, which group is capable of binding or reacting to form a covalent bond with a residue in the meenine. In some embodiments of the invention, a compound or salt of formula (I) or (II) is capable of (a) being covalently bonded to menin and (b) inhibiting the interaction of menin with MIX.

In some embodiments of the invention, for a compound of formula (I) or (II), R ^C includes a functional group that reacts to form a covalent bond with one or more residues in the meenine. In some embodiments, a functional group is reacted to form a covalent bond with one or more cysteine residues in meenine. In some embodiments, the functional group interacts to form a covalent bond with the cysteine in the menin at position corresponding to position 329 in SEQ ID NO: 2 when it is optimally aligned, or at position corresponding to position 334 in SEQ ID NO: 1 when it is optimally aligned. ...

In some embodiments, for a compound of formula (I) or (II), R ^C is an alpha, beta unsaturated carbonyl radical; alpha, beta unsaturated sulfonyl; epoxide; aldehyde; sulfonyl fluoride; halomethylcarbonyl, dihalomethylcarbonyl, or trihalomethylcarbonyl.

In some embodiments, for a compound of formula (I) or (II), R ^{C is} selected from:

where L ^{5 is} selected from the link; and

C _1-6 αalkylene, C _1-6 heteroalkylene, C _2-6 alkenylene, and C _2-6 alkynylene, each independently optionally substituted with one or more R ³² ;

R ²² and R ²³ are each independently selected from:

hydrogen, halogen, -OR ²⁰ , -SR ²⁰ , -N (R ²⁰ ) 2, -N (R ²⁰ ) C (O) R ²⁰ , -C (O) R ²⁰ , -C (O) OR ²⁰ , - C (O) N (R ²⁰ ) 2,

- 49 038388

-OC (O) R ²⁰ , -S (O) 2R ²⁰ , -S (O) 2N (R ²⁰ ) 2, -N (R ²⁰ ) S (O) 2R ²⁰ , -NO2, = O, = S, = N (R ²⁰ ), -P (O) (OR ²⁰ ) 2, -P (O) (R ²⁰ ) 2,

-OP (O) (OR ²⁰ ) 2 and -CN;

C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —OR ²⁰ , —SR ²⁰ , —N (R ²⁰ ) 2, -N (R ²⁰ ) C (O) R ²⁰ -C (O) R ²⁰ , -C (O) OR ²⁰ , -C (O) N (R ²⁰ ) 2, -OC (O) R ²⁰ , -S (O) 2R ²⁰ , -S (O) 2N (R ²⁰ ) 2, -N (R ²⁰ ) S (O) 2R ²⁰ , -NO2, = O, = S, = N (R ²⁰ ), - P (O) (OR ²⁰ ) 2, —P (O) (R ²⁰ ) 2, —OP (O) (OR ²⁰ ) ₂ , —CN, C _3-10 carbocycle and 3-10 membered heterocycle; and

C _3-10 carbocycle and 3-10 membered heterocycle, each C _3-10 carbocycle and 3-10 membered heterocycle in R ²² and R ²³ independently optionally substituted with one or more substituents selected from halogen, -OR ²⁰ , - SR ²⁰ , -N (R ²⁰ ) 2, -N (R ²⁰ ) C (O) R ²⁰ , -C (O) R ²⁰ , -C (O) OR ²⁰ , -C (O) N (R ²⁰ ) 2, -OC (O) R ²⁰ , -S (O) 2R ²⁰ , -S (O) 2N (R ²⁰ ) 2, -N (R ²⁰ ) S (O) 2R ²⁰ , -NO2, = O, = S, = N (R ²⁰ ), -P (O) (OR ²⁰ ) 2, -P (O) (R ²⁰ ) 2, -OP (O) (OR ²⁰ ) 2, -CN, C _1-6 alkyl , C _2-6 alkenyl and C _2-6 alkynyl; or R ²² and R ²³ together with the carbon atoms to which they are attached form a carbocyclic ring;

R ^{24 is} selected from:

hydrogen, -C (O) R ²⁰ , -C (O) OR ²⁰ , -C (O) N (R ²⁰ ) 2, -OC (O) R ²⁰ , -S (O) 2R ²⁰ u -S (O ) 2N (R ²⁰ ) 2;

C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —OR ²⁰ , —SR ²⁰ , —N (R ²⁰ ) 2, -N (R ²⁰ ) C (O) R ²⁰ -C (O) R ²⁰ , -C (O) OR ²⁰ , -C (O) N (R ²⁰ ) 2, -OC (O) R ²⁰ , -S (O) 2R ²⁰ , -S (O) 2N (R ²⁰ ) 2, -N (R ²⁰ ) S (O) 2R ²⁰ , -NO2, = O, = S, = N (R ²⁰ ), - P (O) (OR ²⁰ ) 2, —P (O) (R ²⁰ ) 2, —OP (O) (OR ²⁰ ) ₂ , —CN, C _3-10 carbocycle and 3-10 membered heterocycle; and

C _3-10 carbocycle and 3-10 membered heterocycle, each C _3-10 carbocycle and 3-10 membered heterocycle in R ²⁴ independently optionally substituted with one or more substituents selected from halogen, —OR ²⁰ , —SR ²⁰ , -N (R ²⁰ ) 2, -N (R ²⁰ ) C (O) R ²⁰ , -C (O) R ²⁰ , -C (O) OR ²⁰ , -C (O) N (R ²⁰ ) 2, - OC (O) R ²⁰ , -S (O) 2R ²⁰ , -S (O) 2N (R ²⁰ ) 2, -N (R ²⁰ ) S (O) 2R ²⁰ , -NO2, = O, = S, = N (R ²⁰ ), -P (O) (OR ²⁰ ) 2, -P (O) (R ²⁰ ) 2, -OP (O) (OR ²⁰ ) 2, -CN, Cl _-6 alkyl, C _{2- 6} alkenyl and C _2-6 alkynyl;

R ^{20 is} independently selected at each occurrence from R ⁵² ; and R ^{32 is} independently selected at each occurrence from R ⁵⁰ .

In some embodiments, L ⁵ is a bond. In some embodiments, L ⁵ is optionally substituted C1-6 alkylene. In some embodiments, L ^{5 is} selected from methylene, ethylene, or propylene. In some embodiments, L ^{5 is} substituted with one or more substituents selected from halogen, —NO2, = O, = S, —OR ²⁰ , —SR ^20, and —N (R ²⁰ ) ₂ .

In some embodiments, R ^{23 is} selected from:

hydrogen;

Cl _-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl, each independently optionally substituted at each occurrence with one or more substituents selected from halogen, OR ²⁰ , —SR ²⁰ , —N (R ²⁰ ) 2, -N (R ²⁰ ) C (O) R ²⁰ , -C (O) R ²⁰ , -C (O) OR ²⁰ , -C (O) N (R ²⁰ ) 2, -OC (O) R ²⁰ , - S (O) 2R ²⁰ , -S (O) 2N (R ²⁰ ) 2, -N (R ²⁰ ) S (O) 2R ²⁰ , -NO2, = O, = S, = N (R ²⁰ ), -P (O) (OR ²⁰ ) 2, —P (O) (R ²⁰ ) 2, —OP (O) (OR ²⁰ ) 2, —CN, C3-1o carbocycle and 3-10 membered heterocycle; and

C _3-10 carbocycle and 3-10 membered heterocycle, each C _3-10 carbocycle and 3-10 membered heterocycle independently optionally substituted with one or more substituents selected from halogen, -OR ²⁰ , -SR ²⁰ , -N ( R ²⁰ ) ₂ , -N (R ²⁰ ) C (O) R ²⁰ , -C (O) R ²⁰ , -C (O) OR ²⁰ , -C (O) N (R ²⁰ ) 2, -OC (O ) R ²⁰ , -S (O) 2R ²⁰ , -S (O) 2N (R ²⁰ ) 2, -N (R ²⁰ ) S (O) 2R ²⁰ , -NO2, = O, = S, = N (R ²⁰ ), -P (O) (OR ²⁰ ) 2, -P (O) (R ²⁰ ) 2, -OP (O) (OR ²⁰ ) ₂ , -CN, C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl. In some embodiments, R ^{23 is} selected from:

hydrogen;

Cl _-6 alkyl optionally substituted with one or more substituents selected from halogen, —OR ²⁰ , —SR ²⁰ , —N (R ²⁰ ) 2, = O, = S, = N (R ²⁰ ) and —CN; and

3-10 membered heterocycle optionally substituted with one or more substituents selected from halogen, —OR ²⁰ , —SR ²⁰ , —N (R ²⁰ ) 2, —N (R ²⁰ ) C (O) R ²⁰ , —C ( O) R ²⁰ , -C (O) OR ²⁰ , -C (O) N (R ²⁰ ) 2, -OC (O) R ²⁰ , -S (O) 2R ²⁰ , -S (O) 2N (R ²⁰ ) 2, -N (R ²⁰ ) S (O) 2R ²⁰ , -NO2, = O, = S, = N (R ²⁰ ), -P (O) (OR ²⁰ ) 2, -P (O) (R ²⁰ ) 2, —OP (O) (OR ²⁰ ) ₂ , —CN, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl.

In some embodiments, R ^{23 is} selected from hydrogen and C 1-6 alkyl optionally substituted with one or more substituents selected from halogen, —OR ²⁰ , —SR ²⁰ , —N (R ²⁰ ) 2, = O, = S, = N (R ²⁰ ) and -CN. In some embodiments, R ^{22 is} selected from: hydrogen and —CN;

Cl _-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —OR ²⁰ , —SR ²⁰ , —N (R ²⁰ ) 2 , -N (R ²⁰ ) C (O) R20, -C (O) R ²⁰ , -C (O) OR ²⁰ , -C (O) N (R ²⁰ ) 2, -OC (O) R ²⁰ , - S (O) 2R ²⁰ , -S (O) 2N (R ²⁰ ) 2, -N (R ²⁰ ) S (O) 2R ²⁰ , -NO2, = O, = S, = N (R ²⁰ ), -P (O) (OR ²⁰ ) 2, —P (O) (R ²⁰ ) 2, —OP (O) (OR ²⁰ ) 2, —CN, C ₃ -1o carbocycle and 3-10 membered heterocycle; and

C _3-10 carbocycle and 3-10 membered heterocycle, each C _3-10 carbocycle and 3-10 membered heterocycle are independently optionally substituted

- 50 038388 one or more substituents selected from halogen, -OR ²⁰ , -SR ²⁰ , -N (R ²⁰ ) 2, -N (R ²⁰ ) C (O) R20,

-C (O) R ²⁰ , -C (O) OR ²⁰ , -C (O) N (R ²⁰ ) 2, -OC (O) R ²⁰ , -S (O) 2R ²⁰ , -S (O) 2N (R ²⁰ ) 2, -N (R ²⁰ ) S (O) 2R ²⁰ , -NO2, = O, = S, = N (R ²⁰ ), -P (O) (OR ²⁰ ) 2, -P (O ) (R ²⁰ ) 2, —OP (O) (OR ²⁰ ) ₂ , —CN, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl.

In some embodiments, R ^{22 is} selected from hydrogen, —CN, and C _1-6 alkyl optionally substituted with one or more substituents selected from halogen, —OR ²⁰ , —SR ^20, and —N (R ²⁰ ) 2.

In some embodiments, R ²² and R ²³ , together with the carbon atoms to which they are attached, form a 5-, 6-, or 7-membered carbocyclic ring.

In some embodiments, R ^{24 is} selected from hydrogen and C _1-6 alkyl optionally substituted with one or more substituents selected from halogen, —OR ²⁰ , —SR ²⁰ , —N (R ²⁰ ) 2, —NO2, = O, and -CN.

In some embodiments, R ^{21 is} selected from

Any combination of groups described above for various variations is contemplated in the present invention. Throughout the present description, groups and substituents thereof can be selected to provide stable moieties and compounds.

The chemical entities described in the present invention can be synthesized in accordance with one or more illustrative schemes in the present invention and / or methods known in the art.

The materials used in the present invention are either commercially available or obtained by synthetic methods generally known in the art. These schemes are not limited to the compounds listed in the examples or any specific substituents that are used for illustrative purposes. Although the various steps are described and depicted in Scheme 1 and in Examples 1 to 5, the steps in some cases may be performed in an order different from the order shown in Scheme 1 and Examples 1 to 5. Various modifications of these synthetic reaction schemes may be made and will be offered to specialists in this field of technology, referring to the disclosure contained in this application. The numbering or groups R in each scheme do not necessarily correspond to those of the claims or other schemes or tables in the present description.

Unless otherwise indicated, the reactions described in the present invention take place at atmospheric pressure, usually in the temperature range from -10 to 200 ° C. In addition, unless otherwise indicated, the timing and reaction conditions should be approximate, for example, at atmospheric pressure in a temperature range from about -10 to about 110 ° C for a period of time from about 1 to about 24 hours; the reaction mixtures are left overnight, on average, for about 16 hours. In general, the compounds of the present invention can be prepared according to the following reaction scheme:

- 51 038388

Scheme 1

In some embodiments, a compound of Formula 1-7 can be prepared according to Scheme 1. For example, methanesulfonyl chloride can be added to a solution of alcohol 1-1 and triethylamine to provide mesylate 1-2. Adding mesylate 1-2 to a solution of Cs ₂ CO ₃ and amine 1-3 can provide a compound of formula 1-4. Coupling of aldehyde 1-4 to amine 1-5 can take place in the presence of a suitable reducing agent such as NaBH (OAc) ₃ to provide a compound of formula 1-6. The addition of TFA can reveal a free amine, which can optionally be reacted with R ⁵⁷ -LG, where LG is a suitable leaving group, to provide a compound of Formula 1-7. In some embodiments of the invention, a compound of the present invention, for example, a compound of the formula shown in table. 1 or 2 are synthesized according to one of the general routes outlined in Scheme 1, Examples 1-5, or methods generally known in the art. In some embodiments, exemplary compounds may include, but are not limited to, a compound or a salt thereof selected from table. 1.

- 52 038388

Table 1

No. Structure MW (calculated) m / z (found) 1 § 0¼ 687.78 688.45 [M + H] ⁺ 2 O —Λ 688.83 689.40 [M + H] ⁺ 3 pX ^CF> 687.84 688.45 [M + H] ⁺ 4 A ^ P 702.86 703.55 [M + H] ⁺ 5 ° x ~ π ANw ^ ¹ ΝγΧ / - ™ Per> “ 652.78 653.55 [M + H] ⁺

- 53 038388

6 ° y-n Π CrV ¹ 638.75 639.50 [M + H] ⁺ 7 o, ° y-NH ₂ (rVyT ^F · 0 ^{ΗΝ Ό} ^ 9> - 689.82 690.50 [M + H] ⁺ eight VA ιίΆ P n ^ zU / -4. 703.84 704.55 [M + H] ⁺ nine O ° Ά liV ^ ’P ΝγΧ ^ Ζ 688.83 689.45 [M + H] ⁺ ten o ° sr ^ ^F 0 IL 688.83 689.40 [M + H] ⁺

- 54 038388

eleven O '(iVp ^CF 702.86 703.55 [M + H] ⁺ 12 ° oL V nOx / -A 716.88 717.55 [M + H] ⁺ 13 ... ° Y- N < 702.86 703.55 [M + H] ⁺ fourteen Ο- Υ) ζχο γ 702.86 703.55 [M + H] ⁺ 15 ° / 'iiVp ^c \ P nOO 702.86 703.50 [M + H] ⁺

- 55 038388

16 iVvA '0 ^ΗΝ η ^ φχ 702.86 703.60 [M + H] ⁺ 17 O 702.86 703.35 [M + H] ⁺ eighteen .. <Ή ζχχ · D ^? 702.86 703.35 [M + H] ⁺ 19 p \ ° Ά Ub pX \ ^J 702.86 703.35 [M + H] ⁺ twenty o \ ° ^ Vn i ^N Y ^s w ^CF3 Xi ^ 702.86 703.35 [M + H] ⁺

- 56 038388

21 (iV ^ ’ 716.88 717.35 [M + H] ⁺ 22 o ° * / - Y ^N ) ..... i ^N rW ^Fs , ⁿ ^ -A ^HN n ^ 9> ™ 716.88 717.35 [M + H] ⁺ 23 ή liVp ^CF y 714.87 715.25 [M + H] ⁺ 24 (iV ^ F 0 716.88 717.45 [M + H] ⁺ 25 o ° s- liV ^ F 'n ^ A / - < ^HN n ^ 9> ™ 716.88 717.40 [M + H] ⁺

- 57 038388

26 O·,*. ^Η Χυφ> ™ 716.88 717.40 [Μ + Η] ⁺ 27 ο ^ΗΝ η ^ φ> “ 28 ο ° γ D-M ζΧΗ 0 ^ΗΝ η ^ 9> - 714.87 715.35 [Μ + Η] ⁺ 29 <ιτγγ · Ρ ^{Χ Η} Χυφ> ™ 716.88 717.40 [Μ + Η] ⁺ thirty “-D Κ ^Ν i0H ^F · ^ ^ΗΝ η ^ 9> - 700.84 701.35 [Μ + Η] ⁺

- 58 038388

- 59 038388

36 s. ¹ ^ ΝΗ CF ₃ ^hn oj9> - 37 hL / N _S CF ₃ J NH Il ^- 38 o ° 'X ^F liV ^ 0 39 AH 'X' 40 p CY ii ^N Y / W ^CF3 n ^ xA ^ z

- 60 038388

41 O 42 o / < ^N ) iVo ^ ^cF CV 43 o °? < ^N V ^S \ / ^CF3 Il /) - '/ ^h Yj9> - 688.83 689.45 [M + H] ⁺ 44 O ' _г у = ₽, ΝγλΖ ^ ^{4 hn} yj9> - 702.86 703.45 [M + H] ⁺ 45 O Q ΝχΟΌ < 688.83 689.40 [M + H] ⁺

- 61 038388

46 X Yy ζχχ- y 702.86 703.45 [M + H] ⁺ 47 f-v ^ 702.86 703.50 [M + H] ⁺ 48 X ..... / N ^ s CF ₃ < 702.86 703.55 [M + H] ⁺ 49 .. < _rV s .. GU 702.86 703.55 [M + H] ⁺ 50 p ° 's% X) J ⁿ HLrU

- 62 038388

51 r-γ ^ D Il /) - / < 52 О о X. α у ^ΗΝ η ^ φ> “ 728.89 729.55 [Μ + Η] ⁺ 53 ψ ζχρ ^ερ 714.87 715.30 [Μ + Η] ⁺ 54 ο = μ О ζχν ^ρ · ^ΗΝ η ^ α ™ 714.87 715.30 [Μ + Η] ⁺ 55 Ο -'_ ζχΗ ς ^{ΗΝ Ό} ^ 9> ™ 700.84 701.30 [Μ + Η] ⁺

- 63 038388

56 O 714.87 715.35 [M + H] ⁺ 57 o ^ΗΝ η ^ 9> - 686.81 687.25 [M + H] ⁺ 58 sg ™ pl9> - 700.84 701.35 [M + H] ⁺ 59 o = V (Sur-O ' 687.84 688.45 [M + H] ⁺ 60 ° * V op- p ^HN n ^ 9> ™ 687.84 688.50 [M + H] ⁺

- 64 038388

61 o '° °> pA C 700.84 701.30 [M + H] ⁺ 62 O Λτν- 0 63 ° \ ¹ N-nh ^hn dj9> ™ 64 o P 1 V-NH 0 cf ₃ N000 ^ i.'L ^ΗΝ ηνφ> ™ 703.84 704.25 [M + H] ⁺ 65 Un G) i ^N rW ^F3 PP o ^ 9> ^cn 638.75 639.20 [M + H] ⁺

- 65 038388

66 cl, ° / y-NH f ^N ) 703.84 704.25 [M + H] ⁺ 67 V Π l- \ y n + W 638.75 639.25 [M + H] ⁺ 68 X 667.79 668.35 [M + H] ⁺ 69 P N ifVxX Ny> L / ^ and '^ 720.27 721.3 70 o ^ J? π rrWy · ..... 4 " ^ΗΝ Όυφχ 706.25 707.3

- 66 038388

71 ό ^ΗΝ ηχφ>" 706.25 707.2 72 ν r ^N ) A- \ y O ΝγΧχΖ ^, ..- ¼ 668.29 689.2 73 , ° / X ° "s / / N SU ζχν ..... <; ^J 729.88 730.30 [Μ + Η] ⁺ 74 About π liVyy 75 o οΟ / Ρ'Ν Ο ^Η liVyy · X ΝχΟ-Ο —Od ό _ν ^ 2> ™

- 67 038388

76 A b ..... i ^N Y ^S W ^CF3 nA / D 77 o ° '42 / *? N b nAV - (D HN ^ / ^ N ^D u ^ 9> ™ 78 pd ° jA □ YA ζΧΥ ¹ A 79 Οχ 'ζχγ Y ΎνφΑ 80 „ ^{О H} 2 ^N A ^ N iVW ^F3

- 68 038388

81 o i ^N T ^s w ^CF3 82 ⁿ Γ ^Ν) ΐίΎγ ^ρ · ^«J 83 ο rfVw ^ V ^ΗΝ η ^ λ- 84 ° ^ ΝΗ ζΐΗ ^ρ γ 85 ° = Υ'ΟΗ π ζχν ^ρ> ... γ ^HN njp> ™

- 69 038388

86 o-7 ~ ^he l ⁿ S CP, V 87 o ° ^ V Γ) 'ζΧΗ ^Ρ Υ 717.29 718.35 [M + H] ⁺ 88 νη ₂ / Ν ГУ riVyj * V ^{ΗΝ Ό} ^ φ> ™ 89 о SV ГГ '^ ^F γ ^{ΗΝ Ό} ^ φ> ™ 717.29 718.25 [M + H] ⁺ 90 o θ ^ΗΝ η ^ λ-

- 70 038388

91 o U) ..... iV ^s W ^CF3 92 o \ ⁰ · ^ Y ”) ..... ζΧΗ ^Ρ · ..... 93 HN '\ _sSS “rb9>“ 672.26 673.2667 94 o ° ^ Y / —N _, c np 'iV i / ⁿ “Uf ™ 714.27 715.2 [M + H] ⁺ 95 Λ ^Ν \ ^н i ^N rW ^F3 V ^{ΗΝ Ό} ^ 9> -

- 71 038388

96 ο ^ θ sG Yjpx " 97 - nj f 5 V ir ^N rW ^F A 98 o4 _f Ί γ 99 Cj ^ i ^N r ^s ^ Y ν, / Α- ^ Ζ -A 'sn 100 _C ^N c £ ^ Y ^F> Y ^hn o ^ 9> -

- 72 038388

101 π у ууЛ -Ч ^ΗΝ η ^ φ> - 102 π (τύ ^. y yyL - y 103 (Γ ^ uz ^. Y muL - A ^HN rc9> ™ 104 ^{o =: =} CH ό HlNyN ^ s CF ₃ VU ^HN n ^ 9> - 105 ο. 'S-NH ^ n'o ii ^N Y ^s w ^CF3 - ( ^hn oj9 ^

- 73 038388

- 74 038388

- 75 038388

115 ooC 'cY ^ ^f> , γ 714.27 715.45 [M + H] ⁺ 116 О-DL С) yo ^cf> γ 730.31 731.50 [M + H] ⁺ 117 on .....WITH 678.31 679.50 [M + H] ⁺ 118 ° yCF ₃ Г) ^ ^F '\ ^J 706.26 707.40 [M + H] ⁺ 119 pto ~ s__ P o ^H _Ν ςχΗ ^ρ · ... у ^h Yj9> ™ 717.29 718.25 [M + H] ⁺

- 76 038388

120 ° 'S ° Γ'Ν ^ ^N AND pCA ^CF ' ..... 745.32 746.30 [M + H] ⁺ 121 _O X ° 7'νΛ A ipx ^F> , γ 729.29 730.45 [M + H] ⁺ 122 ^o yJ ^CF π rpx ^F Y 720.28 721.40 [M + H] ⁺ 123 Ο Ω 0 ^ '2 г N γ ^HN n ^ 9> - 747.30 748.45 [M + H] ⁺ 124 <, μ P 734.28 735.2 [M + H] ⁺

- 77 038388

125 R o VF n ^H ^ XA ^F> ..... 753.27 754.45 [M + H] ⁺ 126 o OyA ^Ces P ζΧΑ ^Ρ1 Y 756.25 757.35 [M + H] ⁺ 127 o l ρ> ^ ^ρ> ... γ ^HN nj9>" 728.29 729.45 [M + H] ⁺ 128 o O Y 'Z?' N A \ ⁿ ^ Ύ ³ ^ ³ j 702.27 703.35 [M + H] ⁺ 129 9 zF About e A ^ Ά ΓΝ l ⁿ ^ CA ^{CP> ... Y ΗΝ η ^ φ>} " 735.28 736.40 [M + H] ⁺

- 78 038388

130 Τ ³ Π ..... 771.26 772.40 [Μ + Η] ⁺ 131 _ 2 / ОН Ρ'Ν 0 ..... <( ^ΗΝ Όυφ> - 733.28 734.45 [Μ + Η] ⁺ 132 ο ^ζ ? Ν Π ^Η Η, Ν Ν ..... <( 718.28 719.45 [Μ + Η] ⁺ 133 ° v ° ^ ^ sop, ..... ™ ηυφ> ™ 682.30 683.50 [Μ + Η] ⁺ 134 L ^δ ° O ^ tS £ X 653.29 654.40 [Μ + Η] ⁺

- 79 038388

135 D) H ₂ NN _s CF ₃ ..... ζ, 703.27 704.40 [M + H] ⁺ 136 \ n Π \ U'U n + n ^ HY Hu 652.29 653.45 [M + H] ⁺ 137 o □ udu d) Yry L ..... (“XjpX 720.27 721.45 [M + H] ⁺ 138 0 ° y Π yyyy L ..... <( ⁿ Xd ^ x 702.27 703.50 [M + H] ⁺ 139 o ° χ / rN n ⁿ 6r№vX ^F 6+ / yy ..... 717.29 718.50 [M + H] ⁺

- 80 038388

140 about “Zn-? with Г ζχν ^ρ , .γ 715.27 716.40 [M + H] ⁺ 141 O . O _C 7 g Ν p ⁿ U 731.30 732.45 [M + H] ⁺ 142 o oY / N if'VYV ¹ > JU ..... r ΗΝγ ^ UnJ ^ Cz- 745.32 746.40 [M + H] ⁺ 143 ° ^ N Π, γ ^HN n ^ 9> ™ 679.30 680.50 [M + H] ⁺ 144 o / ^F 'Ύ ΓY £ ^ H ^F · „Y ^ΗΝ η ^ φ>" 724.24 725.40 [M + H] ⁺

- 81 038388

145 Y ... γ 720.27 721.45 [M + H] ⁺ 146 o ° ^ 4 'o \ / Ν, ___ _{s CF} , \ J γ __G ^{3 N} ..... f 728.29 729.45 [M + H] ⁺ 147 o ^ ° ^{, S} X7 _f V H ₂ NN _s CF ₃ ..... ζ. 729.29 730.40 [M + H] ⁺ 148 H iW ^f - 0 nyF ..... <; ^HN n ^ 9> - 610.28 611.3 [M + H] ⁺ 149 Η ₂ Ν _γ Ν _s CF ₃ NxxJZ u- ( 721.26 722.45 [M + H] ⁺

- 82 038388

150 G) . γ 686.29 687.3 [Μ + Η] ⁺ 151 ° '? - Η Π / N _V N _s CF ₃ ΝγΜ and ( ^HN V ^ ZVN 717.29 718.55 [Μ + Η] ⁺ 152 O Yy ζχγ, γ 734.28 735.40 [Μ + Η] ⁺ 153 ου ° 0-4 ^ D ^ην ό »^ 9> ™ 696.31 154 νη ₂ ° γ π ζχγ Υ 667.30 668.35 [Μ + Η] ⁺

- 83 038388

155 A AYV- ⁰ ..... 702.28 703.35 [M + H] ⁺ 156 _{νη 2} -Α μ < 681.32 682.45 [M + H] ⁺ 157 \ ζ ΝΗ £ ^ P ^CF 700.30 701.40 [M + H] ⁺ 158 Η ₂ Ν Ν CF ₃ \ J ..... ™ pe9>" 702.27 703.40 [M + H] ⁺ 159 \ η Π ('' rV '' .....G HN ΗΟγ ^. ν UnJU ~ A “ 640.26 641.40 [M + H] ⁺

- 84 038388

160 π ^ s cf, HyJ ^ ..... G HN γ-h HO γ ^, ν 690.24 691.35 [M + H] ⁺ 161 o D ° '> - ^D p ^N o / N ^ _s cf ° 7 <T ^D | f YW ^F3 D NpD NsA / p D 696.31 697.3 [M + H] ⁺ 162 o _x / O ^ s NH ζΧΗ ^Ρ1 Y 659.23 660.2 [M + H] ⁺ 163 p ° Ltr 731.26 732.40 [M + H] ⁺ 164 ⁿ Y / \ ^HN n ^ 9> - 731.26 732.35 [M + H] ⁺

- 85 038388

165 O 701.28 702.40 [M + H] ⁺ 166 H ₂ NN _s CF ₃ ζΡ v-4 667.34 668.45 [M + H] ⁺ 167 p -A H ₂ NN _s CF ₃ 0 703.27 704.40 [M + H] ⁺ 168 Η ₂ Ν _γ Ν _s CF ₃ (^ 5 660.28 661.40 [M + H] ⁺ 169 I HN- ^ o A ° ii ^N Y ^s w ^CF3 674.24

- 86 038388

170 o ° ° '? 0 ίγΙ / Α ..... 731.30 732.40 [M + H] ⁺ 171 about θ-χ and ^ VW ^ ³ ..... ( 716.29 717.45 [M + H] ⁺ 172 <А Η ₂ Ν _γ Ν _s CF ₃ S У HN x / \ ΗΟγΧχ, n UJJA 705.25 706.45 [M + H] ⁺ 173 o A l A y ^Y DX ^SRz 728.29 729.45 [M + H] ⁺ 174 o ° L "A ^ Ν _γ ΓΚ, ₃ CH C ΝγΛΑ ..... 731.30 732.45 [M + H] ⁺

- 87 038388

175 nh ₂ W * S ,, - (^ 682.31 683.45 [M + H] ⁺ 176 \ NH Ct Η ₂ Ν _γ Ν _s CF ₃ k J nY-O „- ( 696.33 697.60 [M + H] ⁺ 177 С / Η ₂ Ν _γ Ν _s CF ₃ n ^ CC „- (ΗNч / \ HN UnJUU ^ ^cn 720.26 721.50 [M + H] ⁺ 178 nh ₂ ^{o ==} sw 0 681.32 682.45 [M + H] ⁺ 179 ° -Ά О ..... H ₂ NN CF ₃ N0O „- ( 731.30 732.50 [M + H] ⁺

- 88 038388

180 o b ..... Η ₂ Ν _γ Ν ^ _δ CF ₃ 731.30 732.50 [Μ + Η] ⁺ 181 \ N Л Η ₂ Ν _γ Ν _s CF ₃ к _n J 710.35 711.50 [Μ + Η] ⁺ 182 nh _{2 ο} γ n Γ) ^zN y ⁿ yV ^F3 PP Ur ..... ς 696.33 697.60 [Μ + Η] ⁺ 183 o P pp Νγί ^ Ζ υ'Υ ^Η Υνφ> “ 718.27 719.45 [Μ + Η] ⁺ 184 о оУ 'Ζ Ρ'Ν Г \ ^н H ₂ N _v N _s CF ₃ „γ ^ΗΝ η ^ 9> - 717.29 718.45 [Μ + Η] ⁺

- 89 038388

185 o JZ P'N r \ ^H / NN CF ₃ V ..... 731.30 732.45 [M + H] ⁺ 186 o OH / r'N G \ ^H \ ^N YV ^F 'V ..... ς UL-N u ^ 2> “ 716.29 717.45 [M + H] ⁺ 187 o ° y% ^ he H ₂ NN _s CF ₃ ζ3 ..... ^hn oj9> - 733.28 734.45 [M + H] ⁺ 188 h ₂ n _v n ^ s cf ₃ ζ_7 626.28 627.40 [M + H] ⁺ 189 HN ^ o ^ S Η fA zz ^u .xS CF, RJ N ^ xiX # ^/ , H (Τφ “ 710.35 711.45 [M + H] ⁺

- 90 038388

190 H H ₂ NN _s CF ₃ ..... 665.32 666.45 [Μ + Η] ⁺ 191 \ Ν 'Η Π / _v V \ F ^Fl N ^{J Η} Όγφ ^ 724.36 725.45 [Μ + Η] ⁺ 192 ° Ά Η Π ^Η χΝ Ν S.OF, V Ν ^ Λ ^ 732.30 733.45 [Μ + Η] ⁺ 193 ο ^Η / / χ- Ν _s CF, V ..... ^ΗΝ η ^ φ> - 716.29 717.45 [Μ + Η] ⁺ 194 π cf, 4 _{J Ν ^^ (υ · (Η} Ν · χΧ \ Η Ο Ν OLdl ^sy 719.26 720.55 [Μ + Η] ⁺

- 91 038388

195 Λ ’χΝγΝ SCF, Y 674.29 675.50 [M + H] ⁺ 196 γ ^ΗΝ ηζφ> ™ 788.32 789.45 [M + H] ⁺ 197 \ Α ° ^ N / ^Ν \ / Ν Ν _s Cj ..... ς 774.31 775.3 [M + H] ⁺ 198 ο ° 'S ^ ^F Η rr ^ ϊ ^ η ^ρ γ 735.28 736.45 [M + H] ⁺ 199 7 'χΝ Ν _s CF ₃ ..... ς ^ΗΝ ν—> Z4r-N OnJQ> - 677.32 678.55 [M + H] ⁺

- 92 038388

200 о ον ..... ζ T CO ₂ Et / 760.28 761.40 [Μ + Η] ⁺ 201 O Ο 702.27 703.45 [Μ + Η] ⁺ 202 \ ^Χ V Ο \ _r ..... ^Η Χοφ> “ 723.37 724.55 [Μ + Η] ⁺ 203 ° ζ _ζ Ο Η f ^S ) _Ζ Ν _γ Ν ^ 8 CF, 5 J νΥ-0 ..... 4 688.26 689.40 [Μ + Η] ⁺ 204 νη ₂ X / Ν _γ Ν s CF ₃ \ Ο Ν.0Ζ, υ · ( ^Η Υοφ> - 695.33 696.60 [Μ + Η] ⁺

- 93 038388

205 „? / ^N ..... l 733.28 734.55 [Μ + Η] ⁺ 206 \ ΝΗ А / Ν Ν _s CF ₃ Ν-γΑ # wA 709.35 710.55 [Μ + Η] ⁺ 207 rt '^ Ύνν ^ ³ ..... С ^H Nx / \ u ^ 9> “ 668.32 669.55 [Μ + Η] ⁺ 208 o ° Ά Η Π / Ν _χ Ν _s CF ₃ ΗΝγ ^ Ζ ^ Ν D ^ 2> “ 717.29 718.40 [Μ + Η] ⁺ 209 ο Ν ₄ ° 'Ά η t ^N ) χΝ Ν scp, < _ν 7 ΝγλΖ ^ ..... <( ^H Yc9> ™ 742.28 743.40 [Μ + Η] ⁺

- 94 038388

210 n D) ^xN y ⁿ yW ^F3 V 731.30 732.40 [Μ + Η] ⁺ 211 o ° ^ Ύ7 Η cv ..... (( 743.30 744.40 [Μ + Η] ⁺ 212 ηνΥ ^ Η ό ^ yVW ¹ ..... <( 707.33 708.45 [Μ + Η] ⁺ 213 η A ^ ⁿ y ⁿ yv> ^f X ΝγλΖ ^ ..... Υι ^ φγ- 709.35 710.50 [Μ + Η] ⁺ 214 oJ / Ρ'Ν Γ \ ^Η ^ ^o yVW ^F3 V ΝγΑΑ υ. ^ 732.29 733.40 [Μ + Η] ⁺

- 95 038388

215 Ϋ 711.33 712.45 [Μ + Η] ⁺ 216 Η ₂ ν4 ο / Ν Ν _s fj ..... ς ην ^ 683.30 684.45 [Μ + Η] ⁺ 217 ... Ϋ ^χ Υ Y ^S \ _Γ * ΝψΧ <Ζ and '^ ^Η Τνφ> “ 697.31 698.3 [Μ + Η] ⁺ 218 ° Y 0 219 ?., <> 9. About γ γ \ _r ν ^Η Χυφ> ™ 673.25 674.2 [Μ + Η] ⁺

- 96 038388

220 HN ^ mA / u - ( 694.34 695.50 [M + H] ⁺ 221 \ Ν ' 708.35 709.50 [M + H] ⁺ 222 o ° γ Π YyW ^F3 * P ^ΗΝ ηγ> - 706.25 707.2561 225 Η A / Ν Ν _s CF ₃ AA-? ..... (° 226 y ^ y XiS / y

- 97 038388

228 Y about HN ' ^S \ ^H I / / NN CF ₃ XY N ^ / Xa' --- ( 229 A H // NH / NyN ^ s CF ₃ y = / N ^ / XP -P χΆ ^ 648.26 230 H // ^N 'nh / Ν _γ Ν _s CF ₃ W N ^ Xa -X 621.26 622.2 [M + H] ⁺ 231 H - ^N * l / NN HN Ί n ^ Xa '-X 232 o ° = s% ' ^HiN X / N _V N _s CF ₃ N ^ fX-A' ..... 233 p „ ^H0 X n ^ LA .....

- 98 038388

234 \ NH ° ^ s X H χΝ N CF ₃ ν, 0Ύ, - (Τύφο ™ 235 n Π / NN _s c _F3 \ О nY-0 ^/ o- ( 688.26 689.40 [M + H] ⁺ 236 p ° 0 0 "JO ..... ζ H-Og Lg 237 O 0 ..... \ 238 o ° ό 0 ijy ..... c T co ₂ H / Υυφο-

- 99 038388

239 V _s CF ₃ ..- (HN ^ \ 1 p-CN 717.27 718.45 [M + H] ⁺ 240 Я 0 NH 's = 0 f ^N Y ^s w ^CF · 0 ...... ( ^Η Ν ^ Χ \ / V ^N UJy> ^CN 793.32 794.3244 241 A giot όΥ 720.27 721.35 242 Γ ^Ν ) AA '..- (^ 716.29 717.3 [M + H] ⁺ 243 ^h YyV ^f 0 ° ^{0 hn} oj9> - 667.30 668.45 [M + H] ⁺ 244 H / ^N x ⁿ G 0 ° / Ν N _S CF ₃ ΗΝ ^ γ UnJuly ⁰ 653.29 654.45 [M + H] ⁺

- 100 038388

245 o Ύγν ..... < HN ^ x 1 ОCN 760.28 761.2872 246 O f ^N ) know Xs. V Ο ..... <? HN ^ ^ x, _N UnOJO ^cn 718.27 719.2776 247 o = X ¹ f ^N ) HNyys CF ₃ VO N0 <7 --1 716.29 717.56 [M + H] ⁺ 248 A - / - ' ¹ 0 ^N ) ^HN vV \ / ^CF = M ..... 759.33 760.50 [M + H] ⁺ 249 Xo HN ' ^S \ h 0 / NN _s ΝγΧΖ ^ ..... ^HN 0jp ^ 731.30 732.45 [M + H] ⁺

- 101 038388

250 ^h f) n ^ Ay hn dj9> - 251 \ ΖΙ ι ^Ζ Α 47 _; V- ^ Ό ° Ύ Hy-o ζ —Yy 745.32 746.3 [Μ + Η] ⁺ 252 4η Γ ^Ν ) / Ν_ν _s CF ₃ \ Α Ν ^ ΥΎ υ ... ( ^ην Ό _ν 4 ^ 731.30 732.3 [Μ + Η] ⁺ 253 Η - ⁿ YYP ^f ρν ₄ хda '° 254 ^Η Ό ^ ^ν 255 Υσ ^ ^ρ μ ^Ν > ο « ^{ΗΝ Ό} ^ ^{% 0} 256 Η - ^Ν γγ \ Ζ ^ρ ρ _Ν% ^ΗΝ Ό20 °

- 102 038388

257 H ₂ NN _s CF _{3 CN4} X _J-N N- T 1 B— '55 ° γί о 258 1 o ex Λ / h) Jpp 259 6 o unit L ho X IZ \ 260 W ^v 261 b o cx xh 262 Yo X xz \ 263 Yo .ZJI ^ O <er 0 X Mo 264 \ ZT I, ^z = <X X О X

- 103 038388

265 s cf ₃ ™ Υ ΝΗ ^ΗΝ ΊΧ0 ^V 266 X ο Ρ 267 Η Y ¥ u ^F3 ΡΝ ρ Τ 1 / ^NV νη ΗΝ ^ ___ to ___ 268 ^Н1Ы Жу> £ Л Τ Γ / ^{Ν- /} ^ ΝΗ ^ΗΝ Ό30 269 <uh, ° i 270 ° e □ Γμγι Ρ ΙΖ \ 271 RNE 272 \ ζτ χ? = <A Ον

- 104 038388

- 105 038388

281 0 ° 'Ά Π 635.27 636.27 [M + H] ⁺ 282 ρ Η / - E Αχ 743.30 744.31 [M + H] ⁺ 283 ^Ο Χ r \ V ^ yA ^F y 728.29 729.30 [M + H] ⁺ 284 --N / ΝγΝ _S CF ₃ V> i ° ..... $ ^HN V% uAp> ^cN 285 ° = L / η A ^ζ γΥν7 V ^s y ^ / 'en' k ^ΗΝ νΥ / ^ - N 286 o / \ he P dXn ns CF ₃ \ J D υ Ζ odr> ^c 287 'XrA - O 288 CN <x \ - / O = S. o ^z

- 106 038388

In some embodiments, exemplary compounds may include, but are not limited to, a compound or a salt thereof selected from table. 2.

table 2

No. Structure MW (calculated) m / z (found) 1000 / ΗΝ '^ ΓΟ A ° 1001 £ ^ ^CF Y 1002 T ^ ^{CN ί Ν} γΚ Y 1003 dUsm γ 1004 Η < ^Ν £ ^ H ^F - γ

- 107 038388

1005 (rVW 'well? 1006 \ so ₂ oh nyuy u ^t shchu 1007 \ so ₂ xy // Nyy __ / ^HN γΎ ДЧ-N 1008 \ so ₂ y ^N Y ^s yY ^F3 J 1009 y C / / N ^ s CF ₃ \ E \

- 108 038388

- 109 038388

1015 0 == 4 NH htsu 1016 NH hL Η ₂ Ν _γ Ν _S CF ₃ p / NpLy U ^HN Y ^/ \ ZM 673.26 337.6 [M + 2H] ²⁺ 1017 _D P HN— \ 0 ° HC)> 1018 θζ, Ο HN ' ^S \ 1019 \ ΣΙ ijH > '/ φΑ> § 0¼

- 110 038388

Pharmaceutical compositions.

The compositions and methods of the present invention can be used to treat an individual in need thereof. In some embodiments, the individual is a mammal, such as a human, or a non-human mammal. At

111 038388 administration to an animal, such as a human, the composition or compound is preferably administered as a pharmaceutical composition containing, for example, a compound or salt of formula (I) or (II) and a pharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In yet other embodiments, the pharmaceutical compositions comprise a compound disclosed in the present invention and an additional therapeutic agent (eg, an anticancer agent). Non-limiting examples of such therapeutic agents are described below.

Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, and intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

In certain embodiments of the invention, a composition of a compound or salt of formula (I) or (II) is administered locally rather than systemically, for example by injection of the compound directly into an organ, often in a depot or sustained release formulation. In specific embodiments, the long acting compositions are administered by implantation (eg, subcutaneous or intramuscular) or by intramuscular injection. In addition, in other embodiments of the invention, the compound or salt of formula (I) or (II) is delivered in a targeted drug delivery system, for example, in a liposome coated with an organospecific antibody. In such embodiments, the liposomes are targeted and selectively targeted by an organ. In other embodiments, the composition is provided in the form of an immediate release composition, in the form of an extended release composition, or in the form of an intermediate release composition. In other embodiments, the composition is administered topically.

A compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, can be effective over a wide range of dosages. For example, in the treatment of adults, dosages of 0.01 to 1000 mg per day, 0.5 to 100 mg per day, 1 to 50 mg per day, and 5 to 40 mg per day are examples of dosages that can be used in some embodiments of the invention. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.

In some embodiments, the compound or salt of formula (I) or (II) is administered in a single dose. Typically, such administration is by injection, such as intravenous injection, in order to deliver the agent more quickly. However, other routes of administration are used as needed. In some embodiments, a single dose of a compound or salt of formula (I) or (II) is used to treat an acute condition. In some embodiments, the compound or salt of formula (I) or (II) is administered in multiple doses. In some embodiments, the dosage is about one, two, three, four, five, six, or six times a day. In other embodiments, the dosing is about once a month, once every two weeks, once a week, or once every two days. In another embodiment, a compound or salt of formula (I) or (II) and another agent are administered together from about once a day to about 6 times a day. In another embodiment, administration of a compound or salt of formula (I) or (II) and agent continues for less than about 7 days. In yet another embodiment, administration continues for more than about 6 days, more than about 10 days, more than about 14 days, more than about 28 days, more than about two months, more than about six months, or one year or more. In some cases, continuous dosing is achieved and maintained for as long as necessary.

The introduction of a compound or salt of formula (I) or (II) can be continued as long as necessary. In some embodiments, a compound of the present invention is administered for more than 1, more than 2, more than 3, more than 4, more than 5, more than 6, more than 7, more than 14, or more than 28 days. In some embodiments, a compound of the invention is administered for 28 days or less, 14 days or less, 7 days or less, 6 days or less, 5 days or less, 4 days or less, 3 days or less, 2 days or less, or 1 day or part of it. In some embodiments, the compound or salt of formula (I) or (II) is administered on a long-term, continuous basis, for example, to treat chronic effects.

In some embodiments, the compound or salt of formula (I) or (II) is administered in doses. It is known in the art that due to intersubject variability in the pharmacokinetics of the compounds, individualization of the dosage regimen is necessary for optimal therapy. The dosage of a compound or salt of formula (I) or (II) can be determined by routine experimentation in the light of the present disclosure.

In some embodiments, the compound or salt of formula (I) or (II) is formulated into pharmaceutical compositions. In certain embodiments, the pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers containing excipients and adjuvants that facilitate the processing of the active compounds into formulations that can be used for pharmaceutical purposes. The correct composition depends on the chosen route of administration. Any pharmaceutically acceptable techniques, carriers and excipients are used as suitable for formulating the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa .: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y. 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

The present invention provides pharmaceutical compositions comprising a compound or salt of formula (I) or (II) and a pharmaceutically acceptable diluent (s), excipient (s) or carrier (s). In some embodiments, the disclosed compounds or salts are administered as pharmaceutical compositions in which a compound or salt of formula (I) or (II) is mixed with other active ingredients, as in combination therapy. All combinations of active ingredients set forth in the combination therapy section below and throughout this specification are encompassed by the present invention. In specific embodiments, the pharmaceutical compositions comprise one or more compounds of formula (I) or (II), or a pharmaceutically acceptable salt thereof. A pharmaceutical composition as used in the present invention refers to a mixture of a compound or salt of formula (I) or (II) with other chemical components such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents and / or excipients. In certain embodiments of the invention, the pharmaceutical composition facilitates administration of the compound to the body. In some embodiments of the invention, during the practicing methods of treatment or use provided herein, a therapeutically effective amount of a compound or salt of formula (I) or (II) is administered in a pharmaceutical composition to a mammal having the disease, disorder, or health condition to be treated. In specific embodiments, the mammal is a human. In certain embodiments of the invention, the therapeutically effective amounts will vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. A compound or salt of formula (I) or (II) can be used alone or in combination with one or more therapeutic agents as components of mixtures.

In one embodiment of the invention, a compound or salt of formula (I) or (II) is formulated in aqueous solution. In specific embodiments of the invention, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer such as Hank's solution, Ringer's solution, or physiological saline buffer. In other embodiments, a compound or salt of formula (I) or (II) is formulated for transmucosal administration. In specific embodiments of the invention, formulations for transmucosal use include penetrants that are suitable for penetrating the barrier. In other embodiments of the invention, where the compound or salt of formula (I) or (II) is formulated for other parenteral injection, suitable formulations include aqueous or non-aqueous solutions. In specific embodiments of the invention, such solutions include physiologically compatible buffers and / or excipients.

In another embodiment, the compound or salt of formula (I) or (II) is formulated for oral administration. A compound or salt of formula (I) or (II) can be formulated by combining the active compounds with, for example, pharmaceutically acceptable carriers or excipients. In various embodiments, a compound or salt of formula (I) or (II) is formulated into oral dosage unit forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, gruels. , suspensions, etc.

In certain embodiments of the invention, pharmaceutical preparations for oral use are prepared by mixing one or more solid excipients with a compound or salt of formula (I) or (II), optionally grinding the resulting mixture, and treating the mixture of granules after adding suitable excipients, if necessary, to obtain tablets or pills.

Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulosic preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl-113 038388 cellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrating agents are optionally added.

Disintegrants include, by way of example only, crosslinked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

In one embodiment of the invention, dosage forms such as dragees and tablets are provided with one or more suitable coatings. In specific embodiments of the invention, concentrated sugar solutions are used to coat a dosage form. The sugar solutions optionally contain additional components, for example, by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, varnish solutions, and suitable organic solvents or solvent mixtures. Colorants and / or pigments are also optionally added to the coatings for identification purposes. In addition, dyes and / or pigments are optionally used to characterize different combinations of doses of active compound. In certain embodiments of the invention, a therapeutically effective amount of a compound or salt of formula (I) or (II) is formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made from gelatin and soft sealed capsules made from gelatin and a plasticizer such as glycerin or sorbitol. In certain embodiments, push-fit capsules contain the active ingredients in admixture with one or more excipients. Fillers include, by way of example only, lactose, binders such as starches and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In other embodiments, soft capsules contain one or more active compounds that are dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added.

In other embodiments, a therapeutically effective amount of a compound or salt of formula (I) or (II) is formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, troches, or gels. In other embodiments, a compound or salt of formula (I) or (II) is formulated for parenteral injection, including compositions suitable for bolus injection or continuous infusion. In specific embodiments of the invention, compositions for injection are presented in unit dosage form (eg, ampoules) or in multi-dose containers. Preservatives are optionally added to the injectables. In other embodiments, the pharmaceutical compositions are formulated for parenteral injection as sterile suspensions, solutions, or emulsions in oily or aqueous bases. Compositions for parenteral injection optionally contain auxiliary agents such as suspending, stabilizing and / or dispersing agents. In specific embodiments of the invention, pharmaceutical compositions for parenteral administration comprise aqueous solutions of the active compounds in a water-soluble form. In additional embodiments of the invention, the suspension of the compound or salt of formula (I) or (II) is formulated as suitable oily injection suspensions. Suitable lipophilic solvents or agents for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil or synthetic fatty acid esters such as ethyl oleate or triglycerides or liposomes. In some specific embodiments of the invention, aqueous injection suspensions contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents that increase the solubility of the compounds to provide highly concentrated solutions. In certain embodiments of the invention, the active ingredient is in powder form for reconstitution with a suitable carrier, eg sterile, pyrogen-free water, prior to use.

In yet other embodiments, a compound or salt of formula (I) or (II) is administered topically (topically). The compound or salt of formula (I) or (II) can be formulated in various topical compositions such as solutions, suspensions, lotions, gels, pastes, medicinal sticks, balms, creams or ointments. Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicizers, buffers and preservatives.

In other embodiments, the compound or salt of formula (I) or (II) is formulated for transdermal administration. In transdermal formulations, transdermal delivery devices and transdermal patches can be used, and lipophilic emulsions or buffered aqueous solutions dissolved and / or dispersed in a polymer or adhesive can be used. In various embodiments of the invention, such patches are designed for continuous, pulsatile delivery of pharmaceutical agents, or delivery on demand. In additional

114,038388 embodiments of the invention, the transdermal delivery of a compound or salt of formula (I) or (II) is via iontophoretic patches and the like. In certain embodiments of the invention, transdermal patches provide controlled delivery of a compound or salt of formula (I) or (II). In certain embodiments of the invention, the rate of absorption is slowed down by the use of rate-controlling membranes or by entrapment of the compound in a polymer matrix or gel. In alternative embodiments of the invention, absorption enhancers are used to increase absorption. Absorption enhancers or carriers include absorbable pharmaceutically acceptable solvents that facilitate skin penetration. For example, in one embodiment of the invention, the transdermal devices are in the form of a dressing comprising a support member, a reservoir containing a compound or salt of formula (I) or (II), optionally with carriers, optionally a rate-regulating barrier to deliver the compound to the skin of a patient with controlled and a predetermined speed over a long period of time; and a means for attaching the device to the skin. In other embodiments, the compound or salt of formula (I) or (II) is formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists, or powders. Pharmaceutical compositions of a compound or salt of formula (I) or (II) are typically delivered as an aerosol spray from pressurized containers or a nebulizer using a suitable propellant (eg, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In certain embodiments of the invention, the dose of the pressurized aerosol is determined using a valve to deliver a measured amount. In certain embodiments, capsules and cartridges, for example, by way of example only, gelatin for use in an inhaler or insufflator, comprise a powder mixture of a compound or salt of formula (I) or (II) and a suitable powder base such as lactose or starch. In other embodiments, the compound or salt of formula (I) or (II) is formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, gummy suppositories, or retention enemas containing conventional suppository bases such as as cocoa butter or other glycerides, and synthetic polymers such as polyvinylpyrrolidone, PEG and the like. The suppository forms of the compositions first melt a low melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter. In certain embodiments of the invention, the pharmaceutical compositions are prepared by any conventional method using one or more physiologically acceptable carriers, including excipients and adjuvants that facilitate the processing of the active compounds into preparations that can be used for pharmaceutical purposes. The exact composition depends on the chosen route of administration. Any pharmaceutically acceptable methods, carriers and excipients can optionally be used as appropriate. Pharmaceutical compositions containing a compound or salt of formula (I) or (II) are manufactured in a conventional manner, for example, by way of example only, by conventional mixing, dissolving, granulating, dragee making, trituration, emulsification, encapsulation, entrainment or compression processes. ...

Pharmaceutical compositions comprise at least one pharmaceutically acceptable carrier, diluent or excipient and a compound or salt of formula (I) or (II), sometimes referred to in the present invention as an active agent or ingredient. The active ingredient can be in the free acid or free base form, or in the form of a pharmaceutically acceptable salt. In addition, the compound or salt of formula (I) or (II) can be in unsolvated or solvated forms with pharmaceutically acceptable solvents such as water and ethanol. In addition, the pharmaceutical compositions optionally include other drugs or pharmaceuticals, carriers, adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, solubilizing agents, salts for adjusting the osmotic pressure, buffers and / or other therapeutically valuable substances.

Methods for preparing compositions containing a compound or salt of formula (I) or (II) include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid preparation. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which the compound dissolves, emulsions containing the compound, or a solution containing liposomes, micelles or nanoparticles containing a compound or salt of formula (I) or (II). Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The form of pharmaceutical compositions of the compound or salt of formula (I) or (II) includes liquid solutions or suspensions, solid forms suitable for dissolution, or suspensions obtained in liquids before use, or in the form of emulsions. These compositions also optionally contain minor amounts of non-toxic adjuvants such as wetting or emulsifying agents, pH buffering agents, etc. In some embodiments of the invention, a pharmaceutical composition with

115 038388 containing the compound or salt of formula (I) or (II) is in the form of a liquid, wherein the agents are present in solution, in suspension, or both. Typically, when the composition is administered as a solution or suspension, the first portion of the agent is present in the solution and the second portion of the agent is present as particles suspended in a liquid matrix. In some embodiments, the liquid composition comprises a gel formulation. In other embodiments, the liquid composition is aqueous.

In certain embodiments of the invention, aqueous suspensions contain one or more polymers as suspending agents. Polymers include water-soluble polymers such as cellulosic polymers such as hydroxypropyl methylcellulose and water-insoluble polymers such as crosslinked carboxyl-containing polymers. Certain pharmaceutical compositions described in the present invention comprise a mucoadhesive polymer selected, for example, from carboxymethyl cellulose, carbomer (acrylic acid polymer), poly (methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid-butyl acrylate copolymer, sodium alginate and dextran. The pharmaceutical compositions also optionally include solubilizing agents to aid in the solubility of a compound of the present invention. The term solubilizing agent generally includes agents that result in the formation of a micellar solution or true solution of the agent. Some suitable nonionic surfactants, such as polysorbate 80, are useful as solubilizing agents, as are ophthalmologically acceptable glycols, polyglycols, such as polyethylene glycol 400, and glycol ethers. The pharmaceutical compositions optionally include one or more pH adjusting or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric, and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris-hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases and buffers are included in an amount necessary to maintain the pH of the composition within an acceptable range.

In addition, useful compositions also optionally include one or more salts in an amount necessary to provide the osmolality of the composition within an acceptable range. Such salts include salts containing sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate. The pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridine chloride. Pharmaceutical compositions can include one or more surfactants to improve physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and polyoxyethylene alkyl phenyl ethers such as octoxynol 10, octoxynol 40.

The pharmaceutical compositions may include one or more antioxidants to enhance chemical stability as needed. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

In certain embodiments of the invention, the aqueous suspension compositions are packaged as a single dose in non-resealable containers. Alternatively, multi-dose reusable containers are used, in which case a preservative is usually included in the composition.

In certain embodiments of the invention, delivery systems for hydrophobic pharmaceutical compounds are used. Liposomes and emulsions are examples of delivery vehicles or carriers useful in the present invention. Organic solvents such as N-methylpyrrolidone are also used in certain embodiments of the invention. In additional embodiments of the invention, the compound or salt of formula (I) or (II) is delivered using a sustained release system such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained release materials can be used in the present invention. In some embodiments, the sustained release capsules release the compounds over several weeks to more than 100 days. Depending on the chemical nature and biological stability of the therapeutic reagent, additional protein stabilization strategies are used. In certain embodiments, the compositions described herein comprise one or more antioxidants, metal chelating agents, thiol-containing compounds, and / or other general stabilizing agents. Examples of such stabilizing agents include, but are not limited to, (a) from about 0.5 to about 2% w / v. glycerin, (b) from eye

- 116 038388 lo 0.1 to about 1% w / v. methionine, (c) from about 0.1 to about 2% wt./about. monothioglycerol, (d) about 1 to about 10 mM EDTA, (e) about 0.01 to about 2% w / v. ascorbic acid, (f) 0.003 to about 0.02% w / v. polysorbate 80, (g) 0.001 to about 0.05% w / v. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof. In some embodiments, the concentration of a compound or salt of formula (I) or (II) provided in the pharmaceutical compositions is less than about 100, 90, 80, 70, 60, 50, 40, 30, 20, 19, 18, 17 , 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.4, 0.3, 0.2, 0 , 1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03,

0.02, 0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, 0.001, 0.0009, 0.0008, 0.0007, 0.0006, 0.0005, 0.0004, 0.0003, 0.0002, or 0.0001% w / w, w / v or about./about.

In some embodiments, the concentration of a compound or salt of formula (I) or (II) provided in pharmaceutical compositions is greater than about: 90, 80, 70, 60, 50, 40, 30, 20, 19.75, 19, 50, 19.25, 19, 18.75, 18.50, 18.25, 18, 17.75, 17.50, 17.25, 17, 16.75, 16.50, 16.25, 16,

15.75, 15.50, 15.25, 15, 14.75, 14.50, 14.25, 14, 13.75, 13.50, 13.25, 13, 12.75, 12.50, 12.25 11.75, 11.50, 11.25, 11, 10.75, 10.50, 10.25, 10, 9.75, 9.50, 9.25, 9, 8.75, 8 , 50, 8.25, 8, 7.75, 7.50, 7.25, 7, 6.75, 6.50, 6.25, 6, 5.75,

5.50, 5.25, 5, 4.75, 4.50, 4.25, 4, 3.75, 3.50, 3.25, 3, 2.75, 2.50, 2.25, 2, 1.75, 1.50, 1.25, 1, 0.5, 0.4, 0.3, 0.2, 0.1,

0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, 0.001,

0.0009, 0.0008, 0.0007, 0.0006, 0.0005, 0.0004, 0.0003, 0.0002 or 0.0001% w / w, w / v or about./about.

In some embodiments, the concentration of a compound or salt of formula (I) or (II) ranges from about 0.0001 to about 50%, from about 0.001 to about 40%, from about 0.01 to about 30%, from about 0.02 to about 29%, about 0.03 to about 28%, about

0.04 to about 27%, about 0.05 to about 26%, about

0.06 to about 25%, about 0.07 to about 24%, about

0.08 to about 23%, about 0.09 to about 22%, about

0.1 to about 21%, about 0.2 to about 20%, about

0.3 to about 19%, about 0.4 to about 18%, about

0.5 to about 17%, about 0.6 to about 16%, about

0.7 to about 15%, about 0.8 to about 14%, about

0.9 to about 12%, about 1 to about 10% w / w, w / v. or about./about.

In some embodiments, the concentration of a compound or salt of formula (I) or (II) ranges from about 0.001 to about 10%, from about 0.01 to about 5%, from about 0.02 to about 4.5%, from about

0.03 to about 4%, about 0.04 to about 3.5%, about

0.05 to about 3%, about 0.06 to about 2.5%, about

0.07 to about 2%, about 0.08 to about 1.5%, about

0.09 to about 1%, about 0.1 to about 0.9% w / w, w / v / v / v

In some embodiments, the amount of a compound or salt of formula (I) or (II) is equal to or less than about 10, 9.5, 9.0, 8.5, 8.0, 7.5, 7.0, 6, 5, 6.0, 5.5, 5.0, 4.5, 4.0, 3.5, 3.0, 2.5, 2.0, 1.5, 1.0, 0.95, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0, 3, 0.25, 0.2, 0.15, 0.1, 0.09, 0.08,

0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, 0.001, 0.0009, 0.0008, 0.0007, 0.0006, 0.0005, 0.0004, 0.0003, 0.0002 or 0.0001 g.

In some embodiments, the amount of a compound or salt of formula (I) or (II) is greater than about 0.0001, 0.0002, 0.0003, 0.0004, 0.0005, 0.0006, 0.0007, 0, 0008, 0.0009 0.001 0.0015 0.002 0.0025 0.003 0.0035 0.004 0.0045 0.005 0.0055 0.006 0.0065 0.007 0.0075 0.008 0.0085, 0.009, 0.0095, 0.01, 0.015, 0.02, 0.025, 0.03, 0.035, 0.04, 0.045, 0.05, 0.055, 0.06, 0.065, 0.07, 0.075, 0.08, 0.085, 0.09, 0.095, 0, 1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 or 10 g.

In some embodiments, the amount of one or more compounds of the invention ranges from 0.0001 to 10 g, 0.0005 to 9 g, 0.001 to 8 g, 0.005 to 7 g, 0.01 to 6 g , 0.05 to 5 g, 0.1 to 4 g, 0.5 to 4 g, or 1 to 3 g.

Kits and articles thereof are also provided for use in the therapeutic applications described in the present invention. In some embodiments, such kits comprise a carrier, package, or container that is divided into portions to receive one or more containers such as vials, vials, and the like, each of the container (s) containing one of the separate items that should be used in the method described in the present invention. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers are made of various materials such as glass or plastic.

The articles provided in the present invention made in accordance with the present invention comprise packaging materials. Packaging materials for use in packaging pharmaceutical products include those contained, for example, in US patents

- 117 038388 # 5323907, 5052558 and 5033252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles and any packaging material suitable for the selected drug and the intended route of administration and treatment. For example, container (s) comprise a compound or salt of formula (I) or (II), optionally in a composition or in combination with another agent as described herein. The container (s) optionally have a sterile access port (for example, the container is an intravenous solution bag or a vial with a stopper pierced by a hypodermic needle). Such kits optionally contain a compound with an identifying description or label or instructions related to its use in the methods described herein. For example, a kit typically includes one or more additional containers, each containing one or more different materials (such as reagents, optionally in concentrated form, and / or devices) commercially and user-desirable for use with the compound described. in the present invention. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; carrier, packaging, container, vial and / or vial labels and / or instructions for use, and package inserts with instructions for use. Usually a set of instructions is also included. The label is not necessarily on the container or connected to the container. For example, a label is on a container when letters, numbers, or other symbols forming a label are attached, molded, or etched onto the container itself, the label is attached to the container when present in a slot or on a carrier that also holds the container, for example, as liner. In addition, the label is used to indicate that the content is to be used for a specific therapeutic use. In addition, the label indicates directions of use of the content, such as the methods described in the present invention. In certain embodiments of the invention, the pharmaceutical composition is presented in a packaging or dispensing device that contains one or more unit dosage forms containing a compound provided in the present invention. The packaging, for example, contains metal or plastic foil, such as a blister pack. In addition, the packaging or dispensing device is accompanied by instructions for administration, or the package or dispenser is accompanied by a notification related to the container, in the form prescribed by the government agency regulating the production, use or sale of pharmaceutical products, where the notification reflects the approval of the form of the drug for administration by the agency. human or veterinary administration. For example, such a notice is a FDA-approved prescription drug label or an approved product insert. In some embodiments, compositions containing a compound provided herein are formulated in a compatible pharmaceutical carrier, placed in a suitable container, and labeled to treat the condition.

The ways

The present invention relates to a method for inhibiting the interaction of menin with one or more proteins (eg, MLL1, MLL2, MLL or MLL partial tandem duplication fusion protein), comprising contacting a cell with an effective amount of a compound or salt of formula (I) or (II). Inhibition of the interaction of menin with one or more proteins (eg, MLL1, MLL2, MLL fusion protein, or MLL with partial tandem duplication) can be evaluated and demonstrated using a wide variety of methods known in the art. Non-limiting examples include reference to (a) reducing the binding of menin to one or more proteins or protein fragments (eg, MLL1, MLL2, MLL fusion protein, tandem duplicate MLL, or a peptide fragment thereof); (b) reducing cell proliferation and / or cell viability; (c) increased cell differentiation; (d) reducing the levels of downstream targets MLL1, MLL2, MLL fusion protein and / or MLL with partial tandem duplication (eg, Hoxa9, DLX2 and MeiS1); and / or (e) reducing tumor volume and / or tumor growth rate. Kits and commercially available assays can be used to determine one or more of the above.

The present invention also relates to methods of using the compounds or pharmaceutical compositions of the present invention for the treatment of diseases, including, but not limited to, conditions associated with menin, MLL, MLL1, MLL2 and / or MLL fusion proteins (eg, cancer).

In some embodiments, the invention provides a method for treating cancer, comprising administering an effective amount of any of the aforementioned pharmaceutical compositions containing a compound or salt of formula (I) or (II) to a subject in need thereof. In some embodiments, the cancer is mediated by an MLL fusion protein. In other embodiments, the cancer is leukemia, breast cancer, prostate cancer, pancreatic cancer, lung cancer, liver cancer, skin cancer, or brain tumor. In some embodiments, the cancer is leukemia. In some embodiments

- 118 038388 of the invention, cancer contains a solid tumor. In some embodiments, the present invention provides a method of treating a disorder in a subject in need thereof, wherein the method comprises determining whether the subject has an MLL fusion protein, and if the subject is determined to have an MLL fusion protein, then comprising administering to the subject therapeutically an effective dose of a compound or salt of formula (I) or (II). MLL fusion proteins have also been identified in hematologic malignancies (eg, cancers that affect the blood, bone marrow, and / or lymph nodes). Accordingly, some embodiments of the invention are directed to the administration of a compound or salt of formula (I) or (II) to a patient in need of hematologic cancer treatment. Such cancers include, but are not limited to, leukemias and lymphomas. For example, the compounds disclosed in the present invention can be used to treat diseases such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), small cell lymphocytic lymphoma (SLL), chronic myelogenous leukemia (CML) , acute monocytic leukemia (AMoL), hairy cell leukemia and / or other leukemias. In other embodiments, the compounds can be used to treat lymphomas such as all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma.

Determining whether a tumor or cancer may contain an MLL fusion protein can be carried out by evaluating the nucleotide sequence encoding the MLL fusion protein, by evaluating the amino acid sequence of the MLL fusion protein, or by evaluating the characteristics of the putative MLL fusion protein. Methods for detecting the nucleotide sequence of an MLL fusion protein are known to those skilled in the art. These methods include, but are not limited to, polymerase chain reaction (polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)), polymerase chain reaction (polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), real-time PCR, PCR sequencing, mutant allele-specific PCR amplification (MASA), direct sequencing, primer extension reactions, electrophoresis, ligation assays oligonucleotides, hybridization assays, TaqMan assays, SNP genotyping assays, high resolution melting assays, and microarray assays. In some embodiments, the MLL fusion protein is identified, for example, using a method for direct sequencing of specific regions (eg, exon 2 and / or exon 3) in the MLL or fusion partner gene. This technique identifies all possible mutations in the sequencing domain.

Methods for detecting an MLL fusion protein are known to those skilled in the art. These methods include, but are not limited to, detecting the MLL fusion protein using a binding agent (eg, an antibody) specific for the fusion protein, electrophoresis and Western blotting of the protein, and direct peptide sequencing.

Various samples can be used in methods for detecting whether a tumor or cancer contains an MLL fusion protein. In some embodiments, the sample is taken from a subject having a tumor or cancer. In some embodiments, the sample is taken from a subject having cancer or tumor. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed sample embedded in paraffin. In some embodiments, the sample is processed into a cell lysate. In some embodiments, the sample is processed into DNA or RNA. The present invention also relates to a method of treating a hyperproliferative disorder in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound or salt of formula (I) or (II). In some embodiments, the method relates to the treatment of cancer such as acute myeloid leukemia, adolescent cancer, pediatric adrenocortical carcinoma, AIDS-related cancer (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoid , basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain glioma, brain tumor, breast cancer, bronchial tumors, Burkitt's lymphoma, carcinoid tumor, atypical teratoid, embryonic tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, heart tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma situ (ductal carcinoma in situ (DCIS)), embryonic tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesionuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extraganal germ cell tumor, eye cancer, fibrous bone histiocytoma, gallbladder cancer, stomach cancer, gastrointestinal carcinoid tumor, gastrointestinal (GIST) germ cell tumors , gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer,

- 119 038388 heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, neuroendogenous pancreatic tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (lobular carcinoma in situ (LCIS)), lung cancer, lymphoma, metastatic squamous cell carcinoma of the neck with an unidentified primary tumor with detected metastases, midline carcinoma, oral cancer, multiple endocrine neoplasia syndromes, multiple myeloma / plasma cell neoplasm, fungoid mycosis, myelodysplastic syndromes, myelodysplastic syndromes myeloproliferative neoplasms, multiple myeloma, merkel cell carcinoma, malignant mesothelioma, malignant fibrous bone histiocytoma and osteosarcoma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell carcinoma (NSC) oral cavity, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, direct cancer colon, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastrointestinal) cancer, small cell lung cancer, small bowel cancer, soft tissue sarcoma, T cell lymphoma, testicular cancer, throat cancer, thymoma and carcinoma of the thymus, cancer of the thyroid gland, cancer of transitional cells of the kidney and ureter, trophoblastic tumor, unusual types of cancer in children, cancer of the urethra, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer.

In some embodiments, the method relates to the treatment of a benign hyperproliferative disorder such as uncomplicated hyperplasia of the skin (eg, psoriasis), restenosis, or prostate gland (eg, benign prostatic hypertrophy (BPH)). In some cases, the method relates to the treatment of leukemia, hematological malignant neoplasm, solid tumor cancer, prostate cancer (e.g., castration-resistant prostate cancer), breast cancer, Ewing's sarcoma, bone sarcoma, primary bone sarcoma, T-cell prolymphocytic leukemia, glioma , glioblastoma, liver cancer (eg, hepatocellular carcinoma), or diabetes. In some cases, leukemia includes AML, ALL, mixed leukemia, or leukemia with partial tandem duplications of MLL.

In some specific embodiments, the present invention relates to methods for treating lung cancers, the methods comprising administering an effective amount of any compound as described above (or a pharmaceutical composition containing it) to a subject in need thereof. In some embodiments, the lung cancer is non-small cell lung carcinoma (NSCLC), eg, adenocarcinoma, squamous cell lung carcinoma, or large cell lung carcinoma. In other embodiments, the lung cancer is small cell lung carcinoma. Other lung cancers treatable with the disclosed compounds include, but are not limited to, glandular tumors, carcinoid tumors, and undifferentiated carcinomas.

Subjects that can be treated with compounds of the invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, tautomer, stereoisomer, isotopologue, hydrate, or derivative of a compound according to the methods of this invention include, for example, subjects who have been diagnosed with acute myeloid leukemia, acute myeloid leukemia, cancer in adolescents, adrenocortical carcinoma in children, cancers associated with AIDS (eg, lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoid, basal cell carcinoma, bile duct cancer, cancer bladder, bone cancer, brain glioma, brain tumor, breast cancer, bronchial tumors, Burkitt's lymphoma, carcinoid tumor, atypical teratoid, embryo tumors, germ cell tumors, primary lymphoma, cervical cancer, childhood cancers, chordoma, heart tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chr onic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngo uterus, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonic tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesionuroblastoma, sarcoma germ cell tumor, extraganal germ cell tumor, eye cancer, fibrous bone histiocytoma, gallbladder cancer, stomach cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia head and neck, heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic tumors, kidney cancer, laryngeal cancer, lip and oral cancer, liver cancer, lobar carcinoma in situ (LCIS) , lung cancer, lymphoma, metastatic squamous cell carcinoma of the neck with unidentified primary cancer choli with detected metastases, midline carcinoma, oral cancer, multiple endocrine neoplasia syndromes, multiple myeloma / plasma cell neoplasm, fungoid mycosis,

- 120 038388 myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, multiple myeloma, merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinus cancer, non-malignant pulmonary cell carcinoma , oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous lymphoma systems (CNS), prostate cancer, rectal cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastrointestinal) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, lymphoma T cell, testicular cancer, throat cancer, thymoma and thymoma carcinoma mustache, thyroid cancer, cancer of the transitional cells of the kidney and ureter, trophoblastic tumor, unusual types of cancer in children, cancer of the urethra, uterine sarcoma, vaginal cancer, vulvar cancer, virus-induced cancer, leukemia, hematological malignant tumor, cancer with solid tumor, prostate cancer, castration-resistant prostate cancer, breast cancer, Ewing's sarcoma, bone sarcoma, primary bone sarcoma, T-cell prolymphocytic leukemia, glioma, glioblastoma, hepatocellular carcinoma, liver cancer, or diabetes. In some embodiments, subjects treated with compounds of the invention include subjects that have been diagnosed as having a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (eg, psoriasis), restenosis, or prostate gland (eg, benign prostatic hypertrophy (BPH)) ... In addition, the present invention relates to methods for modulating the interaction of menin with one or more proteins (e.g., MLL1, MLL2, MLL or MLL fusion protein with partial tandem duplication) by contacting menin with an effective amount of a compound or salt of formula (I) or (II) ... Modulation can inhibit or activate the protein activity of menin, one or more of its binding partners, and / or one or more of the downstream targets of menin, or one or more of its binding partners. In some embodiments, the present invention provides methods for inhibiting the interaction of menin with one or more proteins (e.g., MLL1, MLL2, MLL or MLL tandem duplication fusion protein) by contacting menin with an effective amount of a compound or salt of formula (I) or ( II). In some embodiments, the present invention provides methods for inhibiting the interaction of menin with one or more proteins (e.g., MLL1, MLL2, MLL or MLL fusion protein with partial tandem duplication) by contacting a cell, tissue, or organ that expresses menin, MLL1, MLL2, MLL and / or MLL fusion protein with partial tandem duplication. In some embodiments, methods of inhibiting protein activity in a subject, including but not limited to rodents and mammals (eg, humans), are disclosed by administering to the subject an effective amount of a compound or salt of formula (I) or (II). In some embodiments, the modulation percentage is greater than 25, 30, 40, 50, 60, 70, 80, or 90%. In some embodiments, the percent inhibition is greater than 25, 30, 40, 50, 60, 70, 80, or 90%.

In some embodiments, the present invention provides methods for inhibiting the interaction of menin and one or more proteins (e.g., MLL1, MLL2, MLL or MLL fusion protein with partial tandem duplication) in a cell by contacting the cell with an amount of a compound of the present invention sufficient to inhibiting the interaction of menin and one or more proteins (eg, MLL1, MLL2, MLL fusion protein, or MLL with partial tandem duplication) in the cell. In some embodiments, the invention relates to methods of inhibiting the interaction of menin with one or more proteins (e.g., MLL1, MLL2, MLL fusion protein, or tandem partial duplication MLL) in tissue by contacting the tissue with an amount of a compound or salt of formula (I) or (Ii) sufficient to inhibit the interaction of menin and one or more proteins (eg, MLL1, MLL2, MLL or MLL fusion protein with partial tandem duplication) in tissue. In some embodiments, the invention relates to methods of inhibiting the interaction of menin and one or more proteins (e.g., MLL1, MLL2, MLL or MLL tandem duplication fusion protein) in an organism by contacting the organism with an amount of a compound or salt of formula (I) or ( II) sufficient to inhibit the interaction of menin and one or more proteins (e.g., MLL1, MLL2, MLL or MLL fusion protein with partial tandem duplication) in the body. In some embodiments, the disclosure provides methods for inhibiting the interaction of menin with one or more proteins (e.g., MLL1, MLL2, MLL or MLL partial tandem duplication fusion protein) in an animal by contacting the animal with an amount of a compound or salt of formula (I) or (II ) sufficient to inhibit the interaction of menin and one or more proteins (e.g., MLL1, MLL2, MLL or MLL fusion protein with partial tandem duplication) in the animal. In some embodiments, the present invention provides methods for inhibiting the interaction of menin with one or more proteins (e.g., MLL1, MLL2, fusion

- 121 038388 MLL or MLL proteins with partial tandem duplication) in a mammal, by contacting the mammal with an amount of a compound or salt of formula (I) or (II) sufficient to inhibit the interaction of menin and one or more proteins (e.g. MLL1, MLL2, fusion protein MLL or MLL with partial tandem duplication) in a mammal. In some embodiments, the present invention provides methods for inhibiting the interaction of menin with one or more proteins (e.g., MLL1, MLL2, MLL or MLL tandem duplication fusion protein) in a human by contacting the person with an amount of a compound or salt of formula (I) or (Ii) sufficient to inhibit the interaction of menin and one or more proteins (eg, MLL1, MLL2, MLL or MLL fusion protein with partial tandem duplication) in humans. The present invention relates to methods of treating a disease mediated by the interaction of menin and one or more proteins (eg, MLL1, MLL2, MLL fusion protein, or MLL with partial tandem duplication) in a subject in need of such treatment.

The present invention also relates to methods of treating a disorder mediated by the interaction of menin with one or more proteins (e.g., MLL1, MLL2, MLL fusion protein or MLL with partial tandem duplication) by administering to a subject in need a therapeutically effective amount of a compound or salt of formula (I) or (ii).

The present invention further provides methods for treating a disorder mediated by a chromosomal rearrangement on chromosome 11q23 in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or salt of formula (I) or (II).

The present invention also provides methods for treating a disease or condition by administering an effective amount of a compound or salt of formula (I) or (II) to a subject suffering from the disease or condition. The present invention further relates to methods of treating a disease or condition by administering a compound or salt of formula (I) or (II) to a subject suffering from a disease or condition, wherein the compound binds to mesenine and inhibits the interaction of mesenine with one or more proteins (e.g., MLL1, MLL2, MLL fusion protein or MLL with partial tandem duplication). The present invention further relates to methods for stabilizing menin, comprising contacting the menin with a compound or salt of formula (I) or (II). In some embodiments, the contacting step comprises contacting the menin with an amount of the compound sufficient to stabilize the menin. In some embodiments, the contacting step occurs in vivo. In some embodiments, the contacting step occurs in vitro. In some embodiments, the contacting step occurs in a cell.

The present invention also relates to combination therapy methods in which an agent known to be involved in modulating other pathways, or other components of the same pathway, or even overlapping sets of target enzymes, is used in combination with a compound or salt of formula (I ) or (II). In one aspect, such therapy includes, but is not limited to, the combination of one or more compounds of the invention with chemotherapeutic agents, therapeutic antibodies, and radiation therapy to provide a synergistic or additive therapeutic effect. If desired, a compound or pharmaceutical composition of the present invention can be used in combination with Notch inhibitors and / or c-Myb inhibitors. If desired, a compound or pharmaceutical composition of the present invention can be used in combination with MLL-WDR5 inhibitors and / or Dot11 inhibitors.

Currently, many chemotherapeutic agents are known in the art and can be used in combination with a compound of the invention. In some embodiments, the chemotherapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens.

Non-limiting examples are chemotherapeutic agents, cytotoxic agents and non-peptide small molecules such as Gleevec® (imatinib mesylate), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib) and adriamycin, and a host of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXANTM); alkyl sulfonates such as busulfan, imsulfan, and pyrossulfan; aziridines such as benzodopa, carbocon, meturedopa, and uredopa; ethyleneimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine; nitrogenous mustards such as chlorambucil, chloronaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembicin, fenesterol, prednimustine, trophosphamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinimines, actinomycin, outriramine, azaserin, bleomycins, cactinomycin, calicheamycin, carbabicin, carminomycin, carzinophilin, casodextrim, chromomycins, dactinomycin, daunorubicin, detorubicin,

- 122 038388

6-diazo-5-oxo-E-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellcomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, kelamycin, streporubicinosin , zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacytidine, 6azauridine, karmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, fluxuridine, androgens such as kalastone, dromonostanol propionate, epitiostanol, mepitonostan; antiadrenal drugs such as aminoglutethimide, mitotane, trilostane; a folic acid substitute such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bizanthrene; edatraxate; defopamine; demecolcine; diaziquon; elfomitin; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguason; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pyirubicin; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK.RTM .; razoxane; sizophyran; spirogermanium; tenuazonic acid; triaziquon; 2,2 ', 2''trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotep; taxanes such as paclitaxel (TAXOLTM, Bristol-Myers Squibb Oncology, Princeton, N.J.) and docetaxel (TAXOTERETM, Rhone-Poulenc Rorer, Antony, France); retinoic acid; esperamicins; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above.

In addition, antihormonal agents that act to regulate or inhibit the hormonal activity of tumors, such as antiestrogens, including, for example, tamoxifen, (NolvadexTM), raloxifene, aromatase inhibitors 4 (5 ) -imidazoles, 4-hydroxy tamoxifen, trioxifene, keoxifen, LY117018, onpristone and toremifene (Fareston); and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbin; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11); RFS 2000 topoisomerase inhibitor; difluoromethylornithine (DMFO). Where desired, the compounds or pharmaceutical composition of the present invention can be used in combination with commonly prescribed anti-cancer drugs such as Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, abagovomab, acridinocarboxamide, adecatumumab, 17-Nalllylamino-17-demethoxygeldanamycin, alfaradin, alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafid, anthracenedione, anti-CD22-immunotoxins, atopodimo-rimo- bendamustine, BIBW 2992, birikodar, brostallicin, bryostatin, butthionine sulfoximine, CBV (chemotherapy), caliculin, nonspecific antineoplastic agents of the cell cycle, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, epothilinus, eribusin fosfestrol, -chemotherapy ICE, IT-101, imexon, imiquimod, indolocarbazole, irofulven, l aniquidar, larotaxel, lenalidomide, lucanton, lurtotecan, mafosfamide, mitozolomide, naphoxidine, nedaplatin, olaparib, orthataxel, PAC-1, azimine extract, pixantrone, proteasome inhibitor, rebeccamycin, resiquimod, rubitecan, saporamine, SN-38 V, swainsonin, thalaporfin, tarikvidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris- (2-chloroethyl) amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126 or zosuquidar.

This disclosure further relates to a method of using a compound or salt of formula (I) or (II) or a pharmaceutical composition of the present invention in combination with radiation therapy to inhibit abnormal cell growth or treat a hyperproliferative disorder in a mammal. Techniques for using radiation therapy are known in the art, and these techniques can be used in the combination therapy described in the present invention. The administration of a compound of the present invention in a given combination therapy can be determined as described in the present invention.

Radiation therapy can be applied through one of several methods or a combination of methods, including, without limitation, external radiation therapy, internal radiation therapy, radiation using an implant, stereotaxic radiosurgery, systemic radiation therapy, radiation therapy, and permanent or temporary interstitial brachytherapy. In the context of this document, the term brachytherapy refers to radiation therapy performed by spatially confined radioactive material injected into the body in a tumor, or near a tumor, or elsewhere proliferative due to tissue disease. The term, without limitation, is intended to include exposure to radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioactive isotopes Lu). Suitable radiation sources for use as a cell enhancing agent of the present invention include

- 123 038388 both solids and liquids. As a non-limiting example, the radiation source can be a radionuclide such as I-125, I-131, Yb-169, IR-192 as a solid source, I-125 as a solid source, or other radionuclides that emit photons, beta- particles, gamma rays or other therapeutically active rays. The radioactive material can also be a liquid obtained from any solution of the radionuclide (s), such as a solution of I-125 or I-131, or the radioactive liquid can be prepared using a suspension of a suitable liquid containing small particles of solid radionuclides, such as Au-198 , Y-90. Moreover, the radionuclide (s) can be incorporated into a gel or radioactive microspheres.

The compounds or pharmaceutical compositions of this invention can be used in combination with an amount of one or more substances selected from antiangiogenesis agents, signal transduction inhibitors, antiproliferative agents, glycolysis inhibitors, or autophagy inhibitors.

Anti-angiogenesis agents such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors and COX-11 (cyclooxygenase 11) inhibitors can be used in combination with a compound of the present invention and pharmaceutical compositions described herein. document. Antiangiogenesis agents include, for example, rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of suitable COX-P inhibitors include CELEBREXTM (alecoxib), valdecoxib, and rofecoxib. Examples of suitable inhibitors of matrix metalloproteinase are described in WO 96/33172 (published October 24, 1996), WO 96/27583 (published March 7, 1996), European patent application No. 97304971.1 (filed July 8, 1997), application for European Patent No. 99308617.2 (filed October 29, 1999), WO 98/07697 (published February 26, 1998), WO 98/03516 (published January 29, 1998), WO 98/34918 (published August 13, 1998) ), WO 98/34915 (published August 13, 1998), WO 98/33768 (published August 6, 1998), WO 98/30566 (published July 16, 1998), European Patent Publication No. 606046 (published July 13 1994), European Patent Publication No. 931788 (published July 28, 1999), WO 90/05719 (published May 31, 1990), WO 99/52910 (published October 21, 1999), WO 99/52889 ( published October 21, 1999), WO 99/29667 (published June 17, 1999), PCT International Application No. PCT / 1B98 / O1113 (filed July 21, 1998 .), European Patent Application No. 99302232.1 (filed March 25, 1999), UK Patent Application No. 9912961.1 (filed June 3, 1999), US Provisional Patent Application No. 60/148464 (filed August 12, 1999) , U.S. Patent 5,863,949 (issued January 26, 1999), U.S. Patent No. 5,861,510 (issued January 19, 1999), and European Patent Publication No. 780,386 (published June 25, 1997), all of which are incorporated herein in their entirety. completeness by reference. Preferred inhibitors of MMP-2 and MMP-9 are those that have little or no MMP-1 inhibitory activity. More preferred are inhibitors that selectively inhibit MMP-2 and / or AMP-9 over other matrix metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP- 7, MMP-8, MMP-10, MMP-11, MMP-12 and MMP-13). Some specific examples of MMP inhibitors useful in the present invention are AG-3340, RO 32-3555 and RS 13-0830.

Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil ™), bafilomycin A1, 5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid, autophagy suppressants, which inhibit algal toxins type 2 1, cAMP analogs and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. In addition, you can also use antisense or siRNA, which inhibits the expression of proteins, including, without limitation, ATG5 (which are involved in autophagy).

In some embodiments, the compounds described herein are formulated or administered in combination with liquid or solid tissue barriers, also known as lubricants. Examples of tissue barriers include, but are not limited to, polysaccharides, polyglycans, seprafilm, interceed, and hyaluronic acid.

In some embodiments, the drugs that are administered in combination with the compounds described herein include any suitable drugs that are effectively delivered by inhalation, eg, analgesics, eg, codeine, dihydromorphine, ergotamine, fentanyl, or morphine; anginal drugs such as diltiazem; antiallergic agents such as cromoglycate, ketotifen, or nedocromil; anti-infectious agents such as cephalosporins, penicillins, streptomycin, sulfonamides, tetracyclines, or pentamidine; antihistamines such as metapirylene; anti-inflammatory drugs such as beclomethasone, flunisolide, budesonide, tipredan, triamcinolone acetonide, or fluticasone; antitussives such as noscapine; bronchodilators, for example ephedrine, epinephrine, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutaline, isoeterol, tulobutaline

- 124 038388 prenaline or (-) - 4-amino-3,5-dichloro-a - [[[6- [2- (2-pyridinyl) ethoxy] hexyl] amino] methyl] benzenemethanol; diuretics such as amiloride; anticholinergics such as ipratropium, atropine, or oxytropium; hormones such as cortisone, hydrocortisone, or prednisolone; xanthines such as aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; and therapeutic proteins and peptides such as insulin or glucagon. The person skilled in the art will understand that, if necessary, the drugs are used in the form of a salt (for example, in the form of alkali metal or amine salts or in the form of acid addition salts), or in the form of esters (for example, esters of lower alkyls) , or in the form of solvates (eg, hydrates) to optimize the activity and / or stability of the drug.

Other illustrative therapeutic agents useful in combination therapy include, but are not limited to, the agents listed above, radiation therapy, hormone antagonists, hormones and their releasing factors, thyroid and antithyroid drugs, estrogens and progestins, androgens, adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogues; inhibitors of the synthesis and action of adrenocortical hormones, insulin, oral hypoglycemic agents and pharmacology of the endocrine pancreas, agents affecting calcification and bone remodeling: calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitamins, such as water-soluble vitamins, complex , ascorbic acid, fat-soluble vitamins, vitamins A, K and E, growth factors, cytokines, chemokines, muscarinic receptor agonists and antagonists; anticholinesterase agents; agents acting on the neuromuscular synapse and / or autonomic ganglia; catecholamines, sympathomimetic drugs, and adrenergic receptor agonists or antagonists; and 5-hydroxytryptamine (5-HT, serotonin) receptor agonists and antagonists.

Therapeutic agents may include agents for pain and inflammation such as histamine and histamine antagonists, bradykinin and bradykinin antagonists, 5-hydroxytryptamine (serotonin), lipid substances that are formed by biotransformation of the products of selective hydrolysis of membrane phospholipids, eicosinos, thromboxanes, prostagboxanes, prostagboxanes, aspirin, non-steroidal anti-inflammatory drugs, analgesics, antipyretics, drugs that inhibit the synthesis of prostaglandins and thromboxanes, selective inhibitors of inducible cyclooxygenase, selective inhibitors of inducible cyclooxygenase-2, autacoids, paracrine hormones, cytumatostatin, gastrin, mediating hormones, cytumatostatin, gastrin mediated immune responses derived from lipids autakoids, eicosanoids, β-adrenergic agonists, ipratropium, glucocorticoids, methylxanthines, sodium channel blockers, opioid receptor agonists, calcium channel blockers, m stabilizers membranes and leukotriene inhibitors.

Additional therapeutic agents contemplated by the present invention include diuretics, vasopressin, renal water retention agents, rennin, angiotensin, agents useful in the treatment of myocardial ischemia, antihypertensive agents, angiotensin converting enzyme converting enzyme inhibitors, beta-adrenoreceptor receptor antagonists, for the treatment of hypercholesterolemia; and an agent for the treatment of dyslipidemia. Other contemplated therapeutic agents include drugs used to regulate gastric acidity, agents for treating peptic ulcers, agents for treating gastroesophageal reflux disease, prokinetic agents, antiemetics, agents used for irritable bowel syndrome, agents used for diarrhea, agents, drugs used for constipation, drugs used for inflammatory bowel disease, drugs used for diseases of the biliary tract, drugs used for diseases of the pancreas. Therapeutic agents used to treat protozoal infections include drugs used to treat malaria, amebiasis, giardiasis, trichomoniasis, trypanosomiasis and / or leishmaniasis, and / or drugs used in chemotherapy for helminthiasis. Other therapeutic agents include antimicrobials, sulfonamides, trimethoprimsulfamethoxazole quinolones and drugs for urinary tract infections, penicillins, cephalosporins and other P-lactam antibiotics, aminoglycoside-containing agent, protein synthesis inhibitors, drugs used in chemotherapy of tuberculosis-induced tuberculosis, disease, disease, avium, and leprosy, antifungal agents, antiviral agents, including non-retroviral agents and antiretroviral agents.

Examples of therapeutic antibodies that can be combined with a compound of the present invention include, but are not limited to, antibodies to receptor tyrosine kinase (cetuximab, panitumumab, trastuzumab), antibodies to CD20 (rituximab, tositumomab), and other antibodies such as alemtuzumab, bevacizumab, and gem ...

Moreover, therapeutic agents used for immunomodulation, such as immunomodulators, immunosuppressive agents, tolerogens and immunostimulants, are contemplated in the methods herein. In addition, therapeutic agents affecting the blood and hematopoietic organs, hematopoietic agents, growth factors, minerals and vitamins, anticoagulant, thrombolytic and antiplatelet drugs. For the treatment of renal cell carcinoma,

125 038388 but combine a compound of the present invention with sorafenib and / or avastin. For the treatment of endometrial disorder, a compound of the present invention can be combined with doxorubicin, taxotere (taxol) and / or cisplatin (carboplatin). For the treatment of ovarian cancer, a compound of the present invention can be combined with cisplatin (carboplatin), taxotere, doxorubicin, topotecan and / or takmoxifen. For the treatment of breast cancer, a compound of the present invention can be combined with Taxotere (Taxol), Gemcitabine (Capecitabine), Tamoxifen, Letrozole, Tarcea, Lapatinib, PD0325901, Avastin, Herceptin, OSI-906 and / or OSI-930. For the treatment of lung cancer, a compound of the present invention can be combined with Taxotere (Taxol), Gemcitabine, Cisplatin, Pemetrexed, Tarcea, PD0325901 and / or Avastin. Additional therapeutic agents that can be combined with a compound of the present invention are found in Goodman and Gilman The Pharmacological Basis of Therapeutics, Tenth Edition, edited by Hardman, Limbird and Gilman or Physician's Desk Reference, both of which are incorporated herein in their entirety. through a link.

The compounds described herein can be used in combination with the agents disclosed in this invention or other suitable agents depending on the condition being treated. Therefore, in some embodiments, one or more of the compounds of the present invention will be co-administered with other agents as described above. When used in combination therapy, the compounds described in this invention are administered with the second agent simultaneously or separately. This administration in combination may include simultaneous administration of two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compound described in this invention and any of the agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound of the present invention and any of the agents described above can be administered simultaneously, with both agents being present in separate formulations. Alternatively, the compound of the present invention can be administered only after the means described above, or vice versa. In some embodiments of the separate administration protocol, the compound of the present invention and any of the agents described above are administered at intervals of several minutes one after the other, or at intervals of several hours one after the other, or at intervals of several days one after the other. another.

The following examples are given to illustrate various embodiments of the invention and are not intended to limit the present invention in any way. The present examples, along with the methods and compositions described herein, are herein representative of preferred embodiments of the invention, are illustrative, and are not intended to limit the scope of the disclosure. Variations therein and other uses that are covered in the spirit of the disclosure as defined within the scope of the claims will take place for those skilled in the art.

Examples of

Example 1. Synthesis of compound 59 in the table. 1.

Step A. Obtaining compound 59-2.

To a solution of ethyl 2- (diethoxyphosphoryl) acetate (1.91 g, 8.5 mmol) in THF (30 ml) was added NaH (421 mg, 10.5 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 0.5 h before adding 59-1 (2 g, 8 mmol). The reaction mixture was stirred at room temperature for 5 hours. Ice water (50 ml) was added and the product was extracted with ethyl acetate (50 ml x 2). The combined organic layer was washed with saturated brine (50 ml), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (eluted with 20% EtOAc in petroleum ether) to give 2.15 g of 59-2 as a white solid (yield: 85%).

Step B. Preparation of Compound 59-3.

To a solution of compound 59-2 (905 mg, 2.85 mmol) in MeOH (20 ml) were added (Boc) ₂ O (1.24 g, 5.71 mmol) and a Pd / C catalyst. The reaction mixture was stirred at room temperature for 8 hours under an atmosphere of H ₂ . TLC showed the reaction was complete. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (eluted with 20% EtOAc in petroleum ether) to give 59-3 as a solid (740 mg, 91% yield).

Step C. Preparation of Compound 59-4.

To a solution of compound 59-3 (670 mg, 2.35 mmol) in THF (20 ml) was added LiAlH ₄ (179 mg, 4.7 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 2 h, then 0.2 ml of H2O, 0.2 ml of 15% NaOH, and 0.5 ml of H2O were added. The mixture was stirred at room temperature for 1 hour. The mixture was filtered and the organic solution was concentrated. The residue was purified by silica gel column chromatography (elution with 40% EtOAc in petroleum ether) to give Compound 59-4 as a solid (525 mg, yield: 92%).

Step D. Preparation of Compound 59-5.

To a solution of compound 59-4 (486 mg, 2 mmol) and Et ₃ N (404 mg, 4 mmol) in CH ₂ Cl ₂ (20 ml) was added MsCL (344 mg, 3 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 1 hour. TLC indicated the reaction was complete. The combined organic layer was washed with H ₂ O and brine, dried over sodium sulfate and concentrated in vacuo to give 500 mg of Compound 59-5 as a white solid (yield: 78%).

Step E. Preparation of Compound 59-6.

A mixture of compound 59-5 (500 mg, 1.56 mmol), Cs ₂ CO ₃ (846 mg, 2.33 mmol) and 5-formyl-4-methyl-1Nindole-2-carbonitrile (143 mg, 0.78 mmol ) was mixed in DMF (20 ml). The reaction mixture was heated at 85 ° C for 3 h. EtOAc (200 ml) was added to the resulting mixture. The combined organic layer was washed with H ₂ O and brine, dried over sodium sulfate and concentrated. The residue was purified by a flash column (eluted with 30% EtOAc in petroleum ether) to give 278 mg of Compound 59-6 as a white solid (yield: 43%).

Step F. Preparation of Compound 59-7.

A mixture of compound 59-6 (278 mg, 0.68 mmol), N- (piperidin-4-yl) -6- (2,2,2-trifluoroethyl) thieno [2,3d] pyrimidin-4-amine (280 mg , 0.88 mmol) and Et ₃ N (412 mg, 4.08 mmol) in CH ₂ Cl ₂ (20 ml) were stirred at room temperature for 1 h. NaBH (OAC) ₃ (865 mg, 4.08 mmol ) was added to the reaction mixture placed in an ice bath and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (elution with 2.5% MeOH in dichloromethane) to give Compound 59-7 as a white solid (400 mg, yield: 82%).

Step G. Preparation of compound 59-8.

A solution of compound 59-7 (200 mg, 0.28 mmol) in TFA (15 ml) was stirred at room temperature for 2 hours. The solvent was removed and a solution of NH ₃ (7N) in MeOH (10 ml) was added. The resulting mixture was concentrated and the residue was purified by silica gel column chromatography (elution with 10% MeOH in dichloromethane) to give Compound 59-8 as an oil (164 mg, yield: 96%).

Step H. Preparation of Compound 59.

To a solution of 59-8 (127 mg, 0.21 mmol) and Et ₃ N (43 mg, 0.42 mmol) in CH ₂ Cl ₂ (20 ml) was added MsCL (29 mg, 0.25 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 1 hour. TLC indicated the reaction was complete. The combined organic layer was washed with H 2 O and brine, dried over sodium sulfate and concentrated in vacuo to give 45 mg of Compound 59 as a white solid (yield: 31%).

1H NMR (400 MHz, DMSO) δ: 8.33 (s, 1H), 7.87 (s, 1H), 7.67 (s, 1H), 7.45-7.56 (m, 3H), 4.35-4.32 (m, 2H) 4.02 (m, 4H), 3.57-3.54 (m, 3H), 3.17 (m, 1H, 2.88-2.83 ( m, 6H), 2.54 (s, 3H), 2.20-1.47 (m, 12H), 1.25 (d, 3H).

ESI-MS m / z: 688.84 (M + H).

- 127 038388

Example 2. Synthesis of compound 48 in the table. 1.

Step A. Obtaining compound 48-2.

A mixture of compound 48-1 (300 mg, 1.40 mmol), 2-bromoethanol (347 mg, 2.80 mmol) and K ₂ CO ₃ (772 mg, 5.60 mmol) in CH3CN (30 ml) was stirred at 90 ° C under N2 overnight. TLC showed the reaction was complete. The solid was removed by filtration and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (eluted with 2.5% MeOH in dichloromethane) to give 48-2 as a yellow oil (296 mg, yield: 82%).

Step B. Preparation of Compound 48-3.

To a mixture of compound 48-2 (296 mg, 1.15 mmol) and Et ₃ N (232 mg, 2.30 mmol) in dichloromethane (20 ml) was added MsCL (197 mg, 1.73 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 1 hour. TLC indicated the reaction was complete. _{Saturated aqueous NaHCO 3} solution was added to the reaction mixture. The organic layer was separated, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (eluted with petroleum) to give compound 48-3 as an oil (270 mg, yield: 70%).

Step C. Obtaining Compound 48-4.

A mixture of compound 48-3 (270 mg, 0.8 mmol), 5-formyl-4-methyl-1H-indole-2-carbonitrile (123 mg, 0.67 mmol) and Cs ₂ CO ₃ (524 mg, 1, 6 mmol) in DMF (10 ml) was stirred at 80 ° C under nitrogen atmosphere overnight. The solid was removed by filtration before the reaction mixture was diluted with water and ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous Na ₂ SO ₄ , concentrated and purified by silica gel column chromatography (eluted with 20% ethyl acetate in oil) to give compound 48-4 as an oil (169 mg, yield: 50%) ...

ESI-MS m / z: 424.54 (M + H).

Step D. Obtaining Compound 48-5.

A mixture of compound 48-4 (169 mg, 0.4 mmol), N- (piperigin-4-yl) -6- (2,2,2-trifluoroethyl) thieno [2,3d] pyrimidin-4-amine (190 mg , 0.6 mmol) and Et ₃ N (242 mg, 2.4 mmol) in CH ₂ Cl ₂ (20 ml) were stirred at room temperature for 1 h. NaBH (OAC) ₃ (508 mg, 2.4 mmol ) was added to the reaction while cooling in an ice bath and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (elution with 2.5% MeOH in dichloromethane) to give compound 48-5 as an oil (174 mg, yield: 60%).

ESI-MS m / z: 724.88 (M + H).

Step E. Preparation of compound 48-6.

To a solution of compound 48-5 (174 mg, 0.24 mmol) in CH ₂ Cl ₂ (15 ml) was added TFA (5 ml). The reaction mixture was stirred at room temperature for 2 hours until the solvent was removed. _{NH 3} / MeOH solution (7N, 10 ml) was added and the resulting mixture was concentrated. The residue was purified by silica gel column chromatography (eluted with 10% MeOH in dichloromethane) to give compound 48-6 as an oil (120 mg, yield: 80%).

ESI-MS m / z: 624.30 (M + H).

- 128 038388

Step F. Preparation of compound 48.

To a mixture of compound 48-6 (120 mg, 0.192 mmol) and Et ₃ N (39 mg, 0.384 mmol) in CH ₂ Cl ₂ (10 mL) was added slowly methanesulfonyl chloride (33 mg, 0.288 mmol) in CH ₂ Cl ₂ (5 ml) at -20 ° C under N2. The reaction mixture was stirred at room temperature for 2 hours. TLC indicated the reaction was complete. _{Saturated aqueous NaHCO 3} solution was added to the reaction mixture. The organic layer was separated, washed with brine, dried over anhydrous Na ₂ SO ₄ , concentrated and purified by silica gel column chromatography (eluted with 10% MeOH in dichloromethane) to give the final product 48 as a solid (54 mg, yield: 40%) ...

¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.48 (s, 1H), 7.38 (d, 1H), 7.21 (s, 1H), 7.15 (d, 1H), 7, 08 (s, 1H), 5.10 (d, 1H), 4.34 (m, 2H), 4.24 (m, 1H), 3.87 (m, 2H), 3.65 (m, 4H ), 2.93 (m, 5H), 2.71 (m, 2H), 2.63 (m, 2H), 2.57 (s, 3H), 2.29 (m, 2H), 2.21 (m, 2H), 2.10 (d, 2H), 1.61 (m, 2H), 1.31 (d, 6H);

ESI-MS m / z: 702.27 (M + H).

Example 3. Synthesis of compound 2 in table. 1.

Step A. Obtaining compound 2-2.

To a suspension of K2CO3 (3.6 g, 26.5 mmol) and tert-butyl piperazine-1-carboxylate (1.0 g, 5.3 mmol) in CH ₃ CN (15 mL) was added methyl 2-bromopropanoate (2, 2 g, 13.4 mmol). The reaction mixture was stirred at 80 ° C for 10 hours. TLC showed that the reaction was complete. The reaction mixture was allowed to cool to room temperature, then the solid was filtered off and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ / MeOH = 50: 1) to give tert-butyl 4- (1-methoxy-1-oxopropan-2-yl) piperazine-1-carboxylate (2-2) as an oil brown (1.4 g, yield: 99%).

Stage B. Obtaining compound 2-3.

LiAlH ₄ (1.0 ml, 2, 5 mol in THF) at 0 ° C dropwise. The reaction mixture was stirred at the same temperature for 2 hours. TLC showed that the reaction was complete. The reaction was quenched with EtOAc. The reaction mixture was partitioned between EtOAc and H ₂ O and the organic layer was washed with brine and dried over Na ₂ SO ₄ , The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (CH ₂ Cl ₂ / MeOH = 20: 1) to give tert-butyl -4- (1-hydroxypropan-2-yl) piperazine-1-carboxylate (2-3) as a brown oil (300 mg, yield: 65%).

Step C. Obtaining Compound 2-5.

To a solution of tert-butyl 4- (1-hydroxypropan-2-yl) piperazine-1-carboxylate (200 mg, 0.82 mmol) and Et ₃ N (171 mg, 1.64 mmol) in CH ₂ Cl ₂ ( 10 ml) was added MsCL (112 mg, 0.98 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with NaHCO ₃ , washed with brine and dried over Na ₂ SO ₄ . The solvent was removed in vacuo

129 038388 to obtain tert-butyl 4- (1 - ((methylsulfonyl) oxy) propan-2-yl) piperazine-1-carboxylate (2-4), which was used in the next step without further purification.

To a mixture of Cs ₂ CO ₃ (682 mg, 2.1 mmol) and 5-formyl-4-methyl-1H-indole-2-carbonitrile (77 mg, 0.42 mmol) in DMF was added tert-butyl-4- ( 1 - ((methylsulfonyl) oxy) propan-2-yl) piperazine-1 carboxylate in DMF. The reaction mixture was stirred at 100 ° C for 10 hours. The reaction mixture was partitioned between EtOAc and H2O and the organic layer was washed with brine and dried over Na ₂ SO ₄ . The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 5: 1-3: 1) to give tert-butyl 4- (1- (2-cyano-5-formyl-4methyl-1H-indole -1-yl) propan-2-yl) piperazine-1-carboxylate (2-5) as a yellow solid (90 mg, yield: 53%).

Step D. Obtaining Compound 2-6.

A mixture of tert-butyl 4- (1 - (2-cyano-5-formyl-4-methyl-1 N-indol-1-yl) propan-2-yl) piperazine-1 carboxylate (90 mg, 0.22 mmol ), 6- (2,2,2-trifluoroethyl) -N- (piperidin-4-yl) thieno [2,3-d] pyrimidine-4amine (100 mg, 0.26 mmol) and Et ₃ N (130 mg , 1.32 mmol) in CH ₂ Cl ₂ (10 ml) was stirred at room temperature for 1 h before adding NaBH (OAC) ₃ (280 mg, 1.32 mmol). The reaction mixture was stirred at room temperature overnight, then partitioned between CH ₂ Cl ₂ and NaHCO ₃ . The organic layer was washed with brine and dried over Na ₂ SO ₄ . The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (CH ₂ Cl ₂ : MeOH = 50: 1-20: 1) to give tert-butyl-4- (1- (2-cyano-4-methyl-5- ( (4 - ((6- (2,2,2trifluoroethyl) thieno [2,3 -d] pyrimidin-4-yl) amino) piperidin-1-yl) methyl) -1 H-indol-1-yl) propane- 2yl) piperazine-1-carboxylate (2-6) as a yellow solid (130 mg, yield: 81%).

Step E. Preparation of Compound 2-7.

To a solution of tert-butyl-4- (2- (2-cyano-4-methyl-5 - ((4 - ((6- (2,2,2-trifluoroethyl) thieno [2,3-d] pyrimidin4-yl ) amino) piperidin-1-yl) methyl) -1H-indol-1-yl) -1-hydroxyethyl) piperidine-1-carboxylate (130 mg, 0.21 mmol) in CH ₂ Cl ₂ (3 ml) was added TFA (2 ml). The reaction mixture was stirred for 4 h, after which the solvent was removed in vacuo. The residue was diluted with CH ₂ Cl ₂ and washed with NaHCO ₃ . The organic layer was washed with brine and dried over Na ₂ SO ₄ . The solvent was removed in vacuo and the residue (2-7) was used without further purification as a yellow foam (100 mg, yield: 98%).

Step F. Obtaining Compound 2.

To a solution of 4-methyl-1 - (2- (piperazin-1-yl) propyl) -5 - ((4 - ((6- (2,2,2-trifluoroethyl) thieno [2,3 d] pyrimidine-4 -yl) amino) piperidin-1-yl) methyl) -1H-indole-2-carbonitrile (60 mg, 0.1 mmol) and Et ₃ N (36 mg, 0.4 mmol) in CH ₂ Cl ₂ (10 ml) was added MsCL (21 mg, 0.2 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was quenched with NaHCO ₃ , washed with brine and dried over Na ₂ SO ₄ . The solvent was removed and the residue was purified by Prep-TLC (CH ₂ Cl ₂ : MeOH = 15: 1) to give 4-methyl-1- (2- (4- (methylsulfonyl) piperazin-1-yl) propyl) -5 - (( 4 - ((6 (2,2,2-trifluoroethyl) thieno [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) methyl) -1Н-indole-2carbonitrile (compound 2) as white solid (10 mg, yield: 20%).

¹ H NMR (400 MHz, CDCl ₃ ) 8.48 (s, 1H), 7.36 (d, 1H), 7.20 (s, 1H), 7.00-7.15 (m, 2H), 5.16 (d, 1H), 4.204.40, 2H), 4.00-4.10 (m, 1H), 3.60-3.70 (m, 4H), 3.10-3.30 ( m, 5H), 2.80-2.90 (m, 4H), 2.77 (s, 3H), 2.57, 3H), 1.56-2.53 (m, 8H), 1.08 (d, 3H).

ESI-MS m / z: 689.25 (M + H).

Example 4. Synthesis of compound 61 in table. 1.

Step A. Obtaining compound 61-2.

A mixture of ethyl 1-aminocyclopropanecarboxylate hydrochloride (2.4 g, 14.5 mmol), N-benzyl-2-chloro-N- (2-chloroethyl) ethanamine hydrochloride (4.26 g, 15.8 mmol) and N, N-diisopropylethylamine (25 ml) in

130 038388 ethanol (32 ml) was stirred at reflux for 16 hours. The reaction mixture was concentrated to dryness. The residue was partitioned between dichloromethane and water. The two layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were concentrated.

The residue was purified by a silica gel column (petroleum ether / EtOAc = 1: 0-10: 1) to give ethyl 1- (4benzylpiperazin-1-yl) cyclopropanecarboxylate (61-2, 1.8 g, yield: 43%) as yellow oil.

1H NMR (400 MHz, CDCl ₃ ) δ: 7.37-7.27 (m, 5H), 4.19-4.13 (m, 2H), 3.54 (s, 2H), 3.00 ( brs, 2H), 2H), 1.31-1.26 (m, 5H), 7.52 (m, 1H), 0.93-0.91 (m, 2H).

Step B. Preparation of Compound 61-3.

To a mixture of ethyl 1- (4-benzylpiperazin-1-yl) cyclopropanecarboxylate (880 mg, 3 mmol) in THF (12 mL) was slowly added LiAlH4 (290 mg, 6 mmol) at 0 ° C. The resulting mixture was stirred at 0 ° C for 1 h. Water (0.5 ml) was added followed by ethyl acetate (20 ml). The solid was filtered off and the solvent was removed. The residue was purified by a silica gel column (petroleum ether / EtOAc = 3: 1) to give (1- (4-benzylpiperazin-1-yl) cyclopropyl) methanol (61-3, 660 mg, yield: 88%) as a white solid ...

Step C. Preparation of Compound 61-4.

A mixture of (1- (4-benzylpiperazin-1-yl) cyclopropyl) methanol (600 mg, 2.4 mmol) and Pd / C (10%, 50 mg) in ethanol (10 ml) was stirred at 50 ° C overnight in the H2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated to give (1- (piperazin-1-yl) cyclopropyl) methanol (61-4) as an oil (400 mg, yield: 96%). The crude product was used in the next step without further purification.

Step D. Preparation of Compound 61-5.

To a mixture of (1- (piperazin-1-yl) cyclopropyl) methanol (400 mg, 2.5 mmol) in dichloromethane (10 ml) was added Et ₃ N (1.1 ml, 7.5 mmol), followed by the addition of a mixture of methanesulfonyl chloride (925 mg, 7.5 mmol) in dichloromethane (5 ml). The resulting mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with water and CH ₂ Cl ₂ , the organic layer was dried over Na ₂ SO ₄ and concentrated to give the crude product (1- (4- (methylsulfonyl) piperazine-1yl) cyclopropyl) methyl methanesulfonate (61-5) as a brown oil (500 mg).

Step E. Preparation of Compound 61-6.

A mixture of crude (1- (4- (methylsulfonyl) piperazin-1-yl) cyclopropyl) methyl methanesulfonate (500 mg), 5-formyl-4-methyl-1H-indole-2-carbonitrile (200 mg, 1.1 mmol) and K2CO3 (800 mg, 5.8 mmol) in acetonitrile was stirred at 80 ° C overnight. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by a silica gel column (petroleum ether / EtOAc = 3: 1) to give 5-formyl-4-methyl-1 - ((1 - (4- (methylsulfonyl) piperazin-1-yl) cyclopropyl) methyl) -1H- indole-2carbonitrile (61-6, 330 mg) as a brown solid.

ESI-MS m / z: 401 (M + H).

Step F. Preparation of Compound 61.

A mixture of 5-formyl-4-methyl-1 - ((1- (4- (methylsulfonyl) piperazin-1-yl) cyclopropyl) methyl) -1Nindole-2-carbonitrile (330 mg, crude), N- (piperidine- 4-yl) -6- (2,2,2trifluoroethyl) thieno [2,3-d] pyrimidin-4-amine (391 mg, 1.1 mmol) and Et ₃ N (0.5 ml) in dichloromethane (12 ml) was stirred at room temperature overnight. The reaction mixture was diluted with water and CH ₂ Cl ₂ . The organic layer was separated, dried over Na ₂ SO ₄ and concentrated. The residue was purified by a silica gel column (dichloromethane / methanol = 50: 1-30: 1) to obtain a crude product. The crude product was purified by Prep-TLC with dichloromethane / methanol (7N NH ₃ / MeOH) = 50: 1 to give the product (Compound 61) as a colorless solid (12 mg).

ESI-MS m / z: 701 (M + H).

1H NMR (400 MHz, CDCl ₃ ) δ: 8.46 (s, 1H), 7.20-7.28 (m, 3H), 4.30-4.36 (m, 3H), 3.84 ( br s, 2H), 3.613.68 (m, 2H), 3.09-3.13 (m, 6H), 2.76 (s, 3H), 2.64-2.66 (m, 4H) , 2.59 (s, 3H), 2.40-2.48 (m, 2H), 2.14-2.18 (m, 2H), 1.87-1.90 (m, 2H), 0 , 79-0.82 (t, 2H), 0.61-0.64 (t, 2H).

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Example 5. Synthesis of compound 35 in table. 1.

Step A. Obtaining compound 35-2.

A mixture of tert-butylpiperazine-1-carboxylate (1.9 g, 10 mmol) and Et ₃ N (3 g, 30 mmol) in CH ₂ Cl ₂ (40 ml) was stirred at 0 ° C to 2-chloroacetyl chloride (2.2 d, 20 mmol). The reaction mixture was stirred at 0 ° C under nitrogen atmosphere for 4 h. TLC showed that the reaction was complete. The reaction mixture was partitioned between CH ₂ Cl ₂ and H 2 O and the organic layer was washed with brine and dried over Na ₂ SO ₄ . The solvent was removed in vacuo and the residue (35-2) was used without further purification as a light yellow oil (2.5 g, yield: 95%).

Step B. Preparation of Compound 35-3.

To a mixture of N- (piperudin-4-yl) -6- (2,2,2-trifluoroetulyl) thieno [2,3-d] pyrimidin-4-amine (1 g, 4 mmol) and 5-formula-4- methyl 1H-indole-2-carbonitrile (540 mg, 3 mmol) in THF (10 ml) was added NaH (180 mg, 4.5 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then partitioned between EtOAc and H2O and the organic layer was washed with brine and dried over Na ₂ SO ₄ . The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc = 10: 1-1: 1) to give tert-butyl-4- (2 (2-cyano-5-formyl-4-methyl-1H- indol-1-yl) acetyl) piperazine-1-carboxylate (35-3) as a light yellow solid (60 mg, yield: 4%).

Step C. Preparation of Compound 35-4.

A mixture of methyl tert-butyl-4- (2- (2-cyano-5-formyl-4-methyl-1H-indol-1-yl) acetyl) piperazine-1 carboxylate (40 mg, 0.1 mmol), hydrochloride N- (piperidin-4-yl) -6- (2,2,2-trifluoroethyl) thieno [2,3d] pyrimidin-4-amine (60 mg, 0.2 mmol) and Et ₃ N (60 mg, 0 , 6 mmol) in CH ₂ Cl ₂ (5 ml) was stirred at room temperature for 2 h. Then NaBH (OAc) ₃ (120 mg, 0.6 mmol) was added to the reaction with cooling in an ice bath. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between CH ₂ Cl ₂ and NaHCO ₃ and the organic layer was washed with brine and dried over Na ₂ SO ₄ . The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (CH ₂ Q ₂ : MeOH = 100: 1-20: 1) to give tert-butyl 4- (2- (2-cyano-4-methyl-5 - (( 4 - ((6- (2,2,2-trifluoroethyl) thieno [2,3-d] pyrimidin-4-yl) amino) piperidin-1yl) methyl) -1H-indol-1-yl) acetyl) piperazine- 1-carboxylate (35-4) as a yellow solid (40 mg, yield: 55%).

Step D. Preparation of compound 35-5.

A solution of tert-butyl-4- (2- (2-cyano-4-methyl-5 - ((4 - ((6- (2,2,2-trifluoroetyl) thieno [2,3-d] pyrimidin-4yl) amino) piperidin-1-yl) methyl) -1H-indol-1-yl) acetyl) piperazine-1-carboxylate (40 mg, 0.06 mmol) in HCl-MeOH (10 ml) was stirred at room temperature for 16 including TLC showed that the reaction was complete. The solvent was removed in vacuo and the residue (35-5) was used without further purification in the next step as a yellow solid (35 mg, yield: 85%).

Step E. Preparation of compound 35.

To a mixture of 4-methyl-1- (2-oxo-2- (piperazin-1-yl) ethyl) -5 - ((4 - ((6- (2), 2,2-trifluoroethyl) thieno [2,3d ] pyrimidin-4-yl) amino) piperudin-1-yl) methyl) -1H-indole-2-carbonitrile (35 mg, 0.05 mmol) and Et ₃ N (15 mg, 0.15 mmol) in CH ₂ Cl ₂ (10 ml) was added slowly MsCL (12 mg, 0.1 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 4 h and then partitioned between CH ₂ Cl ₂ and NaHCO ₃ . The organic layer was washed with brine and dried over Na ₂ SO ₄ . The solvent was removed in vacuo and the residue was purified by Prep-TLC (CH ₂ Cl ₂ : MeOH = 20: 1) to give 4-methyl-1- (2- (4 (methylsulfonyl) piperazin-1-yl) -2-oxoethul) - 5 - ((4 - ((6- (2,2,2-trifluoroetyl) thieno [2,3-d] pyrimidin-4ul) amino) piperidin-1-ul) methyl) -1H-indole-2-carbonitrule ( compound 35) as a white solid (16 mg, yield: 56%).

¹ H NMR (400 MHz, CDCl3) 8.42 (s, 1H), 7.84-7.76 (m, 1H), 7.33-7.22 (m, 3H), 5.15 (s, 2H), 4.37-4.08 (m, 2H), 3.78 (s, 3H), 3.69-3.71 (m, 2H), 3.44-3.30 (m, 5H) , 2.86 (s, 3H), 2.70-2.54 (m, 4H), 2.15-2.06 (m, 3H), 1.35

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1.23 (m, 4H), 0.91-0.85 (m, 2H).

Example 6. Analysis of the polarization of fluorescence.

This example illustrates an assay useful for monitoring the binding of MLL to menin. Competitive fluorescent polarization (FP) experiments are conducted to determine the effectiveness with which a compound inhibits the menine-MLL interaction, reported as an IC ₅₀ value. A fluorescein-labeled peptide containing a high affinity binding motif for menin found in MLL was prepared according to Yokoyama et al. (Cell, 2005, 123 (2): 207-218), incorporated herein by reference in its entirety. Binding of the labeled peptide (1.7 kDa) to a much larger mesenine (~ 67 kDa) is accompanied by a significant change in the rotational correlation time of the fluorophore, which leads to a significant increase in fluorescent polarization and fluorescent anisotropy (excitation at 500 nm, emission at 525 nm). The efficacy with which a compound inhibits the menine-MLL interaction is measured in a competitive FP experiment, where a decrease in fluorescence anisotropy is correlated with inhibition of the interaction and is used as a record for determining the IC ₅₀ .

Tab. 3 shows the biological activity of selected compounds in a fluorescence polarization assay. The compound numbers correspond to the numbers and structures shown in table. 1 and 2 and examples 1-5.

Table 3

Less than 50 nM (++++) 50 nM to less than 250 nM (+++) 250 nM to 1000 nM (++) More than 1000 nM (+) Menin MLL 4-43 1C ₅ o (nM) 6, 8, 10,12, 13, 14, 18, 20, 22, 27, 28, 64, 65, 73, 80, 85, 88, 89, 90, 92, 93, 115, 119, 123, 129, 131, 132, 134, 135, 136, 138, 139, 141, 147, 148, 149, 151, 154, 158, 163, 165, 166, 172, 175, 176, 177, 178, 181, 182, 183, 184, 186, 187, 189, 191, 192, 193, 194, 196, 197, 202, 203, 204, 205, 206, 207, 209, 210, 212, 213, 214, 215, 216, 217, 219, 220, 221, 222, 225, 226, 229, 233, 239, 243, 244, 246, 247, 248, 249, 250, 251, 281, 282, 283, 1020, 1021, 1022, 1024, 1025, 1026, 1027 2, 4, 5, 7, I, 17, 19, 21, 25, 29, 30, 43, 46, 48, 49, 54, 61, 68, 69, 70, 72, 74, 84, 87, 91, 94, 116, 117, 120, 121, 122, 124, 125, 126, 127, 128, 130, 133, 137, 140, 142, 143, 144, 145, 146, 150, 152, 153, 155, 156, 159, 160, 161, 162, 164, 167, 168, 171, 174, 179, 180, 185, 188, 190, 195, 198, 199, 208, 211, 230, 241, 245, 280, 1002, 1003, 1013, 1023 1, 3, 24, 26, 44, 45, 52, 53, 55, 56, 57, 58, 59, 66, 67, 82, 118, 157, 169, 173, 201, 1000, 1001, 1011 9, 15, 16, 23, 35, 47, 60, 62, 71, 170, 200, 242, 252, 1010, 1012

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Example 7. Time resolved homogeneous fluorescence (HTRF) assay.

Homogeneous time-resolve fluorescence (HTRF) assay is used as a secondary assay to confirm FP assay results. In some embodiments, the HTRF assay is the primary assay and the FP assay is used as a secondary assay to confirm the results. HTRF is based on the nonradiative energy transfer of long-lived emission from the cryptate donor Europium (Eu ³⁺ -criptate) to the acceptor allophycocyanin (XL665) in combination with time-resolved detection. Donor Eu ³⁺ -criptate is conjugated to a murine monoclonal antibody against 6His (which binds His-tagged menin), and acceptor XL665 is conjugated to streptavidin (which binds biotinylated MLL peptide). When these two fluorophores are brought together by the interaction of menin with the MLL peptide, the transfer of energy to the acceptor results in an increase in fluorescence emission at 665 nm and an increase in the HTRF ratio (emission intensity at 665 nm / emission intensity at 620 nm). Inhibition of the menine-MLL interaction separates the donor from the acceptor, resulting in a decrease in emission at 665 nm and a decrease in the HTRF ratio. Example 8: Analysis of Menin Interaction. Sample preparation: 2.5 μl of 100 μM compound is added to 47.5 μl of 526 nM menin in PBS (5 μM compound of 500 nM menin in 5% DMSO final concentration). The reaction mixture is incubated at room temperature for various incubation times and the reaction is stopped with 2.5 μl of 4% formic acid (FA, 0.2% final concentration). Method: A Thermo Finnigan Surveyor Autosampler, PDA Plus UV detector and MS Pump were used to collect sample data together with an LTQ linear mass spectrometric ion trap controlled by XCalibur software. 5 μL of the sample in no waste mode was injected into a Phenomenex Jupiter 5u 300A C5 (safety column) 2x4.00 mm at 45 ° C. Mobile phase composition: buffer A (95: 5 water: acetonitrile, 0.1% FA) and buffer B (acetonitrile, 0.1% FA). A gradient elution was used with an initial mobile phase of 85:15 (buffer A: B) and a flow rate of 250 μl / min. After injection 85:15 A: B was held for 1.3 min, buffer B was increased to 90% within 3.2 min, held for 1 min, and then returned to initial conditions after 0.1 min and held for 2.4 minutes The total running time was 8 minutes. During the first 2 min of the sampling method, a downstream transfer valve was used to direct salts from the free volume to waste. A buffer A blank was used between each injection of the sample. A needle wash was used with a 1: 1 mixture of acetonitrile: water with 0.1% FA. The ESI source used a capillary temperature of 300 ° C, 40 shielding gas flow units, 20 auxiliary gas flow units, 3 purge gas flow units, 3.5 kV atomizer voltage, 120 V tubular lens. Data Acquisition: Data Acquisition was performed in the mode of full scanning of positive ions 550-1500 Da, 10 microscans, maximum ionization time 200 ms. Data Analysis: Protein mass spectra were obtained as XCalibur data files. The best scans have been summarized using the XCalibur Qual Browser. Spectra were displayed using a View / Spectrum List with the Display option to display all peaks. The Edit / Copy menu was used to copy the mass spectrum to the PC clipboard. The spectrum in the PC clipboard has been pasted into Excel. The first two columns (m / z and intensity) have been retained, and the third column (Relative) has been removed. The other two columns were then saved from Excel as a tab-delimited file (m / z and intensity) as filename.txt. The Masslynx Databridge program was then used to convert the tab-delimited file filename.txt to Masslynx format. In some cases, Masslynx has used an external calibration using a (similarly transformed) myoglobin spectrum to correct the m / z data for the Menin protein. The MaxEntl software from the MassLynx software package was used to deconvolve the mass spectrum to obtain the average MW of the protein (s). The percentage of covalent adduct formation was determined from the deconvolution spectrum and used to calculate the reaction rate (k) of the covalent reaction.

Example 9. Assay of cell proliferation.

The ability of the compound of the present invention to inhibit the growth of cells such as human leukemia cells, VCaP, LNCaP, 22RV1, DU145, LNCaP-AR, MV4; 11, KOPN-8, ML-2, MOLM-13, bone marrow cells (BMC), MLL-AF9, MLL-ENL, MLL-CBP, MLL-GAS7, MLL-AFlp, MLL-AF6, HM-2, E2A-HLF, HL-60 and NB4 were tested using a cell viability assay such as Promega CellTiter- Glo® Luminescent Cell Viability Assay (Promega Technical Bulletin, 2015, CellTiter-Glo® Luminescent Cell Viability Assay: 1-15, incorporated herein by reference in its entirety). Cells are seeded at appropriate concentrations, for example, from about 1x10 ⁵ to about 2x105 cells / well in a 96-well plate. The compound of the present invention is added at a concentration of up to about 2 μM with eight 2-fold serial dilutions for each compound. The cells are incubated at 37 ° C for a specified period of time, for example 72 hours, then the cells in the control wells are counted. The medium is changed to restore the number of viable cells to the original concentration, and the compounds are fed again. Proliferation is measured after about 72 hours using Promega CellTiter-Glo® reagents according to the kit instructions.

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Certain compounds disclosed in the present invention showed GI50 values less than

250 or less than 50 nM when tested in MV4 cells; 11. As used in the examples, the GI50 of a compound is the concentration of the compound for 50% maximum inhibition of cell proliferation.

Tab. 4 shows the biological activities of selected compounds in a cell proliferation assay. The compound numbers correspond to the numbers and structures shown in table. 1 and 2 and examples 1-5.

Table 4

Less than 10 nM (++++) 10 nM to less than 50 nM (+++) 50 nM to less than 250 nM (++) 250 nM to 1000 nM (+) MLL-AF9 IUD GI50 (nM) 132, 135, 151, 163, 165, 172, 177, 183, 199, 203,205,207,214 10, 80, 138, 139, 171, 174, 175, 176, 181.217 nine

Example 10 RT-PCR analysis of downstream targets of MLL fusion proteins.

The effect of a compound of the present invention on the expression of one or more downstream targets of MLL fusion proteins is assessed by RT-PCR. Cells such as VCaP, LNCaP, 22RV1, DU145, LNCaP-AR, MV4; 11, KOPN-8, ML-2, MOLM-13, bone marrow cells (BMCs), MLL-AF9, MLLENL, MLL-CBP, MLL -GAS7, MLL-AFlp, MLL-AF6, HM-2, E2A-HLF, HL-60 and NB4 are treated with an effective concentration of the compound for about 7 days or less and then the total RNA is extracted from the cells using the RNeasy mini kit (QIAGEN) ... Total RNA is reverse transcribed using the High Capacity cDNA Reverse Transcription Kit (Applied Biosystems) and the relative quantification of the respective gene transcripts (eg Hoha9, DLX2 and Meisl) is determined by real-time PCR. Effective inhibition of the meninges.MLL interaction is expected to result in downregulation of downstream MLL targets, including Hoha9, DLX2, and Meisl.

Example 11. Pharmacokinetic studies in mice.

The pharmacokinetics of menin-MLL inhibitors were determined in female C57BL / 6 mice following an intravenous (iv) dosing of 15 mg / kg and an oral (po) dosing of 30 mg / kg. Compounds are dissolved in a vehicle containing 25% (v / v) DMSO, 25% (v / v) PEG-400 and 50% (v / v) PBS. Serial blood samples (50 μl) are collected over 24 hours, centrifuged at 15,000 rpm for 10 minutes and saved for analysis. Plasma concentrations of compounds are determined by the LC-MS / MS method developed and validated for this study. The LC-MS / MS method consists of an Agilent 1200 HPLC system and chromatographic separation of the test compound is achieved using an Agilent Zorbax Extend-C18 column (5 cm x 2.1 mm, 3.5 μm; Waters). For detection, an AB Sciex QTrap 3200 mass spectrometer is used, equipped with an electrospray ionization source (ABISciex, Toronto, Canada) in the mode of monitoring multiple positive ion reactions (MRM). All pharmacokinetic parameters are calculated in a non-compartmentalized manner using WinNonlin® version 3.2 (Pharsight Corporation, Mountain View, CA, USA).

Example 12. Study of efficacy in a xenograft tumor model in mice.

Immunodeficient mice such as 8-10 week old female athymic (nu / nu) mice are used for in vivo efficacy studies in accordance with the guidelines approved by the IACUC. Leukemia cells, such as human leukemia cells MV4-11, available from ATCC, are implanted subcutaneously through a needle in female nude mice (5 x 10 ⁶ cells / mouse). When the tumor in the mouse reaches a size of approximately 150 to 250 mm ³ , the tumor bearing mice are randomly assigned to a vehicle control group or a treatment group (8 animals per group). Animals are treated with a compound of the present invention by oral gavage or intraperitoneal injection at appropriate amounts and frequencies that can be determined by the skilled artisan without undue experimentation. The subcutaneous tumor volume in nude mice and the body weight of the mice are measured twice a week. Tumor volumes are calculated by measuring the two perpendicular diameters with calipers (V = (length x width ² ) / 2). The percentage of tumor growth inhibition (% TGI = 1- [change in tumor volume in the treatment group / change in tumor volume in the control group] * 100) is used to assess the antitumor efficacy. Statistical significance is assessed using a one-tailed two-sample t test. P <0.05 is considered statistically significant.

Example 13. Study of efficacy in a xenograft model of a prostate tumor.

Immunodeficient mice such as 4-6 week old male CB17 mice with severe combined immunodeficiency (SCID) are used for in vivo efficacy studies in accordance with the recommendations approved by the IACUC. Parental prostate cancer cells such as VCaP or LNCaP-AR cells are implanted subcutaneously in male CB.17.SCID mice (3-4x10 ⁶ cells per

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50% Matrigel). When the tumor reaches a measurable size of approximately 80 mm ³ , tumor-bearing mice are randomly assigned to a vehicle control group or a treatment group (6 or more animals per group). Animals are treated with a compound of the present invention by intraperitoneal injection at an appropriate amount and frequency that can be determined by the skilled artisan without undue experimentation. In one example, mice are treated daily with 40 mg / kg of a compound of the present invention by intraperitoneal injection for two weeks, then 5 days a week. Subcutaneous tumor volume and body weight of mice are measured twice a week. Tumor volumes are calculated by measuring the two perpendicular diameters with calipers (V = (length x width ² ) / 2).

Example 14. Study of efficacy in a xenograft model of castration-resistant prostate tumor (VCaP).

Immunodeficient mice such as 4-6 week old male CB17 mice with severe combined immunodeficiency (SCID) are used for in vivo efficacy studies in accordance with the recommendations approved by the IACUC. Parental prostate cancer cells such as VCaP cells are implanted subcutaneously in male CB.17.SCID mice (3-4x10 ⁶ cells in 50% Matrigel). When the tumor reaches a size of approximately 200-300 mm ³ , the tumor bearing mice are physically castrated and the tumor is observed to regress and recover to approximately 150 mm ³ . The tumor bearing mice are randomly assigned to a vehicle control group or a compound treatment group (6 or more animals per group). Animals are treated with a compound of the present invention by intraperitoneal injection at an appropriate amount and frequency that can be determined by the skilled artisan without undue experimentation. In one example, mice are treated daily with 40 mg / kg of a compound of the present invention by ip injection. Subcutaneous tumor volume and body weight of the mice are measured twice a week. Tumor volumes are calculated by measuring the two perpendicular diameters with calipers (V = (length x width ² ) / 2).

Example 15 Efficacy study in a castration-resistant prostate tumor xenograft model (LNCaP-AR).

Immunodeficient mice such as 4-6 week old male CB17 mice with severe combined immunodeficiency (SCID) are used for in vivo efficacy studies in accordance with the recommendations approved by the IACUC. CB.17.SCID mice are surgically castrated and allowed to recover for 2-3 weeks prior to implantation of parental prostate cancer cells, such as LNCaP-AR cells, subcutaneously (3-4x10 ⁶ cells in 50% Matrigel). When the tumor reaches a size of approximately 80-100 mm ³ , tumor bearing mice are randomly assigned to a vehicle control group or a compound treatment group (6 or more animals per group). Animals are treated with a compound of the present invention by intraperitoneal injection at an appropriate amount and frequency that can be determined by the skilled artisan without undue experimentation. In one example, mice are treated daily with 60 mg / kg of a compound of the present invention by ip injection for 27 days. Subcutaneous tumor volume and body weight of mice are measured twice a week. Tumor volumes are calculated by measuring the two perpendicular diameters with calipers (V = (length x width ² ) / 2).

Example 16. Cellular Thermal Shift Assay (CETSA).

For CETSA experiments on cell lysate, cultured cells from cell lines (eg, HEK293, bone marrow samples) are harvested and washed with PBS. Cells are diluted in kinase buffer (KB) (25 mM tris- (hydroxymethyl) -aminomethane hydrochloride (Tris-HCl, pH 7.5), 5 mM beta glycerophosphate, 2 mM dithiothreitol (DTT), 0.1 mM sodium vanadium oxide, 10 mM magnesium chloride) or in phosphate buffered saline (PBS) (10 mM phosphate buffer (pH 7.4), 2.7 mM potassium chloride and 137 mM sodium chloride). All buffers are supplemented with Complete Protease Inhibitor Blend. Cell suspensions are frozen-thawed three times using liquid nitrogen. The soluble fraction (lysate) is separated from the cell debris by centrifugation at 20,000xg for 20 min at 4 ° C. Cell lysates are diluted with an appropriate buffer and divided into two aliquots, one aliquot treated with drug and another aliquot treated with inhibitor diluent (control). After a 10-30 minute incubation at room temperature, the corresponding lysates are divided into smaller (50 μl) aliquots and heated individually at different temperatures for 3 minutes, followed by cooling for 3 minutes at room temperature. The corresponding temperatures are determined in preliminary CETSA experiments. The heated lysates are centrifuged at 20,000xg for 20 min at 4 ° C to separate the soluble fractions from the sediments. Supernatants are transferred to new microtubes and analyzed by polyacrylamide gel electrophoresis with dodecyl sulfate (SDS-PAGE) followed by Western blotting analysis.

For experiments with intact cells, drug-treated cells from the in vitro experiments described above are heated as previously described followed by KB (30 μl) and lysed using 2 freeze-thaw cycles with liquid nitrogen. Soluble fractions are isolated and analyzed by Western blotting.

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For in vivo experiments in mice, frozen tissue lysates are used. Frozen organs (eg liver or kidney) are thawed on ice and rinsed briefly with PBS. The organs were homogenized in cold PBS using tissue grinders, followed by 3 freeze-thaw cycles using liquid nitrogen. Tissue lysates are separated from cellular debris and lipids. Tissue lysates are diluted with PBS containing protease inhibitors, divided in 50 μl aliquots and heated at different temperatures. Soluble fractions are isolated and analyzed by Western blotting. Aliquots treated with one or more of the compounds of the present invention are expected to exhibit increased thermal stabilization of menin compared to control aliquots.

Example 17 CETSA-like dot blot experiments on purified proteins.

Purified protein (0.5 μg) is added to the wells of the PCR plate and the volume is adjusted to 50 μl by adding buffer or cell lysates and ligands, depending on the experimental setup. The samples are heated for a specified time and temperature in a thermal cycler. After heating, samples are immediately centrifuged for 15 min at 3000xg and filtered using a 0.65 μm Multiscreen HTS 96-well filter plate. 3 μl of each filtrate is blotted onto a nitrocellulose membrane. The primary antibody and the secondary conjugate are used for immunoblotting. All membranes are blocked with a blocking buffer; use the standard transfer and Western blotting protocols recommended by the manufacturers. All antibodies are diluted with blocking buffer. Dot blotting is being developed. Chemiluminescence intensities are detected and visualized. Images with clear dot blots are processed. The background is subtracted and the intensities are quantified. Graphs are plotted and fitted using a sigmoidal dose-response curve (variable slope).

Example 18. Assay of cell proliferation.

The ability of a compound of the present invention to inhibit cell growth was tested in MLL leukemia lines (e.g. MV4; 11, MOLM13 and / or KOPN8) and control cell lines (e.g. K562, REH, U937, KG-1 and / or HL-60) with using the MTT cell proliferation assay (ATCC® 30-1010K). One or more compounds disclosed in the present invention, for example, the compound shown in table. 3, having an IC ₅₀ value of less than 1 μM, preferably less than 50 nM (a measurement reflecting the ability of a compound to disrupt the meningine-MLL interaction, measured according to Example 6), inhibit the proliferation of MLL leukemia cell lines (MV4; 11 and MOLM13 cells), but have a much weaker inhibitory effect on the proliferation of control cell lines (for example, K562 and REH cells) at the same concentration. Cells were seeded at about 1x10 ⁵ cells per well in a 96-well plate. The compound of the present invention was added at a concentration of up to about 2 μM with seven 2-fold serial dilutions for each compound. The cells were incubated at 37 ° C for 72 h, after which the cells in the control wells were counted. The medium was changed to restore viable cell numbers to the original concentration, and compounds were re-supplied. Proliferation was measured after 96 h using MTT reagents according to the kit instructions. The GI50 value of a compound of the present invention, such as Compound B in FIG. 4 was 35 nM in MV4 cells; 11 (MLL-AF4 AML), 75 nM in MOLM13 cells (MLL-AF9 AML), 1500 nM in K562 cells, and 2000 nM in REH cells as measured by the MTT cell proliferation assay. The GI50 value of a compound of the present invention, such as Compound C in FIG. 8, was 15 nM in MV4 cells; 11 (MLL-AF4 AML), 16 nM in MOLM13 cells (MLL-AF9 AML), 20 nM in KOPN8 cells (MLL-ENL AML), 1500 nM in REH cells, more than 6000 nM in K562 cells and over 6000 nM in U937 cells as measured by the MTT cell proliferation assay. _{The GI 50} value of a compound of the present invention, such as Compound D in FIG. 11 was 10 nM in MV4 cells; 11 (MLL-AF4 AML), 17 nM in MOLM13 cells (MLL-AF9 AML), 18 nM in KOPN8 cells (MLL-ENL AML), more than 2000 nM in HL-60 cells and more than 2000 nM in U937 cells. REH, K562, KG-1 and U937 cells were control cell lines without MLL fusions. Certain compounds disclosed in the present invention showed GIso values ranging from 1500 to more than 6000 nM when tested in REH, K562, KG-1 and U937 cells. Certain compounds disclosed in the present invention showed GI50 values in the range of 5 to 25 nM when tested in MV4; 11 cells (MLL-AF4 AML), MOLM13 cells (MLL-AF9 AML), mouse bone marrow cells (rMML-AF9 AML ), KOPN8 (MLL-ENL AML), RS4 cells; 11 (MLL-AF4 ALL) or SEM (MLL-AF4 ALL).

Example 19. Study of efficacy in a mouse xenograft tumor model.

One or more compounds disclosed in the present invention, for example, the compound shown in table. 3, having an IC ₅₀ value of less than 1 μM, preferably less than 50 nM (a measurement reflecting the ability of a compound to disrupt the menine-MLL interaction, measured according to example 6), provides suppression of tumor growth MV4; 11 (human leukemia) in mouse xenograft models. Immunocompromised 8-10 week old females (nu / nu) were used for in vivo efficacy studies according to IACUC guidelines. Human cage

- 137,038388 leukemia leukemia MV4; 11, available from ATCC, were implanted subcutaneously in female athymic mice (5/10 ⁶ cells / mouse). When the tumor reached a size of approximately 150 to 250 mm ³ , tumor bearing mice were randomly assigned to a vehicle control group or a treatment group (8 animals per group). The mice in each treatment group were administered a compound of the present invention via oral gavage at said dose (50 mg / kg bid (twice daily); 50 g / kg qd (once daily); 100 mg / kg , bid; 100 mg / kg, qd; 200 mg / kg, qd; or 200 mg / kg, bid). Subcutaneous tumor volume and body weight of the mice were measured twice a week. Tumor volumes were calculated by measuring the two perpendicular diameters with calipers (V = (length / width ² ) / 2). As shown in FIG. 4, the compound shown in table. 3, which had an IC ₅₀ value of less than 50 nM (a measurement reflecting the ability of a compound to disrupt the menin-MLL interaction, measured according to Example 6), labeled Compound B in the figure inhibited tumor growth and induced tumor regression relative to the vehicle control group in a dose-dependent manner. As shown in FIG. 8, the compound shown in table. 3, which had an IC ₅₀ value of less than 50 nM (a measure reflecting the ability of a compound to disrupt the menine-MLL interaction, measured according to Example 6), labeled Compound C in the figure inhibited tumor growth and induced tumor regression relative to the vehicle control group in a dose-dependent manner.

Example 20. Study of efficacy in a murine xenograft model of MLL leukemia.

One or more compounds disclosed in the present invention, for example, the compound shown in table. 3, having an IC ₅₀ value of less than 1 μM, preferably less than 50 nM (a measurement reflecting the ability of a compound to disrupt the meningine-MLL interaction, measured according to Example 6), provides suppression of MV4 tumor growth; 11 in a murine xenograft model of MLL leukemia. Immunocompromised 8-10 week old NSG mice were used for in vivo efficacy studies according to IACUC guidelines. Luciferase-expressing human leukemia cells MV4; 11 (MV4; 11-luC) were grafted intravenously by injection into the tail vein (1/10 ⁷ cells / animal). When the mean luminescence of the cells reached about 1.5 / 10 ⁶ , the tumor bearing mice were randomly assigned to a vehicle control group or a compound treatment group (5 animals per group). Animals in each of the treatment groups were administered a different compound of the present invention via oral gavage (120, 150, 200 or 200 mg / kg qd). Body weight was measured daily, while mean luminescence was measured 6 days after starting treatment with compound or vehicle.

As shown in FIG. 5, the 200 mg / kg bid regimen of Compound B of the present invention inhibited tumor growth and induced tumor regression relative to the vehicle control group. On the contrary, the compound presented in table. 3 having an IC ₅₀ value greater than 1 μM (a measurement reflecting the ability of a compound to disrupt the menine-MLL interaction, measured according to Example 6), labeled Compound A in FIG. 5, inhibited tumor growth but did not induce tumor regression relative to the vehicle control group when administered at a dose of 200 mg / kg. As shown in FIG. 11, the treatment regimen bid 200 mg / kg Compound 165 - the compound shown in Table. 3 having an IC50 value of less than 50 nM (a measure reflecting the ability of a compound to disrupt the menine-MLL interaction, measured according to Example 6), and labeled Compound D in the Figures inhibited tumor growth and induced tumor regression relative to the vehicle control group in a dose-dependent manner.

Animals were sacrificed on the 7th day of treatment and bone marrow samples were collected and prepared for gene expression analysis. The expression levels of the target genes of the MLL HOXA9, DLX2 and / or MEIS1 fusion proteins were measured by qRT-PCR and are shown in FIG. 6, 9 and 12 as fold changes normalized to GAPDH expression. Expression of the differentiation marker CD11b was increased in bone marrow samples from Compound B treated animals, Compound C treated animals, and Compound D treated animals, indicating that these cells were undergoing differentiation. In addition, the expression levels of MEIS1 and HOXA9 were significantly reduced by treatment with Compound B, Compound C or Compound D, which is consistent with the inhibition of leukemia progression caused by this compound.

Example 21 Survival study in a mouse xenograft model of MLL leukemia.

For survival studies of MV4 xenotransplantation; 11 xenograft model, 6-8 week old female NSG mice were intravenously injected 1/10 of ⁷ luciferase expressing MV4 cells; 11 carrying an MLL-AF4 translocation. On day 12 post-transplant, Compound B treatment was initiated, 120 mg / kg, bid, po. or vehicle (20% 2-hydroxypropyl-β-cyclodextrin with 5% Cremophor) and continued for 22 consecutive days. As shown in FIG. 7, Compound B of the present invention increases the median survival time compared to the vehicle control group. Compound B-treated mice had a mean survival time of 54 days, while mice in the control group had a mean survival time of 37 days, indicating a survival advantage of 17 days (46%) for compound-treated mice.

- 138 038388

For survival studies in xenograft MOLM13 xenograft model 6-8 week old female NSG mice were intravenously injected with 0.5x10 ⁶ MOLM13 cells carrying the MLL-AF9 translocation. On day 4 post-transplant, Compound C treatment, 75 mg / kg, bid, P.o was initiated. or vehicle (20% 2-hydroxypropyl-β-cyclodextrin with 5% Cremophor), which was continued for 16 consecutive days in compound-treated mice, or until vehicle-treated mice developed terminal leukemias. As shown in FIG. 10, Compound C of the present invention lengthened the median survival time relative to the vehicle control group. Similarly, 120 mg / kg of Compound D was started on day 6 after MOLM13 transplantation and continued for 16 consecutive days in compound-treated mice or until vehicle-treated mice developed terminal leukemias. As shown in FIG. 13, Compound D of the present invention extended the median survival time to 24 days relative to the median survival time of 16 days for mice in the vehicle control group, indicating an advantage of survival for 18 days (75%) for mice treated with the compound.

Although preferred embodiments of the present invention have been shown and described in the present invention, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, alterations, and substitutions will now take place for those skilled in the art without departing from disclosure. It should be understood that various alternatives to the embodiments described in the present invention may be used in the practice of the invention. It is intended that the following claims define the scope of the invention and that methods and structures falling within the scope of these claims and their equivalents are intended to be embraced as such.

Claims (23)

CLAIM 1. Compound of formula (II-A) or a pharmaceutically acceptable salt thereof, wherein C is selected from a C _3-12 carbocycle and a 4-12 membered monocyclic or bicyclic heterocycle having 3-8 C, 1-2 N, 0-1 O and 0-1 S ring atoms; L ^{2 is} selected from a bond, -O-, -S-, -N (R ⁵¹ ) -, -N (R ⁵¹ ) CH2-, -C (O) -, -C (O) O-, -OC (O ) -, -C (O) N (R ⁵¹ ) -, -N (R ⁵¹ ) C (O) -, -N (R ⁵¹ ) C (O) N (R ⁵¹ ) -, -S (O) 2 -, -S (O) -, -N (R ⁵¹ ) S (O) 2-, -S (O) 2N (R ⁵¹ ) -, -N (R ⁵¹ ) S (O) 2N (R ⁵¹ ) - , C1-6 αalkylene and C _2-6 α alkenylene, where C _1-6 α alkyl and C _2-6 alkenylene are each optionally substituted with one or more R ⁵⁰ ; L ^{3 is} selected from C _1-6 αalkylene, C _2-6 α alkenylene and C _2-6 alkynylene, each of which is substituted with one or two R ⁵⁶ and optionally further substituted with one or more R ⁵⁰ ; R ¹ , R ² and R ³ _; each independently selected at each occurrence from hydrogen and R ⁵⁰ ; R ^a , R ^b and RC are each independently selected at each occurrence from R ⁵⁰ or two RA groups, two R ^B groups or two RC groups attached to the same atom or different atoms, together may optionally form c _{1- 3} moctuk; m, n and p are each independently an integer from 0 to 6; R ^{50 is} independently selected at each occurrence from: halogen, -NO2, -CN, -OR ⁵² , -SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N ( R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, - NR ⁵² c (O) NR ⁵³ R ⁵⁴ , -c (O) N (R ⁵² ) 2, -c (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) ( R ⁵² ) 2, = O, = S, = N (R ⁵² ); C _1-10 α alkyl, C _2-10 alkenyl and C _2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO2, —CN, —OR ⁵² , —SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O ) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -c (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ) and C3.12 carbocycle; and C _3-12 carbocycle and 4,5-dihydrooxazol-2-yl; R ^{51 is} independently selected at each occurrence from: hydrogen, —C (O) R ⁵² , —C (O) OR ⁵² , —C (O) N (R ⁵² ) 2, —C (O) NR ⁵³ R ⁵⁴ ; C _1-6 αalkyl, C _2-6 α alkenyl and C _2-6 α alkyl, each independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO2, —CN, —OR ⁵² , —SR ⁵² , -N (R ⁵² ) 2, -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , - 139 038388 -NR ⁵² S (= O) ₂ N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OCiO) \ iR '^; ) .. -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O ) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) ₂ , -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ) and Cs-12 carbocycle; R ^{52 is} independently selected at each occurrence from hydrogen and C _{I. 20} alkyl, C ₂ . ₂₀ alkenyl and C _2-2 oalkynyl, each of which is optionally substituted with halogen, —CN, —NO ₂ , —NH ₂ , —NHCH ₃ , —NHCH ₂ CH ₃ , = O, —OH, —OCH3, or —OCH2CH3; R ⁵³ and R ⁵⁴ are taken together with the nitrogen atom to which they are attached to form aziridinyl or azetidinyl optionally substituted with one or more R ⁵⁰ ; R ^{56 is} independently selected at each occurrence from: -NO ₂ , -OR ⁵⁹ , -SR ⁵² , -NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, - S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , - C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , - C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ), C _{| - | 0} alkyl, C _{2- | 0} alkenyl and C _{2- | 0} alkynyl and C _{3- | 2} carbocycle, each C _{| - | 0} alkyl, C _{2- | 0} alkenyl and C _{2- | 0} alkynyl in R ^{56 is} independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO ₂ , —CN, —OR ⁵⁹ , —SR ⁵² , —N (R ⁵² ) 2, —NR ⁵³ R ⁵⁴ , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S ( = O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ) and C3- | ₂ carbocycles; or two R ⁵⁶ groups attached to the same atom are joined together to form cyclopropyl; and R ^{59 is} independently selected at each occurrence from C _{| -20} alkyl, C _2-20 alkenyl and C _2-20 alkynyl, each of which is optionally substituted with halogen, —CN, —NO ₂ , —NH ₂ , —NHCH ₃ , —NHCH ₂ CH ₃ , = O, —OH, —OCH _3, or —OCH2CH3, where for a compound or salt of formula (II-A) when R ⁵⁶ is —CH3, L ^{3 is} not further substituted with —OH, —NH2, or —CN ... 2. A compound according to claim 1, wherein RC is selected from -C (O) R ⁵² , -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , = O, C | -3alkyl and C | -3haloalkyl, or two R ^C groups attached to different atoms can together form C | -3 bridge. 3. The compound of claim 1, wherein C is a 5-12 membered saturated heterocycle. 4. The compound of claim 3, wherein the heterocycle is selected from piperidinyl and piperazinyl. 5. A compound according to claim 1, wherein C is selected from: R ^c R ^c A xR ⁵⁷ / X xR ⁵⁷ Ar ⁵⁷ Π Ο Π Υ, ρ Jy, _and _ where R ^{57 is} selected from -S (= O) R ⁵² , -Si O); R ^; ... -S (O); \ | R5 ^; ) .. -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= OhR ⁵² and C |. _{| O} alkyl substituted with one or more substituents selected from -S (= O) R ⁵² , -S ( = O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ and -NR ⁵² S (= O) 2R ⁵² . 6. The compound of claim 5, wherein R ^{57 is} selected from -S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) ₂ and -NR ⁵² S ( = O) 2R ⁵² . 7. A compound according to claim 6, wherein R ^{57 is} selected from -S (= O) CH ₃ , -S (= O) ₂ CH ₃ , -S (= O) ₂ NH ₂ , -NHS (= O) ₂ CH ₃ and -S (= O) 2NHCH3. 8. A compound according to claim 1, wherein R ^{2 is} selected from hydrogen, halogen, -OH, -OR ⁵² , -NH2, -N (R ⁵² ) 2, -CN, C _{| -3} alkyl, C _{| -3} alkyl-N (R ⁵² ) ₂ , C _{| -3} haloalkyl, C _2-3 alkenyl and C _2-3 alkynyl; and R ^{3 is} selected from hydrogen, halogen, —OH, —N (R ⁵² ) 2, —CN, —C (O) OR ⁵² , C | -3alkyl, and C _{| -3} haloalkyl. 9. A compound according to claim 1, wherein R1 is C _{| -3} haloalkyl. 10. A compound according to claim 1, wherein m is 0. II. The compound of claim 1, wherein n is an integer from I to 3. 12. A compound according to claim 1, wherein L ² is C _{| -4} alkylene optionally substituted with one or more R ⁵⁰ . I3. The compound of claim 1, wherein L ³ is C _{| -6} alkylene substituted with one R ⁵⁶ and optionally substituted with one or more R ⁵⁰ . I4. The compound of claim 13, wherein L ³ is C ₂ alkylene substituted with at least one C _{| -3} alkyl or C _{| -3} haloalkyl, and optionally further substituted with one or more R ⁵⁰ . I5. A compound according to clauses I3, I4, in which L ^{3 is} substituted with = O, C | -6alkyl, C | -6haloalkyl, C | -3alkyl (cyclopropyl), CI-3alkyl (NR ⁵² C (O) R ⁵² ) or -O (CI-6alkyl). I6. The compound of claim I5, wherein L ^{3 is} substituted with —CH ₃ . - I40 038388 R56, X 0 (R) \ (S) 17. A compound according to claim 1, wherein L ^{3 is} selected from and, 18. A compound according to claim 17 wherein R ⁵⁶ is methyl. 19. A compound according to claim 1, wherein L ^{2 is} selected from —O—, —S—, —NH— and —CH ₂ -; L ^{3 is} selected from C _1-6 αalkylene, C _2-6 α alkenylene and C _2-6 alkynylene, each of which is substituted with one or two 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 ^A groups, two R ^B groups or two R ^C groups attached to the same atom or different atoms, together may optionally form C _1-3 bridge; m 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: -OR ⁵⁹ , = O, C _1-10 αalkyl, C _2-10 alkenyl and C _2-10 alkynyl, each C _1-10 α alkyl, C _2-10 alkenyl and C _2-10 alkynyl in R ⁵⁶ independently optionally substituted in each case, one or more substituents selected from halogen, —NO ₂ , —CN, —OR ⁵⁹ , —SR ⁵² , —N (R ⁵² ) 2, —NR ⁵³ R ⁵⁴ , —S (= O) R ⁵² , -S (= O) 2R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² , -NR ⁵² S (= O) 2N (R ⁵² ) 2, -NR ⁵² S (= O) 2NR ⁵³ R ⁵⁴ , -C (O) R ⁵² , -C (O) OR ⁵² , -OC (O) R ⁵² , -OC (O) OR ⁵² , -OC (O) N (R ⁵² ) 2, -OC (O) NR ⁵³ R ⁵⁴ , -NR ⁵² C (O) R ⁵² , -NR ⁵² C (O) OR ⁵² , -NR ⁵² C (O) N (R ⁵² ) 2, -NR ⁵² C (O) NR ⁵³ R ⁵⁴ , -C (O) N (R ⁵² ) 2, -C (O) NR ⁵³ R ⁵⁴ , -P (O) (OR ⁵² ) 2, -P (O) (R ⁵² ) 2, = O, = S, = N (R ⁵² ) and C3-12 carbocycle; additionally, in which R ⁵⁶ optionally forms a bond with ring C, or two R ⁵⁶ groups attached to the same atom form a bond; and R ^{59 is} independently selected at each occurrence from C _1-20 αalkyl, C _2-20 alkenyl and C _2-20 alkynyl, each of which is optionally substituted with halogen, —CN, —NO ₂ , —NH ₂ , —NHCH ₃ , —NHCH ₂ CH ₃ , = O, -OH, -OCH ₃ or -OCH2CH3. 20. The compound of claim 19, wherein C is substituted with —S (= O) ₂ R ⁵² , —S (= O) 2N (R ⁵² ) 2, or —S (= O) ₂ NR ⁵³ R ⁵⁴ . 21. A compound according to claim 19, wherein R ^{2 is} selected from hydrogen, halogen, -OH, -OR ⁵² , -NH2, -N (R ⁵² ) 2, -CN, C _1-3 α-alkyl, C _1-3 α-alkyl-OR ⁵² , C1-3 alkyl-N ( R ⁵² ) 2, C _1-3 haloalkyl, C _2-3 alkenyl and C _2-3 alkynyl; L ² represents -CH ₂ -; / x .R ⁵⁷ L ⁵⁷ .R p Ν <ΝГ | ΥΎ> ^Ν χΎ ^Λ (П and C selected from '' R ^{57 is} selected from -S (= O) R ⁵² , -S (= OhR ⁵² , -S (= O) 2N (R ⁵² 0 -S (= O) 2NR ⁵³ R ⁵⁴ , -NR ⁵² S (= O) 2R ⁵² and C1-1oalkyl substituted with one or more substituents selected from -S (= O) R ⁵² , -S (= O) ₂ R ⁵² , -S (= O) 2N (R ⁵² ) 2, -S ( = O) 2NR ⁵³ R ⁵⁴ and -NR ⁵² S (= O) 2R ⁵² ; and p is 0. 22. A compound according to claim 21, wherein R ^{2 is} selected from —NH ₂ , —CH _3, and —NHCH ₃ . Me .... ... ... ^And ' 24. A compound according to claim 1, wherein the compound has the structure of formula (II-F) or formula (II-H): 25. A compound according to claim 1, wherein the compound of formula (II-A) is selected from: - 141 038388 - 142 038388 - 143 038388 - 144 038388 - 145 038388 - 146 038388 - 147 038388 - 148 038388 - 149 038388 - 150 038388 - 151 038388 - 152 038388 - 153 038388 - 154 038388 - 155 038388 - 156 038388 26. A compound or a pharmaceutically acceptable salt thereof, which is: - 157 038388 27. A pharmaceutical composition for the treatment of cancer, comprising a compound according to any one of claims 1 to 26 and a pharmaceutically acceptable carrier. 28. A method of inhibiting the interaction of menin with one or more MLL1, MLL2, MLL fusion protein (MLL - mixed line leukemia) and a partial tandem duplication of MLL, comprising contacting menin with an effective amount of a compound according to any one of claims 1 to 26. 29. A method of treating a disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to claim 27 or a compound according to any one of claims 1 to 26, in which the disease or condition comprises leukemia, hematological malignant tumor, cancer with a solid tumor, prostate cancer, breast cancer, liver cancer, or brain tumor.