KR20100075508A - Compounds for inhibiting ksp kinesin activity - Google Patents

Abstract

The present invention relates to compounds of Formula (I), below, (wherein X, R, R, R, R, R, p, E, ring A, and ring B are as defined herein). The present invention also relates to compositions (including pharmaceutically acceptable compositions) comprising these compounds, alone and in combination with one or more additional therapeutic agents, and to methods for their use in inhibiting KSP kinesin activity, and for treating cellular proliferative diseases or disorders associated with KSP kinesin activity.

Description

Compound for inhibition of PSP kinesin activity {COMPOUNDS FOR INHIBITING KSP KINESIN ACTIVITY}

preference

This application claims the benefit of priority of US Provisional Patent Application No. 60 / 986,799, filed November 9, 2007, the contents of which are incorporated herein by reference in their entirety.

Field of invention

The present invention relates to compounds and compositions useful for treating cell proliferative diseases or disorders associated with kinesin activity and for inhibiting KSP kinesin activity.

Cancer is the leading cause of death in the United States and around the world. Cancer cells are often characterized by constitutive proliferative signals, defects in cell cycle checkpoints, as well as defects in apoptosis pathways. There is a great demand for the development of new chemotherapeutic drugs that can block cell proliferation and enhance tumor cell apoptosis. Conventional therapeutic agents used to treat cancer include taxanes and vinca alkaloids that target microtubules. Microtubules are integral structural components of mitotic spindles that are involved in the distribution of sister chromatids that overlap with each of the daughter cells resulting from cell division. Disruption of microtubules or obstruction with microtubule motive force can inhibit cell division and induce apoptosis.

However, microtubules are also important structural components in non-proliferative cells. For example, they are required for organelle and vesicle transport intracellularly or along axons. Microtubule-targeted drugs do not distinguish between their different structures, but they may have undesirable side effects that limit their usefulness and dosage. Therefore, there is a need for chemotherapeutic agents that improve specificity to avoid side effects and improve efficacy.

Microtubules rely on two classes of power proteins, kinesin and dynein, for their action. Kinesin is a power protein that produces motion along microtubules. They are characterized by conserved power domains, which are approximately 320 amino acids in length. The power domain binds to and hydrolyzes ATP as an energy source to drive directional movement of cell transport along microtubules and also includes microtubule-binding interfaces (Mandelkow and Mandelkow, Trends Cell Biol. 2002, 12: 585). -591).

Kinesin exhibits a high level of functional diversity and some kinesins are specifically required during mitosis and cell division. Different mitotic kinesins are involved in all aspects of mitosis including bipolar spindle formation, spindle dynamics and chromosomal movement. Thus, obstruction due to the action of mitotic kinesin can disrupt normal mitosis and block cell division. In particular, mitotic kinesin KSP (aka EG5), which is required for centrosome separation, has been found to have an essential action during mitosis. Cells with inhibited KSP action inhibit mitosis using unsegregated centrosomes (Blangy et al., Cell 1995, 83: 1159-1169). This results in the formation of a monoastral array of microtubules with overlapping chromosomes at their ends attached in a rosette-like configuration. In addition, these mitotic chromatids are attached within rosette-like structures. In addition, this mitotic inhibition results in growth inhibition of tumor cells (Kaiser et al., J. Biol. Chem. 1999, 274: 18925-18931). Inhibitors of KSP may be desirable for the treatment of proliferative diseases such as cancer.

Kinesin inhibitors are known and several molecules have recently been described in the literature. For example, adokiasulfate-2 inhibits microtubule-stimulated ATPase activity of several kinesins including CENP-E (Sakowicz et al., Science 1998, 280: 292-295). Another non-selective inhibitor, Rose Bengal lactone, interferes with kinesin action by blocking microtubule binding sites (Hopkins et al., Biochemistry 2000, 39: 2805-2814). Monastrol, a compound isolated using a phenotypic screen, is a selective inhibitor of the KSP kinetic domain (Mayer et al., Science 1999, 286: 971-974). Treatment of cells with monastrol inhibits cells upon mitosis with unipolar spindles.

KSP inhibitors are described in patents and publications that include: WO2006 / 031348, WO2006 / 110390, WO2006 / 068933, WO2006 / 023083, WO2006 / 007491, WO2006 / 086358, WO2003 / 105855, WO2006 / 023440, WO2003 / 079973 , WO2004 / 087050, WO2004 / 111193, WO2004 / 112699, WO2006 / 007497, WO2006 / 101761, WO2006 / 007496, WO2005 / 017190, WO0224 / 037171, WO2005 / 019205, WO2005 / 019206, WO2005 / 102996, WO2006 / 101780, WO2006 / 007501, WO2005 / 018547, WO2004 / 058148, WO2004 / 058700, WO2005 / 018638, WO2007 / 054138, WO2006 / 133805, WO2006 / 002726, WO2006 / 133821, WO2005 / 108355, WO2006 / 094602, WO2005 / 092011, WO2006 / 031607 , WO2004 / 111023, WO2006 / 137490, WO2006 / 101102, WO2006 / 101103, WO2006 / 101104, WO2006 / 101105, WO2004 / 092147, WO2005 / 035512, WO2006 / 044825, WO2006 / 044825, WO2006 / 119146, US2006 / 0247178, WO2006 / 098961, WO2006 / 098962, US2006 / 0258699, US2007 / 0213380, US2007 / 0112044, US2007 / 0155804, US2008 / 0194653, WO2008 / 042928, US2007 / 0249636, US2007 / 0287703, US2008 / 0153854, and US2007 / 0037853.

KSP, and other mitotic kinesins, are attractive targets for the discovery of novel chemotherapy with anti-proliferative activity. There is a need for compounds useful in the inhibition of KSP and the treatment of proliferative diseases such as cancer.

Summary of the Invention

In one embodiment, the invention provides a compound of Formula 1 (or Formula (I)), or a pharmaceutically acceptable salt, solvate, ester, prodrug or isomer of the compound:

In the above formula (1)

R ¹ , R ² , R ³ , p, R ²⁷ , R ²⁸ , E, ring A and ring B are independently selected from each other, where:

p is 0, 1, 2, 3 or 4;

Ring A (including indicated E and unsaturated) is a 4-8 membered cycloalkenyl or heterocycloalkenyl ring;

E is -O-, -S-, -S (O)-, -S (O) _2- , -C (R ⁴ ) (R ⁵ )-, -N (R ⁶ )-, -N (C ( Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-, -C (O) -N (R ¹¹ )- , -N (R ¹¹ ) -C (O)-, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) _2- , -C (O) -O- , -OC (O)-, -ON (R ⁶ )-, -N (R ⁶ ) -O-, -N (R ⁶ ) -N (R ¹² )-. -N = N-, -C (R ⁷ ) = N-, -C (O) -C (R ⁷ ) = N-, -C (O) -N = N-, -0-C (Y)- N (R ¹¹ )-, -N (R ¹¹ ) -C (Y) -O-, -N (R ¹¹ ) -C (Y) -N (R ¹² )-, -C (Y) -N (R ¹¹ ) -O-, -C (Y) -N (R ¹¹ ) -N (R ¹² )-, -0-N (R ¹¹ ) -C (Y)-and -N (R ¹² ) -N (R ¹¹ ) -C (Y)-, and

Where Y is (= 0), (= S), (= N (R ¹³ )), (= N (CN)), (= N (OR ¹⁴ )), (= N (R ¹⁵ ) ( R ¹⁶ )) and (═C (R ¹⁷ ) (R ¹⁸ )) independently;

Ring B is an aromatic or heteroaromatic ring, or a partially unsaturated alicyclic ring, or a partially unsaturated heterocyclic ring,

Wherein the ring is optionally substituted with one or more substituents which may be unsubstituted or may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, halo Alkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ ,- OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ ,- C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ Is independently selected from the group consisting of -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ ;

R ¹ is selected from the group consisting of aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl and heterocycloalkenyl,

Wherein each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or may be the same or different Optionally independently substituted with one or more substituents, each substituent being halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, hetero Aryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² ,- NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and from the group consisting of ^{-NR 23 C (O) NR 25} R 26 It is selected for neutral;

R ² is —C (Z) R ⁷ , -C (Z) NR ⁹ R ¹⁰ , -C (Z) OR ⁸ , -SO ₂ NR ⁹ R ¹⁰ , alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, Selected from the group consisting of cycloalkenyl, heterocycloalkyl and heterocycloalkenyl,

Where each Z is (= 0), (= S), (= N (R ¹³ )), (= N (CN)), (= N (OR ¹⁴ )), (= N (R ¹⁵ ) ( R ¹⁶ )) and (= C (R ¹⁷ ) (R ¹⁸ )), independently

Wherein each said alkyl, each said heteroalkyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl and each said heterocycloal Kenyl is optionally substituted with one or more substituents which may be unsubstituted or may be the same or different, and each substituent is oxo provided the aryl and heteroaryl are not substituted with oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl , Heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C ( O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ ,- S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C ( O) NR ²⁵ R ²⁶ is independently selected from the group consisting of;

R ²⁷ (when not combined with R ²⁸ ) is H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, hetero Cycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ ,- NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ independently Selected,

Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group;

R ²⁸ (when not combined with R ²⁷ ) is H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, hetero Cycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ ,- NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ independently Selected,

Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group; or

Alternatively, R ²⁷ and R ²⁸ are heterocycloalkyl rings containing 1 to 3 heteroatoms selected from the group consisting of cycloalkyl, cycloalkenyl, N, O and S together with the carbon atoms to which they are attached Or form a heterocycloalkenyl ring containing 1 to 3 heteroatoms selected from the group consisting of N, O and S,

Wherein the heterocycloalkyl ring and the heterocycloalkenyl ring are each independently substituted with one or more substituents which may be unsubstituted or the same or different, and each substituent is oxo, halogen, -CN, -NO ₂ , Alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, Heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O ) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O ) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ ;

Each R ³ (if present) is alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, Halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C ( O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (S) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ ,- SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ , -NR ²³ C (O) NR ²⁵ R ²⁶ and- Independently selected from the group consisting of NR ²³ -C (NH) -N (R ²⁶ ) ₂ ,

Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group, or

Alternatively, when p is 2, 3 or 4, the two R ³ groups bonded to the same ring carbon atom together with the carbon atom to which they are attached are spirocycloalkyl, spirocycloalkenyl, or -NH-, -NR Spiroheterocycloalkyl rings containing 1 to 3 ring heteroatoms independently selected from the group consisting of ^6- , -S-, -S (O)-, -S (O) ₂ -and -O-, or Spiro containing 1 to 3 ring heteroatoms independently selected from the group consisting of -NH-, -NR ^6- , -S-, -S (O)-, -S (O) _2-, and -O- To form a heterocycloalkenyl ring, or

Alternatively, R ² and R ³ together with the atoms to which they are attached, together with the carbon atoms to which they are attached, cycloalkyl, cycloalkenyl, -NH-, -NR ^6- , -S-, -S (O) -, A heterocycloalkyl ring containing 1 to 3 ring heteroatoms independently selected from the group consisting of -S (O) ₂ -and -O-, or -NH-, -NR ^6- , -S-, To form a heterocycloalkenyl ring containing 1 to 3 ring heteroatoms independently selected from the group consisting of -S (O)-, -S (O) ₂ -and -O-;

Each R ⁴ (unless combined with R ⁵ ) is H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl , Heterocycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ From the group consisting of R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ Independently selected,

Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group;

Each R ⁵ (when not combined with R ⁴ ) is H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl , Heterocycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ From the group consisting of R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ Independently selected,

Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group; or

Alternatively, R ⁴ and R ⁵ are heterocycloalkyl rings containing 1 to 3 heteroatoms selected from the group consisting of cycloalkyl, cycloalkenyl, N, O and S together with the carbon atoms to which they are attached Or form a heterocycloalkenyl ring containing 1 to 3 heteroatoms selected from the group consisting of N, O and S,

Wherein the heterocycloalkyl ring and the heterocycloalkenyl ring are each independently substituted with one or more substituents which may be unsubstituted or the same or different, and each substituent is oxo, halogen, -CN, -NO ₂ , Alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, Heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O ) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O ) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ ;

Each R ⁶ is H, alkyl, -C (O) R ²⁴ , -C (O) OR ²⁰ , -C (S) R ²⁴ , heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, Independently selected from the group consisting of aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl,

Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (S) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N Independently from -CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ ;

Each R ⁷ is from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl Independently selected,

Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group;

Each R ⁸ is from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl Independently selected,

Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group;

Each R ⁹ (when not bonded to R ¹⁰ ) is H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl Is independently selected from the group consisting of heterocycloalkenyl,

Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group;

Each R ¹⁰ (when not bonded to R ⁹ ) is H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl Is independently selected from the group consisting of heterocycloalkenyl,

Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group; or

Alternatively, R ⁹ and R ¹⁰ together with the N atom to which they are attached form a heterocycloalkyl or heterocycloalkenyl ring containing 1 to 3 heteroatoms selected from the group consisting of N, O and S and,

Wherein the heterocycloalkyl ring and the heterocycloalkenyl ring are each independently substituted with one or more substituents which may be unsubstituted or the same or different, and each substituent is oxo, halogen, -CN, -NO ₂ , Alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, Heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O ) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O ) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ ;

Each R ¹¹ is from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl Independently selected,

Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group;

Each R ¹² is from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl Independently selected,

Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group;

Each R ¹³ is from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl Independently selected,

Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group;

Each R ¹⁴ is from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl Independently selected,

Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group;

Each R ¹⁵ (when not combined with R ¹⁶ ) is H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl Is independently selected from the group consisting of heterocycloalkenyl,

Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group;

Each R ¹⁶ (when not combined with R ¹⁵ ) is H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl Is independently selected from the group consisting of heterocycloalkenyl,

Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group; or

Alternatively, R ¹⁵ and R ¹⁶ together with the N atom to which they are attached form a heterocycloalkyl or heterocycloalkenyl ring containing 1 to 3 heteroatoms selected from the group consisting of N, O and S and,

Wherein the heterocycloalkyl ring and the heterocycloalkenyl ring are each independently substituted with one or more substituents which may be unsubstituted or the same or different, and each substituent is oxo, halogen, -CN, -NO ₂ , Alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, Heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O ) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O ) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ ;

Each R ¹⁷ (when not combined with R ¹⁸ ) is H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl , Heterocycloalkenyl, -CN, -OC (O) OR ²⁰ , -OR ¹⁹ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C ( O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC ( O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ , independently

Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group;

Each R ¹⁸ (when not bonded to R ¹⁷ ) is H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl , Heterocycloalkenyl, -CN, -OC (O) OR ²⁰ , -OR ¹⁹ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C ( O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC ( O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ , independently

Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group; or

Alternatively, R ¹⁷ and R ¹⁸ are heterocycloalkyl rings containing 1 to 3 heteroatoms selected from the group consisting of cycloalkyl, cycloalkenyl, N, O and S together with the carbon atoms to which they are attached Or form a heterocycloalkenyl ring containing 1 to 3 heteroatoms selected from the group consisting of N, O and S,

Wherein the heterocycloalkyl ring and the heterocycloalkenyl ring are each independently substituted with one or more substituents which may be unsubstituted or the same or different, and each substituent is oxo, halogen, -CN, -NO 2, Alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, hetero Cycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ ;

Each R ¹⁹ is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl;

Each R ²⁰ is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl;

Each R ²¹ (when not bonded to R ²² ) is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl;

Each R ²² (when not combined with R ²¹ ) is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl; or

Alternatively, R ²¹ and R ²² together with the N atom to which they are attached form a heterocycloalkyl or heterocycloalkenyl ring containing 1 to 3 heteroatoms selected from the group consisting of N, O and S and;

Each R ²³ is H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl. Independently selected from the group consisting of aryl, heteroaryl, cycloalkyl, halocycloalkyl;

Each R ²⁴ is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl;

Each R ²⁵ (when not bonded to R ²⁶ ) is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl;

Each R ²⁶ (when not combined with R ²⁵ ) is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl; or

Alternatively, R ²⁵ and R ²⁶ together with the N atom to which they are attached form a heterocycloalkyl or heterocycloalkenyl ring containing 1 to 3 heteroatoms selected from the group consisting of N, O and S do.

As described in more detail below, it should be understood that Ring A may have unsaturation in addition to the unsaturations shown in the general formula provided herein.

Pharmaceutical formulations or compositions are provided comprising a therapeutically effective amount of one or more compounds of the invention and / or pharmaceutically acceptable salts, solvates, esters, prodrugs or isomers thereof and a pharmaceutically acceptable carrier. A therapeutically effective amount of one or more compounds of the invention (and / or pharmaceutically acceptable salts, solvates, esters, prodrugs or isomers thereof) and pharmaceutically acceptable carriers, together with one or more additional active ingredients Pharmaceutical formulations or compositions are also contemplated.

Treating a cell proliferative disease, a disease associated with KSP kinesin activity and / or KSP kinesin activity, comprising administering an effective amount of one or more compounds of the invention or a formulation or composition according to the invention to a subject in need thereof A method of suppressing is provided. The method according to the invention can be used as a single formulation regime or as part of multiple formulation regimens as suitably determined by those skilled in the art.

In addition to the working examples, or unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and the like, as used in the specification and claims, are to be understood as being modified in all instances by the term "about". .

details

In one embodiment, the compounds of the present invention have a structure represented by Formula 1 and include pharmaceutically acceptable salts, solvates, esters, prodrugs or isomers of the compounds.

. 추가의 비-제한적인 예는As shown in Formula 1 (and other formulas described herein depicting various embodiments of the compounds of the present invention), Ring A is a 4-8 membered cycloalkenyl or heterocycloalkenyl ring. It should be understood that such cycloalkenyl or heterocycloalkenyl rings of ring A may have unsaturation in addition to the unsaturations shown in the general formula provided herein. For illustrative purposes only, non-limiting examples of such additional unsaturations in Ring A include:

. Further non-limiting examples are

It includes.

In one embodiment, in Formula 1, Ring A is a cycloalkenyl ring.

In one embodiment, in Formula 1, Ring A is a heterocycloalkenyl ring.

In one embodiment, in Formula 1, Ring A is a four membered ring.

In one embodiment, in Formula 1, Ring A is a five membered ring.

In one embodiment, in Formula 1, Ring A is a 6 membered ring.

In one embodiment, in Formula 1, Ring A is a 7 membered ring.

In one embodiment, in Formula 1, Ring A is an 8 membered ring.

In one embodiment, in Formula 1, Ring A (including the unsaturated shown) is mono-unsaturated.

In one embodiment, in Formula 1, Ring A (including the unsaturated shown) is polyunsaturated.

In one embodiment, in formula 1, E is -C (R ⁴ ) (R ⁵ )-.

In one embodiment, in Formula 1, E is -O-, -S-, -S (O)-, -S (O) _2- , -N (R ⁶ )-, -N (C (Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-, -C (O) -N (R ¹¹ )-, -N (R ¹¹ ) -C (O)-, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) _2- , -C (O) -O-, -0 -C (O)-, -ON (R ⁶ )-, -N (R ⁶ ) -0-, -N (R ⁶ ) -N (R ¹² )-, -N = N-, -C (R ⁷ ) = N-, -C (O) -C (R ⁷ ) = N-, -C (O) -N = N-, -0-C (Y) -N (R ¹¹ )-. -N (R ¹¹ ) -C (Y) -O-, -N (R ¹¹ ) -C (Y) -N (R ¹² )-, -C (Y) -N (R ¹¹ ) -O-,- C (Y) -N (R ¹¹ ) -N (R ¹² )-, -ON (R ¹¹ ) -C (Y)-, and -N (R ¹² ) -N (R ¹¹ ) -C (Y)- It is selected from the group consisting of.

In one embodiment, in Formula 1, E is selected from the group consisting of -O-, -S-, -S (O)-, -S (O) _2-, and -N (R ⁶ )-.

In one embodiment, in Formula 1, E is selected from the group consisting of -O-, -S-, -S (O)-, -S (O) _2-, and -N (R ⁶ )-, wherein R ⁶ is selected from the group consisting of H, alkyl, -C (O) R ²⁴ , -C (O) OR ²⁰ and -C (S) R ²⁴ .

In one embodiment, in formula 1, E is selected from the group consisting of -O- and -N (R ⁶ )-, wherein R ⁶ is H, alkyl, -C (O) R ²⁴ , -C (O ) OR ²⁰ and -C (S) R ²⁴ .

In one embodiment, in formula 1, when E is -N (R ⁶ )-, p is O and R ³ is absent. In such embodiments, non-limiting examples of R ⁶ include H, alkyl, —C (O) R ²⁴ , —C (O) OR ²⁰ and —C (S) R ²⁴ .

In one embodiment, in formula 1, E is -O-.

In one embodiment, in Formula 1, E is -S-.

In one embodiment, in Formula 1, E is -S (O)-.

In one embodiment, in formula 1, E is -S (O) _2- .

In one embodiment, in formula (1), E is -CH _2- .

In one embodiment, in Formula 1, E is -CHR ^4- .

In one embodiment, in formula 1, E is -CR ⁴ R ^5- .

In one embodiment, in formula 1, E is -N (R ⁶ )-.

In one embodiment, in formula 1, E is -N (C (Y) R ⁷ )-.

In one embodiment, in formula 1, E is -N (C (Y) OR ⁸ )-.

In one embodiment, in Formula 1, E is -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-.

In one embodiment, in Formula 1, E is -C (O) -N (R ¹¹ )-.

In one embodiment, in Formula 1, E is -N (R ¹¹ ) -C (O)-.

In one embodiment, in Formula 1, E is -S (O) ₂ -N (R ¹¹ )-.

In one embodiment, in Formula 1, E is -N (R ¹¹ ) -S (O) _2- .

In one embodiment, in formula 1, E is —C (O) —O—.

In one embodiment, in Formula 1, E is -O-C (O)-.

In one embodiment, in formula 1, E is -ON (R ⁶ )-.

In one embodiment, in Formula 1, E is -N (R ⁶ ) -O-.

In one embodiment, in Formula 1, E is -N (R ⁶ ) -N (R ¹² )-.

In one embodiment, in formula 1, E is -N = N-.

In one embodiment, in Formula 1, E is -C (R ⁷ ) = N-.

In one embodiment, in Formula 1, E is -C (O) -C (R ⁷ ) = N-.

In one embodiment, in Formula 1, E is -C (O) -N = N-.

In one embodiment, in Formula 1, E is -0-C (Y) -N (R ¹¹ )-.

In one embodiment, in Formula 1, E is -N (R ¹¹ ) -C (Y) -O-.

In one embodiment, in Formula 1, E is -N (R ¹¹ ) -C (Y) -N (R ¹² )-.

In one embodiment, in Formula 1, E is -C (Y) -N (R ¹¹ ) -O-.

In one embodiment, in Formula 1, E is -C (Y) -N (R ¹¹ ) -N (R ¹² )-.

In one embodiment, in formula 1, E is -ON (R ¹¹ ) -C (Y)-.

In one embodiment, in Formula 1, E is -N (R ¹² ) -N (R ¹¹ ) -C (Y)-.

In one embodiment, in Formula 1, Y is (= 0).

In one embodiment, in Formula 1, Y is (= S).

In one embodiment, in Formula 1, Y is (= N (R ¹³ )).

In one embodiment, in Formula 1, Y is (= N (CN)).

In one embodiment, in Formula 1, Y is (= N (OR ¹⁴ )).

In one embodiment, in Formula 1, Y is (= N (R ¹⁵ ) (R ¹⁶ )).

In one embodiment, in Formula 1, Y is (═C (R ¹⁷ ) (R ¹⁸ )).

In one embodiment, in Formula 1, Ring A is a 4-7 membered cycloalkylene ring and E is -C (R ⁴ ) (R ⁵ )-.

In one embodiment, in Formula 1, Ring A is a 5-7 membered heterocycloalkylene ring, E is -O-, -S-, -S (O)-, -S (O) ₂ -,- N (R ⁶ )-, -N (C (Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-, -C (O) -N (R ¹¹ )-, -N (R ¹¹ ) -C (O)-, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O ) _2- , -C (O) -O-, -OC (O)-, -ON (R ⁶ )-, -N (R ⁶ ) -O-, -N (R ⁶ ) -N (R ¹² ) -, -N = N-, -C (R ⁷ ) = N-, -C (O) -C (R ⁷ ) = N-, -C (O) -N = N-, -0-C (Y ) -N (R ¹¹ )-, -N (R ¹¹ ) -C (Y) -O-, -N (R ¹¹ ) -C (Y) -N (R ¹² )-, -C (Y) -N (R ¹¹ ) -O-, -C (Y) -N (R ¹¹ ) -N (R ¹² )-, -ON (R ¹¹ ) -C (Y)-and -N (R ¹² ) -N (R ¹¹ ) -C (Y)-.

In one embodiment, in Formula 1, Ring A is a 5-6 membered heterocycloalkylene ring, E is -O-, -S-, -S (O)-, -S (O) ₂ -,- N (R ⁶ ) —, —C (O) —N (R ¹¹ ) — and —N (R ¹¹ ) —C (O) —.

In one embodiment, in Formula 1, Ring A is a 5-6 membered heterocycloalkylene ring, E is -O-, -S-, -S (O)-, -S (O) ₂ -and- N (R ⁶ )-. In one such embodiment, in formula 1, R ⁶ is selected from the group consisting of H, alkyl, -C (O) R ²⁴ , -C (O) OR ²⁰ and -C (S) R ²⁴ .

In one embodiment, in Formula 1, Ring A is a 5-6 membered heterocycloalkylene ring, and E is selected from the group consisting of -O- and -N (R ⁶ )-. In one such embodiment, in formula 1, R ⁶ is selected from the group consisting of H, alkyl, -C (O) R ²⁴ , -C (O) OR ²⁰ and -C (S) R ²⁴ . In one such embodiment, in Formula 1, Ring A is a 5-membered heterocycloalkylene ring. In another such embodiment, in Formula 1, Ring A is a 6 membered heterocycloalkylene ring.

In one embodiment, in Formula 1, Ring A is a four membered ring and E is -C (R ⁴ ) (R ⁵ )-.

In one embodiment, in Formula 1, Ring A is a four membered ring, E is -O-, -S-, -S (O)-, -S (O) _2- , -N (R ⁶ )-, -N (C (Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-, -C (O) -N (R ¹¹ )-, -N (R ¹¹ ) -C (O)-, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) _2- , -C ( O) -O-, -OC (O)-, -ON (R ⁶ )-, -N (R ⁶ ) -O-, -N (R ⁶ ) -N (R ¹² )-, -N = N- , -C (R ⁷ ) = N-, -C (O) -C (R ⁷ ) = N-, -C (O) -N = N-, -OC (Y) -N (R ¹¹ )-, -N (R ¹¹ ) -C (Y) -O-, -N (R ¹¹ ) -C (Y) -N (R ¹² )-, -C (Y) -N (R ¹¹ ) -O-,- C (Y) -N (R ¹¹ ) -N (R ¹² )-, -0-N (R ¹¹ ) -C (Y)-, and -N (R ¹² ) -N (R ¹¹ ) -C (Y) Is selected from the group consisting of-.

In one embodiment, in Formula 1, Ring A is a four membered ring, E is -O-, -S-, -S (O)-, -S (O) ₂ -and -N (R ⁶ )- Selected from the group consisting of:

In one embodiment, in Formula 1, Ring A is a four membered ring, E is -O-, -S-, -S (O)-, -S (O) ₂ -and -N (R ⁶ )- And R ⁶ is selected from the group consisting of H, alkyl, -C (O) R ²⁴ , -C (O) OR ²⁰ and -C (S) R ²⁴ .

In one embodiment, in Formula 1, Ring A is a four membered ring and E is selected from the group consisting of -O- and -N (R ⁶ )-, wherein R ⁶ is H, alkyl, -C (O ) R ²⁴ , -C (O) OR ²⁰ and -C (S) R ²⁴ .

In one embodiment, in Formula 1, Ring A is a four membered ring, E is -O-, -S-, -S (O)-, -S (O) _2- , -C (R ⁴ ) (R ⁵ )-, -N (R ⁶ )-, -N (C (Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-.

In one embodiment, in Formula 1, A is a four membered ring and E is selected from the group consisting of —CH ₂ —, —CH (R ⁴ ) —, —C (R ⁴ ) (R ⁵ ) —.

In one embodiment, in Formula 1, Ring A is a 5 membered ring and E is -C (R ⁴ ) (R ⁵ )-.

In one embodiment, in Formula 1, Ring A is a 5-membered ring, E is -O-, -S-, -S (O)-, -S (O) _2- , -N (R ⁶ )-, -N (C (Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-, -C (O) -N (R ¹¹ )-, -N (R ¹¹ ) -C (O)-, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) _2- , -C ( O) -O-, -OC (O)-, -ON (R ⁶ )-, -N (R ⁶ ) -O-, -N (R ⁶ ) -N (R ¹² )-, -N = N- , -C (R ⁷ ) = N-, -C (O) -C (R ⁷ ) = N-, -C (O) -N = N-, -0-C (Y) -N (R ¹¹ ) -, -N (R ¹¹ ) -C (Y) -O-, -N (R ¹¹ ) -C (Y) -N (R ¹² )-, -C (Y) -N (R ¹¹ ) -O- , -C (Y) -N (R ¹¹ ) -N (R ¹² )-, -ON (R ¹¹ ) -C (Y)-, and -N (R ¹² ) -N (R ¹¹ ) -C (Y) Is selected from the group consisting of-.

In one embodiment, in Formula 1, Ring A is a 5-membered ring, and E is —O—, —S—, —S (O) —, —S (O) ₂ — and —N (R ⁶ ) — It is selected from the group consisting of.

In one embodiment, in Formula 1, Ring A is a 5-membered ring, and E is —O—, —S—, —S (O) —, —S (O) ₂ — and —N (R ⁶ ) — And R ⁶ is selected from the group consisting of H, alkyl, -C (O) R ²⁴ , -C (O) OR ²⁰ and -C (S) R ²⁴ .

In one embodiment, in Formula 1, Ring A is a 5-membered ring and E is selected from the group consisting of -O- and -N (R ⁶ )-, wherein R ⁶ is H, alkyl, -C (O ) R ²⁴ , -C (O) OR ²⁰ and -C (S) R ²⁴ .

In one embodiment, in Formula 1, Ring A is a 5-membered ring, E is -O-, -S-, -S (O)-, -S (O) _2- , -C (R ⁴ ) (R ⁵ )-, -N (R ⁶ )-, -N (C (Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-, -C (O) -N (R ¹¹ )-, -N (R ¹¹ ) -C (O)-, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) _2- , -C (O) -O-, -OC (O)-, -ON (R ⁶ )-, -N (R ⁶ ) -O-, -N (R ⁶ )- N (R ¹² )-, -N = N- and -C (R7) = N-.

In one embodiment, in Formula 1, A is a 5-membered ring and E is -O-.

In one embodiment, in Formula 1, A is a 5 membered ring and E is -S-.

In one embodiment, in formula 1, A is a 5 membered ring and E is -S (O)-.

In one embodiment, in formula 1, A is a 5-membered ring, and E is -S (O) _2- .

In one embodiment, in Formula 1, A is a 5 membered ring and E is -C (R ⁴ ) (R ⁵ )-.

In one embodiment, in formula 1, A is a 5 membered ring and E is -N (R ⁶ )-.

In one embodiment, in Formula 1, A is a 5 membered ring and E is -N (C (Y) R ⁷ )-.

In one embodiment, in Formula 1, A is a 5 membered ring and E is -N (C (Y) OR ⁸ )-.

In one embodiment, in Formula 1, A is a 5 membered ring and E is -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-.

In one embodiment, in Formula 1, A is a 5 membered ring and E is -C (O) -N (R ¹¹ )-.

In one embodiment, in Formula 1, A is a 5 membered ring and E is -N (R ¹¹ ) -C (O)-.

In one embodiment, in Formula 1, A is a 5-membered ring and E is -S (O) ₂ -N (R ¹¹ )-.

In one embodiment, in formula 1, A is a 5 membered ring and E is —N (R ¹¹ ) —S (O) ₂ —.

In one embodiment, in Formula 1, A is a 5 membered ring and E is -C (O) -O-.

In one embodiment, in Formula 1, A is a 5 membered ring and E is -O-C (O)-.

In one embodiment, in Formula 1, A is a 5-membered ring and E is -ON (R ⁶ )-.

In one embodiment, in Formula 1, A is a 5 membered ring and E is -N (R ⁶ ) -O-.

In one embodiment, in Formula 1, A is a 5 membered ring and E is -N (R ⁶ ) -N (R ¹² )-.

In one embodiment, in Formula 1, A is a 5 membered ring and E is -N = N-.

In one embodiment, in Formula 1, A is a 5 membered ring and E is -C (R ⁷ ) = N-.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is -C (R ⁴ ) (R ⁵ )-.

In one embodiment, in Formula 1, Ring A is a 6 membered ring, E is -O-, -S-, -S (O)-, -S (O) _2- , -N (R ⁶ )-, -N (C (Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-, -C (O) -N (R ¹¹ )-, -N (R ¹¹ ) -C (O)-, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) _2- , -C ( O) -O-, -OC (O)-, -ON (R ⁶ )-, -N (R ⁶ ) -O-, -N (R ⁶ ) -N (R ¹² )-, -N = N- , -C (R ⁷ ) = N-, -C (O) -C (R ⁷ ) = N-, -C (O) -N = N-, -0-C (Y) -N (R ¹¹ ) -, -N (R ¹¹ ) -C (Y) -O-, -N (R ¹¹ ) -C (Y) -N (R ¹² )-, -C (Y) -N (R ¹¹ ) -O- , -C (Y) -N (R ¹¹ ) -N (R ¹² )-, -ON (R ¹¹ ) -C (Y)-, and -N (R ¹² ) -N (R ¹¹ ) -C (Y) Is selected from the group consisting of-.

In one embodiment, in Formula 1, Ring A is a 6 membered ring, E is -O-, -S-, -S (O)-, -S (O) _2-, and -N (R ⁶ )- It is selected from the group consisting of.

In one embodiment, in Formula 1, Ring A is a 6 membered ring, E is -O-, -S-, -S (O)-, -S (O) _2-, and -N (R ⁶ )- And R ⁶ is selected from the group consisting of H, alkyl, -C (O) R ²⁴ , -C (O) OR ²⁰ and -C (S) R ²⁴ .

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is selected from the group consisting of -O- and -N (R ⁶ )-, wherein R ⁶ is H, alkyl, -C (O ) R ²⁴ , -C (O) OR ²⁰ and -C (S) R ²⁴ .

In one embodiment, in Formula 1, A is a 6 membered ring, E is —O—, —S—, —S (O) —, —S (O) ₂ —, —C (R ⁴ ) (R ⁵ )-, -N (R ⁶ )-, -N (C (Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-, -C (O) -N (R ¹¹ )-, -N (R ¹¹ ) -C (O)-, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) _2- , -C (O) -O-, -OC (O)-, -ON (R ⁶ )-, -N (R ⁶ ) -O-, -N (R ⁶ ) -N (R ¹² )-, -N = N-, -C (R ⁷ ) = N-, -C (O) -C (R ⁷ ) = N-, -C (O) -N = N-, -0 -C (Y) -N (R ¹¹ )-, -N (R ¹¹ ) -C (Y) -O-, -N (R ¹¹ ) -C (Y) -N (R ¹² )-, -C ( Y) -N (R ¹¹ ) -O-, -C (Y) -N (R ¹¹ ) -N (R ¹² )-, -ON (R ¹¹ ) -C (Y)-and -N (R ¹² ) -N (R ¹¹ ) -C (Y)-is selected from the group consisting of.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is -O-.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is -S-.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is -S (O)-.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is -S (O) _2- .

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is -C (R ⁴ ) (R ⁵ )-.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is -N (R ⁶ )-.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is -N (C (Y) R ⁷ )-.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is -N (C (Y) OR ⁸ )-.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is —C (O) —N (R ¹¹ ) —.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is -N (R ¹¹ ) -C (O)-.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is -S (O) ₂ -N (R ¹¹ )-.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is —N (R ¹¹ ) —S (O) ₂ —.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is —C (O) —O—.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is -O-C (O)-.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is -ON (R ⁶ )-.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is -N (R ⁶ ) -O-.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is -N (R ⁶ ) -N (R ¹² )-.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is -N = N-.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is -C (R ⁷ ) = N-.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is —C (O) —C (R ⁷ ) = N—.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is —C (O) —N═N—.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is -0-C (Y) -N (R ¹¹ )-.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is -N (R ¹¹ ) -C (Y) -O-.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is -N (R ¹¹ ) -C (Y) -N (R ¹² )-.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is -C (Y) -N (R ¹¹ ) -O-.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is -C (Y) -N (R ¹¹ ) -N (R ¹² )-.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is -ON (R ¹¹ ) -C (Y)-.

In one embodiment, in Formula 1, Ring A is a 6 membered ring and E is -N (R ¹² ) -N (R ¹¹ ) -C (Y)-.

In one embodiment, in Formula 1, Ring A is a 7 membered ring and E is -C (R ⁴ ) (R ⁵ )-.

In one embodiment, in Formula 1, Ring A is a 7 membered ring, E is -O-, -S-, -S (O)-, -S (O) _2- , -N (R ⁶ )-, -N (C (Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-, -C (O) -N (R ¹¹ )-, -N (R ¹¹ ) -C (O)-, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) _2- , -C ( O) -O-, -OC (O)-, -ON (R ⁶ )-, -N (R ⁶ ) -O-, -N (R ⁶ ) -N (R ¹² )-, -N = N- , -C (R ⁷ ) = N-, -C (O) -C (R ⁷ ) = N-, -C (O) -N = N-, -0-C (Y) -N (R ¹¹ ) -, -N (R ¹¹ ) -C (Y) -O-, -N (R ¹¹ ) -C (Y) -N (R ¹² )-, -C (Y) -N (R ¹¹ ) -O- , -C (Y) -N (R ¹¹ ) -N (R ¹² )-, -ON (R ¹¹ ) -C (Y)-, and -N (R ¹² ) -N (R ¹¹ ) -C (Y) Is selected from the group consisting of-.

In one embodiment, in Formula 1, Ring A is a 7 membered ring, E is —O—, —S—, —S (O) —, —S (O) ₂ — and —N (R ⁶ ) — It is selected from the group consisting of.

In one embodiment, in Formula 1, Ring A is a 7 membered ring, E is —O—, —S—, —S (O) —, —S (O) ₂ — and —N (R ⁶ ) — And R ⁶ is selected from the group consisting of H, alkyl, -C (O) R ²⁴ , -C (O) OR ²⁰ and -C (S) R ²⁴ .

In one embodiment, in Formula 1, Ring A is a 7 membered ring and E is selected from the group consisting of -O- and -N (R ⁶ )-, wherein R ⁶ is H, alkyl, -C (O ) R ²⁴ , -C (O) OR ²⁰ and -C (S) R ²⁴ .

In one embodiment, in Formula 1, Ring A is a 7 membered ring, E is -O-, -S-, -S (O)-, -S (O) _2- , -C (R ⁴ ) (R ⁵ )-, -N (R ⁶ )-, -N (C (Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-, -C (O) -N (R ¹¹ )-, -N (R ¹¹ ) -C (O)-, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) _2- , -C (O) -O-, -OC (O)-, -ON (R ⁶ )-, -N (R ⁶ ) -O-, -N (R ⁶ )- N (R ¹² )-, -N = N-, -C (R ⁷ ) = N-, -C (O) -C (R ⁷ ) = N-, -C (O) -N = N-,- OC (Y) -N (R ¹¹ )-, -N (R ¹¹ ) -C (Y) -O-, -N (R ¹¹ ) -C (Y) -N (R ¹² )-, -C (Y ) -N (R ¹¹ ) -O-, -C (Y) -N (R ¹¹ ) -N (R ¹² )-, -ON (R ¹¹ ) -C (Y)-and -N (R ¹² )- N (R ¹¹ ) -C (Y)-.

In one embodiment, in Formula 1, A is a 7 membered ring and E is -O-.

In one embodiment, in Formula 1, A is a 7 membered ring and E is -S-.

In one embodiment, in Formula 1, A is a 7 membered ring and E is -S (O)-.

In one embodiment, in Formula 1, A is a 7 membered ring and E is -S (O) _2- .

In one embodiment, in formula 1, A is a 7 membered ring and E is —C (R ⁴ ) (R ⁵ ) —.

In one embodiment, in Formula 1, A is a 7 membered ring and E is -N (R ⁶ )-.

In one embodiment, in Formula 1, A is a 7 membered ring and E is -N (C (Y) R ⁷ )-.

In one embodiment, in Formula 1, A is a 7 membered ring and E is -N (C (Y) OR ⁸ )-.

In one embodiment, in Formula 1, A is a 7 membered ring and E is -N (C (Y) N (R ⁹ HR ¹⁰ ))-.

In one embodiment, in formula 1, A is a 7 membered ring and E is —C (O) —N (R ¹¹ ) —.

In one embodiment, in formula 1, A is a 7 membered ring and E is —N (R ¹¹ ) —C (O) —.

In one embodiment, in formula 1, A is a 7 membered ring and E is —S (O) ₂ —N (R ¹¹ ) —.

In one embodiment, in formula 1, A is a 7 membered ring and E is —N (R ¹¹ ) —S (O) ₂ —.

In one embodiment, in formula 1, A is a 7 membered ring and E is —C (O) —O—.

In one embodiment, in formula 1, A is a 7 membered ring and E is —O—C (O) —.

In one embodiment, in Formula 1, A is a 7 membered ring and E is -ON (R ⁶ )-.

In one embodiment, in Formula 1, A is a 7 membered ring and E is -N (R ⁶ ) -O-.

In one embodiment, in Formula 1, A is a 7 membered ring and E is -N (R ⁶ ) -N (R ¹² )-.

In one embodiment, in Formula 1, A is a 7 membered ring and E is -N = N-.

In one embodiment, in formula 1, A is a 7 membered ring and E is —C (R ⁷ ) ═N—.

In one embodiment, in formula 1, A is a 7 membered ring and E is —C (O) —C (R ⁷ ) ═N—.

In one embodiment, in formula 1, A is a 7 membered ring and E is —C (O) —N═N—.

In one embodiment, in formula 1, A is a 7 membered ring and E is —0-C (Y) —N (R ¹¹ ) —.

In one embodiment, in formula 1, A is a 7 membered ring and E is —N (R ¹¹ ) —C (Y) —O—.

In one embodiment, in Formula 1, A is a 7 membered ring and E is -N (R ¹¹ ) -C (Y) -N (R ¹² )-.

In one embodiment, in formula 1, A is a 7 membered ring and E is —C (Y) —N (R ¹¹ ) —O—.

In one embodiment, in Formula 1, A is a 7 membered ring and E is -C (Y) -N (R ¹¹ ) -N (R ¹² )-.

In one embodiment, in Formula 1, A is a 7 membered ring and E is -ON (R ¹¹ ) -C (Y)-.

In one embodiment, in Formula 1, A is a 7 membered ring and E is -N (R ¹² ) -N (R ¹¹ ) -C (Y)-.

In one embodiment, in Formula 1, Ring A is an 8 membered ring and E is -C (R ⁴ ) (R ⁵ )-.

In one embodiment, in Formula 1, Ring A is an 8 membered ring, E is -O-, -S-, -S (O)-, -S (O) _2- , -N (R ⁶ )-, -N (C (Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-, -C (O) -N (R ¹¹ )-, -N (R ¹¹ ) -C (O)-, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) _2- , -C ( O) -O-, -OC (O)-, -ON (R ⁶ )-, -N (R ⁶ ) -O-, -N (R ⁶ ) -N (R ¹² )-, -N = N- , -C (R ⁷ ) = N-, -C (O) -C (R ⁷ ) = N-, -C (O) -N = N-, -0-C (Y) -N (R ¹¹ ) -, -N (R ¹¹ ) -C (Y) -O-, -N (R ¹¹ ) -C (Y) -N (R ¹² )-, -C (Y) -N (R ¹¹ ) -O- , -C (Y) -N (R ¹¹ ) -N (R ¹² )-, -ON (R ¹¹ ) -C (Y)-, and -N (R ¹² ) -N (R ¹¹ ) -C (Y) Is selected from the group consisting of-.

In one embodiment, in Formula 1, Ring A is an 8 membered ring, E is -O-, -S-, -S (O)-, -S (O) ₂ -and -N (R ⁶ )- It is selected from the group consisting of.

In one embodiment, in Formula 1, Ring A is an 8 membered ring, E is -O-, -S-, -S (O)-, -S (O) ₂ -and -N (R ⁶ )- And R ⁶ is selected from the group consisting of H, alkyl, -C (O) R ²⁴ , -C (O) OR ²⁰ and -C (S) R ²⁴ .

In one embodiment, in Formula 1, Ring A is an 8 membered ring and E is selected from the group consisting of -O- and -N (R ⁶ )-, wherein R ⁶ is H, alkyl, -C (O ) R ²⁴ , -C (O) OR ²⁰ and -C (S) R ²⁴ .

In one embodiment, in Formula 1, Ring A is an 8 membered ring, E is -O-, -S-, -S (O)-, -S (O) _2- , -C (R ⁴ ) (R ⁵ )-, -N (R ⁶ )-, -N (C (Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-, -C (O) -N (R ¹¹ )-, -N (R ¹¹ ) -C (O)-, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) _2- , -C (O) -O-, -OC (O)-, -ON (R ⁵ )-, -N (R ⁶ ) -O-, -N (R ⁶ )- N (R ¹² )-, -N = N-, -C (R ⁷ ) = N-, -C (O) -C (R ⁷ ) = N-, -C (O) -N = N-,- OC (Y) -N (R ¹¹ )-, -N (R ¹¹ ) -C (Y) -O-, -N (R ¹¹ ) -C (Y) -N (R ¹² )-, -C (Y ) -N (R ¹¹ ) -O-, -C (Y) -N (R ¹¹ ) -N (R ¹² )-, -ON (R ¹¹ ) -C (Y)-and -N (R ¹² )- N (R ¹¹ ) -C (Y)-.

In one embodiment, in Formula 1, A is an 8 membered ring and E is -O-.

In one embodiment, in Formula 1, A is an 8 membered ring and E is -S-.

In one embodiment, in Formula 1, A is an 8 membered ring and E is -S (O)-.

In one embodiment, in formula 1, A is an 8 membered ring and E is —S (O) ₂ —.

In one embodiment, in formula 1, A is an 8 membered ring and E is —C (R ⁴ ) (R ⁵ )-.

In one embodiment, in Formula 1, A is an 8 membered ring and E is -N (R ⁶ )-.

In one embodiment, in Formula 1, A is an 8 membered ring and E is -N (C (Y) R ⁷ )-.

In one embodiment, in Formula 1, A is an 8 membered ring and E is -N (C (Y) OR ⁸ )-.

In one embodiment, in Formula 1, A is an 8 membered ring and E is -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-.

In one embodiment, in formula 1, A is an 8 membered ring and E is —C (O) —N (R ¹¹ ) —.

In one embodiment, in Formula 1, A is an 8 membered ring and E is -N (R ¹¹ ) -C (O)-.

In one embodiment, in Formula 1, A is an 8 membered ring and E is -S (O) ₂ -N (R ¹¹ )-.

In one embodiment, in formula 1, A is an 8 membered ring and E is —N (R ¹¹ ) —S (O) ₂ —.

In one embodiment, in formula 1, A is an 8 membered ring and E is —C (O) —O—.

In one embodiment, in Formula 1, A is an 8 membered ring and E is —O—C (O) —.

In one embodiment, in Formula 1, A is an 8 membered ring and E is -ON (R ⁶ )-.

In one embodiment, in formula 1, A is an 8 membered ring and E is —N (R ⁶ ) —O—.

In one embodiment, in Formula 1, A is an 8 membered ring and E is -N (R ⁶ ) -N (R ¹² )-.

In one embodiment, in Formula 1, A is an 8 membered ring and E is -N = N-.

In one embodiment, in formula 1, A is an 8 membered ring and E is —C (R ⁷ ) ═N—.

In one embodiment, in formula 1, A is an 8 membered ring and E is —C (O) —C (R ⁷ ) ═N—.

In one embodiment, in formula 1, A is an 8 membered ring and E is —C (O) —N═N—.

In one embodiment, in formula 1, A is an 8 membered ring and E is —0-C (Y) —N (R ¹¹ ) —.

In one embodiment, in Formula 1, A is an 8 membered ring and E is -N (R ¹¹ ) -C (Y) -O-.

In one embodiment, in Formula 1, A is an 8 membered ring and E is -N (R ¹¹ ) -C (Y) -N (R ¹² )-.

In one embodiment, in formula 1, A is an 8 membered ring and E is —C (Y) —N (R ¹¹ ) —O—.

In one embodiment, in Formula 1, A is an 8 membered ring, and E is -C (Y) -N (R ¹¹ ) -N (R ¹² )-.

In one embodiment, in Formula 1, A is an 8 membered ring and E is -ON (R ¹¹ ) -C (Y)-.

In one embodiment, in Formula 1, A is an 8 membered ring and E is -N (R ¹² ) -N (R ¹¹ ) -C (Y)-.

In one embodiment, in Formula 1, Ring B is unsubstituted or substituted benzo or unsubstituted or substituted thiophenyl ring.

In one embodiment, in Formula 1, Ring B is unsubstituted benzo or unsubstituted thiophenyl ring.

In one embodiment, in Formula 1, Ring B is an unsubstituted aromatic ring or an aromatic ring substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl , Heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocyclo Alkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , —C (O) NR ²⁵ R ²⁶ , —NR ²³ C (N—CN) NR ²⁵ R ²⁶ and —NR ²³ C (O) NR ²⁵ R ²⁶ .

In one embodiment, in Formula 1, Ring B is an unsubstituted benzo ring or a benzo ring substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl , Heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocyclo Alkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , —C (O) NR ²⁵ R ²⁶ , —NR ²³ C (N—CN) NR ²⁵ R ²⁶ and —NR ²³ C (O) NR ²⁵ R ²⁶ .

In one embodiment, in Formula 1, Ring B is an unsubstituted or substituted heteroaromatic ring or a heteroaromatic ring substituted with one or more substituents which may be the same or different and each substituent is halogen, -CN,- NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC Independently selected from the group consisting of (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ . In one such embodiment, in Formula 1, Ring B is a 5-6 membered heteroaromatic ring having 1 to 3 ring heteroatoms which may be the same or different and each hetero ring atom is N, S, O , S (O) and S (O) ₂ are independently selected.

In one embodiment, in Formula 1, Ring B is benzo, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thidiazolyl , Unsubstituted or substituted residue selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.

In one embodiment, in Formula 1, Ring B is an unsubstituted aromatic ring.

In one embodiment, in Formula 1, Ring B is an unsubstituted benzo ring and Formula 1 has the structure:

In one embodiment, in Formula 1, B is an aromatic ring substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl , Haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ are independently selected.

In one embodiment, in Formula 1, B is a benzo ring substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl , Haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ are independently selected.

In one embodiment, in formula 1, B is an unsubstituted heteroaromatic ring.

In one embodiment, in Formula 1, B is an unsubstituted 5 to 6 membered heteroaromatic ring having 1 to 3 ring heteroatoms which may be the same or different and each hetero ring atom is N, S, Independently from the group consisting of O, S (O) and S (O) ₂ .

In one embodiment, in Formula 1, B is a heteroaromatic ring substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, al Kenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In one embodiment, in Formula 1, B is a 5-6 membered heteroaromatic ring having 1 to 3 ring heteroatoms which may be the same or different and each heterocyclic atom is N, S, O, S Independently selected from the group consisting of (O) and S (O) ₂ , wherein the heteroaromatic ring is substituted with one or more substituents which may be the same or different and each substituent is halogen, -CN, -NO ₂ , alkyl , Heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocyclo Alkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ Independently selected from the group consisting of.

In one embodiment, in Formula 1, B is an unsubstituted 6-membered heteroaromatic ring having from 1 to 3 ring heteroatoms which may be the same or different and each hetero ring atom consists of N, S and O Independently from the group.

In one embodiment, in Formula 1, B is a 6 membered heteroaromatic ring having 1 to 3 ring heteroatoms which may be the same or different and each heterocyclic atom is independent from the group consisting of N, S and O Wherein the heteroaromatic ring is substituted with one or more substituents which may be the same or different, and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, Alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁶ R ²⁶ , -C (O ) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR Group consisting of ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ Independently from.

In one embodiment, in Formula 1, B is an unsubstituted 6 membered heteroaromatic ring having two ring heteroatoms, each ring heteroatom selected independently from N, S and O.

In one embodiment, in Formula 1, B is a 6 membered heteroaromatic ring having 2 ring heteroatoms, each ring heteroatom is independently selected from N, S and O, wherein the heteroaromatic rings may be the same or different May be substituted with one or more substituents, each substituent being halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl -Alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ ,- SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and- NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In one embodiment, in Formula 1, B is a 5-membered heteroaromatic ring having unsubstituted 1 or 2 ring heteroatoms which may be the same or different and each heterocyclic atom is a group consisting of N, S and O Independently from.

In one embodiment, in Formula 1, B is a 5 membered heteroaromatic ring having 1 or 2 ring heteroatoms which may be the same or different and each heterocyclic atom is independently from a group consisting of N, S and O Wherein the heteroaromatic ring is substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl , Haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C ^{(N-CN) NR 25 R} 26 and -NR ²³ C (O) NR ²⁵ R ²⁶ group coming consisting of It is independently selected from.

In one embodiment, in Formula 1, B is a 5 membered heteroaromatic ring having 1 ring heteroatom selected from N, S and O.

In one embodiment, in Formula 1, B is one 5-membered heteroaromatic ring selected from N, S and O, wherein said heteroaromatic ring is substituted with one or more substituents which may be the same or different and each substituent is halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloal Kenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ Is selected.

In one embodiment, in Formula 1, B is a 5 membered heteroaromatic ring having S as ring heteroatom, which heteroaromatic ring is substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN , -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, Heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , Independently selected from the group consisting of -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ do.

In one embodiment, in Formula 1, B is a 5 membered heteroaromatic ring having S as the ring heteroatom.

In one embodiment, in Formula 1, B is a thiophenyl group.

In one embodiment, in Formula 1, B is

It is selected from the group consisting of.

In one embodiment, in Formula 1, B is a partially unsaturated alicyclic ring, which ring is unsubstituted.

In one embodiment, in Formula 1, B is a partially unsaturated alicyclic ring, which ring is substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl , Haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, Azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ ,- SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ ,- C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In one embodiment, in Formula 1, B is a partially unsaturated heterocyclic ring, which ring is unsubstituted.

In one embodiment, in Formula 1, B is a partially unsaturated heterocyclic ring substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, halo Alkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C ( O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In one embodiment, in Formula 1, R ¹ is unsubstituted aryl or aryl substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl , Haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azi Degrees, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C Independently selected from the group consisting of (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In one embodiment, in Formula 1, R ¹ is phenyl substituted with 1 to 4 substituents which may be the same or different and each substituent is halo, —OH, —CN, —NO ₂ , —NR ²¹ R ²² , and haloalkyl.

In one embodiment, in formula 1, R ¹ is unsubstituted aryl.

In one embodiment, in formula 1, R ¹ is unsubstituted phenyl.

In one embodiment, in formula 1, R ¹ is unsubstituted naphthyl.

In one embodiment, in formula 1, R ¹ is substituted aryl.

In one embodiment, in formula 1, R ¹ is substituted phenyl.

In one embodiment, in formula 1, R ¹ is substituted naphthyl.

In one embodiment, in Formula 1, R ¹ is aryl substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl , Haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , —NR ²³ C (N—CN) NR ²⁵ R ²⁶ and —NR ²³ C (O) NR ²⁵ R ²⁶ .

In one embodiment, in Formula 1, R ¹ is phenyl substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl , Haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , —NR ²³ C (N—CN) NR ²⁵ R ²⁶ and —NR ²³ C (O) NR ²⁵ R ²⁶ .

In one embodiment, in Formula 1, R ¹ is phenyl substituted with 1 to 4 substituents which may be the same or different and each substituent is halo, —OH, —CN, —NO ₂ , —NR ²¹ R ²² , and haloalkyl.

In one embodiment, in formula 1, R ¹ is selected from the group consisting of:

이다.In one embodiment, in formula 1, R ¹ is

to be.

In one embodiment, in formula 1, R ¹ is phenyl substituted with 1 to 3 fluoro groups.

In one embodiment, in formula 1, R ¹ is phenyl substituted with two fluoro groups.

In one embodiment, in formula 1, R ¹ is phenyl substituted with one fluoro group.

이다.In one embodiment, in formula 1, R ¹ is

to be.

In one embodiment, in formula 1, R ²⁷ is H.

In one embodiment, in formula 1, R ²⁷ is alkyl.

In one embodiment, in formula 1, R ²⁸ is H.

In one embodiment, in formula 1, R ²⁸ is alkyl.

In one embodiment, in formula 1, R ²⁷ and R ²⁸ are each independently selected from the group consisting of H and alkyl.

In one embodiment, in formula (1), R ²⁷ and R ²⁸ include, in combination with the carbon atom to which they are attached, one to three heteroatoms selected from the group consisting of cycloalkyl, cycloalkenyl, N, O and S To form a cycloalkyl ring or a heterocycloalkenyl ring comprising one to three heteroatoms selected from the group consisting of N, O and S.

In one embodiment, in formula 1, R ² is selected from the group consisting of —C (O) R ⁷ , —C (O) NR ⁹ R ¹⁰ , and —C (O) OR ⁸ .

In one embodiment, in formula 1, R ² is —C (Z) R ⁷ .

In one embodiment, in formula 1, R ² is —C (Z) NR ⁹ R ¹⁰ .

In one embodiment, in formula 1, R ² is —C (Z) OR ⁸ .

In one embodiment, in formula 1, R ² is —SO ₂ NR ⁹ R ¹⁰ .

In one embodiment, in formula 1, R ² is alkyl.

In one embodiment, in formula 1, R ² is heteroalkyl.

In one embodiment, in formula 1, R ² is aryl.

In one embodiment, in formula 1, R ² is heteroaryl.

In one embodiment, in formula 1, R ² is cycloalkyl.

In one embodiment, in formula 1, R ² is cycloalkenyl.

In one embodiment, in formula 1, R ² is heterocycloalkyl.

In one embodiment, in formula 1, R ² is heterocycloalkenyl.

In one embodiment, in Formula 1, Z is (= 0).

In one embodiment, in Formula 1, Z is (= S).

In one embodiment, in Formula 1, Z is (= N (R ¹³ )).

In one embodiment, in Formula 1, Z is (= N (CN)).

In one embodiment, in Formula 1, Z is (= N (OR ¹⁴ )).

In one embodiment, in Formula 1, Z is (= N (R ¹⁵ ) (R ¹⁶ )).

In one embodiment, in Formula 1, Z is (═C (R ¹⁷ ) (R ¹⁸ )).

In one embodiment, in Formula 1, R ² is —C (Z) R ⁷ and Z is (= 0).

In one embodiment, in formula 1, R ² is —C (O) H.

In one embodiment, in formula 1, R ² is —C (O) alkyl.

In one embodiment, in formula 1, R ² is —C (O) CH ₃ .

In one embodiment, in Formula 1, R ² is —C (O) R ⁷ wherein R ⁷ is alkyl substituted with one or more substituents which may be the same or different and each substituent is oxo, halogen, — CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azi Degrees, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C Independently selected from the group consisting of (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In one embodiment, in Formula 1, R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl substituted with 1 to 3 substituents which may be the same or different and each substituent is —OR ¹⁹ , -NR ²¹ R ²² , and cycloalkyl.

In one embodiment, in formula 1, R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl, wherein alkyl is substituted with alkyl and —OH.

In one embodiment, in Formula 1, R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl substituted with 1 to 3 substituents, which may be the same or different, and each substituent is selected from —OH, -NH ₂ , and cyclopropyl are independently selected.

In one embodiment, in Formula 1, R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl substituted with 1 or 2 substituents, which may be the same or different, and each substituent is —NH ₂ And and cyclopropyl.

In one embodiment, in formula 1, R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl substituted with —OH.

In one embodiment, in formula 1, R ² is —C (O) R ⁷ , wherein R ⁷ is unsubstituted heterocycloalkyl.

In one embodiment, in formula 1, R ² is —C (O) R ⁷ , wherein R ⁷ is substituted heterocycloalkyl.

In one embodiment, in Formula 1, R ² is —C (O) R ⁷ wherein R ⁷ is heterocycloalkyl substituted with one or more substituents which may be the same or different and each substituent is oxo, halogen , -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl , Azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , Independently from the group consisting of —C (O) NR ²⁵ R ²⁶ , —NR ²³ C (N—CN) NR ²⁵ R ²⁶ and —NR ²³ C (O) NR ²⁵ R ²⁶ .

In one embodiment, in Formula 1, R ² is —C (O) R ⁷ , wherein R ⁷ is piperidine, substituted piperazine, substituted morpholine, substituted pyrrolidine, and substituted azetidine It is selected from the group consisting of.

In one embodiment, in formula 1, R ² is a residue selected from the group consisting of:

In one embodiment, in formula 1, R ² is —C (O) NR ⁹ R ¹⁰ .

In one embodiment, in formula 1, R ² is —C (O) NH ₂ .

In one embodiment, in formula 1, R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ and R ¹⁰ may be the same or different and each is independently selected from alkyl.

In one embodiment, in formula 1, R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ is unsubstituted heterocycloalkyl and R ¹⁰ is selected from the group consisting of H and alkyl.

In one embodiment, in formula 1, R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ is substituted heterocycloalkyl and R ¹⁰ is selected from the group consisting of H and alkyl.

In one embodiment, in Formula 1, R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ is heterocycloalkyl substituted with 1 to 3 substituents, which may be the same or different, and each Substituents are selected from alkyl and R ¹⁰ is selected from the group consisting of H and alkyl.

In one embodiment, in Formula 1, R ² is alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C (O) R ⁷ , -C (O) OR ⁸ , and -C (O) NR ⁹ R ^It is selected from the group consisting of ¹⁰ .

Non-limiting examples of R ² include the following residues:

이다.In one embodiment, in formula 1, R ² is

to be.

이다.In one embodiment, in formula 1, R ² is

to be.

이다.In one embodiment, in formula 1, R ² is

to be.

이다.In one embodiment, in formula 1, R ² is

to be.

이다.In one embodiment, in formula 1, R ² is

to be.

이다.In one embodiment, in formula 1, R ² is

to be.

이다.In one embodiment, in formula 1, R ² is

to be.

이다.In one embodiment, in formula 1, R ² is

to be.

In one embodiment, in formula 1, p is 0 and R ³ is absent.

In one embodiment, in Formula 1, p is 1.

In one embodiment, in formula 1, p is 2.

In one embodiment, in formula 1, p is 3.

In one embodiment, in formula 1, p is 4.

In one embodiment, in formula 1, p is 2, 3 or 4 and at least two groups R ³ are attached to the same ring atom.

In one embodiment, in formula 1, p is 1, 2, 3 or 4 and each R ³ is alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO ₂ , -OR ¹⁹ , -OC From the group consisting of (O) OR ²⁰ , -NR ²¹ R ²² , -C (O) R ²⁴ , -C (S) R ²⁴ , -C (O) OR ²⁰ , and -C (O) NR ²⁵ R ²⁶ Are independently selected, wherein each said alkyl, each said heteroalkyl, each said alkenyl and each said heteroalkenyl is optionally substituted with one or more substituents which may be unsubstituted or may be the same or different And each substituent is oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl , Heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ ,- NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ are independently selected.

In one embodiment, in Formula 1, p is 1 and R ³ is alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl , Heterocycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ From the group consisting of R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ Selected independently.

In one embodiment, in Formula 1, p is 2, 3 or 4 and each R ³ is alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cyclo Alkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ Independently from the group consisting of R ²⁶ .

In one embodiment, in Formula 1, p is 2, 3 or 4 and at least two groups R ³ are bonded to the same ring carbon atom, wherein each R ³ may be the same or different and is alkyl, heteroalkyl , Alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ ,- OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ ,- C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ are selected independently.

In one embodiment, in Formula 1, p is 2, 3 or 4 and at least two groups R ³ are bonded to the same ring carbon atom, wherein the two R ³ groups can be the same or different and to which they are attached Cycloalkyl, cycloalkenyl, or a heterocycloalkyl ring containing 1 to 3 heteroatoms selected from the group consisting of N, O and S together with carbon atoms, or 1 selected from the group consisting of N, O and S To form a heterocycloalkenyl ring containing from 3 to 3 heteroatoms.

In one embodiment, in Formula 1, each R ³ (if present) is alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (S) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ , -NR ²³ C (O) NR ²⁵ R ²⁶ , and -NR ²³ -C (NH) -NR ²⁶ R ²⁶ . Wherein each said alkyl, each said heteroalkyl, each said alkenyl and each said heteroalkenyl is optionally independently substituted with one or more substituents which may be unsubstituted or the same or different, each Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cyclo Alkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ From the group consisting of R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ Selected independently.

In one embodiment, in Formula 1, each R ³ (if present) is alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , Independently selected from the group consisting of —NR ²¹ R ²² , —C (O) R ²⁴ , —C (S) R ²⁴ , —C (O) OR ²⁰ , and —C (O) NR ²⁵ R ²⁶ , Each said alkyl, each said heteroalkyl, each said alkenyl and each said heteroalkenyl is optionally independently substituted with one or more substituents which may be unsubstituted or the same or different and each substituent is Oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, hetero Cycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ Independently selected from the group consisting of C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula 1, p is 1 and R ³ is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, wherein each said alkyl, each said heteroalkyl, Each said alkenyl and each said heteroalkenyl is optionally substituted independently with one or more substituents which may be unsubstituted or the same or different, and each substituent is oxo, halogen, -CN, -NO ₂ , alkyl , Heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ ,- OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ ,- C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR Independently from the group consisting of ²⁵ R ²⁶ .

.In one embodiment, in formula (1), p is 2, 3 or 4, and two R ³ groups bonded to the same ring A atom are taken together with the carbon atom to which they are attached to spirocycloalkyl, spirocycloalkenyl, Containing 1 to 3 ring heteroatoms independently selected from the group consisting of —NH—, —NR ⁶ —, —S—, —S (O) —, —S (O) ₂ —, and —O— One to three independently selected from the group consisting of a spiroheterocycloalkyl ring, or -NH-, -NR ^6- , -S-, -S (O)-, -S (O) _2- , and -O- To form a spiroheterocycloalkenyl ring containing two ring heteroatoms. Non-limiting examples of compounds of the invention such that two R ³ groups are taken include:

.

.In one embodiment, in Formula 1, R ² and R ³ together with the carbon atoms to which they are attached cycloalkyl, cycloalkenyl, -NH-, -NR ^6- , -S-, -S (O)-,- Heterocycloalkyl ring containing 1 to 3 ring heteroatoms independently selected from the group consisting of S (O) _2- , and -O-, or -NH-, -NR ^6- , -S-, -S To form a heterocycloalkenyl ring comprising 1 to 3 ring heteroatoms independently selected from the group consisting of (O)-, -S (O) ₂ -and -O-. As such, non-limiting examples of compounds of the invention wherein R ² and R ³ are taken together include the following compounds:

.

In one embodiment, in formula 1, R ³ is alkyl.

In one embodiment, in formula 1, R ³ is heteroalkyl.

In one embodiment, in formula 1, R ³ is alkenyl.

In one embodiment, in formula 1, R ³ is heteroalkenyl.

In one embodiment, in formula 1, R ³ is alkynyl.

In one embodiment, in formula 1, R ³ is heteroalkynyl.

In one embodiment, in formula 1, R ³ is aryl.

In one embodiment, in formula 1, R ³ is heteroaryl.

In one embodiment, in formula 1, R ³ is cycloalkyl.

In one embodiment, in formula 1, R ³ is cycloalkenyl.

In one embodiment, in formula 1, R ³ is heterocycloalkyl.

In one embodiment, in formula 1, R ³ is heterocycloalkenyl.

In one embodiment, in formula 1, R ³ is halogen.

In one embodiment, in formula 1, R ³ is -CN.

In one embodiment, in formula 1, R ³ is -NO ₂ .

In one embodiment, in formula 1, R ³ is -OR ¹⁹ .

In one embodiment, in formula 1, R ³ is -OC (O) OR ²⁰ .

In one embodiment, in formula 1, R ³ is -NR ²¹ R ²² .

In one embodiment, in formula 1, R ³ is -NR ²³ SO ₂ R ²⁴ .

In one embodiment, in formula 1, R ³ is -NR ²³ C (O) OR ²⁰ .

In one embodiment, in formula 1, R ³ is -NR ²³ C (O) R ²⁴ .

In one embodiment, in formula 1, R ³ is -SO ₂ NR ²⁵ R ²⁶ .

In one embodiment, in formula 1, R ³ is -C (O) R ²⁴ .

In one embodiment, in formula 1, R ³ is -C (S) R ²⁴ .

In one embodiment, in formula 1, R ³ is -C (O) OR ²⁰ .

In one embodiment, in formula 1, R ³ is -SR ¹⁹ .

In one embodiment, in formula 1, R ³ is -S (O) R ¹⁹ .

In one embodiment, in formula 1, R ³ is -SO ₂ R ¹⁹ .

In one embodiment, in formula 1, R ³ is -OC (O) R ²⁴ .

In one embodiment, in formula 1, R ³ is —C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula 1, R ³ is —NR ²³ C (N—CN) NR ²⁵ R ²⁶ .

In one embodiment, in formula 1, R ³ is —NR ²³ C (O) NR ²⁵ R ²⁶ .

Non-limiting examples of R ³ include methyl, ethyl, propyl (straight or branched), butyl (straight or branched), pentyl (straight or branched), phenyl,

.

In one embodiment, in formula (1), when E is -NR ^6- , R ³ is absent.

In one embodiment, Formula 1 is represented by Formula (1.a) [or, Formula (I.a); Hereinbelow, the general structural formulas shown in

Formula 1.a

In one embodiment, Formula 1 has the general structural formula represented by Formula (1.b):

Formula 1.b

In one embodiment, Formula 1 has the general structural formula represented by Formula (1.c):

Formula 1.c

Where p is 0, 1, 2 or 3.

In one embodiment, Formula 1 has the general structural formula represented by Formula (1.d):

Formula 1.d

Where p is 0, 1, 2 or 3.

In one embodiment, Formula 1 has the general structural formula represented by Formula (1.e):

Formula 1.e

Where p is 0, 1, 2 or 3.

In one embodiment, Formula 1 has the general structural formula represented by Formula (1.f):

Formula 1.f

Where p is 0, 1, 2 or 3.

In one embodiment, Formula 1 has the general structural formula represented by Formula (1.g):

Formula 1.g

Where p is 0, 1, 2, or 3.

이고, 본 발명의 화합물은 다음 화학식 (1.h)에서 나타낸 구조식을 갖는다:In some embodiments, in Formula 1, (1.a), (1.b), (1.c), (1.d), (1.e), (1.f) and (1.g), R ¹ is

And the compound of the present invention has the structural formula shown in the following formula (1.h):

Formula 1.h

Where p is 0, 1, 2, or 3.

In some embodiments, Formula 1, (1.a), (1.b), (1.c), (1.d), (1.e), (1.f), (1.g), and In (1.h), p is 0.

In the various embodiments of the invention described herein, it should be understood that certain variables of the structural formulas not explicitly defined herein are as defined in the formulas to which the relevant embodiments refer. It should be understood that each R ^3, if present, is attached to the ring heteroatom of ring A by substituting the available hydrogen atoms.

In another embodiment, each of Formulas 1, (1.a), (1.b), (1.c), (1.d), (1.e), (1.f), (1.g) ), And (1.h):

Ring A is a 4-7 membered cycloalkenyl ring

E is -C (R ⁴ ) (R ⁵ )-,

Ring B is a benzo ring or a 5 or 6 membered heteroaromatic ring,

Wherein said ring is optionally substituted independently by one to three substituents which may be unsubstituted or the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, al Kenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In another embodiment, in each of Formulas 1, 1.a, 1.b, 1.c, 1.d, 1.e, 1.f, and 1.g:

Ring A is a 4-7 membered cycloalkenyl ring;

E is -C (R ⁴ ) (R ⁵ )-;

Ring B is a benzo ring or a 5 or 6 membered heteroaromatic ring,

Wherein said ring is optionally substituted independently with one to three substituents which may be unsubstituted or the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl , Haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ are independently selected from the group consisting of;

R ¹ is phenyl substituted with 1 to 4 substituents which may be the same or different and each substituent is from the group consisting of halo, —OH, —CN, —NO ₂ , —NR ²¹ R ²² , and haloalkyl Independently selected;

R ² is selected from the group consisting of alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C (O) R ⁷ , -C (O) OR ⁸ , and -C (O) NR ⁹ R ¹⁰ ,

Each R ³ (if present) is alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (S) R ²⁴ ,- C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N- CN) NR ²⁵ R ²⁶ , -NR ²³ C (O) NR ²⁵ R ²⁶ , and -NR ²³ -C (NH) -NR ²⁶ R ²⁶ , wherein each of said alkyls, each Wherein said heteroalkyl, each said alkenyl and each said heteroalkenyl are optionally substituted independently with one or more substituents which may be unsubstituted or the same or different and each substituent is oxo, halogen, -CN, -NO _2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, H. Rosayi claw alkenyl, ^{azido, -OR 19, -OC (O)} OR 20, -NR 21 R 22, -NR 23 SO 2 R 24, -NR 23 C (O) OR 20, -NR 23 C (O ) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O ) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In another embodiment, in each of Formulas 1, 1.a, 1.b, 1.c, 1.d, 1.e, 1.f, and 1.g:

Ring A is a 4-7 membered cycloalkenyl ring;

E is -C (R ⁴ ) (R ⁵ )-;

Ring B is a benzo ring or a 5 or 6 membered heteroaromatic ring,

Wherein said ring is optionally substituted independently with one to three substituents which may be unsubstituted or the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl , Haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ are independently selected from the group consisting of

R ¹ is phenyl substituted with 1 to 4 substituents which may be the same or different and each substituent is independent from the group consisting of halo, —OH, —CN, —NO ₂ , —NR ²¹ R ²² and haloalkyl Is selected;

R ² is selected from the group consisting of alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C (O) R ⁷ , -C (O) OR ⁸ , and -C (O) NR ⁹ R ¹⁰ ,

And each R ^3, if present, is alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -C ( O) R ²⁴ , -C (S) R ²⁴ , -C (O) OR ²⁰ , and -C (O) NR ²⁵ R ²⁶ , wherein each said alkyl, each said heteroalkyl , Each said alkenyl and each said heteroalkenyl is optionally substituted independently with one or more substituents which may be unsubstituted or may be the same or different and each substituent is oxo, halogen, -CN, -NO ₂ , Alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ are independently selected.

In another embodiment, in each of Formulas 1, 1.a, 1.b, 1.c, 1.d, 1.e, 1.f, and 1.g:

Ring A is a 4-7 membered cycloalkenyl ring;

E is -C (R ⁴ ) (R ⁵ )-;

Ring B is a benzo ring or a 5 or 6 membered heteroaromatic ring,

Wherein said ring is optionally substituted independently with one to three substituents which may be unsubstituted or the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl , Haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ are independently selected from the group consisting of;

R ¹ is phenyl substituted with 1 to 4 substituents which may be the same or different and each substituent is independent from the group consisting of halo, —OH, —CN —NO ₂ , —NR ²¹ R ²² , and haloalkyl Is selected;

R ² is selected from the group consisting of alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C (O) R ⁷ , -C (O) OR ⁸ , and -C (O) NR ⁹ R ¹⁰ ,

p is 1 and R ³ is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl and each said heteroal Kenyl is optionally substituted independently with one to three substituents that may be unsubstituted or the same or different, and each substituent is oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl , Haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN ) independently from the group consisting of NR ²⁵ R ²⁶ and ^{-NR 23 C (O) NR 25} R 26 It is selected to be.

In another embodiment, in Formula 1, 1.a, 1.b, 1.c, 1.d, 1.e, 1.f, 1.g, and 1.h, respectively:

Ring A is a 5 or 6 membered heterocycloalkenyl ring;

E is -O-, -S-, -S (O)-, -S (O) _2- , -N (R ⁶ )-, -N (C (Y) R ⁷ )-, -N (C ( Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-, -C (O) -N (R ¹¹ )-, -N (R ¹¹ ) -C (O) -, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) _2- , -C (O) -O-, -OC (O)-, -QN (R ⁶ )-, -N (R ⁶ ) -O-, -N (R ⁶ )-, N (R ¹² )-, -N = N-, -C (R ⁷ ) = N-, -C (O) -C (R ⁷ ) = N-, -C (O) -N = N-, -OC (Y) -N (R ¹¹ )-, -N (R ¹¹ ) -C (Y) -O-,- N (R ¹¹ ) -C (Y) -N (R ¹² )-, -C (Y) -N (R ¹¹ ) -O-, -C (Y) -N (R ¹¹ ) -N (R ¹² ) -, -ON (R ¹¹ ) -C (Y)-, and -N (R ¹² ) -N (R ¹¹ ) -C (Y)-;

Ring B is a benzo ring or a 5 or 6 membered heteroaromatic ring,

Wherein said ring is optionally substituted independently with one to three substituents which may be unsubstituted or the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl , Haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ are independently selected.

In another embodiment, in each of Formulas 1, 1.a, 1.b, 1.c, 1.d, 1.e, 1.f, and 1.g:

Ring A is a 5 or 6 membered heterocycloalkenyl ring;

E is selected from the group consisting of -O-, -S-, -S (O)-, -S (O) _2- , and -N (R ⁶ )-, wherein R ⁶ is H, alkyl,- C (O) R ²⁴ , -C (O) OR ²⁰ , and -C (S) R ²⁴ .

Ring B is a benzo ring or a 5 or 6 membered heteroaromatic ring,

Wherein said ring is optionally substituted independently with one to three substituents which may be unsubstituted or the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl , Haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ are independently selected from the group consisting of

R ¹ is phenyl substituted with 1 to 4 substituents which may be the same or different and each substituent is from the group consisting of halo, —OH, —CN, —NO ₂ , —NR ²¹ R ²² , and haloalkyl Independently selected;

R ² is selected from the group consisting of alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C (O) R ⁷ , -C (O) OR ⁸ , and -C (O) NR ⁹ R ¹⁰ ,

Each R ³ (if present) is alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (S) R ²⁴ ,- C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N- CN) NR ²⁵ R ²⁶ , -NR ²³ C (O) NR ²⁵ R ²⁶ , and -NR ²³ -C (NH) -NR ²⁶ R ²⁶ , wherein each of said alkyls, each Wherein said heteroalkyl, each said alkenyl and each said heteroalkenyl are optionally substituted independently with one or more substituents which may be unsubstituted or the same or different and each substituent is oxo, halogen, -CN, -NO _2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, H. Rosayi claw alkenyl, ^{azido, -OR 19, -OC (O)} OR 20, -NR 21 R 22, -NR 23 SO 2 R 24, -NR 23 C (O) OR 20, -NR 23 C (O ) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O ) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In another embodiment, in Formula 1, 1.a, 1.b, 1.c, 1.d, 1.e, 1.f, and 1.g:

Ring A is a 5 or 6 membered heterocycloalkenyl ring;

E is selected from the group consisting of -O-, -S-, -S (O)-, -S (O) _2- , and -N (R ⁶ )-, wherein R ⁶ is H, alkyl,- C (O) R ²⁴ , -C (O) OR ²⁰ , and -C (S) R ²⁴ ,

Ring B is a benzo ring or a 5 or 6 membered heteroaromatic ring,

Wherein said ring is optionally substituted independently with one to three substituents which may be unsubstituted or the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl , Haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ are independently selected from the group consisting of

R ¹ is phenyl substituted with 1 to 4 substituents which may be the same or different and each substituent is independent from the group consisting of halo, —OH, —CN —NO ₂ , —NR ²¹ R ²² , and haloalkyl Is selected,

R ² is selected from the group consisting of alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C (O) R ⁷ , -C (O) OR ⁸ , and -C (O) NR ⁹ R ¹⁰ ,

And each R ^3, if present, is alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -C ( O) R ²⁴ , -C (S) R ²⁴ , -C (O) OR ²⁰ , and -C (O) NR ²⁵ R ²⁶ , wherein each said alkyl, each said heteroalkyl , Each said alkenyl and each said heteroalkenyl is optionally substituted independently with one or more substituents which may be unsubstituted or the same or different, and each substituent is oxo, halogen, -CN, -NO ₂ , Alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , —C (O) NR ²⁵ R ²⁶ , —NR ²³ C (N—CN) NR ²⁵ R ²⁶ and —NR ²³ C (O) NR ²⁵ R ²⁶ .

In another embodiment, in each of Formulas 1, 1.a, 1.b, 1.c, 1.d, 1.e, 1.f, and 1.g:

Ring A is a 5 or 6 membered heterocycloalkenyl ring;

E is selected from the group consisting of -O-, -S-, -S (O)-, -S (O) _2- , and -N (R ⁶ )-, wherein R ⁶ is H, alkyl,- C (O) R ²⁴ , -C (O) OR ²⁰ , and -C (S) R ²⁴ ,

Ring B is a benzo ring or a 5 or 6 membered heteroaromatic ring,

Wherein said ring is optionally substituted independently with one to three substituents which may be unsubstituted or the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl , Haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ are independently selected from the group consisting of

R ¹ is phenyl with one to four substituents which may be the same or different and each substituent is independently from the group consisting of halo, —OH, —CN, —NO ₂ , —NR ²¹ R ²² , and haloalkyl Selected;

R ²⁷ and R ²⁸ are independently selected from the group consisting of H and alkyl;

R ² is selected from the group consisting of alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C (O) R ⁷ , -C (O) OR ⁸ , and -C (O) NR ⁹ R ¹⁰ ,

p is 1 and R ³ is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl and each said heteroal Kenyl is optionally substituted independently with one to three substituents that may be unsubstituted or the same or different, and each substituent is oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl , Haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN ) independently from the group consisting of NR ²⁵ R ²⁶ and ^{-NR 23 C (O) NR 25} R 26 It is selected to be.

In one embodiment, a compound of the invention has a structural formula represented by Formula 2 (or Formula II; hereinafter expressed in the same manner) and includes pharmaceutically acceptable salts, solvates, esters, prodrugs or isomers of the compound do:

In formula 2 above, R ¹ , R ² , R ²⁷ , R ²⁸ , E, and ring B are independently selected from each other,

E is -O-, -S-, -S (O)-, -S (O) _2- , -C (R ⁴ ) (R ⁵ )-, -N (R ⁶ )-, -N (C ( Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, and -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-;

Ring B, X, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ²⁷ , R ²⁸ , Y, and any substituents on ring B are As defined in one of the embodiments described in Formula 1.

In one embodiment, in formula (II):

E is selected from the group consisting of -O-, -S-, -S (O)-, -S (O) _2- , -C (R ⁴ ) (R ⁵ )-, and -N (R ⁶ )- Become;

Ring B is unsubstituted or is substituted with benzo, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyri Substituted moiety selected from the group consisting of dazinyl, pyrimidinyl, pyrazinyl and triazinyl;

R ¹ is phenyl substituted with 1 to 4 substituents which may be the same or different and each substituent is from the group consisting of halo, —OH, —CN, —NO ₂ , —NR ²¹ R ²² , and haloalkyl Independently selected; R ² is independently selected from the group consisting of —C (O) R ⁷ , —C (O) NR ⁹ R ¹⁰ , and —C (O) OR ⁸ .

In one embodiment, in formula (II):

이다.R ¹ is

to be.

In one embodiment, the compounds of the present invention are of formula (II.a) [or, formula 2.a; Or pharmaceutically acceptable salts, solvates, esters, prodrugs or isomers of the compounds having the structure shown below.

II.a

In this formula,

R ¹ , R ² , R ²⁷ , R ²⁸ , E, and ring B are independently selected from each other, where

E is -O-, -S-, -S (O)-, -S (O) _2- , -C (R ⁴ ) (R ⁵ )-, -N (R ⁶ )-, -N (C ( Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, and -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-,

Ring B is a substituted or unsubstituted aromatic ring;

R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ²⁷ , R ²⁸ , Y, any of the substituents on Ring B are those embodiments described above in Formula 1 As defined in any one of these.

In one embodiment, Formula (II.a.) is represented by Formula (II.a.1) Formula 2.a.1; Hereafter, it has the general structural formula shown in the same manner.

In one embodiment, Formula (II.a.) has the general structural formula shown in Formula (II.a.2):

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), E is -C (R ⁴ ) (R ⁵ )-.

In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), E is -O-, -S-, -S (O)-,- S (O) _2- , and -N (R ⁶ )-.

In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), E is -O-, -S-, -S (O)-,- S (O) _2- , and -N (R ⁶ )-, wherein R ⁶ is H, alkyl, -C (O) R ²⁴ , and -C (S) R ²⁴ Is selected from.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), E is selected from the group consisting of -O- and -N (R ⁶ )- Wherein R ⁶ is selected from the group consisting of H, alkyl, -C (O) R ²⁴ , and -C (S) R ²⁴ .

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), E is —O—.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), E is -S-.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), E is -S (O)-.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), E is —S (O) ₂ —.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), E is -C (R ⁴ ) (R ⁵ )-.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), E is -N (R ⁶ )-.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), E is -N (C (Y) R ⁷ )-.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), E is -N (C (Y) OR ⁸ )-.

In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), E is —N (C (Y) N (R ⁹ ) (R ¹⁰ ) )-to be.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), Y is (═O).

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), Y is (= S).

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), Y is (= N (R ¹³ )).

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), Y is (= N (CN)).

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), Y is (= N (OR ¹⁴ )).

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), Y is (= N (R ¹⁵ ) (R ¹⁶ )).

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), Y is (= C (R ¹⁷ ) (R ¹⁸ )).

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), B is an unsubstituted aromatic ring.

. In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), B is an unsubstituted benzo ring, and Formula (II.a.) is It has a general structural formula:

.

.In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), B is an unsubstituted benzo ring, and Formula (II.a.) is It has a general structural formula:

.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), B is an aromatic ring substituted with one or more substituents which may be the same or different, Each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl- , Cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ^It is independently selected from the group consisting of ²⁶ .

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), B is a benzo ring substituted with one or more substituents which may be the same or different, Each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl- , Cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ^It is independently selected from the group consisting of ²⁶ .

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ¹ is unsubstituted aryl.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ¹ is unsubstituted phenyl.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ¹ is unsubstituted naphthyl.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ¹ is substituted aryl.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ¹ is substituted phenyl.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ¹ is substituted naphthyl.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ¹ is aryl substituted with one or more substituents which may be the same or different, Each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, Cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C ( O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ^ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ It is independently selected from the group consisting of.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ¹ is phenyl substituted with one or more substituents which may be the same or different, Each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, Cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C ( O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ Independently selected from the group consisting of.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ¹ is substituted with 1 to 4 substituents, which may be the same or different. Phenyl, and each substituent is independently selected from the group consisting of halo, -OH, -CN, -NO ₂ , -NR ²¹ R ²² , and haloalkyl.

In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R ¹ is selected from the group consisting of:

이다.In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ¹ is

to be.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ¹ is phenyl substituted with 1 to 3 fluoro groups.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ¹ is phenyl substituted with two fluoro groups.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ¹ is phenyl substituted with one fluoro group.

이다.In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ¹ is

to be.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ²⁷ and R ²⁸ are each independently selected from the group consisting of H and alkyl .

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ² is —C (Z) R ⁷ .

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ² is —C (Z) NR ⁹ R ¹⁰ .

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ² is —C (Z) OR ⁸ .

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ² is —SO ₂ NR ⁹ R ¹⁰ .

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ² is alkyl.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ² is heteroalkyl.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ² is aryl.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ² is heteroaryl.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ² is cycloalkyl.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ² is cycloalkenyl.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ² is heterocycloalkyl.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ² is heterocycloalkenyl.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), Z is (= 0).

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), Z is (= S).

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), Z is (= N (R ¹³ )).

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), Z is (= N (CN)).

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), Z is (= N (OR ¹⁴ )).

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), Z is (= N (R ¹⁵ ) (R ¹⁶ )).

In some embodiments, in each Formula (II.a.), (II.a.1), and (II.a.2), Z is (= C (R ¹⁷ ) (R ¹⁸ )).

In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R ² is —C (Z) R ⁷ and Z is (= 0) to be.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ² is —C (O) H.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ² is —C (O) alkyl.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ² is —C (O) CH ₃ .

In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R ² is —C (O) R ⁷ , wherein R ⁷ is Alkyl substituted with one or more substituents which may be the same or different, each substituent being oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalky Nyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C And independently selected from the group consisting of (O) NR ²⁵ R ²⁶ .

In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R ² is —C (O) R ⁷ , wherein R ⁷ is the same Or alkyl substituted with 1 to 3 substituents which may be different or different, and each substituent is independently selected from the group consisting of —OR ¹⁹ , —NR ²¹ R ²² , and cycloalkyl.

In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl Wherein alkyl is substituted with alkyl and -OH.

In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R ² is —C (O) R ⁷ , wherein R ⁷ is the same Or alkyl substituted with 1 to 3 substituents, which may be different or different, and each substituent is independently selected from the group consisting of —OH, —NH ₂ , and cyclopropyl.

In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R ² is —C (O) R ⁷ , wherein R ⁷ is Alkyl substituted with one or two substituents, which may be the same or different, and each substituent is independently selected from the group consisting of -NH ₂ , and cyclopropyl.

In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R ² is —C (O) R ⁷ , wherein R ⁷ is − Alkyl substituted with OH.

In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R ² is —C (O) R ⁷ , wherein R ⁷ is Unsubstituted heterocycloalkyl.

In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R ² is —C (O) R ⁷ , wherein R ⁷ Is substituted heterocycloalkyl.

In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R ² is —C (O) R ⁷ , wherein R ⁷ is the same Or heterocycloalkyl substituted with one or more substituents, which may be different or different, and each substituent is oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, halo Alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ Independently from the group consisting of C (O) NR ²⁵ R ²⁶ .

In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R ² is —C (O) R ⁷ , wherein R ⁷ is substituted Piperidine, substituted piperazine, substituted morpholine, substituted pyrrolidine, and substituted azetidine.

.In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R ² is selected from the group consisting of:

.

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ² is —C (O) NR ⁹ R ¹⁰ .

In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ² is —C (O) NH ₂ .

In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ And R ¹⁰ may be the same or different and each is independently selected from alkyl.

In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ Is unsubstituted heterocycloalkyl and R ¹⁰ is selected from the group consisting of H and alkyl.

In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ Is substituted heterocycloalkyl and R ¹⁰ is selected from the group consisting of H and alkyl.

In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ Is heterocycloalkyl substituted with 1 to 3 substituents which may be the same or different and each substituent is selected from the group consisting of H and alkyl.

In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R ² is alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, —C (O) R ⁷ , -C (O) OR ⁸ , and -C (O) NR ⁹ R ¹⁰ .

Non-limiting examples of R ² include the following residues:

이다.In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ² is

to be.

이다.In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ² is

to be.

이다.In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ² is

to be.

이다.In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ² is

to be.

이다.In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ² is

to be.

이다.In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ² is

to be.

이다.In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ² is

to be.

이다.In some embodiments, in each formula (II.a.), (II.a.1), and (II.a.2), R ² is

to be.

In one embodiment, the compounds of the invention have the structure shown in Formula (II.b) and include pharmaceutically acceptable salts, solvates, esters, prodrugs or isomers of the compounds:

Formula II.b

In this formula,

R ¹ , R ² , E, R ²⁷ , R ²⁸ , and ring B are independently selected from each other,

E is -O-, -S-, -S (O)-, -S (O) _2- , -C (R ⁴ ) (R ⁵ )-, -N (R ⁶ )-, -N (C ( Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, and -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-,

Ring B is a substituted or unsubstituted heteroaromatic ring,

R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ²⁷ , R ²⁸ , Y, and any substituents on ring B are those embodiments shown above in Formula 1 As defined in one of the following.

In one embodiment, Formula (II.b.) has the general structural formula shown in Formula (II.b.1):

Formula II.b.1

In one embodiment, Formula (II.b.) has the general structural formula shown in Formula (II.b.2):

Formula II.b.2

In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), E is -C (R ⁴ ) (R ⁵ )-.

In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), E is -O-, -S-, -S (O)-, -S (O) _2- , and -N (R ⁶ )-.

In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), E is -O-, -S-, -S (O)-, -S (O) _2- , and -N (R ⁶ )-, wherein R ⁶ is selected from the group consisting of H, alkyl, -C (O) R ²⁴ , and -C (S) R ²⁴ Is selected.

In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), E is selected from the group consisting of -O- and -N (R ⁶ )- , Wherein R ⁶ is selected from the group consisting of H, alkyl, -C (O) R ²⁴ , and -C (S) R ²⁴ .

In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), E is —O—.

In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), E is -S-.

In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), E is -S (O)-.

In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), E is —S (O) ₂ —.

In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), E is -C (R ⁴ ) (R ⁵ )-.

In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), E is -N (R ⁶ )-.

In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), E is —N (C (Y) R ⁷ ) —.

In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), E is —N (C (Y) OR ⁸ ) —.

In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), E is -N (C (Y) N (R ⁹ ) (R ¹⁰ )) -to be.

In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), Y is (= 0).

In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), Y is (= S).

In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), Y is (= N (R ¹³ )).

In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), Y is (= N (CN)).

In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), Y is (= N (OR ¹⁴ )).

In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), Y is (= N (R ¹⁵ ) (R ¹⁶ )).

In some embodiments, in each Formula (II.b), (II.b.1), and (II.b.2), Y is (= C (R ¹⁷ ) (R ¹⁸ )).

In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), B is an unsubstituted heteroaromatic ring.

In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), B is unsubstituted having from 1 to 3 ring heteroatoms, which may be the same or different And 5 to 6 membered heteroaromatic rings, each hetero ring atom is independently selected from the group consisting of N, S, O, S (O) and S (O) ₂ .

In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), B is a heteroaromatic ring substituted with one or more substituents which may be the same or different, Each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl- , Cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ^It is independently selected from the group consisting of ²⁶ .

In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), B has 5 having 1 to 3 ring heteroatoms which may be the same or different Or a 6 membered heteroaromatic ring, each hetero ring atom is independently selected from the group consisting of N, S, O, S (O) and S (O) ₂ , wherein the heteroaromatic ring is one or more which may be the same or different Substituents, each substituent being halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, Heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ ,- S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), B has 1 to 3 ring heteroatoms which may be the same or different Unsubstituted 6-membered heteroaromatic ring, each hetero ring atom is independently selected from the group consisting of N, S and O.

In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), B has 6 having from 1 to 3 ring heteroatoms which may be the same or different Is a heteroaromatic ring, each heterocyclic atom is independently selected from the group consisting of N, S and O, wherein the heteroaromatic ring is substituted with one or more substituents which may be the same or different, and each substituent is halogen,- CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl , Heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ ,- NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR Independently from the group consisting of ²⁵ R ²⁶ .

In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), B is the same or different, each independently selected from the group consisting of N, S, and O 5-membered heteroaromatic ring having 1 or 2 ring heteroatoms which may be used.

In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), B is a 5 membered having 1 or 2 ring heteroatoms which may be the same or different Heteroaromatic ring, each ring heteroatom is substituted with one or more substituents which may be the same or different, and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, —OR ¹⁹ , — NR ²¹ R ²² , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , and -C And independently selected from the group consisting of (O) NR ²⁵ R ²⁶ .

In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), B is an unsubstituted 5 having one heteroatom selected from N, S and O It is a membered heteroaromatic ring.

In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), B is substituted with one or more substituents, which may be the same or different, N, S and A 5-membered heteroaromatic ring having 1 heteroatom selected from O, each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl , Aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN ) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), B is an unsubstituted 5 having one heteroatom selected from N, S and O It is a membered heteroaromatic ring.

In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), B is a 5-membered heteroaromatic having one heteroatom selected from N, S, and O And the heteroaromatic ring is substituted with one or more substituents, each substituent being halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, -OR ¹⁹ , -NR ²¹ R ²² , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , and -C (O) NR ²⁵ R ²⁶ Independently from.

In some embodiments, in each Formula (II.b), (II.b.1), and (II.b.2), B is a heteroaromatic ring substituted with one or more substituents which may be the same or different A 5-membered heteroaromatic ring having S as heteroatom, each substituent being halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, -OR ¹⁹ , -NR ²¹ R ²² , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , and -C (O) NR ²⁵ R ²⁶ Selected independently.

In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), B is an unsubstituted 5-membered heteroaromatic ring having S as ring heteroatom.

In one embodiment, Formula (II.b.) has the following general structural formula:

In one embodiment, Formula (II.b.) has the following general structural formula:

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ¹ is unsubstituted aryl.

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ¹ is unsubstituted phenyl.

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ¹ is unsubstituted naphthyl.

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ¹ is substituted aryl.

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ¹ is substituted phenyl.

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ¹ is substituted naphthyl.

In some embodiments, in Formulas (II.b.), (II.b.1), and (II.b.2), R ¹ is aryl substituted with one or more substituents, which may be the same or different, and each Substituents are halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl , Cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ ,- SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ Independently from the group.

In some embodiments, in Formulas (II.b.), (II.b.1), and (II.b.2), R ¹ is phenyl substituted with one or more substituents, which may be the same or different, and each Substituents are halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl , Cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ ,- SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ Independently from the group.

In some embodiments, in Formulas (II.b.), (II.b.1), and (II.b.2), R ¹ is phenyl substituted with 1 to 4 substituents, which may be the same or different, Each substituent is independently selected from the group consisting of halo, -OH, -CN, -NO ₂ , -NR ²¹ R ²² , and haloalkyl.

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ¹ is selected from the group consisting of:

이다.In some embodiments, in Formulas (II.b.), (II.b.1), and (II.b.2), R ¹ is

to be.

In some embodiments, in Formulas (II.b.), (II.b.1), and (II.b.2), R ¹ is phenyl substituted with 1 to 3 fluoro groups.

In some embodiments, in Formulas (II.b.), (II.b.1), and (II.b.2), R ¹ is phenyl substituted with two fluoro groups.

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ¹ is phenyl substituted with one fluoro group.

이다.In some embodiments, in Formulas (II.b.), (II.b.1), and (II.b.2), R ¹ is

to be.

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ²⁷ and R ²⁸ are independently selected from the group consisting of H and alkyl.

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ² is —C (Z) R ⁷ .

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ² is —C (Z) NR ⁹ R ¹⁰ .

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ² is —C (Z) OR ⁸ .

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ² is —SO ₂ NR ⁹ R ¹⁰ .

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ² is alkyl.

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ² is heteroalkyl.

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ² is aryl.

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ² is heteroaryl.

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ² is cycloalkyl.

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ² is cycloalkenyl.

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ² is heterocycloalkyl.

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ² is heterocycloalkenyl.

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ² is Z is (═O).

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), Z is (= S).

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ² is (= N (R ¹³ )).

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), Z is (= N (CN)).

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), Z is (= N (OR ¹⁴ )).

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), Z is (= N (R ¹⁵ ) (R ¹⁶ )).

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), Z is (= C (R ¹⁷ ) (R ¹⁸ )).

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ² is —C (Z) R ⁷ and Z is (═O).

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ² is —C (O) H.

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ² is —C (O) alkyl.

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ² is —C (O) CH ₃ .

In some embodiments, in Formulas (II.b.), (II.b.1), and (II.b.2), R ² is —C (O) R ⁷ , wherein R ⁷ is the same or Alkyl substituted with one or more substituents which may be different, and each substituent is oxo, halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, Aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O ) NR ²⁵ R ²⁶ is independently selected from the group consisting of.

In some embodiments, in Formulas (II.b.), (II.b.1), and (II.b.2), R ² is —C (O) R ⁷ , wherein R ⁷ is the same or Alkyl substituted with 1 to 3 substituents which may be different, and each substituent is independently selected from the group consisting of —OR ¹⁹ , —NR ²¹ R ²² , and cycloalkyl.

In some embodiments, in Formulas (II.b.), (II.b.1), and (II.b.2), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl, Wherein said alkyl is substituted with alkyl and -OH.

In some embodiments, in Formulas (II.b.), (II.b.1), and (II.b.2), R ² is —C (O) R ⁷ , wherein R ⁷ is the same or different. Alkyl substituted with 1 to 3 substituents, each substituent being independently selected from the group consisting of —OH, —NH ₂ , and cyclopropyl.

In some embodiments, in Formulas (II.b.), (II.b.1), and (II.b.2), R ² is —C (O) R ⁷ , wherein R ⁷ is the same or Alkyl substituted with one or two substituents, which may be different, and each substituent is independently selected from the group consisting of -NH ₂ , and cyclopropyl.

In some embodiments, in Formulas (II.b.), (II.b.1), and (II.b.2), R ² is —C (O) R ⁷ , wherein R ⁷ is —OH Substituted with alkyl.

In some embodiments, in Formulas (II.b.), (II.b.1), and (II.b.2), R ² is —C (O) R ⁷ , wherein R ⁷ is unsubstituted Heterocycloalkyl.

In some embodiments, in Formulas (II.b.), (II.b.1), and (II.b.2), R ² is —C (O) R ⁷ , wherein R ⁷ is substituted Heterocycloalkyl.

In some embodiments, in Formulas (II.b.), (II.b.1), and (II.b.2), R ² is —C (O) R ⁷ , wherein R ⁷ is the same or different. Heterocycloalkyl substituted with one or more substituents, each substituent being oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl , Aryl, heteroaryl, cycloalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ ,- NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S ( O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) Independently from the group consisting of NR ²⁵ R ²⁶ .

In some embodiments, in Formulas (II.b.), (II.b.1), and (II.b.2), R ² is —C (O) R ⁷ , wherein R ⁷ is substituted Selected from the group consisting of piperidine, substituted piperazine, substituted morpholine, substituted pyrrolidine, and substituted azetidine.

.In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ² is selected from:

.

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ² is —C (O) NR ⁹ R ¹⁰ .

In some embodiments, in formulas (II.b.), (II.b.1), and (II.b.2), R ² is —C (O) NH ₂ .

In some embodiments, in Formulas (II.b.), (II.b.1), and (II.b.2), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ and R ¹⁰ May be the same or different and each is independently selected from alkyl.

In some embodiments, in Formulas (II.b.), (II.b.1), and (II.b.2), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ is substituted Unsubstituted heterocycloalkyl and R ¹⁰ is selected from the group consisting of H and alkyl.

In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ is Substituted heterocycloalkyl, R ¹⁰ is selected from the group consisting of H and alkyl.

In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ is Heterocycloalkyl substituted with one to three substituents, which may be the same or different, each substituent is independently selected from alkyl, and R ¹⁰ is selected from the group consisting of H and alkyl.

In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R ² is alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, —C ( O) R ⁷ , -C (O) OR ⁸ , and -C (O) NR ⁹ R ¹⁰ .

Non-limiting examples of R ² include the following residues:

이다. In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), R ² is

to be.

이다. In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), R ² is

to be.

이다. In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), R ² is

to be.

이다.In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), R ² is

to be.

이다. In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), R ² is

to be.

이다.In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), R ² is

to be.

이다.In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), R ² is

to be.

이다.In some embodiments, in each formula (II.b), (II.b.1), and (II.b.2), R ² is

to be.

In one embodiment, the compounds of the present invention are formula (III.1) [or, formula 3.1; Hereinafter, represented in a similar manner, and include the pharmaceutically acceptable salts, solvates, esters, prodrugs or isomers of the compounds:

Formula (III.1)

In the above formula (III.1), R ¹ , R ² , R ³ , R ²⁷ , R ²⁸ , p, E, and ring B are independently selected from each other, where:

E is -O-, -S-, -S (O)-, -S (O) _2- , -C (R ⁴ ) (R ⁵ )-, -N (R ⁶ )-, -N (C ( Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, and -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-;

p is 0, 1, or 2;

Ring B, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ²⁷ , R ²⁸ , Y, and any substituent on Ring B are as defined above in Formula 1 As defined in one optional embodiment.

In one embodiment, in formula (III.1):

E is selected from the group consisting of -C (R ⁴ ) (R ⁵ )-, -O-, -S-, -S (O)-, -S (O) _2- , and -N (R ⁶ )- Become;

Ring B is an unsubstituted or substituted aromatic ring or a substituted 5- to 6-membered heteroaromatic ring having 1 to 3 ring heteroatoms which may be unsubstituted or the same or different, each ring heteroatom being N, S , O, S (O), and S (O) ₂ , independently selected from the group consisting of the aromatic ring or the substituent on the heteroaromatic ring, if any, are halogen, -CN, -NO ₂ , alkyl , Heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocyclo Alkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) Independently selected from the group consisting of NR ²⁵ R ²⁶ ;

R ¹ is unsubstituted aryl or aryl substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl , Alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁶ R ²⁶ , -C (O ) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR Independently selected from the group consisting of ²³ C (N—CN) NR ²⁵ R ²⁶ and —NR ²³ C (O) NR ²⁵ R ²⁶ ;

R ² is selected from the group consisting of —C (O) R ⁷ , —C (O) NR ⁹ R ¹⁰ , and —C (O) OR ⁸ ;

p is 0 or 1;

And each R ^3, if present, is alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -C ( O) R ²⁴ , -C (S) R ²⁴ , -C (O) OR ²⁰ , and -C (O) NR ²⁵ R ²⁶ , each independently selected from the above alkyl, each said Heteroalkyl, each said alkenyl, and each said heteroalkenyl is optionally substituted with one or more substituents which may be unsubstituted or the same or different and each substituent is oxo, halogen, -CN,- NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido,- OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -S O ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ Independently from.

In one embodiment, in formula (III.1):

Ring B is unsubstituted or is substituted with benzo, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyri Substituted moiety selected from the group consisting of dazinyl, pyrimidinyl, pyrazinyl, and triazinyl;

R ¹ is phenyl substituted with 1 to 4 substituents which may be the same or different and each substituent is from the group consisting of halo, —OH, —CN, —NO ₂ , —NR ²¹ R ²² , and haloalkyl Independently selected;

R ²⁷ and R ²⁸ are each independently selected from the group consisting of H and alkyl;

R ² is selected from the group consisting of —C (O) R ⁷ , —C (O) NR ⁹ R ¹⁰ , and —C (O) OR ⁸ ;

p is 0 or 1;

Each R ³ (if present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and Each said heteroalkenyl is optionally independently substituted with one or more substituents that may be unsubstituted or the same or different, and each substituent is oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, Alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N -CN) part of a group of NR ²⁵ R ²⁶ and ^{-NR 23 C (O) NR 25} R 26 It is independently selected.

In one such embodiment, in formula (III.1):

이고;R ¹ is

ego;

R ⁶ is selected from the group consisting of H, alkyl, -C (O) R ²⁴ , -C (O) OR ²⁰ , and -C (S) R ²⁴ .

In one embodiment, the compounds of the present invention are of formula (III.2) [or, formula 3.2; And pharmaceutically acceptable salts, solvates, esters, prodrugs or isomers of the compounds,

Formula (III.2)

In formula (III.2) above, R ¹ , R ² , R ³ , R ²⁷ , R ²⁸ , p, E, and ring B are independently selected from each other,

E is -O-, -S-, -S (O)-, -S (O) _2- , -C (R ⁴ ) (R ⁵ )-, -N (R ⁶ )-, -N (C ( Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, and -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-;

p is 0, 1, or 2,

Ring B, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ²⁷ , R ²⁸ , Y, and any substituents on ring B are as defined above in Formula 1 As defined in one optional embodiment.

In one embodiment, in formula (III.2):

E is selected from the group consisting of -C (R ⁴ ) (R ⁵ )-, -O-, -S-, -S (O)-, -S (O) _2- , and -N (R ⁶ )- Become;

Ring B is an unsubstituted or substituted aromatic ring, or a substituted 5- to 6-membered heteroaromatic ring having 1 to 3 ring heteroatoms which may be unsubstituted or the same or different, each ring heteroatom Is independently selected from the group consisting of N, S, O, S (O), and S (O) ₂ , wherein the substituents on the aromatic ring or the heteroaromatic ring, if present, are halogen, -CN,- NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR Independently selected from the group consisting of ²⁵ R ²⁶ and —NR ²³ C (O) NR ²⁵ R ²⁶ ;

R ¹ is unsubstituted aryl or aryl substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl , Alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O ) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR Independently selected from the group consisting of ²³ C (N—CN) NR ²⁵ R ²⁶ and —NR ²³ C (O) NR ²⁵ R ²⁶ ;

R ² is selected from the group consisting of —C (O) R ⁷ , —C (O) NR ⁹ R ¹⁰ , and —C (O) OR ⁸ ;

p is 0 or 1;

And each R ^3, if present, is alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -C ( O) R ²⁴ , -C (S) R ²⁴ , -C (O) OR ²⁰ , and -C (O) NR ²⁵ R ²⁶ , each independently selected from the above alkyl, each said Heteroalkyl, each said alkenyl, and each said heteroalkenyl is optionally independently substituted with one or more substituents that may be unsubstituted or the same or different, and each substituent is oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO _{From the group of 2} R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ Selected independently.

In one embodiment, in formula (III.2):

Ring B is unsubstituted or is substituted with benzo, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyri Substituted moiety selected from the group consisting of dazinyl, pyrimidinyl, pyrazinyl, and triazinyl;

R ¹ is phenyl substituted with 1 to 4 substituents which may be the same or different and each substituent is independent from the group consisting of halo, —OH, —CN, —NO ₂ , —NR ²¹ R ²² , and haloalkyl Is selected;

R ²⁷ and R ²⁸ are each independently selected from the group consisting of H and alkyl;

R ² is selected from the group consisting of —C (O) R ⁷ , —C (O) NR ⁹ R ¹⁰ , —C (O) OR ⁸ ;

p is 0 or 1;

Each R ³ (if present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and Each of said heteroalkenyl is optionally independently substituted with one or more substituents that may be unsubstituted, identical or different, and each substituent is oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, al Kenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ ,- NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ ,- C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N- the group consisting of CN) NR ²⁵ R ²⁶ and ^{-NR 23 C (O) NR 25} R 26 It is independently selected from.

In one such embodiment, in formula (III.2):

이고;R ¹ is

ego;

R ⁶ is selected from the group consisting of H, alkyl, -C (O) R ²⁴ , -C (O) OR ²⁰ , and -C (S) R ²⁴ .

In one embodiment, the compounds of the present invention are formula (III.a) [or, formula 3.a; Hereinafter, represented in a similar manner, and include the pharmaceutically acceptable salts, solvates, esters, prodrugs or isomers of the compounds:

Formula (III.a.)

In the above formula (III.a.),

R ¹ , R ² , R ³ , R ²⁷ , R ²⁸ , p, E, ring A, and ring B are independently selected from each other,

Ring A (including E and unsaturated shown) is a 5-membered cycloalkenyl or heterocycloalkenyl ring;

E is -O-, -S-, -S (O)-, -S (O) _2- , -C (R ⁴ ) (R ⁵ )-, -N (R ⁶ )-, -N (C ( Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-, -C (O) -N (R ¹¹ )- , -N (R ¹¹ ) -C (O)-, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) _2- , -C (O) -O- , -OC (O)-, -ON (R ⁶ )-, -N (R ⁶ ) -O-, -N (R ⁶ ) -N (R ¹² )-, -N = N-, and -C ( R ⁷ ) = N-;

Ring B is a substituted or unsubstituted aromatic ring;

p, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ²⁷ , R ²⁸ , Y, and ring B phase Optional substituents are as defined in any of the embodiments described above in Formula (1).

. In one embodiment, Formula (III.a) has the general structural formula:

.

.In one embodiment, Formula (III.a) has the general structural formula:

.

In one embodiment, in formula (III.a.), p is 0, 1, or 2.

In one embodiment, in formula (III.a.), ring A is a cycloalkenyl ring and E is -C (R ⁴ ) (R ⁵ )-.

를 포함한다. In one embodiment, in Formula (III.a.), Ring A is a heterocycloalkenyl ring, E is -C (O) -N (R ¹¹ )-, -N (R ¹¹ ) -C (O) -, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) _2- , -C (O) -O-, -OC (O)-, -ON (R ⁶ )-, -N (R ⁶ ) -O-, -N (R ⁶ ) -N (R ¹² )-, -N = N-, and -C (R ⁷ ) = N- . By way of non-limiting description, in the example of a compound of formula (III.a.), E is -C (O) -N (R ¹¹ )-,

It includes.

In one embodiment, in formula (III.a.), ring A is a heterocycloalkenyl ring, E is —O—, —S—, —S (O) —, —S (O) ₂ —, and -N (R ⁶ )-is selected from the group consisting of.

In one embodiment, in formula (III.a.), E is a group consisting of —O—, —S—, —S (O) —, —S (O) ₂ —, and —N (R ⁶ ) — Wherein R ⁶ is selected from the group consisting of H, alkyl, -C (O) R ²⁴ , and -C (S) R ²⁴ .

In one embodiment, in formula (III.a.), E is selected from the group consisting of -O- and -N (R ⁶ )-, wherein R ⁶ is H, alkyl, -C (O) R ²⁴ , And -C (S) R ²⁴ .

In one embodiment, in formula (III.a.), E is -O-.

In one embodiment, in formula (III.a.), E is -S-.

In one embodiment, in formula (III.a.), E is -S (O)-.

In one embodiment, in formula (III.a.), E is -S (O) _2- .

In one embodiment, in formula (III.a.), E is -C (R ⁴ ) (R ⁵ )-.

In one embodiment, in formula (III.a.), E is -N (R ⁶ )-.

In one embodiment, in formula (III.a.), E is -N (C (Y) R ⁷ )-.

In one embodiment, in formula (III.a.), E is -N (C (Y) OR ⁸ )-.

In one embodiment, in formula (III.a.), E is -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-.

In one embodiment, in formula (III.a.), E is -C (O) -N (R ¹¹ )-.

In one embodiment, in formula (III.a.), E is -N (R ¹¹ ) -C (O)-.

In one embodiment, in formula (III.a.), E is -S (O) ₂ -N (R ¹¹ )-.

In one embodiment, in formula (III.a.), E is -N (R ¹¹ ) -S (O) _2- .

In one embodiment, in formula (III.a.), E is -C (O) -O-.

In one embodiment, in formula (III.a.), E is -O-C (O)-.

In one embodiment, in formula (III.a.), E is -0-N (R ⁶ )-.

In one embodiment, in formula (III.a.), E is -N (R ⁶ ) -O-.

In one embodiment, in formula (III.a.), E is -N (R ⁶ ) -N (R ¹² )-.

In one embodiment, in formula (III.a.), E is -N = N-.

In one embodiment, in formula (III.a.), E is -C (R ⁷ ) = N-.

In one embodiment, in formula (III.a.), Y is (= 0).

In one embodiment, in formula (III.a.), Y is (= S).

In one embodiment, in formula (III.a.), Y is (= N (R ¹³ )).

In one embodiment, in formula (III.a.), Y is (= N (CN)).

In one embodiment, in formula (III.a.), Y is (= N (OR ¹⁴ )).

In one embodiment, in formula (III.a.), Y is (= N (R ¹⁵ ) (R ¹⁶ )).

In one embodiment, in formula (III.a.), Y is (═C (R ¹⁷ ) (R ¹⁸ )).

In one embodiment, in formula (III.a.), B is an unsubstituted aromatic ring.

.In one embodiment, in formula (III.a.), B is an unsubstituted benzo ring and formula (III.a.) has the general structure:

.

In one embodiment, in formula (III.a.), B is an aromatic ring substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, Haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azi Degrees, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C Independently selected from the group consisting of (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula (III.a.), B is a benzo ring substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, Haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azi Degrees, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C Independently selected from the group consisting of (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula (III.a.), R ¹ is unsubstituted aryl.

In one embodiment, in formula (III.a.), R ¹ is unsubstituted phenyl.

In one embodiment, in formula (III.a.), R ¹ is unsubstituted naphthyl.

In one embodiment, in formula (III.a.), R ¹ is substituted aryl.

In one embodiment, in formula (III.a.), R ¹ is substituted phenyl.

In one embodiment, in formula (III.a.), R ¹ is substituted naphthyl.

In one embodiment, in formula (III.a.), R ¹ is aryl substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, Haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C ( O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula (III.a.), R ¹ is phenyl substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, Haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C ( O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula (III.a.), R ¹ is phenyl substituted with 1 to 4 substituents which may be the same or different and each substituent is halo, —OH, —CN, —NO ₂ , -NR ²¹ R ²² , and haloalkyl.

In one embodiment, in formula (III.a.), R ¹ is

It is selected from the group consisting of.

이다.In one embodiment, in formula (III.a.), R ¹ is

to be.

In one embodiment, in formula (III.a.), R ¹ is phenyl substituted with 1 to 3 fluoro groups.

In one embodiment, in formula (III.a.), R ¹ is phenyl substituted with two fluoro groups.

In one embodiment, in formula (III.a.), R ¹ is phenyl substituted with one fluoro group.

이다.In one embodiment, in formula (III.a.), R ¹ is

to be.

In one embodiment, in formula (III.a.), R ²⁷ and R ²⁸ are each independently selected from the group consisting of H and alkyl.

In one embodiment, in formula (III.a.), R ² is —C (Z) R ⁷ .

In one embodiment, in formula (III.a.), R ² is —C (Z) NR ⁹ R ¹⁰ .

In one embodiment, in formula (III.a.), R ² is —C (Z) OR ⁸ .

In one embodiment, in formula (III.a.), R ² is —SO ₂ NR ⁹ R ¹⁰ .

In one embodiment, in formula (III.a.), R ² is alkyl.

In one embodiment, in formula (III.a.), R ² is heteroalkyl.

In one embodiment, in formula (III.a.), R ² is aryl.

In one embodiment, in formula (III.a.), R ² is heteroaryl.

In one embodiment, in formula (III.a.), R ² is cycloalkyl.

In one embodiment, in formula (III.a.), R ² is cycloalkenyl.

In one embodiment, in formula (III.a.), R ² is heterocycloalkyl.

In one embodiment, in formula (III.a.), R ² is heterocycloalkenyl.

In one embodiment, in formula (III.a.), Z is (═O).

In one embodiment, in formula (III.a.), Z is (= S).

In one embodiment, in formula (III.a.), Z is (= N (R ¹³ )).

In one embodiment, in formula (III.a.), Z is (= N (CN)).

In one embodiment, in formula (III.a.), Z is (= N (OR ¹⁴ )).

In one embodiment, in formula (III.a.), Z is (= N (R ¹⁵ ) (R ¹⁶ )).

In one embodiment, in formula (III.a.), Z is (= C (R ¹⁷ ) (R ¹⁸ )).

In one embodiment, in formula (III.a.), R ² is —C (Z) R ⁷ and Z is (═O).

In one embodiment, in formula (III.a.), R ² is —C (O) H.

In one embodiment, in formula (III.a.), R ² is —C (O) alkyl.

In one embodiment, in formula (III.a.), R ² is —C (O) CH ₃ .

In one embodiment, in formula (III.a.), R ² is —C (O) R ⁷ wherein R ⁷ is alkyl substituted with one or more substituents which may be the same or different and each substituent Is oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, Heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O ) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O ) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula (III.a.), R ² is —C (O) R ⁷ wherein R ⁷ is alkyl substituted with 1 to 3 substituents, which may be the same or different, Each substituent is independently selected from the group consisting of -OR ¹⁹ , -NR ²¹ R ²² , and cycloalkyl.

In one embodiment, in formula (III.a.), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl, wherein said alkyl is substituted with alkyl and —OH.

In one embodiment, in formula (III.a.), R ² is —C (O) R ⁷ wherein R ⁷ is alkyl substituted with 1 to 3 substituents, which may be the same or different, Each substituent is independently selected from the group consisting of -OH, -NH ₂ , and cyclopropyl.

In one embodiment, in formula (III.a.), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl substituted with 1 to 2 substituents which may be the same or different, Each substituent is independently selected from the group consisting of -NH ₂ , and cyclopropyl.

In one embodiment, in formula (III.a.), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl substituted with —OH.

In one embodiment, in formula (III.a.), R ² is —C (O) R ⁷ , wherein R ⁷ is unsubstituted heterocycloalkyl.

In one embodiment, in formula (III.a.), R ² is —C (O) R ⁷ , wherein R ⁷ is substituted heterocycloalkyl.

In one embodiment, in formula (III.a.), R ² is —C (O) R ⁷ , wherein R ⁷ is heterocycloalkyl substituted with one or more substituents which may be the same or different and each Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC Independently selected from the group consisting of (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula (III.a.), R ² is —C (O) R ⁷ wherein R ⁷ is substituted piperidine, substituted piperazine, substituted morpholine, substituted Pyrrolidinine, and substituted azetidines.

In one embodiment, in formula (III.a.), R ² is

.

In one embodiment, in formula (III.a.), R ² is —C (O) NR ⁹ R ¹⁰ .

In one embodiment, in formula (III.a.), R ² is —C (O) NH ₂ .

In one embodiment, in formula (III.a.), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ and R ¹⁰ may be the same or different and each is independently selected from alkyl do.

In one embodiment, in formula (III.a.), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ is unsubstituted heterocycloalkyl, R ¹⁰ is a group consisting of H and alkyl Is selected from.

In one embodiment, in formula (III.a.), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ is substituted heterocycloalkyl and R ¹⁰ is from a group consisting of H and alkyl Is selected.

In one embodiment, in formula (III.a.), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ is a heterocyclo substituted with 1 to 3 substituents which may be the same or different Alkyl, each substituent is independently selected from alkyl, and R ¹⁰ is selected from the group consisting of H and alkyl.

In one embodiment, in formula (III.a.), R ² is alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, —C (O) R ⁷ , —C (O) OR ⁸ , and —C ( O) NR ⁹ R ¹⁰ .

In one embodiment, in formula (III.a.), R ² is

It is selected from the group consisting of.

이다.In one embodiment, in formula (III.a.), R ² is

to be.

이다.In one embodiment, in formula (III.a.), R ² is

to be.

이다.In one embodiment, in formula (III.a.), R ² is

to be.

이다. In one embodiment, in formula (III.a.), R ² is

to be.

이다.In one embodiment, in formula (III.a.), R ² is

to be.

이다.In one embodiment, in formula (III.a.), R ² is

to be.

이다.In one embodiment, in formula (III.a.), R ² is

to be.

이다.In one embodiment, in formula (III.a.), R ² is

to be.

In one embodiment, in formula (III.a.), p is 0 and R ³ is absent.

In one embodiment, in formula (III.a.), p is 1.

In one embodiment, in formula (III.a.), p is 2.

In one embodiment, in formula (III.a.), p is 3.

In one embodiment, in formula (III.a.), p is 4.

In one embodiment, in formula (III.a.), p is> 2 and at least two groups R ³ are attached to the same ring atom.

In one embodiment, in formula (III.a.), p is 1 and R ³ is alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cyclo Alkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ Independently from the group consisting of R ²⁶ .

In one embodiment, in formula (III.a.), p is 2, 3 or 4 and each R ³ is alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, hetero Aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ Independently from the group consisting of C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula (III.a.), p is 2, 3 or 4 and at least two groups R ³ are bonded to the same ring carbon atom, wherein each R ³ which may be the same or different Silver alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O ) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula (III.a.), p is 2, 3 or 4 and at least two groups R ³ are bonded to the same ring carbon atom, wherein two R ³ which may be the same or different The group is a heterocycloalkyl ring containing 1 to 3 heteroatoms selected from the group consisting of cycloalkyl, cycloalkenyl, N, O and S together with the carbon atoms to which they are attached, or a group consisting of N, O and S To form a heterocycloalkenyl ring containing from 1 to 3 heteroatoms.

In one embodiment, in formula (III.a.), p is 1 or 2 and each R ³ is alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO ₂ , -OR ¹⁹ ,- OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ ,- C (O) R ²⁴ , -C (S) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ ,- C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ , -NR ²³ C (O) NR ²⁵ R ²⁶ , and -NR ²³ -C (NH) -NR ²⁶ R ²⁶ Independently selected from the group consisting of wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl is one or more substituents which may be unsubstituted or the same or different Optionally independently substituted, each substituent is oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl , Four Icycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO _{From the group of 2} R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ Selected independently.

In one embodiment, in formula (III.a.), p is 1 and R ³ is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, wherein each of said alkyl, each Said heteroalkyl, each said alkenyl, and each said heteroalkenyl is optionally substituted independently with one or more substituents which may be unsubstituted or may be the same or different, each substituent being selected from oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ² Independently from the group of ⁶ ;

In one embodiment, in formula (III.a.), p is 2 and any two R ³ groups bonded to the same ring A atom are taken together to form a -C (O)-group.

In one embodiment, in formula (III.a.), p is 2 and any two R ³ groups bonded to the same ring A atom are taken together to be —NH—, —NR ⁶ —, O, S, S Spiroheterocycloalkyl groups having 1 to 3 ring heteroatoms independently selected from the group consisting of (O), and S (O) ₂ , or —NH—, —NR ⁶ —, O, S, S (O) And spiroheterocycloalkenyl groups having 1 to 3 ring heteroatoms independently selected from the group consisting of S (O) ₂ .

In one embodiment, in formula (III.a.), R ³ is alkyl.

In one embodiment, in formula (III.a.), R ³ is heteroalkyl.

In one embodiment, in formula (III.a.), R ³ is alkenyl.

In one embodiment, in formula (III.a.), R ³ is heteroalkenyl.

In one embodiment, in formula (III.a.), R ³ is alkynyl.

In one embodiment, in formula (III.a.), R ³ is heteroalkynyl.

In one embodiment, in formula (III.a.), R ³ is aryl.

In one embodiment, in formula (III.a.), R ³ is heteroaryl.

In one embodiment, in formula (III.a.), R ³ is cycloalkyl.

In one embodiment, in formula (III.a.), R ³ is cycloalkenyl.

In one embodiment, in formula (III.a.), R ³ is heterocycloalkyl.

In one embodiment, in formula (III.a.), R ³ is heterocycloalkenyl.

In one embodiment, in formula (III.a.), R ³ is halogen.

In one embodiment, in formula (III.a.), R ³ is -CN.

In one embodiment, in formula (III.a.), R ³ is -NO ₂ .

In one embodiment, in formula (III.a.), R ³ is -OR ¹⁹ .

In one embodiment, in formula (III.a.), R ³ is -OC (O) OR ²⁰ .

In one embodiment, in formula (III.a.), R ³ is -NR ²¹ R ²² .

In one embodiment, in formula (III.a.), R ³ is -NR ²³ SO ₂ R ²⁴ .

In one embodiment, in formula (III.a.), R ³ is —NR ²³ C (O) OR ²⁰ .

In one embodiment, in formula (III.a.), R ³ is -NR ²³ C (O) R ²⁴ .

In one embodiment, in formula (III.a.), R ³ is —SO ₂ NR ²⁵ R ²⁶ .

In one embodiment, in formula (III.a.), R ³ is -C (O) R ²⁴ .

In one embodiment, in formula (III.a.), R ³ is —C (O) OR ²⁰ .

In one embodiment, in formula (III.a.), R ³ is -SR ¹⁹ .

In one embodiment, in formula (III.a.), R ³ is -S (O) R ¹⁹ .

In one embodiment, in formula (III.a.), R ³ is -SO ₂ R ¹⁹ .

In one embodiment, in formula (III.a.), R ³ is -OC (O) R ²⁴ .

In one embodiment, in formula (III.a.), R ³ is —C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula (III.a.), R ³ is —NR ²³ C (N—CN) NR ²⁵ R ²⁶ .

In one embodiment, in formula (III.a.), R ³ is —NR ²³ C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula (III.a.), R ³ is methyl, ethyl, propyl (straight or branched), butyl (straight or branched), pentyl (straight or branched), phenyl,

It is selected from the group consisting of.

In one embodiment, in formula (III.a.), when E is -NR ^6- , R ³ is absent.

In one embodiment, Formula (III.a) has the general structure (III.a.1):

Formula (III.a.1)

In the above formula (III.a.1),

R ¹ , R ² , R ³ , R ²⁷ , R ²⁸ , p, E, and ring B are independently selected from each other, where:

E is -O-, -S-, -S (O)-, -S (O) _2- , -C (R ⁴ ) (R ⁵ )-, -N (R ⁶ )-, -N (C ( Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, and -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-;

p, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ²⁷ , R ²⁸ , Y, and any substituents on ring B are represented by As defined in any of the embodiments described above in III.a.).

In one embodiment, Formula (III.a.1) has the general structural formula shown in Formula (III.a.1.1):

Formula (III.a.1.1)

In one embodiment, Formula (III.a.) has the general structure (III.a.2):

Formula (III.a.2)

In the above formula (III.a.2),

R ¹ , R ² , R ³ , R ²⁷ , R ²⁸ , p, E and ring B are independently selected from each other, where:

E is -O-, -S-, -S (O)-, -S (O) _2- , -C (R ⁴ ) (R ⁵ )-, -N (R ⁶ )-, -N (C ( Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, and -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-;

p, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ²⁷ , R ²⁸ , Y, and any substituents on ring B are represented by As defined in any of the embodiments described above in III.a.).

In one embodiment, Formula (III.a.2) has the general structural formula shown in Formula (III.a.2.1):

Formula (III.a.2.1)

In one embodiment, Formula (III.a.2) has the general structural formula shown in Formula (III.a.2.2):

Formula (III.a.2.2)

In one embodiment, Formula (III.a.2) has the general structural formula shown in Formula (III.a.2.3):

Formula (III.a.2.3)

In one embodiment, Formula (III.a.2) has the general structural formula shown in Formula (III.a.2.4):

Formula (III.a.2.4)

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), p is zero.

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), p is 1.

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), p is 2.

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), E is -C (R ⁴ ) (R ⁵ )-.

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), E consists of -O-, -S-, -S (O)-, -S (O) _2- , and -N (R ⁶ )- Is selected from the group.

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), E consists of -O-, -S-, -S (O)-, -S (O) _2- , and -N (R ⁶ )- Selected from the group wherein R ⁶ is selected from the group consisting of H, alkyl, -C (O) R ²⁴ , and -C (S) R ²⁴ .

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), (III.a.2.4), E is selected from the group consisting of -O- and -N (R ⁶ )-, wherein R ⁶ is H, alkyl, -C (O) R ²⁴ , And -C (S) R ²⁴ .

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), E is -O-.

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), E is -S-.

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), E is -S (O)-.

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), E is -S (O) _2- .

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), E is -C (R ⁴ ) (R ⁵ )-.

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), E is -N (R ⁶ )-.

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), E is -N (C (Y) R ⁷ )-.

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), E is -N (C (Y) OR ⁸ )-.

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), E is -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-.

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), Y is (═O).

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), Y is (= S).

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), Y is (= N (R ¹³ )).

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), Y is (= N (CN)).

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), Y is (= N (OR ¹⁴ )).

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), Y is (= N (R ¹⁵ ) (R ¹⁶ )).

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), Y is (= C (R ¹⁷ ) (R ¹⁸ )).

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), R ¹ is phenyl substituted with 1 to 4 substituents which may be the same or different and each substituent is halo, —OH, —CN.—NO ₂ , -NR ²¹ R ²² , and haloalkyl.

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), R ¹ is

It is selected from the group consisting of.

이다. In one embodiment, in formula 1, R ¹ is

to be.

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), R ¹ is phenyl substituted with 1 to 3 fluoro groups.

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), R ¹ is phenyl substituted with two fluoro groups.

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), R ¹ is phenyl substituted with one fluoro group.

이다.In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), R ¹ is

to be.

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), R ²⁷ and R ²⁸ are independently selected from the group consisting of H and alkyl.

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), R ² is alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C (O) R ⁷ , -C (O) OR ⁸ , and -C (O) NR ⁹ R ¹⁰ .

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), R ² is

It is selected from the group consisting of.

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), p is 1 or 2, and each R ³ is alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (S) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ , -NR ²³ C (O) NR ²⁵ R ²⁶ , and -NR ²³ -C (NH) -NR ²⁶ R ²⁶ Independently selected from the group consisting of: wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl is one or more substituents which may be unsubstituted or the same or different as optionally substituted independently, wherein each substituent is oxo, halogen, -CN, -NO _2, alkyl, heteroalkyl, haloalkyl, alkenyl, be Alkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, hetero cycloalkenyl, ^{azido, -OR 19, -OC (O)} OR 20, -NR 21 R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR Independently from the group of ²⁵ R ²⁶ and —NR ²³ C (O) NR ²⁵ R ²⁶ .

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), p is 1 and R ³ is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, wherein each of said alkyl, respectively Wherein said heteroalkyl, each said alkenyl, and each said heteroalkenyl are optionally substituted independently with one or more substituents which may be unsubstituted or the same or different, each substituent being oxo, halogen, -CN , -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ Independent from the group Is selected.

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), p is 2 and any two R ³ groups bonded to the same ring A atom are taken together to form a -C (O)-group.

In some embodiments, each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), and (III. a.2.3), and (III.a.2.4), p is 2, and any two R ³ groups bonded to the same ring A atom are taken together to form —NH—, —NR ⁶ —, O, S, Spiroheterocycloalkyl groups having 1 to 3 ring heteroatoms independently selected from the group consisting of S (O), and S (O) ₂ , or —NH—, —NR ⁶ —, O, S, S (O ), And a spiroheterocycloalkenyl group having 1 to 3 ring heteroatoms independently selected from the group consisting of S (O) ₂ .

In one embodiment, the compounds of the invention have the structural formula shown in Formula (III.b) and include pharmaceutically acceptable salts, solvates, esters, prodrugs or isomers of said compounds:

Formula (III.b.)

In the above formula (III.b.),

R ¹ , R ² , R ³ , R ²⁷ , R ²⁸ , p, E, ring A, and ring B are independently selected from each other, wherein ring A (including indicated E and unsaturated) is a 5-membered cycloalkenyl or Heterocycloalkenyl ring;

E is -O-, -S-, -S (O)-, -S (O) _2- , -C (R ⁴ ) (R ⁵ )-, -N (R ⁶ )-, -N (C ( Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-, -C (O) -N (R ¹¹ )- , -N (R ¹¹ ) -C (O)-, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) _2- , -C (O) -O- , -OC (O)-, -ON (R ⁶ )-, -N (R ⁶ ) -O-, -N (R ⁶ ) -N (R ¹² )-, -N = N-, and -C ( R ⁷ ) = N-;

Ring B is a substituted or unsubstituted heteroaromatic ring;

p, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ²⁷ , R ²⁸ , Y, and ring B phase Optional substituents are as defined in any of the embodiments described above in Formula (1).

.In one embodiment, Formula (III.b) has the general structure:

.

.In one embodiment, Formula (III.b) has the general structure:

.

In one embodiment, in formula (III.b.), p is 0, 1, or 2.

In one embodiment, in formula (III.b.), ring A is a cycloalkenyl ring and E is -C (R ⁴ ) (R ⁵ )-.

를 포함한다.In one embodiment, in Formula (III.b.), Ring A is a heterocycloalkenyl ring, E is -C (O) -N (R ¹¹ )-, -N (R ¹¹ ) -C (O) -, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) _2- , -C (O) -O-, -OC (O)-, -ON (R ⁶ )-, -N (R ⁶ ) -O-, -N (R ⁶ ) -N (R ¹² )-, -N = N-, and -C (R ⁷ ) = N- . By way of non-limiting description, in the example of a compound of formula (III.a), E is -C (O) -N (R ¹¹ )-,

It includes.

In one embodiment, in formula (III.b.), ring A is a heterocycloalkenyl ring, E is —O—, —S—, —S (O) —, —S (O) ₂ —, and -N (R ⁶ )-is selected from the group consisting of.

In one embodiment, in formula (III.b.), E is a group consisting of —O—, —S—, —S (O) —, —S (O) ₂ —, and —N (R ⁶ ) — Wherein R ⁶ is selected from the group consisting of H, alkyl, -C (O) R ²⁴ , and -C (S) R ²⁴ .

In one embodiment, in formula (III.b.), E is selected from the group consisting of -O- and -N (R ⁶ )-, wherein R ⁶ is H, alkyl, -C (O) R ²⁴ , And -C (S) R ²⁴ .

In one embodiment, in formula (III.b.), E is -O-.

In one embodiment, in formula (III.b.), E is -S-.

In one embodiment, in formula (III.b.), E is -S (O)-.

In one embodiment, in formula (III.b.), E is -S (O) _2- .

In one embodiment, in formula (III.b.), E is -C (R ⁴ ) (R ⁵ )-.

In one embodiment, in formula (III.b.), E is -N (R ⁶ )-.

In one embodiment, in formula (III.b.), E is -N (C (Y) R ⁷ )-.

In one embodiment, in formula (III.b.), E is -N (C (Y) OR ⁸ )-.

In one embodiment, in formula (III.b.), E is -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-.

In one embodiment, in formula (III.b.), E is -C (O) -N (R ¹¹ )-.

In one embodiment, in formula (III.b.), E is -N (R ¹¹ ) -C (O)-.

In one embodiment, in formula (III.b.), E is -S (O) ₂ -N (R ¹¹ )-.

In one embodiment, in formula (III.b.), E is -N (R ¹¹ ) -S (O) _2- .

In one embodiment, in formula (III.b.), E is -C (O) -O-.

In one embodiment, in formula (III.b.), E is -O-C (O)-.

In one embodiment, in formula (III.b.), E is -ON (R ⁶ )-.

In one embodiment, in formula (III.b.), E is -N (R ⁶ ) -O-.

In one embodiment, in formula (III.b.), E is -N (R ⁶ ) -N (R ¹² )-.

In one embodiment, in formula (III.b.), E is -N = N-.

In one embodiment, in formula (III.b.), E is -C (R ⁷ ) = N-.

In one embodiment, in formula (III.b.), Y is (= 0).

In one embodiment, in formula (III.b.), Y is (= S).

In one embodiment, in formula (III.b.), Y is (= N (R ¹³ )).

In one embodiment, in formula (III.b.), Y is (= N (CN)).

In one embodiment, in formula (III.b.), Y is (= N (OR ¹⁴ )).

In one embodiment, in formula (III.b.), Y is (= N (R ¹⁵ ) (R ¹⁶ )).

In one embodiment, in formula (III.b.), Y is (═C (R ¹⁷ ) (R ¹⁸ )).

In one embodiment, in formula (III.b.), B is an unsubstituted heteroaromatic ring.

In one embodiment, in formula (III.b.), B is an unsubstituted 5 to 6 membered heteroaromatic ring having 1 to 3 ring heteroatoms which may be the same or different and each hetero ring atom is Independently from the group consisting of N, S, O, S (O), and S (O) ₂ .

In one embodiment, in formula (III.b.), B is a heteroaromatic ring substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl , Haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, Azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ ,- SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ ,- C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula (III.b.), B is a 5-6 membered heteroaromatic ring having 1 to 3 ring heteroatoms which may be the same or different and each hetero reducer is N, S, Independently selected from the group consisting of O, S (O), and S (O) ₂ , the heteroaromatic ring is substituted with one or more substituents which may be the same or different and each substituent is halogen, -CN, -NO ₂ , Alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, Heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O ) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O ) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ Independently from the group consisting of:

In one embodiment, in formula (III.b.), B is an unsubstituted 6-membered heteroaromatic ring having 1 to 3 ring heteroatoms which may be the same or different and each hetero ring atom is N, S And are independently selected from the group consisting of O.

In one embodiment, in formula (III.b.), B is a 6 membered heteroaromatic ring having 1 to 3 ring heteroatoms which may be the same or different and each hetero ring atom is N, S, and O Independently selected from the group consisting of: wherein the heteroaromatic ring is substituted with one or more substituents which may be the same or different and each substituent is halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl , Haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ^{25 R 26, -NR 23 C (N} -CN) NR 25 R 26 and ^{-NR 23 C (O) NR 25} R 26 consisting of It is independently selected from the group.

In one embodiment, in formula (III.b.), B is an unsubstituted 6-membered heteroaromatic ring having two ring heteroatoms, each ring heteroatom selected independently from N, S, and O .

In one embodiment, in formula (III.b.), B is a 6 membered heteroaromatic ring having 2 ring heteroatoms, each ring heteroatom is independently selected from N, S, and O, wherein Heteroaromatic rings are substituted with one or more substituents which may be the same or different, and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, —OR ¹⁹ , —NR ²¹ R ²² , —C ( O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , and -C (O) NR ²⁵ R ²⁶ Independently from the group consisting of:

In one embodiment, in formula (III.b.), B is an unsubstituted 5-membered heteroaromatic ring having 1 to 2 ring heteroatoms which may be the same or different and each hetero ring atom is N, S And are independently selected from the group consisting of O.

In one embodiment, in formula (III.b.), B is a 5 membered heteroaromatic ring having 1 to 2 ring heteroatoms which may be the same or different and each hetero ring atom is N, S, and O Independently selected from the group consisting of: wherein the heteroaromatic ring is substituted with one or more substituents which may be the same or different and each substituent is halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl , Haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ^{25 R 26, -NR 23 C (N} -CN) NR 25 R 26 and ^{-NR 23 C (O) NR 25} R 26 consisting of It is independently selected from the group.

In one embodiment, in formula (III.b.), B is an unsubstituted 5-membered heteroaromatic ring having one ring heteroatom selected from N, S, and O.

In one embodiment, in formula (III.b.), B is a 5-membered heteroaromatic ring having one ring heteroatom selected from N, S, and O, wherein the heteroaromatic ring is one that may be the same or different Substituted with one or more substituents, and each substituent is halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, -OR ¹⁹ , -NR ²¹ R ²² , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , and -C (O) NR ²⁵ R ²⁶ are independently selected.

In one embodiment, in formula (III.b.), B is a 5 membered heteroaromatic ring having S as ring heteroatom, wherein the heteroaromatic ring is substituted with one or more substituents which may be the same or different and each Substituents are halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, -OR ¹⁹ , -NR ²¹ R ²² , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ ,- Independently from the group consisting of S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , and -C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula (III.b.), B is an unsubstituted 5-membered heteroaromatic ring having S as the ring heteroatom.

In one embodiment, in formula (III.b.), B is

It is selected from the group consisting of.

In one embodiment, in formula (III.b.), R ¹ is unsubstituted aryl.

In one embodiment, in formula (III.b.), R ¹ is unsubstituted phenyl.

In one embodiment, in formula (III.b.), R ¹ is unsubstituted naphthyl.

In one embodiment, in formula (III.b.), R ¹ is substituted aryl.

In one embodiment, in formula (III.b.), R ¹ is substituted phenyl.

In one embodiment, in formula (III.b.), R ¹ is substituted naphthyl.

In one embodiment, in formula (III.b.), R ¹ is aryl substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, Haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C ( O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula (III.b.), R ¹ is phenyl substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, Haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C ( O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula (III.b.), R ¹ is phenyl substituted with 1 to 4 substituents which may be the same or different and each substituent is halo, —OH, —CN, —NO ₂ , -NR ²¹ R ²² , and haloalkyl.

In one embodiment, in formula (III.b.), R ¹ is

It is selected from the group consisting of.

이다. In one embodiment, in formula (III.b.), R ¹ is

to be.

In one embodiment, in formula (III.b.), R ¹ is phenyl substituted with 1 to 3 fluoro groups.

In one embodiment, in formula (III.b.), R ¹ is phenyl substituted with two fluoro groups.

In one embodiment, in formula (III.b.), R ¹ is phenyl substituted with one fluoro group.

이다.In one embodiment, in formula (III.b.), R ¹ is

to be.

In one embodiment, in formula (III.b.), R ²⁷ and R ²⁸ are each independently selected from the group consisting of H and alkyl.

In one embodiment, in formula (III.b.), R ² is —C (Z) R ⁷ .

In one embodiment, in formula (III.b.), R ² is —C (Z) NR ⁹ R ¹⁰ .

In one embodiment, in formula (III.b.), R ² is —C (Z) OR ⁸ .

In one embodiment, in formula (III.b.), R ² is —SO ₂ NR ⁹ R ¹⁰ .

In one embodiment, in formula (III.b.), R ² is alkyl.

In one embodiment, in formula (III.b.), R ² is heteroalkyl.

In one embodiment, in formula (III.b.), R ² is aryl.

In one embodiment, in formula (III.b.), R ² is heteroaryl.

In one embodiment, in formula (III.b.), R ² is cycloalkyl.

In one embodiment, in formula (III.b.), R ² is cycloalkenyl.

In one embodiment, in formula (III.b.). R ² is heterocycloalkyl.

In one embodiment, in formula (III.b.), R ² is heterocycloalkenyl.

In one embodiment, in formula (III.b.), Z is (═O).

In one embodiment, in formula (III.b.), Z is (= S).

In one embodiment, in formula (III.b.), Z is (= N (R ¹³ )).

In one embodiment, in formula (III.b.), Z is (= N (CN)).

In one embodiment, in formula (III.b.), Z is (= N (OR ¹⁴ )).

In one embodiment, in formula (III.b.), Z is (= N (R ¹⁵ ) (R ¹⁶ )).

In one embodiment, in formula (III.b.), Z is (= C (R ¹⁷ ) (R ¹⁸ )).

In one embodiment, in formula (III.b.), R ² is —C (Z) R ⁷ and Z is (= 0).

In one embodiment, in formula (III.b.), R ² is —C (O) H.

In one embodiment, in formula (III.b.), R ² is —C (O) alkyl.

In one embodiment, in formula (III.b.), R ² is —C (O) CH ₃ .

In one embodiment, in formula (III.b.), R ² is —C (O) R ⁷ wherein R ⁷ is alkyl substituted with one or more substituents which may be the same or different and each substituent Is oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, Heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O ) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O ) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula (III.b.), R ² is —C (O) R ⁷ wherein R ⁷ is alkyl substituted with 1 to 3 substituents, which may be the same or different, Each substituent is independently selected from the group consisting of -OR ¹⁹ , -NR ²¹ R ²² , and cycloalkyl.

In one embodiment, in formula (III.b.), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl, wherein said alkyl is substituted with alkyl and —OH.

In one embodiment, in formula (III.b.), R ² is —C (O) R ⁷ wherein R ⁷ is alkyl substituted with 1 to 3 substituents, which may be the same or different, Each substituent is independently selected from the group consisting of -OH, -NH ₂ , and cyclopropyl.

In one embodiment, in formula (III.b.), R ² is —C (O) R ⁷ wherein R ⁷ is alkyl substituted with 1 to 2 substituents which may be the same or different, Each substituent is independently selected from the group consisting of -NH ₂ , and cyclopropyl.

In one embodiment, in formula (III.b.), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl substituted with —OH.

In one embodiment, in formula (III.b.), R ² is —C (O) R ⁷ wherein R ⁷ is unsubstituted heterocycloalkyl.

In one embodiment, in formula (III.b.), R ² is —C (O) R ⁷ , wherein R ⁷ is substituted heterocycloalkyl.

In one embodiment, in formula (III.b.), R ² is —C (O) R ⁷ , wherein R ⁷ is heterocycloalkyl substituted with one or more substituents which may be the same or different, each Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC Independently selected from the group consisting of (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula (III.b.), R ² is —C (O) R ⁷ wherein R ⁷ is substituted piperidine, substituted piperazine, substituted morpholine, substituted Pyrrolidinine, and substituted azetidines.

In one embodiment, in formula (III.b.), R ² is

.

In one embodiment, in formula (III.b.), R ² is —C (O) NR ⁹ R ¹⁰ .

In one embodiment, in formula (III.b.), R ² is —C (O) NH ₂ .

In one embodiment, in formula (III.b.), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ and R ¹⁰ may be the same or different and each is independently selected from alkyl do.

In one embodiment, in formula (III.b.), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ is unsubstituted heterocycloalkyl, R ¹⁰ is a group consisting of H and alkyl Is selected from.

In one embodiment, in formula (III.b.), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ is substituted heterocycloalkyl and R ¹⁰ is from a group consisting of H and alkyl Is selected.

In one embodiment, in formula (III.b.), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ is a heterocyclo substituted with 1 to 3 substituents which may be the same or different Alkyl, each substituent is independently selected from alkyl, and R ¹⁰ is selected from the group consisting of H and alkyl.

In one embodiment, in formula (III.b.), R ² is alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C (O) R ⁷ , -C (O) OR ⁸ , and -C ( O) NR ⁹ R ¹⁰ .

In one embodiment, in formula (III.b.), R ² is

It is selected from the group consisting of.

이다.In one embodiment, in formula (III.b.), R ² is

to be.

이다. In one embodiment, in formula (III.b.), R ² is

to be.

이다.In one embodiment, in formula (III.b.), R ² is

to be.

이다.In one embodiment, in formula (III.b.), R ² is

to be.

이다.In one embodiment, in formula (III.b.), R ² is

to be.

이다.In one embodiment, in formula (III.b.), R ² is

to be.

이다.In one embodiment, in formula (III.b.), R ² is

to be.

이다.In one embodiment, in formula (III.b.), R ² is

to be.

In one embodiment, in formula (III.b.), p is 0 and R ³ is absent.

In one embodiment, in formula (III.b.), p is 1.

In one embodiment, in formula (III.b.), p is 2.

In one embodiment, in formula (III.b.), p is 3.

In one embodiment, in formula (III.b.), p is 4.

In one embodiment, in formula (III.b.), p is> 2 and at least two groups R ³ are attached to the same ring atom.

In one embodiment, in formula (III.b.), p is 1 and R ³ is alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cyclo Alkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ Independently from the group consisting of R ²⁶ .

In one embodiment, in formula (III.b.), p is 2, 3 or 4 and each R ³ is alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, hetero Aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ Independently from the group consisting of C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula (III.b.), p is 2, 3 or 4 and at least two groups R ³ are bonded to the same ring carbon atom, wherein each R ³ which may be the same or different Silver alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O ) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula (III.b.), p is 2, 3 or 4 and at least two groups R ³ are bonded to the same ring carbon atom, wherein two R ³ which may be the same or different The group is a heterocycloalkyl ring containing 1 to 3 heteroatoms selected from the group consisting of cycloalkyl, cycloalkenyl, N, O and S together with the carbon atoms to which they are attached, or a group consisting of N, O and S To form a heterocycloalkenyl ring containing from 1 to 3 heteroatoms.

In one embodiment, in formula (III.b.), p is 1 or 2 and each R ³ is alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO ₂ , -OR ¹⁹ ,- OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ ,- C (O) R ²⁴ , -C (S) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ ,- C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ , -NR ²³ C (O) NR ²⁵ R ²⁶ , and -NR ²³ -C (NH) -NR ²⁶ R ²⁶ Independently selected from the group consisting of wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl is one or more substituents which may be unsubstituted or the same or different Optionally independently substituted, each substituent is oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl , Four Icycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO _{From the group of 2} R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ Selected independently.

In one embodiment, in formula (III.b.), p is 1 and R ³ is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, wherein each of said alkyl, each Said heteroalkyl, each said alkenyl, and each said heteroalkenyl is optionally substituted independently with one or more substituents which may be unsubstituted or may be the same or different, each substituent being selected from oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ² Independently from the group of ⁶ ;

In one embodiment, in formula (III.b.), p is 2 and any two R ³ groups bonded to the same ring A atom are taken together to form a -C (O)-group.

In one embodiment, in formula (III.b.), p is 2 and any two R ³ groups bonded to the same ring A atom are taken together to be —NH—, —NR ⁶ —, O, S, S Spiroheterocycloalkyl groups having 1 to 3 ring heteroatoms independently selected from the group consisting of (O), and S (O) ₂ , or —NH—, —NR ⁶ —, O, S, S (O) And spiroheterocycloalkenyl groups having 1 to 3 ring heteroatoms independently selected from the group consisting of S (O) ₂ .

In one embodiment, in formula (III.b.), R ³ is alkyl.

In one embodiment, in formula (III.b.), R ³ is heteroalkyl.

In one embodiment, in formula (III.b.), R ³ is alkenyl.

In one embodiment, in formula (III.b.), R ³ is heteroalkenyl.

In one embodiment, in formula (III.b.), R ³ is alkynyl.

In one embodiment, in formula (III.b.), R ³ is heteroalkynyl.

In one embodiment, in formula (III.b.), R ³ is aryl.

In one embodiment, in formula (III.b.), R ³ is heteroaryl.

In one embodiment, in formula (III.b.), R ³ is cycloalkyl.

In one embodiment, in formula (III.b.), R ³ is cycloalkenyl.

In one embodiment, in formula (III.b.), R ³ is heterocycloalkyl.

In one embodiment, in formula (III.b.), R ³ is heterocycloalkenyl.

In one embodiment, in formula (III.b.), R ³ is halogen.

In one embodiment, in formula (III.b.), R ³ is -CN.

In one embodiment, in formula (III.b.), R ³ is -NO ₂ .

In one embodiment, in formula (III.b.), R ³ is -OR ¹⁹ .

In one embodiment, in formula (III.b.), R ³ is -OC (O) OR ²⁰ .

In one embodiment, in formula (III.b.), R ³ is -NR ²¹ R ²² .

In one embodiment, in formula (III.b.), R ³ is -NR ²³ SO ₂ R ²⁴ .

In one embodiment, in formula (III.b.), R ³ is -NR ²³ C (O) OR ²⁰ .

In one embodiment, in formula (III.b.), R ³ is -NR ²³ C (O) R ²⁴ .

In one embodiment, in formula (III.b.), R ³ is -SO ₂ NR ²⁵ R ²⁶ .

In one embodiment, in formula (III.b.), R ³ is -C (O) R ²⁴ .

In one embodiment, in formula (III.b.), R ³ is -C (O) OR ²⁰ .

In one embodiment, in formula (III.b.), R ³ is -SR ¹⁹ .

In one embodiment, in formula (III.b.), R ³ is -S (O) R ¹⁹ .

In one embodiment, in formula (III.b.), R ³ is -SO ₂ R ¹⁹ .

In one embodiment, in formula (III.b.), R ³ is -OC (O) R ²⁴ .

In one embodiment, in formula (III.b.), R ³ is —C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula (III.b.), R ³ is -NR ²³ C (N-CN) NR ²⁵ R ²⁶ .

In one embodiment, in formula (III.b.), R ³ is -NR ²³ C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula (III.b.), R ³ is methyl, ethyl, propyl (straight or branched), butyl (straight or branched), pentyl (straight or branched), phenyl,

It is selected from the group consisting of.

In one embodiment, in formula (III.b.), when E is -NR ^6- , R ³ is absent.

In one embodiment, Formula (III.b.) has the general structure (III.b.1):

Formula (III.b.1)

In the above formula (III.b.1),

R ¹ , R ² , R ³ , R ²⁷ , R ²⁸ , p, E and ring B are independently selected from each other, where:

E is -O-, -S-, -S (O)-, -S (O) _2- , -C (R ⁴ ) (R ⁵ )-, -N (R ⁶ )-, -N (C ( Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, and -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-;

p, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ²⁷ , R ²⁸ , Y, and any substituents on ring B are represented by As defined in any of the embodiments described above in III.b.).

In one embodiment, Formula (III.b) has the general structural formula shown in Formula (III.b.2):

Formula (III.b.2)

In one embodiment, Formula (III.b) has the general structural formula shown in Formula (III.b.2.1):

Formula (III.b.2.1)

In one embodiment, Formula (III.b) has the general structural formula shown in Formula (III.b.2.2):

Formula (III.b.2.2)

In one embodiment, Formula (III.b) has the general structural formula shown in Formula (III.b.2.3):

Formula (III.b.2.3)

In one embodiment, Formula (III.b) has the general structural formula shown in Formula (III.b.2.4):

Formula (III.b.2.4)

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, in the case of .b.2.4), p is zero.

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4).

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4).

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, In .b.2.4), E is -C (R ⁴ ) (R ⁵ )-.

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4), E is selected from the group consisting of -O-, -S-, -S (O)-, -S (O) _2- , and -N (R ⁶ )-.

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4), E is selected from the group consisting of -O-, -S-, -S (O)-, -S (O) _2- , and -N (R ⁶ )-, wherein R ⁶ is selected from the group consisting of H, alkyl, -C (O) R ²⁴ , and -C (S) R ²⁴ .

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4), E is selected from the group consisting of -O- and -N (R ⁶ )-, wherein R ⁶ is H, alkyl, -C (O) R ²⁴ , and -C (S) R ²⁴ is selected from the group consisting of.

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, in .b.2.4), E is -O-.

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, in .b.2.4), E is -S-.

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4), E is -S (O)-.

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4), E is -S (O) _2- .

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, In .b.2.4), E is -C (R ⁴ ) (R ⁵ )-.

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4), E is -N (R ⁶ )-.

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4), E is -N (C (Y) R ⁷ )-.

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4), E is -N (C (Y) OR ⁸ )-.

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, in .b.2.4), E is -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-.

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4), Y is (= O).

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4), Y is (= S).

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4), Y is (= N (R ¹³ )).

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4), Y is (= N (CN)).

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4), Y is (= N (OR ¹⁴ )).

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4), Y is (= N (R ¹⁵ ) (R ¹⁶ )).

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, in .b.2.4), Y is (= C (R ¹⁷ ) (R ¹⁸ )).

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4), R ¹ is phenyl substituted with 1 to 4 substituents which may be the same or different, and each substituent is halo, —OH, —CN, —NO ₂ , —NR ²¹ R ²² , and Independently from the group consisting of haloalkyl.

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4), R ¹ is

It is selected from the group consisting of.

이다.In one embodiment, in formula 1, R ¹ is

to be.

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4), R ¹ is phenyl substituted with 1 to 3 fluoro groups.

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4), R ¹ is phenyl substituted with two fluoro groups.

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4), R ¹ is phenyl substituted with one fluoro group.

이다.In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4), R ¹ is

to be.

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4), R ²⁷ and R ²⁸ are independently selected from the group consisting of H and alkyl.

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4), R ² is alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C (O) R ⁷ , -C (O) OR ⁸ , and -C (O) NR ⁹ R ¹⁰ It is selected from the group consisting of.

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4), R ² is

It is selected from the group consisting of.

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4), p is 1 or 2, and each R ³ is alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (S) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ , -NR ²³ C (O) NR ²⁵ R ²⁶ , and -NR ²³ -C (NH) -NR ²⁶ R ²⁶ . Wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl is optionally independently substituted with one or more substituents which may be unsubstituted or the same or different, each substituent is oxo, halogen, -CN, -NO _2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, Kinil, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, hetero cycloalkenyl, ^{azido, -OR 19, -OC (O)} OR 20, -NR 21 R 22, -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group.

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4), p is 1 and R ³ is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said Alkenyl, and each said heteroalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, and each substituent is oxo, halogen, -CN, -NO ₂ , alkyl, hetero Alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC ( O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C ( O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O ) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ are independently selected.

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4), p is 2 and any two R ³ groups bonded to the same ring A atom are taken together to form a -C (O)-group.

In some embodiments, the formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III), respectively, b.2.4), p is 2, and any two R ³ groups bonded to the same ring A atom are taken together to form —NH—, —NR ⁶ —, O, S, S (O), and S ( O) a spiroheterocycloalkyl group having 1 to 3 ring heteroatoms independently selected from the group consisting of ₂ , or -NH-, -NR ^6- , O, S, S (O), and S (O) To form a spiroheterocycloalkenyl group having 1 to 3 ring heteroatoms independently selected from the group consisting of ₂ .

In one embodiment, the compounds of the present invention have a structure represented by Formula IV and include pharmaceutically acceptable salts, solvates, esters, prodrugs or isomers of said compounds:

Formula IV

In Formula IV above,

R ¹ , R ² , R ³ , R ²⁷ , R ²⁸ , p, E, ring A, and any group attached to ring B and ring B are independently selected from each other, where:

E is selected from the group consisting of -C (R ⁴ ) (R ⁵ )-, -O-, -S-, -S (O)-, -S (O) _2- , and -N (R ⁶ )- Become;

Ring B is an unsubstituted or substituted aromatic ring, or a substituted 5- to 6-membered heteroaromatic ring having unsubstituted or 1 to 3 ring heteroatoms, wherein the ring heteroatoms may be the same or different and And each ring heteroatom is independently selected from the group consisting of N, S, O, S (O), and S (O) ₂ , wherein the substituents on the aromatic ring or the heteroaromatic ring, if any Halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, Cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ independently;

R ¹ is unsubstituted aryl or aryl substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl , Alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O ) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR Independently selected from the group consisting of ²³ C (N—CN) NR ²⁵ R ²⁶ and —NR ²³ C (O) NR ²⁵ R ²⁶ ;

R ² is selected from the group consisting of —C (O) R ⁷ , —C (O) NR ⁹ R ¹⁰ , and —C (O) OR ⁸ ;

p is 0, 1, or 2;

And each R ^3, if present, is alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -C ( O) R ²⁴ , -C (S) R ²⁴ , -C (O) OR ²⁰ , and -C (O) NR ²⁵ R ²⁶ , each independently selected from the above alkyl, each said Heteroalkyl, each said alkenyl, and each said heteroalkenyl is optionally substituted with one or more substituents which may be unsubstituted or the same or different and each substituent is oxo, halogen, -CN,- NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido,- OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -S O ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ Independently from;

All remaining variables are as defined for each embodiment described above in Formula (1).

In one such embodiment, in Formula IV:

E is selected from the group consisting of -O- and -N (R ⁶ )-;

Ring B is unsubstituted or is substituted with benzo, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyri Substituted moiety selected from the group consisting of dazinyl, pyrimidinyl, pyrazinyl, and triazinyl;

R ¹ is phenyl substituted with 1 to 4 substituents which may be the same or different and each substituent is from the group consisting of halo, —OH, —CN, —NO ₂ , —NR ²¹ R ²² , and haloalkyl Independently selected;

R ²⁷ and R ²⁸ are each independently selected from the group consisting of H and alkyl;

R ² is selected from the group consisting of —C (O) R ⁷ , —C (O) NR ⁹ R ¹⁰ , and —C (O) OR ⁸ ;

p is 0 or 1;

Each R ³ (if present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and Each said heteroalkenyl is optionally substituted with one or more substituents which may be unsubstituted or the same or different and each substituent is oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl , Alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C ( N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ^{26 from} the group Are independently selected.

In one such embodiment, in Formula IV:

이고;R ¹ is

ego;

R ⁶ is selected from the group consisting of H, alkyl, -C (O) R ²⁴ , -C (O) OR ²⁰ , and -C (S) R ²⁴ .

In one embodiment, the compounds of the invention have the structural formula shown in Formula (IV.a) and include pharmaceutically acceptable salts, solvates, esters, prodrugs or isomers of the compounds:

Formula (IV.a.)

In the above formula (IV.a.),

R ¹ , R ² , R ³ , R ²⁷ , R ²⁸ , p, E, ring A, and ring B are independently selected from each other, where:

Ring A (including E and unsaturated shown) is a 6-membered cycloalkenyl or heterocycloalkenyl ring;

E is -O-, -S-, -S (O)-, -S (O) _2- , -C (R ⁴ ) (R ⁵ )-, -N (R ⁶ )-, -N (C ( Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-, -C (O) -N (R ¹¹ )- , -N (R ¹¹ ) -C (O)-, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) _2- , -C (O) -O- , -OC (O)-, -ON (R ⁶ )-, -N (R ⁶ ) -O-, -N (R ⁶ ) -N (R ¹² )-, -N = N-, -C (R ⁷ ) = N-, -C (O) -C (R ⁷ ) = N-, -C (O) -N = N-, -0-C (Y) -N (R ¹¹ )-, -N ( R ¹¹ ) -C (Y) -O-, -N (R ¹¹ ) -C (Y) -N (R ¹² )-, -C (Y) -N (R ¹¹ ) -O-, -C (Y ) -N (R ¹¹ ) -N (R ¹² )-, -ON (R ¹¹ ) -C (Y)-, and -N (R ¹² ) -N (R ¹¹ ) -C (Y)- Selected from

Ring B is a substituted or unsubstituted aromatic ring;

p, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ²⁷ , R ²⁸ , Y, and ring B phase Optional substituents are as defined in the respective embodiments described above in Formula (1).

In one embodiment, Formula (IV.a) has the general structural formula shown in Formula (IV.a.1):

Formula (IV.a.1)

In one embodiment, Formula (IV.a) has the general structural formula shown in Formula (IV.a.2):

Formula (IV.a.2)

In one embodiment, Formula (IV.a) has the general structural formula shown in Formula (IV.a.3):

Formula (IV.a.3)

In the above formula (IV.a.3), p is 0, 1, 2, or 3.

In one embodiment, Formula (IV.a) has the general structural formula shown in Formula (IV.a.4):

Formula (IV.a.4)

In the above formula (IV.a.4), p is 0, 1, 2, or 3.

In one embodiment, Formula (IV.a) has the general structural formula shown in Formula (IV.a.5):

Formula (IV.a.5)

In the above formula (IV.a.5), p is 0, 1, 2, or 3.

In one embodiment, Formula (IV.a) has the general structural formula shown in Formula (IV.a.6):

Formula (IV.a.6)

In the above formula (IV.a.6), p is 0, 1, 2, or 3.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), ring A is a cycloalkenyl ring and E is -C (R ⁴ ) (R ⁵ )-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), ring A is a heterocycloalkenyl ring, E is —O—, —S—, —S (O) —, —S (O) ₂ —, and — N (R ⁶ )-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), ring A is a heterocycloalkenyl ring, E is —O—, —S—, —S (O) —, —S (O) ₂ —, and — N (R ⁶ ) —, wherein R ⁶ is selected from the group consisting of H, alkyl, —C (O) R ²⁴ , and —C (S) R ²⁴ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), ring A is a heterocycloalkenyl ring, E is selected from the group consisting of -O- and -N (R ⁶ )-, wherein R ⁶ is H, Alkyl, -C (O) R ²⁴ , and -C (S) R ²⁴ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -O-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -S-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -S (O)-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -S (O) _2- .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -C (R ⁴ ) (R ⁵ )-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -N (R ⁶ )-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -N (C (Y) R ⁷ )-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -N (C (Y) OR ⁸ )-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -C (O) -N (R ¹¹ )-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -N (R ¹¹ ) -C (O)-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -S (O) ₂ -N (R ¹¹ )-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -N (R ¹¹ ) -S (O) _2- .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -C (O) -O-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -OC (O)-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -ON (R ⁶ )-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -N (R ⁶ ) -O-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -N (R ⁶ ) -N (R ¹² )-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -N = N-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -C (R ⁷ ) = N-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -C (O) -C (R ⁷ ) = N-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -C (O) -N = N-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -0-C (Y) -N (R ¹¹ )-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -N (R ¹¹ ) -C (Y) -O-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -N (R ¹¹ ) -C (Y) -N (R ¹² )-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -C (Y) -N (R ¹¹ ) -O-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -C (Y) -N (R ¹¹ ) -N (R ¹² )-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -ON (R ¹¹ ) -C (Y)-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -N (R ¹² ) -N (R ¹¹ ) -C (Y)-.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), Y is (= 0).

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), Y is (= S).

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), Y is (= N (R ¹³ )).

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5) and (IV.a.6), Y is (= N (CN)).

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), Y is (= N (OR ¹⁴ )).

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), Y is (= N (R ¹⁵ ) (R ¹⁶ )).

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), Y is (= C (R ¹⁷ ) (R ¹⁸ )).

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), B is an unsubstituted aromatic ring.

.In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), B is an unsubstituted benzo ring, and formula (IV.a.) has the general structure:

.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), B is an aromatic ring substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, halo Alkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C ( O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), B is a benzo ring substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, halo Alkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C ( O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ¹ is unsubstituted aryl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ¹ is unsubstituted phenyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ¹ is unsubstituted naphthyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ¹ is substituted aryl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ¹ is substituted phenyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ¹ is substituted naphthyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ¹ is aryl substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, halo Alkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁸ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O ) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ¹ is phenyl substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, halo Alkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O ) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ¹ is phenyl substituted with 1 to 4 substituents which may be the same or different and each substituent is halo, —OH, —CN, —NO ₂ , -NR ²¹ R ²² , and haloalkyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and in (IV.a.6), R ¹ is

It is selected from the group consisting of.

이다.In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and in (IV.a.6), R ¹ is

to be.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ¹ is phenyl substituted with 1 to 3 fluoro groups.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ¹ is phenyl substituted with two fluoro groups.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ¹ is phenyl substituted with one fluoro group.

이다.In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and in (IV.a.6), R ¹ is

to be.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ²⁷ and R ²⁸ are independently selected from the group consisting of H and alkyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is —C (Z) R ⁷ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is —C (Z) NR ⁹ R ¹⁰ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is —C (Z) OR ⁸ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is —SO ₂ NR ⁹ R ¹⁰ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is alkyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is heteroalkyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is aryl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is heteroaryl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is cycloalkyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is cycloalkenyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is heterocycloalkyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is heterocycloalkenyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), Z is (= 0).

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), Z is (= S).

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), Z is (= N (R ¹³ )).

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), Z is (= N (CN)).

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), Z is (= N (OR ¹⁴ )).

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), Z is (= N (R ¹⁵ ) (R ¹⁶ )).

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), Z is (= C (R ¹⁷ ) (R ¹⁸ )).

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is -C (Z) R ⁷ and Z is (= 0).

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is —C (O) H.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is —C (O) alkyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is —C (O) CH ₃ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is -C (O) R ⁷ , wherein R ⁷ is alkyl substituted with one or more substituents which may be the same or different and each substituent is Oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, hetero Cycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ are independently selected.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl substituted with 1 to 3 substituents, which may be the same or different and each Substituents of are independently selected from the group consisting of -OR ¹⁹ , -NR ²¹ R ²² , and cycloalkyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl, wherein the alkyl is substituted with alkyl and —OH.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl substituted with 1 to 3 substituents, which may be the same or different and each Substituents of are independently selected from the group consisting of -OH, -NH ₂ , and cyclopropyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl substituted with 1 to 2 substituents, which may be the same or different and each Substituents of are independently selected from the group consisting of -NH ₂ , and cyclopropyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl substituted with —OH.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is —C (O) R ⁷ , wherein R ⁷ is unsubstituted heterocycloalkyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is —C (O) R ⁷ , wherein R ⁷ is substituted heterocycloalkyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is —C (O) R ⁷ , wherein R ⁷ is heterocycloalkyl substituted with one or more substituents which may be the same or different and each Substituents are oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl , Heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C ( O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC ( O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is -C (O) R ⁷ , wherein R ⁷ is substituted piperidine, substituted piperazine, substituted morpholine, substituted pipe Rolidine, and substituted azetidines.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and in (IV.a.6), R ² is

.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is —C (O) NR ⁹ R ¹⁰ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is —C (O) NH ₂ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ and R ¹⁰ may be the same or different and each is independently selected from alkyl .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ is unsubstituted heterocycloalkyl, and R ¹⁰ is from the group consisting of H and alkyl Is selected.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ is substituted heterocycloalkyl, R ¹⁰ is selected from the group consisting of H and alkyl do.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ is heterocycloalkyl substituted with one to three substituents which may be the same or different And each substituent is independently selected from alkyl, and R ¹⁰ is selected from the group consisting of H and alkyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ² is alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C (O) R ⁷ , -C (O) OR ⁸ , and -C (O ) NR ⁹ R ¹⁰ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and in (IV.a.6), R ² is

It is selected from the group consisting of.

이다.In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and in (IV.a.6), R ² is

to be.

이다.In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and in (IV.a.6), R ² is

to be.

이다.In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and in (IV.a.6), R ² is

to be.

이다. In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and in (IV.a.6), R ² is

to be.

이다.In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and in (IV.a.6), R ² is

to be.

이다.In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and in (IV.a.6), R ² is

to be.

이다.In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and in (IV.a.6), R ² is

to be.

이다.In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and in (IV.a.6), R ² is

to be.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), p is 0 and R ³ is absent.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), p is 1.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), p is 2.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), p is 3.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), p is 4.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), p is> 2 and at least two groups R ³ are attached to the same ring atom.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), p is 1 and R ³ is alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloal Kenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R Independently selected from the group consisting of ²⁶ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), p is 2, 3 or 4, and each R ³ is alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl , Cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C And independently selected from the group consisting of (O) NR ²⁵ R ²⁶ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), p is 2, 3 or 4 and at least two groups R ³ are bonded to the same ring carbon atom, wherein each R ^3, which may be the same or different, is Alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO ₂ ,- OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), p is 2, 3 or 4 and at least group R ³ is bonded to the same ring carbon atom, wherein two R ³ groups, which may be the same or different, are A heterocycloalkyl ring containing 1 to 3 heteroatoms selected from the group consisting of cycloalkyl, cycloalkenyl, N, O and S together with the carbon atoms to which they are attached, or selected from the group consisting of N, O and S To form a heterocycloalkenyl ring containing 1 to 3 heteroatoms

In one embodiment, in formula (IV.a), p is 1, 2, 3 or 4 and each R ³ is alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (S) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ , -NR ²³ C (O) NR ²⁵ R ²⁶ , and -NR ²³ -C (NH) -NR ²⁶ Independently selected from the group consisting of R ²⁶ , wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl is unsubstituted or may be the same or different Optionally substituted with any of the above substituents, each substituent being oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl , Cycloalkyl, Cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO _{From the group of 2} R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ Selected independently.

In one embodiment, in formula (IV.a), p is 1 and R ³ is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, wherein each of said alkyl, each of said Heteroalkyl, each said alkenyl, and each said heteroalkenyl is optionally substituted with one or more substituents which may be unsubstituted or the same or different and each substituent is oxo, halogen, -CN,- NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido,- OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ Are independently selected from the group of

In one embodiment, in formula (IV.a), p is 2, 3 or 4 and any two R ³ groups bonded to the same ring A atom are taken together to form a -C (O)-group.

In one embodiment, in formula (IV.a), p is 2, 3 or 4 and any two R ³ groups bonded to the same ring A atom are taken together to form —NH—, —NR ⁶ —, O, Spiroheterocycloalkyl groups having 1 to 3 ring heteroatoms independently selected from the group consisting of S, S (O), and S (O) ₂ , or —NH—, —NR ⁶ —, O, S, And form spiroheterocycloalkenyl groups having 1 to 3 ring heteroatoms independently selected from the group consisting of S (O), and S (O) ₂ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is alkyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is heteroalkyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is alkenyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is heteroalkenyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is alkynyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is heteroalkynyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is aryl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is heteroaryl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is cycloalkyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is cycloalkenyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is heterocycloalkyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is heterocycloalkenyl.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is halogen.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is -CN.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is —NO ₂ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is -OR ¹⁹ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is —OC (O) OR ²⁰ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is -NR ²¹ R ²² .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is —NR ²³ SO ₂ R ²⁴ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is —NR ²³ C (O) OR ²⁰ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is —NR ²³ C (O) R ²⁴ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is —SO ₂ NR ²⁵ R ²⁶ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is —C (O) R ²⁴ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is —C (O) OR ²⁰ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is -SR ¹⁹ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is -S (O) R ¹⁹ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is —SO ₂ R ¹⁹ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is -OC (O) R ²⁴ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is —C (O) NR ²⁵ R ²⁶ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is —NR ²³ C (N—CN) NR ²⁵ R ²⁶ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is —NR ²³ C (O) NR ²⁵ R ²⁶ .

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), R ³ is methyl, ethyl, propyl (straight or branched), butyl (straight or branched), pentyl (straight or branched), phenyl,

It is selected from the group consisting of.

In some embodiments, each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a. 5), and (IV.a.6), E is -NR ⁶ -and R ³ is absent.

In one embodiment, the compounds of the present invention have the structural formula shown in Formula (IV.b.) and include pharmaceutically acceptable salts, solvates, esters, prodrugs or isomers of the compounds:

Formula (IV.b.)

In the above formula (IV.b),

R ¹ , R ² , R ³ , R ²⁷ , R ²⁸ , p, E, ring A, and ring B are independently selected from each other, where:

Ring A (including E and unsaturated shown) is a 6-membered cycloalkenyl or heterocycloalkenyl ring;

E is -O-, -S-, -S (O)-, -S (O) _2- , -C (R ⁴ ) (R ⁵ )-, -N (R ⁶ )-, -N (C ( Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-, -C (O) -N (R ¹¹ )- , -N (R ¹¹ ) -C (O)-, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) _2- , -C (O) -O- , -OC (O)-, -ON (R ⁶ )-, -N (R ⁶ ) -O-, -N (R ⁶ ) -N (R ¹² )-, -N = N-, -C (R ⁷ ) = N-, -C (O) -C (R ⁷ ) = N-, -C (O) -N = N-, -0-C (Y) -N (R ¹¹ )-, -N ( R ¹¹ ) -C (Y) -O-, -N (R ¹¹ ) -C (Y) -N (R ¹² )-, -C (Y) -N (R ¹¹ ) -O-, -C (Y ) -N (R ¹¹ ) -N (R ¹² )-, -O- N (R ¹¹ ) -C (Y)-, and -N (R ¹² ) -N (R ¹¹ ) -C (Y)- Selected from the group consisting of:

Ring B is a substituted or unsubstituted heteroaromatic ring;

p, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ²⁷ , R ²⁸ , Y, and ring B phase Optional substituents are as defined in any of the embodiments described above in Formula (1).

In one embodiment, Formula (IV.b) has the general structural formula shown in Formula (IV.b.1):

Formula (IV.b.1)

In one embodiment, Formula (IV.b) has the general structural formula shown in Formula (IV.b.2):

Formula (IV.b.2)

In one embodiment, Formula (IV.b) has the general structural formula shown in Formula (IV.b.3):

Formula (IV.b.3)

In the above formula (IV.b.3), p is 0, 1, 2, or 3.

In one embodiment, Formula (IV.b) has the general structural formula shown in Formula (IV.b.4):

Formula (IV.b.4)

In the above formula (IV.b.4), p is 0, 1, 2, or 3.

In one embodiment, Formula (IV.b) has the general structural formula shown in Formula (IV.b.5):

Formula (IV.b.5)

In the above formula (IV.b.5), p is 0, 1, 2, or 3.

In one embodiment, Formula (IV.b) has the general structure shown in Formula (IV.b.6):

Formula (IV.b.6)

In the above formula (IV.b.6), p is 0, 1, 2, or 3.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), ring A is a cycloalkenyl ring and E is -C (R ⁴ ) (R ⁵ )-.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is from the group consisting of -O-, -S-, -S (O)-, -S (O) _2- , and -N (R ⁶ )- Is selected.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is from the group consisting of -O-, -S-, -S (O)-, -S (O) _2- , and -N (R ⁶ )- Wherein R ⁶ is selected from the group consisting of H, alkyl, -C (O) R ²⁴ , and -C (S) R ²⁴ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is selected from the group consisting of -O- and -N (R ⁶ )-, wherein R ⁶ is H, alkyl, -C (O) R ²⁴ , And -C (S) R ²⁴ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -O-.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -S-.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -S (O)-.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -S (O) _2- .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -C (R ⁴ ) (R ⁵ )-.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -N (R ⁶ )-.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -N (C (Y) R ⁷ )-.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -N (C (Y) OR ⁸ )-.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -C (O) -N (R ¹¹ )-.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -N (R ¹¹ ) -C (O)-.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -S (O) ₂ -N (R ¹¹ )-.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -N (R ¹¹ ) -S (O) _2- .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -C (O) -O-.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -OC (O)-.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -ON (R ⁶ )-.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -N (R ⁶ ) -O-.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -N (R ⁶ ) -N (R ¹² )-.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -N = N-.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -C (R ⁷ ) = N-.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -C (O) -C (R ⁷ ) = N-.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -C (O) -N = N-.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -OC (Y) -N (R ¹¹ )-.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -N (R ¹¹ ) -C (Y) -O-.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -N (R ¹¹ ) -C (Y) -N (R ¹² )-.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -C (Y) -N (R ¹¹ ) -O-.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -C (Y) -N (R ¹¹ ) -N (R ¹² )-.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -0-N (R ¹¹ ) -C (Y)-.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), E is -N (R ¹² ) -N (R ¹¹ ) -C (Y)-.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), Y is (= O).

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), Y is (= S).

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), Y is (= N (R ¹³ )).

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), Y is (= N (CN)).

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), Y is (= N (OR ¹⁴ )).

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), Y is (= N (R ¹⁵ ) (R ¹⁶ )).

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), Y is (= C (R ¹⁷ ) (R ¹⁸ )).

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), B is an unsubstituted heteroaromatic ring.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), B is an unsubstituted 5 to 6 membered heteroaromatic ring having 1 to 3 ring heteroatoms which may be the same or different and each hetero ring atom is Independently from the group consisting of N, S, O, S (O), and S (O) ₂ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), B is a heteroaromatic ring substituted with one or more substituents which may be the same or different, each substituent being halogen, —CN, —NO ₂ , alkyl, heteroalkyl, Haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azi Degrees, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C Independently selected from the group consisting of (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), B is a 5-6 membered heteroaromatic ring having from 1 to 3 ring heteroatoms which may be the same or different and each heterocycle is N, S, O , S (O), and S (O) ₂ , independently selected from the group consisting of: wherein the heteroaromatic ring is substituted with one or more substituents which may be the same or different, and each substituent is halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl , Heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C ( O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC ( O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), B is an unsubstituted 6-membered heteroaromatic ring having 1 to 3 ring heteroatoms which may be the same or different and each hetero ring atom is N, S And are independently selected from the group consisting of O.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), B is a 6 membered heteroaromatic ring having from 1 to 3 ring heteroatoms which may be the same or different and each hetero ring atom is N, S, and O Independently selected from the group consisting of: wherein the heteroaromatic ring is substituted with one or more substituents which may be the same or different and each substituent is halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl , Haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , Independently from the group consisting of —NR ²³ C (N—CN) NR ²⁵ R ²⁶ and —NR ²³ C (O) NR ²⁵ R ²⁶ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), B is an unsubstituted 6 membered heteroaromatic ring having two ring heteroatoms, each ring heteroatom selected independently from N, S, and O.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), B is a 6 membered heteroaromatic ring having 2 ring heteroatoms, each ring heteroatom is independently selected from N, S, and O, wherein hetero Aromatic rings are substituted with one or more substituents which may be the same or different, and each substituent is halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, -OR ¹⁹ , -NR ²¹ R ²² , -C (O ) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , and -C (O) NR ²⁵ R ²⁶ Independently from the group.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), B is an unsubstituted 5-membered heteroaromatic ring having 1 to 2 ring heteroatoms which may be the same or different and each hetero ring atom is N, S And are independently selected from the group consisting of O.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), B is a 5 membered heteroaromatic ring having 1 to 2 ring heteroatoms which may be the same or different and each hetero ring atom is N, S, and O Independently selected from the group consisting of: wherein the heteroaromatic ring is substituted with one or more substituents which may be the same or different and each substituent is halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl , Haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , Independently from the group consisting of —NR ²³ C (N—CN) NR ²⁵ R ²⁶ and —NR ²³ C (O) NR ²⁵ R ²⁶ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), B is an unsubstituted 5-membered heteroaromatic ring having one ring heteroatom selected from N, S, and O.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5), and (IV.b.6), B is a 5-membered heteroaromatic ring having one ring heteroatom selected from N, S, and O, wherein the heteroaromatic rings are one or more which may be the same or different Substituents, each substituent being halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, -OR ¹⁹ , -NR ²¹ R ²² , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , and -C (O) NR ²⁵ R ²⁶ are independently selected.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), B is a 5-membered heteroaromatic ring having S as ring heteroatom, wherein the hetero ring is substituted with one or more substituents which may be the same or different, each substituent being halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, -OR ¹⁹ , -NR ²¹ R ²² , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ^{24 and} -C (O) NR ²⁵ R ²⁶ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), B is an unsubstituted 5-membered heteroaromatic ring having S as ring heteroatom.

로 이루어진 그룹으로부터 선택된다.In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5) and (IV.b.6), B is

It is selected from the group consisting of.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ¹ is unsubstituted aryl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ¹ is unsubstituted phenyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ¹ is unsubstituted naphthyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ¹ is substituted aryl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ¹ is substituted phenyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ¹ is substituted naphthyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ¹ is aryl substituted with one or more substituents which may be the same or different, wherein each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, halo Alkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O ) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ¹ is phenyl substituted with one or more substituents which may be the same or different, wherein each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, halo Alkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O ) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ¹ is phenyl substituted with 1 to 4 substituents which may be the same or different and each substituent is halo, —OH, —CN ₁ —NO ₂ , —NR ²¹ R ²² and haloalkyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5) and (IV.b.6), R ¹ is

It is selected from the group consisting of.

이다.In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5) and (IV.b.6), R ¹ is

to be.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ¹ is phenyl substituted with 1 to 3 fluoro groups.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ¹ is phenyl as two fluoro groups.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ¹ is phenyl substituted with one fluoro group.

이다.In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5) and (IV.b.6), R ¹ is

to be.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ²⁷ and R ²⁸ are selected from the group consisting of H and alkyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is —C (Z) R ⁷ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is —C (Z) NR ⁹ R ¹⁰ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is —C (Z) OR ⁸ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is —SO ₂ NR ⁹ R ¹⁰ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is alkyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is heteroalkyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is aryl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is heteroaryl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is cycloalkyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is cycloalkenyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is heterocycloalkyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is heterocycloalkenyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), Z is (= 0).

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), Z is (= S).

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), Z is (= N (R ¹³ )).

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), Z is (= N (CN)).

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), Z is (= N (OR ¹⁴ )).

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), Z is (= N (R ¹⁵ ) (R ¹⁶ )).

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), Z is (= C (R ¹⁷ ) (R ¹⁸ )).

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is —C (Z) R ⁷ and Z is (= 0).

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is —C (O) H.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is —C (O) alkyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is —C (O) CH ₃ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is —C (O) R ⁷ where R ⁷ is alkyl substituted with one or more substituents which may be the same or different and each substituent is oxo, halogen , -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl , Azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , Independently from the group consisting of —C (O) NR ²⁵ R ²⁶ , —NR ²³ C (N—CN) NR ²⁵ R ²⁶ and —NR ²³ C (O) NR ²⁵ R ²⁶ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl substituted with 1 to 3 substituents which may be the same or different, wherein each substituent is -OR ¹⁹ , -NR ²¹ R ²² And Independently from the group consisting of cycloalkyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is —C (O) R ⁷ where alkyl is substituted with alkyl and —OH.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl substituted with 1 to 3 substituents which may be the same or different and each substituent is — Independently selected from the group consisting of OH, -NH ₂ and cyclopropyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is —C (O) R ⁷ where R ⁷ is alkyl substituted with —OH.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is —C (O) R ⁷ , wherein R ⁷ is substituted heterocycloalkyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ⁷ is substituted heterocycloalkyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is —C (O) R ⁷ , wherein R ⁷ is heterocycloalkyl substituted with one or more substituents which may be the same or different and each of the substituents Oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, hetero Cycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ are independently selected.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5) and (IV.b.6), R ² is —C (O) R ⁷ , wherein R ⁷ is substituted piperidine, substituted piperazine, substituted morpholine, substituted pyrrolidine and Selected from the group consisting of substituted azetidines.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5) and (IV.b.6), R ² is

It is selected from the group consisting of.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is —C (O) NR ⁹ R ¹⁰ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is —C (O) NH ₂ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ and R ¹⁰ may be the same or different and each is independently selected from alkyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ is unsubstituted heterocycloalkyl and R ¹⁰ is selected from the group consisting of H and alkyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ is unsubstituted heterocycloalkyl and R ¹⁰ is selected from the group consisting of H and alkyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ is heterocycloalkyl substituted with 1 to 3 substituents which may be the same or different, wherein Each substituent is selected from alkyl and R ¹⁰ is selected from the group consisting of H and alkyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ² is alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, —C (O) R ⁷ , —C (O) OR ⁸ and -C (O) NR ⁹ R ¹⁰ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5) and (IV.b.6), R ² is

It is selected from the group consisting of.

이다. In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5) and (IV.b.6), R ² is

to be.

이다. In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5) and (IV.b.6), R ² is

to be.

이다. In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5) and (IV.b.6), R ² is

to be.

이다. In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5) and (IV.b.6), R ² is

to be.

이다. In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5) and (IV.b.6), R ² is

to be.

이다. In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5) and (IV.b.6), R ² is

to be.

이다. In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5) and (IV.b.6), R ² is

to be.

이다. In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5) and (IV.b.6), R ² is

to be.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), p is 0 and R ³ is absent.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), p is 1.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), p is 2.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), p is 3.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), p is 4.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), p is> 2 and two or more groups R ³ are attached to the same ring atom.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), p is 1 and R ³ alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, hetero Cycloalkyl, heterocycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ ,- SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ Independently from the group.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), p is 2, 3 or 4 and each R ³ is alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, Cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ ,- S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C ( O) NR ²⁵ R ²⁶ is independently selected from the group consisting of.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), p is 2, 3 or 4 and at least two groups R ³ are bonded to the same carbon atom, wherein each R ^3, which may be the same or different, is alkyl, hetero Alkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , —NR ²³ C (N—CN) NR ²⁵ R ²⁶ and —NR ²³ C (O) NR ²⁵ R ²⁶ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), p is 2, 3 or 4 and two or more groups R ³ are bonded to the same carbon atom, wherein two R ^3, which may be the same or different, are attached to them Heterocycloalkyl rings comprising 1 to 3 heteroatoms selected from the group consisting of cycloalkyl, cycloalkenyl, N, O and S together with carbon atoms, or 1 to 3 selected from the group consisting of N, O and S To form a heterocycloalkenyl ring containing heteroatoms.

In one embodiment, each of the formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b) .5) and (IV.b.6), p is 1, 2, 3 or 4 and each R ³ is alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (S) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ , -NR ²³ C (O) NR ²⁵ R ²⁶ and -NR ²³ -C (NH) -NR ²⁶ R ²⁶ Independently selected from the group consisting of: wherein each alkyl, each heteroalkyl, each alkenyl and each heteroalkenyl described above is optionally independently substituted with one or more substituents which may be unsubstituted or the same or different And each substituent is oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalky Nil, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl. Heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O ) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O ) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ^{26 and} -NR ²³ C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula (IV.b), p is 1 and R ³ is selected from the group consisting of alkyl, heteroalkyl, alkenyl and heteroalkenyl, wherein each alkyl, each heteroalkyl, each Alkenyl and each heteroalkenyl are optionally independently substituted with one or more substituents that may be unsubstituted or the same or different, and each substituent is oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, halo Alkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C a (N-CN) group consisting of NR ²⁵ R ²⁶ and ^{-NR 23 C (O) NR 25} R 26 It is selected as the site independently.

In one embodiment, in formula (IV.b), p is 2, 3 or 4 and any two R ³ groups bonded to the same ring A are taken together to form a -C (O)-group.

In one embodiment, in formula (IV.b), p is> 2 and any two R ³ groups bonded to the same ring A are taken together to -NH-, -NR ^6- , O, S, S ( Spiroheterocycloalkyl groups having 1 to 3 ring heteroatoms independently selected from the group consisting of O) and S (O) ₂ , or —NH—, —NR ⁶ —, O, S, S (O) and S A spiroheterocycloalkenyl group having 1 to 3 heteroatoms independently selected from the group consisting of (O) ₂ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ³ is alkyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ³ is heteroalkyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ³ is alkenyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ³ is heteroalkenyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ³ is alkynyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ³ is heteroalkynyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ³ is aryl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ³ is heteroaryl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ³ is cycloalkyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ³ is cycloalkenyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ³ is heterocycloalkyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ³ is heterocycloalkenyl.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ³ is halogen.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ³ is -CN.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ³ is —NO ₂ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ³ is -OR ¹⁹ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ³ is —OC (O) OR ²⁰ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5) and (IV.b.6), R ³ is -NR ²¹ R ²² .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ³ is —NR ²³ SO ₂ R ²⁴ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ³ is —NR ²³ C (O) OR ²⁰ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ³ is —NR ²³ C (O) R ²⁴ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ³ is —SO ₂ NR ²⁵ R ²⁶ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ³ is —C (O) R ²⁴ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ³ is —C (O) OR ²⁰ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ³ is -SR ¹⁹ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ³ is -S (O) R ¹⁹ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ³ is —SO ₂ R ¹⁹ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ³ is -OC (O) R ²⁴ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), R ³ is —C (O) NR ²⁵ R ²⁶ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5) and (IV.b.6), R ³ is -NR ²³ C (N-CN) NR ²⁵ R ²⁶ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5) and (IV.b.6), R ³ is —NR ²³ C (O) NR ²⁵ R ²⁶ .

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. 5) and (IV.b.6), R ³ is methyl, ethyl, propyl (straight or branched), butyl (straight or branched), pentyl (straight or branched), phenyl,

It is selected from the group consisting of.

In some embodiments, each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b. In 5) and (IV.b.6), E is -NR ⁶ -and R ³ is absent.

In one embodiment, the compounds of the present invention are of formula (V.a) [or, formula 5.a; Or pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers of the compounds,

Formula V.a

In Chemical Formula V.a,

R ¹ , R ² , R ³ , R ²⁷ , R ²⁸ , p, E, ring A and ring B are independently selected from each other, wherein ring A (including indicated E and unsaturated) is a 7 or 8 membered cycloalkenyl or Heterocycloalkenyl ring,

E is -O-, -S-, -S (O)-, -S (O) _2- , -C (R ⁴ ) (R ⁵ )-, -N (R ⁶ )-, -N (C ( Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-, -C (O) -N (R ¹¹ )- , -N (R ¹¹ ) -C (O)-, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) _2- , -C (O) -O- , -OC (O)-, -ON (R ⁶ )-, -N (R ⁶ ) -O-, -N (R ⁶ ) -N (R ¹² )-, -N = N-, -C (R ⁷ ) = N-, -C (O) -C (R ⁷ ) = N-, -C (O) -N = N-, -0-C (Y) -N (R ¹¹ )-, -N ( R ¹¹ ) -C (Y) -O-, -N (R ¹¹ ) -C (Y) -N (R ¹² )-, -C (Y) -N (R ¹¹ ) -O-, -C (Y ) -N (R ¹¹ ) -N (R ¹² )-, -ON (R ¹¹ ) -C (Y)-and -N (R ¹² ) -N (R ¹¹ ) -C (Y)- Selected,

Ring B is an unsubstituted or substituted aromatic ring,

p, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ²⁷ , R ²⁸ , Y and on ring B Optional substituents are as defined in each of the embodiments described above in Formula (1).

In one embodiment, Formula (V.a) has the general structural formula shown in Formula (V.a.1):

Formula V.a.1

In one embodiment, Formula (V.a) has the general structural formula shown in Formula (V.a.2):

Formula V.a.2

In one embodiment, Formula (V.a) has the general structure shown in Formula (V.a.3):

Formula V.a.3

In this formula,

P is 0, 1, 2 or 3.

In one embodiment, Formula (V.a) has the general structural formula shown in Formula (V.a.4):

Formula V.a.4

In this formula,

P is 0, 1, 2 or 3.

In one embodiment, Formula (V.a) has the general structural formula shown in Formula (V.a.5):

Formula V.a.5

In this formula,

P is 0, 1, 2 or 3.

In one embodiment, Formula (V.a) has the general structural formula shown in Formula (V.a.6):

Formula V.a.6

In this formula,

P is 0, 1, 2 or 3.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), ring A is a cycloalkenyl ring and E is -C (R ⁴ ) (R ⁵ )-.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), ring A is a heterocycloalkenyl ring and E is -O- , -S-, -S (O)-, -S (O) _2-, and -N (R ⁶ )-.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -O-, -S-, -S (O )-, -S (O) ₂ -and -N (R ⁶ )-, wherein R ⁶ is H, alkyl, -C (O) R ²⁴ and -C (S) R ²⁴ is selected from the group consisting of.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -O- and -N (R ⁶ )- And R ⁶ is selected from the group consisting of H, alkyl, -C (O) R ²⁴ and -C (S) R ²⁴ .

In some embodiments, in each formula (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5) and (V.a.6), E is -O-.

In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5) and (V.a.6), E is -S-.

 In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -S (O)- to be.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -S (O) _2- .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -C (R ⁴ ) (R ⁵ )- .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -N (R ⁶ )-.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -N (C (Y) R ⁷ )- .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -N (C (Y) OR ⁸ )- ^.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -C (O) -N (R ¹¹ )- to be.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -N (R ¹¹ ) -C (O)- to be.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -S (O) ₂ -N (R ¹¹ ) -to be.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -N (R ¹¹ ) -S (O) ₂ -to be.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -C (O)- O-.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -OC (O)- to be.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -0-N (R ⁶ )-.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -N (R ⁶ ) -O-.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -N (R ⁶ ) -N (R ¹² ) -to be.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -N = N- .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -C (R ⁷ ) = N-.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -C (O) -C (R ⁷ ) = N-.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -C (O)- N = N-.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -0-C (Y) -N (R ^11). )-to be.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -N (R ¹¹ ) -C (Y)- O-.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -N (R ¹¹ ) -C (Y)- N (R ¹² )-.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -C (Y) -N (R ¹¹ )- O-.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -C (Y) -N (R ¹¹ )- N (R ¹² )-.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -ON (R ¹¹ ) -C (Y)- to be.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), E is -N (R ¹² ) -N (R ¹¹ ) -C (Y)-.

In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5) and (V.a.6), Y is (= 0).

In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5) and (V.a.6), Y is (= S).

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), Y is (= N (R ¹³ )).

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), Y is O = N (CN) )to be.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), Y is (= N (OR ¹⁴ )).

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), Y is (= N (R ¹⁵ ) (R ¹⁶ )) to be.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), Y is (= C (R ¹⁷ ) (R ¹⁸ )) to be.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), B is an unsubstituted aromatic ring .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), B is an unsubstituted benzo ring Formula (IV.a.) [or Formula 4.a; Hereafter expressed in the same manner has the following general structure:

Formula IV.a

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), B is substituted with one or more substituents which may be the same or different Aromatic ring, each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, hetero Aryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), B is substituted with one or more substituents which may be the same or different Benzo ring, each substituent is halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, hetero Aryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and Independently selected from the group consisting of NR ²³ C (O) NR ²⁵ R ²⁶ .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ¹ is unsubstituted aryl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ¹ is unsubstituted phenyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ¹ is unsubstituted naphthyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ¹ is substituted aryl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ¹ is substituted phenyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ¹ is substituted naphthyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ¹ is substituted with one or more substituents which may be the same or different Aryl, each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, hetero Aryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ ,- NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S ( O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ¹ is substituted with one or more substituents which may be the same or different Phenyl, each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, hetero Aryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ ,- NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S ( O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ¹ is 1 to 4 substituents which may be the same or different Is phenyl substituted with each substituent being halogen, -OH, -CN, -NO ₂ , -NR ²¹ R ²² and Independently from the group consisting of haloalkyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ¹ is

It is selected from the group consisting of.

이다.In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ¹ is

to be.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ¹ is phenyl substituted with 1 to 3 fluoro groups to be.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ¹ is phenyl substituted with two fluoro groups.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ¹ is phenyl substituted with one fluoro group.

이다.In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ¹ is

to be.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ²⁷ and R ²⁸ is each independently selected from the group consisting of H and alkyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is —C (Z) R ⁷ .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is —C (Z) NR ⁹ R ¹⁰ .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is —C (Z) OR ⁸ .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is —SO ₂ NR ⁹ R ¹⁰ .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is alkyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is heteroalkyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is aryl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is heteroaryl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is cycloalkyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is cycloalkenyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is heterocycloalkyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is heterocycloalkenyl.

In some embodiments, in each formula (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5) and (V.a.6), Z is (= 0).

In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5) and (V.a.6), Z is (= S).

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), Z is (= N (R ¹³ )).

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), Z is (= N (CN) )to be.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), Z is (= N (OR ¹⁴ )).

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), Z is (= N (R ¹⁵ ) (R ¹⁶ )) to be.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), Z is (= C (R ¹⁷ ) (R ¹⁸ )) to be.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is -C (Z) R ⁷ and Z is ( = 0).

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is —C (O) H.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is —C (O) alkyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is —C (O) CH ₃ .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl substituted with one or more substituents which may be the same or different and each substituent is oxo, halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl , Haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ ,- SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl substituted with 1 to 3 substituents which may be the same or different and each substituent is selected from —OR ¹⁹ , —NR ²¹ R ²² and Independently selected from the group consisting of cycloalkyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl, wherein alkyl is substituted with alkyl and -OH.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl substituted with 1 to 3 substituents which may be the same or different, and each substituent is —OH, —NH ₂ and Independently selected from the group consisting of cyclopropyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl substituted with 1 to 2 substituents which may be the same or different and each substituent is selected from -NH ₂ and Independently selected from the group consisting of cyclopropyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl substituted with —OH.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is —C (O) R ⁷ , wherein R ⁷ is unsubstituted heterocycloalkyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is —C (O) R ⁷ , wherein R ⁷ is unsubstituted heterocycloalkyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is —C (O) R ⁷ , wherein R ⁷ is heterocycloalkyl substituted with one or more substituents which may be the same or different and each substituent is oxo, halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, Alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² ,- NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ And -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is —C (O) R ⁷ , wherein R ⁷ is selected from the group consisting of substituted piperidine, substituted piperazine, substituted morpholine, substituted pyrrolidine and substituted azetidine.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is

Is selected from.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is —C (O) NR ⁹ R ¹⁰ .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is —C (O) NH ₂ .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is —C (O) NR ⁹ R ¹⁰ , Where R ⁹ and R ¹⁰ may be the same or different and each is independently selected from alkyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is —C (O) NR ⁹ R ¹⁰ , Wherein R ⁹ is unsubstituted heterocycloalkyl and R ¹⁰ is selected from the group consisting of H and alkyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is —C (O) NR ⁹ R ¹⁰ , Wherein R ⁹ is unsubstituted heterocycloalkyl and R ¹⁰ is selected from the group consisting of H and alkyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is —C (O) NR ⁹ R ¹⁰ , Wherein R ⁹ is heterocycloalkyl substituted with 1 to 3 substituents which may be the same or different, each substituent is independently selected from alkyl, and R ¹⁰ is selected from the group consisting of H and alkyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is alkyl, haloalkyl, heteroalkyl, heterohalo Alkyl, -C (0) R ⁷ , -C (0) OR ⁸ and -C (O) NR ⁹ R ¹⁰ .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is

It is selected from the group consisting of.

이다. In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is

to be.

이다. In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is

to be.

이다. In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is

to be.

이다. In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is

to be.

이다. In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is

to be.

이다. In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is

to be.

이다.In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is

to be.

이다.In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ² is

to be.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), p is 0 and R ³ is absent.

In some embodiments, in each formula (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5) and (V.a.6), p is 1.

In some embodiments, in each Formula (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5) and (V.a.6), p is 2.

In some embodiments, in each formula (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5) and (V.a.6), p is 3.

In some embodiments, in each formula (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5) and (V.a.6), p is 4.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), p is> 2 and at least two groups R ³ are the same ring Attached to an atom.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), p is 1 and R ³ is alkyl, heteroalkyl, alkenyl , Heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O ) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), p is 2, 3 or 4, and each R ³ is Alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO ₂ ,- OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), p is 2, 3 or 4 and at least two groups R ³ is bonded to the same ring carbon atom, wherein each R ³ may be the same or different and is alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl , Cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ ,- NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S ( O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), p is 2, 3 or 4 and at least two groups R ³ is bonded to the same ring carbon atom, wherein two R ³ groups may be the same or different and are selected from the group consisting of cycloalkyl, cycloalkenyl, N, O and S together with the carbon atom to which they are attached Heterocycloalkyl ring containing 3 to 3 heteroatoms or heterocycloalkenyl ring containing 1 to 3 heteroatoms selected from the group consisting of N, O and S.

In one embodiment, in formula (Va), p is 1, 2, 3 or 4 and each R ³ is alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (S) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ , -NR ²³ C (O) NR ²⁵ R ²⁶ and -NR ²³ -C (NH) -NR ²⁶ R ²⁶ is independently selected from the group consisting of: each said alkyl, each said heteroalkyl, each said alkenyl and each said heteroalkenyl is unsubstituted Or optionally independently substituted with one or more substituents which may be the same or different and each substituent is oxo, halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl , Heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ ,- SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In one embodiment, in formula Va, p is 1 and R ³ is selected from the group consisting of alkyl, heteroalkyl, alkenyl and heteroalkenyl,

Wherein each said alkyl, each said heteroalkyl, each said alkenyl and each said heteroalkenyl is optionally independently substituted with one or more substituents which may be unsubstituted, identical or different, and each substituent is Oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cydoalkyl, cycloalkenyl, heterocycloalkyl, hetero Cycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group.

In one embodiment, in formula Va, p is 2, 3 or 4 and any two R ³ groups bonded to the same ring A together form a —C (O) — group.

In one embodiment, in formula Va, p is 2, 3 or 4, and any two R ³ groups bonded to the same ring A together are —NH—, —NR ⁶ —, O, S, S (O) And heterocycloalkyl group having 1 to 3 ring heteroatoms independently selected from the group consisting of S (O) ₂ or —NH—, —NR ⁶ —, O, S, S (O) and S (O) ₂ To form a spiroheterocycloalkenyl group having 1 to 3 ring heteroatoms independently selected from the group consisting of:

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is alkyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is heteroalkyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is alkenyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is heteroalkenyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is alkynyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is heteroalkynyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is aryl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is heteroaryl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is cycloalkyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is cycloalkenyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is heterocycloalkyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is heterocycloalkenyl.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is halogen.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is -CN.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is -NO ₂ .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is -OR ¹⁹ .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is -OC (O) OR ²⁰ .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is -NR ²¹ R ²² .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is -NR ²³ SO ₂ R ²⁴ .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is -NR ²³ C (O) OR ²⁰ .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is -NR ²³ C (O) R ²⁴ .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is —SO ₂ NR ²⁵ R ²⁶ .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is -C (O) R ²⁴ .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is —C (O) OR ²⁰ .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is -SR ¹⁹ .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is -S (O) R ¹⁹ .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is -SO ₂ R ¹⁹ .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is -OC (O) R ²⁴ .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is —C (O) NR ²⁵ R ²⁶ .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is -NR ²³ C (N-CN) NR ²⁵ R ²⁶ .

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is -NR ²³ C (O) NR ²⁵ R ²⁶ to be.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), R ³ is methyl, ethyl, propyl (straight or branched), Butyl (straight or branched), pentyl (straight or branched), phenyl,

It is selected from the group consisting of.

In some embodiments, in each of Formulas (Va), (Va1), (Va2), (Va3), (Va4), (Va5) and (Va6), when E is -NR ^6- , R ³ is absent .

In one embodiment, the compounds of the present invention have a structure of Formula (V.b) and include pharmaceutically acceptable salts, solvates, esters, prodrugs or isomers of the compounds:

Formula V.b

In this formula,

R ¹ , R ² , R ³ , R ²⁷ , R ²⁸ , p, E, ring A and ring B are independently selected from each other, where:

Ring A (including E and unsaturated shown) is a 7- or 8-membered cycloalkenyl or heterocycloalkenyl ring;

E is -O-, -S-, -S (O)-, -S (O) _2- , -C (R ⁴ ) (R ⁵ )-, -N (R ⁶ )-, -N (C ( Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-, -C (O) -N (R ¹¹ )- , -N (R ¹¹ ) -C (O)-, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) _2- , -C (O) -O- , -OC (O)-, -ON (R ⁶ )-, -N (R ⁶ ) -O-, -N (R ⁶ ) -N (R ¹² )-, -N = N-, -C (R ⁷ ) = N-, -C (O) -C (R ⁷ ) = N-, -C (O) -N = N-, -0-C (Y) -N (R ¹¹ )-, -N ( R ¹¹ ) -C (Y) -O-, -N (R ¹¹ ) -C (Y) -N (R ¹² )-, -C (Y) -N (R ¹¹ ) -O-, -C (Y ) -N (R ¹¹ ) -N (R ¹² )-, -ON (R ¹¹ ) -C (Y)-and -N (R ¹² ) -N (R ¹¹ ) -C (Y)- Selected;

Ring B is a substituted or unsubstituted heteroaromatic ring

P, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ²⁷ , R ²⁸ , Y and optionally on ring B Substituent of is as defined above in formula (I).

In one embodiment, in Formula (V.b.), Ring A is a cycloalkenyl ring.

In one embodiment, in Formula (V.b.), Ring A is a heterocycloalkenyl ring.

In one embodiment, in formula (Vb), E is -C (R ⁴ ) (R ⁵ )-.

In one embodiment, in formula (Vb), E is -O-, -S-, -S (O)-, -S (O) _2- , -N (R ⁶ )-, -N (C (Y ) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-, -C (O) -N (R ¹¹ )-, -N (R ¹¹ ) -C (O)-, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) _2- , -C (O) -O-, -OC (O)-, -ON (R ⁶ )-, -N (R ⁶ ) -O-, -N (R ⁶ ) -N (R ¹² )-, -N = N-, -C (R ⁷ ) = N-, -C (O) -C (R ⁷ ) = N-, -C (O) -N = N-, -0-C (Y) -N (R ¹¹ )-, -N (R ¹¹ ) -C (Y) -O-, -N (R ¹¹ ) -C (Y) -N (R ¹² )-, -C (Y) -N (R ¹¹ ) -O-, -C (Y) Select from the group consisting of -N (R ¹¹ ) -N (R ¹² )-, -ON (R ¹¹ ) -C (Y)-and -N (R ¹² ) -N (R ¹¹ ) -C (Y)- do.

In one embodiment, in formula (Vb), E is selected from the group consisting of -O-, -S-, -S (O)-, -S (O) _2-, and -N (R ⁶ )-.

In one embodiment, in formula (Vb), E is selected from the group consisting of -O-, -S-, -S (O)-, -S (O) _2-, and -N (R ⁶ )-, Wherein R ⁶ is H, alkyl, -C (O) R ²⁴ and -C (S) R ²⁴ is selected from the group consisting of.

In one embodiment, in formula (Vb), E is selected from the group consisting of -O- and -N (R ⁶ )-, wherein R ⁶ is H, alkyl, -C (O) R ²⁴ and -C (S) R ²⁴ is selected from the group consisting of.

In one embodiment, in formula (V.b.), E is -O-.

In one embodiment, in formula (V.b.), E is -S-.

In one embodiment, in formula (V.b.), E is -S (O)-.

In one embodiment, in formula (Vb), E is -S (O) _2- .

In one embodiment, in formula (Vb), E is -C (R ⁴ ) (R ⁵ )-.

In one embodiment, in formula (Vb), E is -N (R ⁶ )-.

In one embodiment, in formula (Vb), E is -N (C (Y) R ⁷ )-.

In one embodiment, in formula (Vb), E is -N (C (Y) OR ⁸ )-.

In one embodiment, in formula (Vb), E is -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-.

In one embodiment, in formula (Vb), E is —C (O) —N (R ¹¹ ) —.

In one embodiment, in formula (Vb), E is -N (R ¹¹ ) -C (O)-.

In one embodiment, in formula (Vb), E is -S (O) ₂ -N (R ¹¹ )-.

In one embodiment, in formula (Vb), E is —N (R ¹¹ ) —S (O) ₂ —.

In one embodiment, in formula (V.b.), E is -C (O) -O-.

In one embodiment, in formula (V.b.), E is -O-C (O)-.

In one embodiment, in formula (Vb), E is -ON (R ⁶ )-.

In one embodiment, in formula (Vb), E is -N (R ⁶ ) -O-.

In one embodiment, in formula (Vb), E is -N (R ⁶ ) -N (R ¹² )-.

In one embodiment, in formula (V.b.), E is -N = N-.

In one embodiment, in formula (Vb), E is -C (R ⁷ ) = N-.

In one embodiment, in formula (Vb), E is —C (O) —C (R ⁷ ) ═N—.

In one embodiment, in formula (V.b.), E is -C (O) -N = N-.

In one embodiment, in formula (Vb), E is -0-C (Y) -N (R ¹¹ )-.

In one embodiment, in formula (Vb), E is —N (R ¹¹ ) —C (Y) —O—.

In one embodiment, in formula (Vb), E is -N (R ¹¹ ) -C (Y) -N (R ¹² )-.

In one embodiment, in formula (Vb), E is —C (Y) —N (R ¹¹ ) —O—.

In one embodiment, in formula (Vb), E is -C (Y) -N (R ¹¹ ) -N (R ¹² )-.

In one embodiment, in formula (Vb), E is -ON (R ¹¹ ) -C (Y)-.

In one embodiment, in formula (Vb), E is -N (R ¹² ) -N (R ¹¹ ) -C (Y)-.

In one embodiment, in formula (V.b.), Y is (═O).

In one embodiment, in formula (V.b.), Y is (= S).

In one embodiment, in formula (Vb), Y is (= N (R ¹³ )).

In one embodiment, in formula (V.b.), Y is (= N (CN)).

In one embodiment, in formula (Vb), Y is (= N (OR ¹⁴ )).

In one embodiment, in formula (Vb), Y is (= N (R ¹⁵ ) (R ¹⁶ )).

In one embodiment, in formula (Vb), Y is (═C (R ¹⁷ ) (R ¹⁸ )).

In one embodiment, in formula (V.b.), B is an unsubstituted heteroaromatic ring.

In one embodiment, in formula (Vb), B is an unsubstituted 5-6 membered heteroaromatic ring having from 1 to 3 ring heteroatoms, which may be the same or different, and each hetero ring is N, S, Independently selected from the group consisting of O, S (O) and S (O) ₂ .

In one embodiment, in formula (Vb), B is a heteroaromatic ring substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl , Alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In one embodiment, in formula (Vb), B is a 5 or 6 membered heteroaromatic ring having 1 to 3 ring heteroatoms which may be the same or different and each hetero ring atom is N, S, O, Independently selected from the group consisting of S (O) and S (O) ₂ , wherein the heteroaromatic ring is substituted with one or more substituents which may be the same or different and each substituent is halogen, -CN, -NO ₂ , alkyl , Heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocyclo Alkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In one embodiment, in formula (Vb), B is an unsubstituted 6-membered heteroaromatic ring having 1 to 3 ring heteroatoms, which may be the same or different, and each hetero ring is N, S and O Independently selected from the group consisting of.

In one embodiment, in formula (Vb), B is a 6 membered heteroaromatic ring having 1 to 3 ring heteroatoms, which may be the same or different and each heterocyclic atom consists of N, S and O Independently selected from the group, said heteroaromatic ring is substituted with one or more substituents which may be the same or different, each substituent being halogen, —CN ₁ —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloal Kenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ ,- NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In one embodiment, in formula (V.b.), B is an unsubstituted six-membered heteroaromatic ring having two heteroatoms, each ring heteroatom selected independently from N, S and O.

In one embodiment, in formula (Vb), B is a 6 membered heteroaromatic ring having 2 ring heteroatoms, each ring heteroatom is independently selected from the group consisting of N, S and O, said hetero Aromatic rings are substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN ₁ —NO ₂ , alkyl, heteroalkyl, haloalkyl, —OR ¹⁹ , —NR ²¹ R ²² , —C (O ) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ and Independently selected from the group consisting of -C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula (Vb), B is an unsubstituted 5 membered heteroaromatic ring having 1 or 2 heteroatoms which may be the same or different and each hetero ring atom is N, S and O Independently selected from the group consisting of.

In one embodiment, in formula (Vb), B is a 5 membered heteroaromatic ring having 1 or 2 heteroatoms, which may be the same or different and each heterocyclic atom is a group consisting of N, S and O Are independently selected from which the heteroaromatic ring is substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl , Alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC ( O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C ( O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ ,- NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In one embodiment, in formula (V.b.), B is an unsubstituted 5 membered heteroaromatic ring having one ring heteroatom selected from N, S and O.

In one embodiment, in formula (Vb), B is a 5-membered heteroaromatic ring having one ring heteroatom selected from N, S and O, wherein the heteroaromatic ring is substituted with one or more substituents which may be the same or different And each substituent is halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, -OR ¹⁹ , -NR ²¹ R ²² , -C (O) R ²⁴ , -C (O) OR ²⁰ ,- SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ and Independently selected from the group consisting of -C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula (Vb), B is a 5-membered heteroaromatic ring having S as ring heteroatom, which heteroaromatic ring is substituted with one or more substituents which may be the same or different and each substituent is halogen , -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, -OR ¹⁹ , -NR ²¹ R ²² , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O ) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ and Independently selected from the group consisting of -C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula (V.b.), B is an unsubstituted 5 membered heteroaromatic ring having S as ring heteroatom.

In one embodiment, in formula (V.b.), B is

It is selected from the group consisting of.

In one embodiment, in formula (Vb), R ¹ is unsubstituted aryl.

In one embodiment, in formula (Vb), R ¹ is unsubstituted phenyl.

In one embodiment, in formula (Vb), R ¹ is unsubstituted naphthyl.

In one embodiment, in formula (Vb), R ¹ is substituted aryl.

In one embodiment, in formula (Vb), R ¹ is substituted phenyl.

In one embodiment, in formula (Vb), R ¹ is substituted naphthyl.

In one embodiment, in formula (Vb), R ¹ is aryl substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, Alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In one embodiment, in formula (Vb), R ¹ is phenyl substituted with one or more substituents, identical or substitutable, each substituent being halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, Alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In one embodiment, in formula (Vb), R ¹ is phenyl substituted with 1 to 4 substituents, which may be the same or different and each substituent is selected from the group consisting of halo, -OH, -CN and haloalkyl Selected independently.

In one embodiment, in formula (Vb), R ¹ is

It is selected from the group consisting of.

이다. In one embodiment, in formula (Vb), R ¹ is

to be.

In one embodiment, in formula (Vb), R ¹ is phenyl substituted with 1 to 3 fluoro groups.

In one embodiment, in formula (Vb), R ¹ is phenyl substituted with two fluoro groups.

In one embodiment, in formula (Vb), R ¹ is phenyl substituted with one fluoro group.

이다.In one embodiment, in formula (Vb), R ¹ is

to be.

In one embodiment, in formula (Vb), R ²⁷ and R ²⁸ is each independently selected from the group consisting of H and alkyl.

In one embodiment, in formula (Vb), R ² is —C (Z) R ⁷ .

In one embodiment, in formula (Vb), R ² is —C (Z) NR ⁹ R ¹⁰ .

In one embodiment, in formula (Vb), R ² is —C (Z) OR ⁸ .

In one embodiment, in formula (Vb), R ² is —SO ₂ NR ⁹ R ¹⁰ .

In one embodiment, in formula (Vb), R ² is alkyl.

In one embodiment, in formula (Vb), R ² is heteroalkyl.

In one embodiment, in formula (Vb), R ² is aryl.

In one embodiment, in formula (Vb), R ² is heteroaryl.

In one embodiment, in formula (Vb), R ² is cycloalkyl.

In one embodiment, in formula (Vb), R ² is cycloalkenyl.

In one embodiment, in formula (Vb), R ² is heterocycloalkyl.

In one embodiment, in formula (Vb), R ² is heterocycloalkenyl.

In one embodiment, in formula (V.b.), Z is (= 0).

In one embodiment, in formula (V.b.), Z is (= S).

In one embodiment, in formula (Vb), Z is (= N (R ¹³ )).

In one embodiment, in formula (V.b.), Z is (= N (CN)).

In one embodiment, in formula (Vb), Z is (= N (OR ¹⁴ )).

In one embodiment, in formula (Vb), Z is (= N (R ¹⁵ ) (R ¹⁶ )).

In one embodiment, in formula (Vb), Z is (═C (R ¹⁷ ) (R ¹⁸ )).

In one embodiment, in formula (Vb), R ² is —C (Z) R ⁷ and Z is (═O).

In one embodiment, in formula (Vb), R ² is —C (O) H.

In one embodiment, in formula (Vb), R ² is —C (O) alkyl.

In one embodiment, in formula (Vb), R ² is —C (O) CH ₃ .

In one embodiment, in formula (Vb), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl substituted with one or more substituents which may be the same or different and each substituent is oxo, halogen , -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl , Azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In one embodiment, in formula (Vb), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl substituted with 1 to 3 substituents, which may be the same or different, and each substituent is -OR ¹⁹ , -NR ²¹ R ²² and Independently selected from the group consisting of cycloalkyl.

In one embodiment, in formula (Vb), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl, wherein said alkyl is substituted with alkyl and —OH.

In one embodiment, in formula (Vb), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl substituted with 1 to 3 substituents, which may be the same or different, and each substituent is -OH, -NH ₂ and Independently selected from the group consisting of cyclopropyl.

In one embodiment, in formula (Vb), R ² is —C (O) R ⁷ wherein R ⁷ may be the same or different and is alkyl substituted with 1 to 3 substituents, each substituent being -NH ₂ and Independently selected from the group consisting of cyclopropyl.

In one embodiment, in formula (Vb), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl substituted with —OH.

In one embodiment, in formula (Vb), R ² is —C (O) R ⁷ , wherein R ⁷ is unsubstituted heterocycloalkyl.

In one embodiment, in formula (Vb), R ² is —C (O) R ⁷ , wherein R ⁷ is unsubstituted heterocycloalkyl.

In one embodiment, in formula (Vb), R ² is —C (O) R ⁷ , wherein R ⁷ is heterocycloalkyl substituted with one or more substituents which may be the same or different and each substituent is oxo , Halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocyclo Alkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In one embodiment, in formula (Vb), R ² is —C (O) R ⁷ , wherein R ⁷ is unsubstituted piperidine, unsubstituted piperazine, unsubstituted morpholine, unsubstituted Selected from the group consisting of pyrrolidine and unsubstituted azetidine.

In one embodiment, in formula (Vb), R ² is

Is selected from.

In one embodiment, in formula (Vb), R ² is —C (O) NR ⁹ R ¹⁰ .

In one embodiment, in formula (Vb), R ² is —C (O) NH ₂ .

In one embodiment, in formula (Vb), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ and R ¹⁰ may be the same or different and each is independently selected from alkyl.

In one embodiment, in formula (Vb), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ is unsubstituted heterocycloalkyl and R ¹⁰ is selected from the group consisting of H and alkyl.

In one embodiment, in formula (Vb), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ is unsubstituted heterocycloalkyl and R ¹⁰ is selected from the group consisting of H and alkyl.

In one embodiment, in formula (Vb), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ is heterocycloalkyl substituted with 1 to 3 substituents, which may be the same or different, and each Substituent of is independently selected from alkyl, R ¹⁰ is selected from the group consisting of H and alkyl.

이다. In one embodiment, in formula (Vb), R ² is

to be.

In one embodiment, in formula (Vb), R ² is to be.

이다. In one embodiment, in formula (Vb), R ² is

to be.

이다.In one embodiment, in formula (Vb), R ² is

to be.

이다.In one embodiment, in formula (Vb), R ² is

to be.

이다.In one embodiment, in formula (Vb), R ² is

to be.

이다.In one embodiment, in formula (Vb), R is

to be.

이다. In one embodiment, in formula (Vb), R ² is

to be.

In one embodiment, in formula (Vb), p is 0 and R ³ is absent.

In one embodiment, in formula (V.b.), p is 1.

In one embodiment, in formula (V.b.), p is 2.

In one embodiment, in formula (V.b.), p is 3.

In one embodiment, in formula (V.b.), p is 4.

In one embodiment, in formula (Vb), p is> 2 and at least two groups R ³ are attached to the same ring atom.

In one embodiment, in formula (Vb), p is 1 and R ³ is alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, hetero Cycloalkyl, heterocycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ ,- SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In one embodiment, in formula (Vb), p is 2, 3 or 4 and each R ³ is alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cyclo Alkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In one embodiment, in formula (Vb), p is 2, 3 or 4 and at least two groups R ³ are bonded to the same ring carbon atom, wherein each R ³ can be the same or different, alkyl, Heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In one embodiment, in formula (Vb), p is 2, 3 or 4 and at least two groups R ³ are bonded to the same ring carbon atom, wherein the two R ³ groups may be the same or different and they are Heterocycloalkyl ring containing 1 to 3 heteroatoms selected from cycloalkyl, cycloalkenyl, N, O and S together with the attached carbon atom or 1 to 3 heteroatoms selected from the group consisting of N, O and S Heterocyclo alkenyl ring containing.

In one embodiment, in formula (Vb), p is> 0 and each R ³ is alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (S) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ , -NR ²³ C (O) NR ²⁵ R ²⁶ and -NR ²³ -C (NH) -NR ²⁶ R ²⁶ is independently selected from the group consisting of

Wherein each said alkyl, each said heteroalkyl, each said alkenyl and each said heteroalkenyl is optionally independently substituted with one or more substituents which may be unsubstituted, identical or different, and each substituent is Oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, hetero Cycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In one embodiment, in formula (Vb), p is 1 and R ³ is selected from the group consisting of alkyl, heteroalkyl, alkenyl and heteroalkenyl, wherein each said alkyl, each said heteroalkyl, Each said alkenyl and each said heteroalkenyl is optionally independently substituted with one or more substituents which may be unsubstituted, identical or different, and each substituent is oxo, halogen, -CN, -NO ₂ , alkyl, Heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In one embodiment, in formula (Vb), p is> 2 and any two R ³ groups bonded to the same A atom together form a —C (O) — group.

In one embodiment, in formula (Vb), p is> 2 and any two R ³ groups bonded to the same ring A atom are taken together with -NH-, -NR ^6- , O, S, S (O) and Spiroheterocycloalkyl groups having 1 to 3 ring heteroatoms independently selected from the group consisting of S (O) ₂ , or —NH—, —NR ⁶ —, O, S, S (O) and S (O) Independently from the group consisting of ₂ a spiroheterocycloalkenyl group having 1 to 3 ring heteroatoms.

In one embodiment, in formula (Vb), R ³ is alkyl.

In one embodiment, in formula (Vb), R ³ is heteroalkyl.

In one embodiment, in formula (Vb), R ³ is alkenyl.

In one embodiment, in formula (Vb), R ³ is heteroalkenyl.

In one embodiment, in formula (Vb), R ³ is alkynyl.

In one embodiment, in formula (Vb), R ³ is heteroalkynyl.

In one embodiment, in formula (Vb), R ³ is aryl.

In one embodiment, in formula (Vb), R ³ is heteroaryl.

In one embodiment, in formula (Vb), R ³ is cycloalkyl.

In one embodiment, in formula (Vb), R ³ is cycloalkenyl.

In one embodiment, in formula (Vb), R ³ is heterocycloalkyl.

In one embodiment, in formula (Vb), R ³ is heterocycloalkenyl.

In one embodiment, in formula (Vb), R ³ is halogen.

In one embodiment, in formula (Vb), R ³ is -CN.

In one embodiment, in formula (Vb), R ³ is —NO ₂ .

In one embodiment, in formula (Vb), R ³ is —OR ¹⁹ .

In one embodiment, in formula (Vb), R ³ is —OC (O) OR ²⁰ .

In one embodiment, in formula (Vb), R ³ is -NR ²¹ R ²² .

In one embodiment, in formula (Vb), R ³ is —NR ²³ SO ₂ R ²⁴ .

In one embodiment, in formula (Vb), R ³ is —NR ²³ C (O) OR ²⁰ .

In one embodiment, in formula (Vb), R ³ is —NR ²³ C (O) R ²⁴ .

In one embodiment, in formula (Vb), R ³ is —SO ₂ NR ²⁵ R ²⁶ .

In one embodiment, in formula (Vb), R ³ is —C (O) R ²⁴ .

In one embodiment, in formula (Vb), R ³ is —C (O) OR ²⁰ .

In one embodiment, in formula (Vb), R ³ is -SR ¹⁹ .

In one embodiment, in formula (Vb), R ³ is -S (O) R ¹⁹ .

In one embodiment, in formula (Vb), R ³ is —SO ₂ R ¹⁹ .

In one embodiment, in formula (Vb), R ³ is -OC (O) R ²⁴ .

In one embodiment, in formula (Vb), R ³ is —C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula (Vb), R ³ is —NR ²³ C (N—CN) NR ²⁵ R ²⁶ .

In one embodiment, in formula (Vb), R ³ is —NR ²³ C (O) NR ²⁵ R ²⁶ .

.In one embodiment, Formula (Vb) has the following general structure:

.

.In one embodiment, Formula (Vb) has the following general structure:

.

In one embodiment, Formula (V.b) has the following general structure:

In this formula,

P is O, 1, 2 or 3.

In one embodiment, Formula (V.b) has the following general structure:

In this formula,

P is 0, 1, 2 or 3.

In one embodiment, Formula (V.b) has the following general structure:

In this formula,

P is 0, 1, 2 or 3.

In one embodiment, Formula (V.b) has the following general structure:

In this formula,

P is 0, 1, 2 or 3.

In one embodiment, the compounds of the present invention have a structure of Formula (VI) and include pharmaceutically acceptable salts, solvates, esters, prodrugs or isomers of the compounds:

In this formula,

R ¹ , R ² , R ³ , R ²⁷ , R ²⁸ , p, E, ring A and ring B are independently selected from each other, where:

Ring A (including E and unsaturated shown) is a 4-8 membered cycloalkenyl or heterocycloalkenyl ring;

E is -O-, -S-, -S (O)-, -S (O) _2- , -C (R ⁴ ) (R ⁵ )-, -N (R ⁶ )-, -N (C ( Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-, -C (O) -N (R ¹¹ )- , -N (R ¹¹ ) -C (O)-, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) _2- , -C (O) -O- , -OC (O)-, -ON (R ⁶ )-, -N (R ⁶ ) -O-, -N (R ⁶ ) -N (R ¹² )-, -N = N-, -C (R ⁷ ) = N-, -C (O) -C (R ⁷ ) = N-, -C (O) -N = N-, -0-C (Y) -N (R ¹¹ )-, -N ( R ¹¹ ) -C (Y) -O-, -N (R ¹¹ ) -C (Y) -N (R ¹² )-, -C (Y) -N (R ¹¹ ) -O-, -C (Y ) -N (R ¹¹ ) -N (R ¹² )-, -ON (R ¹¹ ) -C (Y)-and -N (R ¹² ) -N (R ¹¹ ) -C (Y)- Selected;

Ring B is optionally substituted with an unsubstituted, partially unsaturated alicyclic ring, or a partially unsaturated heterocyclic ring,

p, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ²⁷ , R ²⁸ , Y, and ring B Optional substituents of are as defined above in formula (I).

In one embodiment, in Formula (VI), Ring A is a cycloalkenyl ring.

In one embodiment, in formula (VI), Ring A is a heterocycloalkenyl ring.

In one embodiment, in formula (VI), ring A is a four membered ring.

In one embodiment, in Formula (VI), Ring A is a 5 membered ring.

In one embodiment, in Formula (VI), Ring A is a 6 membered ring.

In one embodiment, in Formula (VI), Ring A is a 7 membered ring.

In one embodiment, in formula (VI), ring A is an 8 membered ring.

In one embodiment, in formula (VI), E is —C (R ⁴ ) (R ⁵ ) —.

In one embodiment, in formula (VI), E is -O-, -S-, -S (O)-, -S (O) _2- , -N (R ⁶ )-, -N (C (Y ) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-, -C (O) -N (R ¹¹ )-, -N (R ¹¹ ) -C (O)-, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) _2- , -C (O) -O-, -OC (O)-, -ON (R ⁶ )-, -N (R ⁶ ) -O-, -N (R ⁶ ) -N (R ¹² )-, -N = N-, -C (R ⁷ ) = N-, -C (O) -C (R ⁷ ) = N-, -C (O) -N = N-, -0-C (Y) -N (R ¹¹ )-, -N (R ¹¹ ) -C (Y) -O-, -N (R ¹¹ ) -C (Y) -N (R ¹² )-, -C (Y) -N (R ¹¹ ) -O-, -C (Y) -N (R ¹¹ ) -N (R ¹² )-, -0-N (R ¹¹ ) -C (Y)-and -N (R ¹² ) -N (R ¹¹ ) -C (Y)- Is selected from.

In one embodiment, in formula (VI), E is selected from the group consisting of —O—, —S—, —S (O) —, —S (O) ₂ —, and —N (R ⁶ ) —.

In one embodiment, in formula (VI), E is selected from the group consisting of —O—, —S—, —S (O) —, —S (O) ₂ —, and —N (R ⁶ ) —, Wherein R ⁶ is H, alkyl, -C (O) R ²⁴ and -C (S) R ²⁴ is selected from the group consisting of.

In one embodiment, in formula (VI), E is selected from the group consisting of —O— and —N (R ⁶ ) —, wherein R ⁶ is H, alkyl, —C (O) R ²⁴ and -C (S) R ²⁴ is selected from the group consisting of.

In one embodiment, in formula (VI), E is -O-.

In one embodiment, in formula (VI), E is -S-.

In one embodiment, in formula (VI), E is -S (O)-.

In one embodiment, in formula (VI), E is —S (O) ₂ —.

In one embodiment, in formula (VI), E is —C (R ⁴ ) (R ⁵ ) —.

In one embodiment, in formula (VI), E is -N (R ⁶ )-.

In one embodiment, in formula (VI), E is -N (C (Y) R ⁷ )-.

In one embodiment, in formula (VI), E is —N (C (Y) OR ⁸ ) —.

In one embodiment, in formula (VI), E is —N (C (Y) N (R ⁹ ) (R ¹⁰ ))-.

In one embodiment, in formula (VI), E is —C (O) —N (R ¹¹ ) —.

In one embodiment, in formula (VI), E is —N (R ¹¹ ) —C (O) —.

In one embodiment, in formula (VI), E is —S (O) ₂ —N (R ¹¹ ) —.

In one embodiment, in formula (VI), E is —N (R ¹¹ ) —S (O) ₂ —.

In one embodiment, in formula (VI), E is —C (O) —O—.

In one embodiment, in formula (VI), E is —O—C (O) —.

In one embodiment, in formula (VI), E is -ON (R ⁶ )-.

In one embodiment, in formula (VI), E is —N (R ⁶ ) —O—.

In one embodiment, in formula (VI), E is -N (R ⁶ ) -N (R ¹² )-.

In one embodiment, in formula (VI), E is -N = N-.

In one embodiment, in formula (VI), E is —C (R ⁷ ) ═N—.

In one embodiment, in formula (VI), E is —C (O) —C (R ⁷ ) ═N—.

In one embodiment, in formula (VI), E is —C (O) —N═N—.

In one embodiment, in formula (VI), E is —0-C (Y) —N (R ¹¹ ) —.

In one embodiment, in formula (VI), E is —N (R ¹¹ ) —C (Y) —O—.

In one embodiment, in formula (VI), E is -N (R ¹¹ ) -C (Y) -N (R ¹² )-.

In one embodiment, in formula (VI), E is —C (Y) —N (R ¹¹ ) —O—.

In one embodiment, in formula (VI), E is —C (Y) —N (R ¹¹ ) —N (R ¹² ) —.

In one embodiment, in formula (VI), E is -ON (R ¹¹ ) -C (Y)-.

In one embodiment, in formula (VI), E is -N (R ¹² ) -N (R ¹¹ ) -C (Y)-.

In one embodiment, in formula (VI), Y is (= 0).

In one embodiment, in formula (VI), Y is (= S).

In one embodiment, in formula (VI), Y is (= N (R ¹³ )).

In one embodiment, in formula (VI), Y is (= N (CN)).

In one embodiment, in formula (VI), Y is (= N (OR ¹⁴ )).

In one embodiment, in formula (VI), Y is (= N (R ¹⁵ ) (R ¹⁶ )).

In one embodiment, in formula (VI), Y is (═C (R ¹⁷ ) (R ¹⁸ )).

In one embodiment, in formula (VI), ring A is a four membered ring, E is —O—, —S—, —S (O) —, —S (O) ₂ —, —C (R ⁴ ) (R ⁵ )-, -N (R ⁶ )-, -N (C (Y) R ⁷ )-, -N (C (Y) OR ⁸ )-and -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-.

In one embodiment, in formula (VI), A is a 4 membered ring and E is selected from the group consisting of -CH _2- , -CH (R ⁴ )-, -C (R ⁴ ) (R ⁵ )- .

In one embodiment, in formula (VI), A is a 5 membered ring and E is —O—, —S—, —S (O) —, —S (O) ₂ —, —C (R ⁴ ) ( R ⁵ )-, -N (R ⁶ )-, -N (C (Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) ( R ¹⁰ ))-, -C (O) -N (R ¹¹ )-, -N (R ¹¹ ) -C (O)-, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) _2- , -C (O) -O-, -OC (O)-, -ON (R ⁶ )-, -N (R ⁶ ) -O-, -N (R ⁶ ) And -N (R ¹² )-, -N = N- and -C (R ⁷ ) = N-.

In one embodiment, in formula (VI), A is a 5 membered ring and E is —O—.

In one embodiment, in formula (VI), A is a 5 membered ring and E is -S-.

In one embodiment, in formula (VI), A is a 5 membered ring and E is -S (O)-.

In one embodiment, in formula (VI), A is a 5 membered ring and E is —S (O) ₂ —.

In one embodiment, in formula (VI), A is a 5 membered ring and E is —C (R ⁴ ) (R ⁵ )-.

In one embodiment, in formula (VI), A is a 5 membered ring and E is —N (R ⁶ ) —.

In one embodiment, in formula (VI), A is a 5 membered ring and E is —N (C (Y) R ⁷ ) —.

In one embodiment, in formula (VI), A is a 5 membered ring and E is —N (C (Y) OR ⁸ ) —.

In one embodiment, in formula (VI), A is a 5 membered ring and E is —N (C (Y) N (R ⁹ ) (R ¹⁰ ))-.

In one embodiment, in formula (VI), A is a 5 membered ring and E is —C (O) —N (R ¹¹ ) —.

In one embodiment, in formula (VI), A is a 5 membered ring and E is —N (R ¹¹ ) —C (O) —.

In one embodiment, in formula (VI), A is a 5 membered ring and E is —S (O) ₂ —N (R ¹¹ ) —.

In one embodiment, in formula (VI), A is a 5 membered ring and E is —N (R ¹¹ ) —S (O) ₂ —.

In one embodiment, in formula (VI), A is a 5 membered ring and E is —C (O) —O—.

In one embodiment, in formula (VI), A is a 5 membered ring and E is —O—C (O) —.

In one embodiment, in formula (VI), A is a 5 membered ring and E is -ON (R ⁶ )-.

In one embodiment, in formula (VI), A is a 5 membered ring and E is —N (R ⁶ ) —O—.

In one embodiment, in formula (VI), A is a 5 membered ring and E is -N (R ⁶ ) -N (R ¹² )-.

In one embodiment, in formula (VI), A is a 5 membered ring and E is -N = N-.

In one embodiment, in formula (VI), A is a 5 membered ring and E is —C (R ⁷ ) = N—.

In one embodiment, in formula (VI), A is a 6 membered ring and E is —O—, —S—, —S (O) —, —S (O) ₂ —, —C (R ⁴ ) ( R ⁵ )-, -N (R ⁶ )-, -N (C (Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) ( R ¹⁰ ))-, -C (O) -N (R ¹¹ )-, -N (R ¹¹ ) -C (O)-, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) _2- , -C (O) -O-, -OC (O)-, -ON (R ⁶ )-, -N (R ⁶ ) -O-, -N (R ⁶ ) -N (R ¹² )-, -N = N-, -C (R ⁷ ) = N-, -C (O) -C (R ⁷ ) = N-, -C (O) -N = N-, -0-C (Y) -N (R ¹¹ )-, -N (R ¹¹ ) -C (Y) -O-, -N (R ¹¹ ) -C (Y) -N (R ¹² )-,- C (Y) -N (R ¹¹ ) -O-, -C (Y) -N (R ¹¹ ) -N (R ¹² )-, -O- N (R ¹¹ ) -C (Y)-and -N (R ¹² ) -N (R ¹¹ ) -C (Y)-.

In one embodiment, in formula (VI), A is a 6 membered ring and E is —O—.

In one embodiment, in formula (VI), A is a 6 membered ring and E is -S-.

In one embodiment, in formula (VI), A is a 6 membered ring and E is —S (O) —.

In one embodiment, in formula (VI), A is a 6 membered ring and E is —S (O) ₂ —.

In one embodiment, in formula (VI), A is a 6 membered ring and E is —C (R ⁴ ) (R ⁵ )-.

In one embodiment, in formula (VI), A is a 6 membered ring and E is —N (R ⁶ ) —.

In one embodiment, in formula (VI), A is a 6 membered ring and E is —N (C (Y) R ⁷ ) —.

In one embodiment, in formula (VI), A is a 6 membered ring and E is —N (C (Y) OR ⁸ ) —.

In one embodiment, in formula (VI), A is a 6 membered ring and E is —N (C (Y) N (R ⁹ ) (R ¹⁰ ))-.

In one embodiment, in formula (VI), A is a 6 membered ring and E is —C (O) —N (R ¹¹ ) —.

In one embodiment, in formula (VI), A is a 6 membered ring and E is —N (R ¹¹ ) —C (O) —.

In one embodiment, in formula (VI), A is a 6 membered ring and E is —S (O) ₂ —N (R ¹¹ ) —.

In one embodiment, in formula (VI), A is a 6 membered ring and E is —N (R ¹¹ ) —S (O) ₂ —.

In one embodiment, in formula (VI), A is a 6 membered ring and E is —C (O) —O—.

In one embodiment, in formula (VI), A is a 6 membered ring and E is —O—C (O) —.

In one embodiment, in formula (VI), A is a 6 membered ring and E is -ON (R ⁶ )-.

In one embodiment, in formula (VI), A is a 6 membered ring and E is —N (R ⁶ ) —O—.

In one embodiment, in formula (VI), A is a 6 membered ring and E is —N (R ⁶ ) —N (R ¹² ) —.

In one embodiment, in formula (VI), A is a 6 membered ring and E is —N═N—.

In one embodiment, in formula (VI), A is a 6 membered ring and E is —C (R ⁷ ) = N—.

In one embodiment, in formula (VI), A is a 6 membered ring and E is —C (O) —C (R ⁷ ) = N—.

In one embodiment, in formula (VI), A is a 6 membered ring and E is —C (O) —N═N—.

In one embodiment, in formula (VI), A is a 6 membered ring and E is —0-C (Y) —N (R ¹¹ ) —.

In one embodiment, in formula (VI), A is a 6 membered ring and E is —N (R ¹¹ ) —C (Y) —O—.

In one embodiment, in formula (VI), A is a 6 membered ring and E is —N (R ¹¹ ) -C (Y) -N (R ¹² )-.

In one embodiment, in formula (VI), A is a 6 membered ring and E is —C (Y) —N (R ¹¹ ) —O—.

In one embodiment, in formula (VI), A is a 6 membered ring and E is —C (Y) —N (R ¹¹ ) —N (R ¹² ) —.

In one embodiment, in formula (VI), A is a 6 membered ring and E is —O—N (R ¹¹ ) -C (Y) —.

In one embodiment, in formula (VI), A is a 6 membered ring and E is -N (R ¹² ) -N (R ¹¹ ) -C (Y)-.

In one embodiment, in formula (VI), A is a 7 membered ring and E is —O—, —S—, —S (O) —, —S (O) ₂ —, —C (R ⁴ ) ( R ⁵ )-, -N (R ⁶ )-, -N (C (Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) ( R ¹⁰ ))-, -C (O) -N (R ¹¹ )-, -N (R ¹¹ ) -C (O)-, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) _2- , -C (O) -O-, -OC (O)-, -ON (R ⁶ )-, -N (R ⁶ ) -O-, -N (R ⁶ ) -N (R ¹² )-, -N = N-, -C (R ⁷ ) = N-, -C (O) -C (R ⁷ ) = N-, -C (O) -N = N-, -0-C (Y) -N (R ¹¹ )-, -N (R ¹¹ ) -C (Y) -O-, -N (R ¹¹ ) -C (Y) -N (R ¹² )-,- C (Y) -N (R ¹¹ ) -O-, -C (Y) -N (R ¹¹ ) -N (R ¹² )-, -O- N (R ¹¹ ) -C (Y)-and -N (R ¹² ) -N (R ¹¹ ) -C (Y)-.

In one embodiment, in formula (VI), A is a 7 membered ring and E is —O—.

In one embodiment, in formula (VI), A is a 7 membered ring and E is -S-.

In one embodiment, in formula (VI), A is a 7 membered ring and E is —S (O) —.

In one embodiment, in formula (VI), A is a 7 membered ring and E is —S (O) ₂ —.

In one embodiment, in formula (VI), A is a 7 membered ring and E is —C (R ⁴ ) (R ⁵ )-.

In one embodiment, in formula (VI), A is a 7 membered ring and E is —N (R ⁶ ) —.

In one embodiment, in formula (VI), A is a 7 membered ring and E is —N (C (Y) R ⁷ ) —.

In one embodiment, in formula (VI), A is a 7 membered ring and E is —N (C (Y) OR ⁸ ) —.

In one embodiment, in formula (VI), A is a 7 membered ring and E is —N (C (Y) N (R ⁹ ) (R ¹⁰ ))-.

In one embodiment, in formula (VI), A is a 7 membered ring and E is —C (O) —N (R ¹¹ ) —.

In one embodiment, in formula (VI), A is a 7 membered ring and E is —N (R ¹¹ ) —C (O) —.

In one embodiment, in formula (VI), A is a 7 membered ring and E is —S (O) ₂ —N (R ¹¹ ) —.

In one embodiment, in formula (VI), A is a 7 membered ring and E is —N (R ¹¹ ) —S (O) ₂ —.

In one embodiment, in formula (VI), A is a 7 membered ring and E is —C (O) —O—.

In one embodiment, in formula (VI), A is a 7 membered ring and E is —O—C (O) —.

In one embodiment, in formula (VI), A is a 7 membered ring and E is -QN (R ⁶ )-.

In one embodiment, in formula (VI), A is a 7 membered ring and E is —N (R ⁶ ) —O—.

In one embodiment, in formula (VI), A is a 7 membered ring and E is —N (R ⁶ ) —N (R ¹² ) —.

In one embodiment, in formula (VI), A is a 7 membered ring and E is -N = N-.

In one embodiment, in formula (VI), A is a 7 membered ring and E is —C (R ⁷ ) = N—.

In one embodiment, in formula (VI), A is a 7 membered ring and E is —C (O) —C (R ⁷ ) = N—.

In one embodiment, in formula (VI), A is a 7 membered ring and E is —C (O) —N═N—.

In one embodiment, in formula (VI), A is a 7 membered ring and E is —0-C (Y) —N (R ¹¹ ) —.

In one embodiment, in formula (VI), A is a 7 membered ring and E is —N (R ¹¹ ) —C (Y) —O—.

In one embodiment, in formula (VI), A is a 7 membered ring and E is —N (R ¹¹ ) -C (Y) -N (R ¹² )-.

In one embodiment, in formula (VI), A is a 7 membered ring and E is —C (Y) —N (R ¹¹ ) —O—.

In one embodiment, in formula (VI), A is a 7 membered ring and E is —C (Y) —N (R ¹¹ ) —N (R ¹² ) —.

In one embodiment, in formula (VI), A is a 7 membered ring and E is —O—N (R ¹¹ ) -C (Y) —.

In one embodiment, in formula (VI), A is a 7 membered ring and E is -N (R ¹² ) -N (R ¹¹ ) -C (Y)-.

In one embodiment, in formula (VI), A is an 8 membered ring and E is —O—, —S—, —S (O) —, —S (O) ₂ —, —C (R ⁴ ) ( R ⁵ )-, -N (R ⁶ )-, -N (C (Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) ( R ¹⁰ ))-, -C (O) -N (R ¹¹ )-, -N (R ¹¹ ) -C (O)-, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) 2-, -C (O) -O-, -OC (O)-, -ON (R ⁶ )-, -N (R ⁶ ) -O-, -N (R ⁶ ) -N (R ¹² )-, -N = N-, -C (R ⁷ ) = N-, -C (O) -C (R ⁷ ) = N-, -C (O) -N = N-, -0-C (Y) -N (R ¹¹ )-, -N (R ¹¹ ) -C (Y) -O-, -N (R ¹¹ ) -C (Y) -N (R ¹² )-,- C (Y) -N (R ¹¹ ) -O-, -C (Y) -N (R ¹¹ ) -N (R ¹² )-, -O- N (R ¹¹ ) -C (Y)-and -N (R ¹² ) -N (R ¹¹ ) -C (Y)-.

In one embodiment, in formula (VI), A is an 8 membered ring and E is —O—.

In one embodiment, in formula (VI), A is an 8 membered ring and E is -S-.

In one embodiment, in formula (VI), A is an 8 membered ring and E is -S (O)-.

In one embodiment, in formula (VI), A is an 8 membered ring and E is —S (O) ₂ —.

In one embodiment, in formula (VI), A is an 8 membered ring and E is —C (R ⁴ ) (R ⁵ )-.

In one embodiment, in formula (VI), A is an 8 membered ring and E is —N (R ⁶ ) —.

In one embodiment, in formula (VI), A is an 8 membered ring and E is —N (C (Y) R ⁷ ) —.

In one embodiment, in formula (VI), A is an 8 membered ring and E is —N (C (Y) OR ⁸ ) —.

In one embodiment, in formula (VI), A is an 8 membered ring and E is —N (C (Y) N (R ⁹ ) (R ¹⁰ ))-.

In one embodiment, in formula (VI), A is an 8 membered ring and E is —C (O) —N (R ¹¹ ) —.

In one embodiment, in formula (VI), A is an 8 membered ring and E is —N (R ¹¹ ) —C (O) —.

In one embodiment, in formula (VI), A is an 8 membered ring and E is —S (O) ₂ —N (R ¹¹ ) —.

In one embodiment, in formula (VI), A is an 8 membered ring and E is —N (R ¹¹ ) —S (O) ₂ —.

In one embodiment, in formula (VI), A is an 8 membered ring and E is —C (O) —O—.

In one embodiment, in formula (VI), A is an 8 membered ring and E is —O—C (O) —.

In one embodiment, in formula (VI), A is an 8 membered ring and E is -ON (R ⁶ )-.

In one embodiment, in formula (VI), A is an 8 membered ring and E is —N (R ⁶ ) —O—.

In one embodiment, in formula (VI), A is an 8 membered ring and E is —N (R ⁶ ) —N (R ¹² ) —.

In one embodiment, in formula (VI), A is an 8 membered ring and E is -N = N-.

In one embodiment, in formula (VI), A is an 8 membered ring and E is —C (R ⁷ ) = N—.

In one embodiment, in formula (VI), A is an 8 membered ring and E is —C (O) —C (R ⁷ ) = N—.

In one embodiment, in formula (VI), A is an 8 membered ring and E is —C (O) —N═N—.

In one embodiment, in formula (VI), A is an 8 membered ring and E is —0-C (Y) —N (R ¹¹ ) —.

In one embodiment, in formula (VI), A is an 8 membered ring and E is —N (R ¹¹ ) —C (Y) —O—.

In one embodiment, in formula (VI), A is an 8 membered ring and E is —N (R ¹¹ ) -C (Y) -N (R ¹² )-.

In one embodiment, in formula (VI), A is an 8 membered ring and E is —C (Y) —N (R ¹¹ ) —O—.

In one embodiment, in formula (VI), A is an 8 membered ring and E is —C (Y) —N (R ¹¹ ) —N (R ¹² ) —.

In one embodiment, in formula (VI), A is an 8 membered ring and E is -ON (R ¹¹ ) -C (Y)-.

In one embodiment, in formula (VI), A is an 8 membered ring and E is -N (R ¹² ) -N (R ¹¹ ) -C (Y)-.

In one embodiment, in formula (VI), B is a partially unsaturated alicyclic ring, which ring is unsubstituted.

In one embodiment, in formula (VI), B is a partially unsaturated alicyclic ring substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl , Haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, Azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ ,- SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ ,- C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In one embodiment, in formula (VI), B is a partially unsaturated heterocyclic ring, which ring is unsubstituted.

In one embodiment, in formula (VI), B is a partially unsaturated heterocyclic ring substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, hetero Alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl , Azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ -OC (O) R ²⁴ ,- C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ are independently selected.

In one embodiment, in formula (VI), R ¹ is unsubstituted aryl.

In one embodiment, in formula (VI), R ¹ is unsubstituted phenyl.

In one embodiment, in formula (VI), R ¹ is unsubstituted naphthyl.

In one embodiment, in formula (VI), R ¹ is substituted aryl.

In one embodiment, in formula (VI), R ¹ is substituted phenyl.

In one embodiment, in formula (VI), R ¹ is substituted naphthyl.

In one embodiment, in formula (VI), R ¹ is aryl substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, Alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In one embodiment, in formula (VI), R ¹ is phenyl substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, Alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In one embodiment, in formula (VI), R ¹ is phenyl substituted with one or more substituents which may be the same or different and each substituent is halo, -OH, -CN, -NO ₂ And -NR ²¹ R ²² and Independently selected from the group consisting of haloalkyl.

In one embodiment, in formula (VI), R ¹ is

It is selected from the group consisting of.

이다.In one embodiment, in formula (VI), R ¹ is

to be.

In one embodiment, in formula (VI), R ¹ is phenyl substituted with one to three fluoro groups.

In one embodiment, in formula (VI), R ¹ is phenyl substituted with two fluoro groups.

In one embodiment, in formula (VI), R ¹ is phenyl substituted with one fluoro group.

이다.In one embodiment, in formula (VI), R ¹ is

to be.

In one embodiment, in formula (VI), R ²⁷ and R ²⁸ is each independently selected from the group consisting of H and alkyl.

In one embodiment, in formula (VI), R ² is —C (Z) R ⁷ .

In one embodiment, in formula (VI), R ² is —C (Z) NR ⁹ R ¹⁰ .

In one embodiment, in formula (VI), R ² is —C (Z) OR ⁸ .

In one embodiment, in formula (VI), R ² is —SO ₂ NR ⁹ R ¹⁰ .

In one embodiment, in formula (VI), R ² is alkyl.

In one embodiment, in formula (VI), R ² is heteroalkyl.

In one embodiment, in formula (VI), R ² is aryl.

In one embodiment, in formula (VI), R ² is heteroaryl.

In one embodiment, in formula (VI), R ² is cycloalkyl.

In one embodiment, in formula (VI), R ² is cycloalkenyl.

In one embodiment, in formula (VI), R ² is heterocycloalkyl.

In one embodiment, in formula (VI), R ² is heterocycloalkenyl.

In one embodiment, in formula (VI), Z is (= 0).

In one embodiment, in formula (VI), Z is (= S).

In one embodiment, in formula (VI), Z is (= N (R ¹³ )).

In one embodiment, in formula (VI), Z is (= N (CN)).

In one embodiment, in formula (VI), Z is (= N (OR ¹⁴ )).

In one embodiment, in formula (VI), Z is (= N (R ¹⁵ ) (R ¹⁶ )).

In one embodiment, in formula (VI), Z is (═C (R ¹⁷ ) (R ¹⁸ )).

In one embodiment, in formula (VI), R ² is —C (Z) R ⁷ , Z is (= 0).

In one embodiment, in formula (VI), R ² is —C (O) H.

In one embodiment, in formula (VI), R ² is —C (O) alkyl.

In one embodiment, in formula (VI), R ² is —C (O) CH ₃ .

In one embodiment, in formula (VI), R ² is —C (O) R ⁷ wherein R ⁷ is alkyl substituted with one or more substituents which may be the same or different and each substituent is oxo, halogen , -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl , Azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently from the group consisting of

In one embodiment, in formula (VI), R ² is —C (O) R ⁷ wherein R ⁷ is alkyl substituted with 1 to 3 substituents, which may be the same or different, and each substituent is -OR ¹⁹ , -NR ²¹ R ²² and Independently selected from the group consisting of cycloalkyl.

In one embodiment, in formula (VI), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl, wherein said alkyl is substituted with alkyl and —OH.

In one embodiment, in formula (VI), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl substituted with 1 to 3 substituents, which may be the same or different, and each substituent is — OH, -NH ₂ and Independently selected from the group consisting of cyclopropyl.

In one embodiment, in formula (VI), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl substituted with 1 to 2 substituents, which may be the same or different, and each substituent is — NH ₂ and Independently selected from the group consisting of cyclopropyl.

In one embodiment, in formula (VI), R ² is —C (O) R ⁷ , wherein R ⁷ is alkyl substituted with —OH.

In one embodiment, in formula (VI), R ² is —C (O) R ⁷ , wherein R ⁷ is unsubstituted heterocycloalkyl.

In one embodiment, in formula (VI), R ² is —C (O) R ⁷ , wherein R ⁷ is substituted heterocycloalkyl.

In one embodiment, in formula (VI), R ² is —C (O) R ⁷ wherein R ⁷ is heterocycloalkyl substituted with one or more substituents which may be the same or different and each substituent is oxo , Halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocyclo Alkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In one embodiment, in formula (VI), R ² is —C (O) R ⁷ , wherein R ⁷ is unsubstituted piperidine, unsubstituted piperazine, unsubstituted morpholine, unsubstituted Selected from the group consisting of pyrrolidine and unsubstituted azetidine.

In one embodiment, in formula (VI), R ² is

Is selected from.

In one embodiment, in formula (VI), R ² is —C (O) NR ⁹ R ¹⁰ .

In one embodiment, in formula (VI), R ² is —C (O) NH ₂ .

In one embodiment, in formula (VI), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ and R ¹⁰ may be the same or different and each is independently selected from alkyl.

In one embodiment, in formula (VI), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ is unsubstituted heterocycloalkyl, and R ¹⁰ is selected from the group consisting of H and alkyl .

In one embodiment, in formula (VI), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ is unsubstituted heterocycloalkyl, and R ¹⁰ is selected from the group consisting of H and alkyl .

In one embodiment, in formula (VI), R ² is alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, —C (O) R ⁷ , —C (O) OR ⁸ and -C (O) NR ⁹ R ¹⁰ is selected from the group consisting of.

In one embodiment, in formula (VI), R ² is

It is selected from the group consisting of.

In one embodiment, in formula (VI), R ² is —C (O) NR ⁹ R ¹⁰ , wherein R ⁹ is heterocycloalkyl substituted with 1 to 3 substituents, which may be the same or different, each Substituent of is independently selected from alkyl, R ¹⁰ is selected from the group consisting of H and alkyl.

이다.In one embodiment, in formula (VI), R ² is

to be.

이다.In one embodiment, in formula (VI), R ² is

to be.

이다.In one embodiment, in formula (VI), R ² is

to be.

이다.In one embodiment, in formula (VI), R ² is

to be.

이다.In one embodiment, in formula (VI), R ² is

to be.

이다.In one embodiment, in formula (VI), R ² is

to be.

이다.In one embodiment, in formula (VI), R ² is

to be.

이다.In one embodiment, in formula (VI), R ² is

to be.

In one embodiment, in formula (VI), p is 0 and R ³ is absent.

In one embodiment, in formula (VI), p is 1.

In one embodiment, in formula (VI), p is 2.

In one embodiment, in formula (VI), p is 3.

In one embodiment, in formula (VI), p is 4.

In one embodiment, in formula (VI), p is> 2 and at least two groups R ³ are attached to the same ring atom.

In one embodiment, in formula (VI), p is 1 and R ³ is alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, hetero Cycloalkyl, heterocycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ ,- SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In one embodiment, in formula (VI), p is 2, 3 or 4 and each R ³ is alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cyclo Alkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In one embodiment, in formula (VI), p is 2, 3 or 4 and at least two groups R ³ are bonded to the same ring carbon atom, wherein each R ³ can be the same or different, alkyl, Heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is selected independently.

In one embodiment, in formula (VI), p is 2, 3 or 4 and at least two R ³ are bonded to the same ring carbon atom, wherein the two R ³ groups can be the same or different and they are A heterocycloalkyl ring containing 1 to 3 heteroatoms selected from the group consisting of cycloalkyl, cycloalkenyl, N, O and S together with the attached carbon atom, or 1 to 1 selected from the group consisting of N, O and S Heterocycloalkenyl rings containing three heteroatoms.

In one embodiment, in formula (VI), p is> O and each R ³ is alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (S) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ , -NR ²³ C (O) NR ²⁵ R ²⁶ and -NR ² ^ C (NH) -NR ²⁶ R ^{26 It} is independently selected from the group consisting of

Wherein each said alkyl, each said heteroalkyl, each said alkenyl and each said heteroalkenyl is optionally independently substituted with one or more substituents which may be unsubstituted, identical or different, and each substituent is Oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, hetero Cycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group.

In one embodiment, in formula (VI), p is 1 and R ³ is selected from the group consisting of alkyl, heteroalkyl, alkenyl and heteroalkenyl, wherein each said alkyl, each said heteroalkyl, Each said alkenyl and each said heteroalkenyl is substituted with one or more substituents which may be unsubstituted, identical or different, and each substituent is oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, Haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group.

In one embodiment, in formula (VI), p is 2, 3 or 4 and any two R ³ groups bonded to the same ring A together form a —C (O) — group.

In one embodiment, in formula (IV), p is 2, 3 or 4 and any two R ³ groups bonded to the same ring A together with the carbon atom to which they are attached spirocycloalkyl, spirocycloalkenyl,- Spiroheterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of NH-, -NR ^6- , -S-, -S (O)-, -S (O) _2-, and -O- Ring or containing 1 to 3 heteroatoms independently selected from the group consisting of -NH-, -NR ^6- , -S-, -S (O)-, -S (O) _2-, and -O- To form a spiroheterocycloalkenyl ring.

In one embodiment, in formula (IV), p is> 0 and R ² and R ³ consists of cycloalkyl, cycloalkenyl, —NH—, —NR ⁶ —, —S—, —S (O) —, —S (O) ₂ —, and —O— with the carbon atoms to which they are attached; Heterocycloalkyl rings containing one to three ring heteroatoms independently selected from the group, or -NH-, -NR ^6- , -S-, -S (O)-, -S (O) _2- , and- To form a heterocycloalkenyl ring containing 1 to 3 ring heteroatoms independently selected from the group consisting of O-.

In one embodiment, in formula (VI), R ³ is alkyl.

In one embodiment, in formula (VI), R ³ is heteroalkyl.

In one embodiment, in formula (VI), R ³ is alkenyl.

In one embodiment, in formula (VI), R ³ is heteroalkenyl.

In one embodiment, in formula (VI), R ³ is alkynyl.

In one embodiment, in formula (VI), R ³ is heteroalkynyl.

In one embodiment, in formula (VI), R ³ is aryl.

In one embodiment, in formula (VI), R ³ is heteroaryl.

In one embodiment, in formula (VI), R ³ is cycloalkyl.

In one embodiment, in formula (VI), R ³ is cycloalkenyl.

In one embodiment, in formula (VI), R ³ is heterocycloalkyl.

In one embodiment, in formula (VI), R ³ is heterocycloalkenyl.

In one embodiment, in formula (VI), R ³ is halogen.

In one embodiment, in formula (VI), R ³ is -CN.

In one embodiment, in formula (VI), R ³ is —NO ₂ .

In one embodiment, in formula (VI), R ³ is —OR ¹⁹ .

In one embodiment, in formula (VI), R ³ is —OC (O) OR ²⁰ .

In one embodiment, in formula (VI), R ³ is —NR ²¹ R ²² .

In one embodiment, in formula (VI), R ³ is —NR ²³ SO ₂ R ²⁴ .

In one embodiment, in formula (VI), R ³ is —NR ²³ C (O) OR ²⁰ .

In one embodiment, in formula (VI), R ³ is —NR ²³ C (O) R ²⁴ .

In one embodiment, in formula (VI), R ³ is —SO ₂ NR ²⁵ R ²⁶ .

In one embodiment, in formula (VI), R ³ is —C (O) R ²⁴ .

In one embodiment, in formula (VI), R ³ is —C (S) R ²⁴ .

In one embodiment, in formula (VI), R ³ is —C (O) OR ²⁰ .

In one embodiment, in formula (VI), R ³ is -SR ¹⁹ .

In one embodiment, in formula (VI), R ³ is —S (O) R ¹⁹ .

In one embodiment, in formula (VI), R ³ is —SO ₂ R ¹⁹ .

In one embodiment, in formula (VI), R ³ is —OC (O) R ²⁴ .

In one embodiment, in formula (VI), R ³ is —C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula (VI), R ³ is —NR ²³ C (N—CN) NR ²⁵ R ²⁶ .

In one embodiment, in formula (VI), R ³ is —NR ²³ C (O) NR ²⁵ R ²⁶ .

In one embodiment, in formula (VI), R ³ is methyl, ethyl, propyl (straight or branched), butyl (straight or branched), pentyl (straight or branched), phenyl

It is selected from the group consisting of.

In one embodiment, in formula (IV), when E is -NR-, R ³ is absent.

.In one embodiment, Formula (VI) has the following general structure:

.

.In one embodiment, Formula (VI) has the following general structure:

.

In one embodiment, Formula (VI) has the following general structure:

In this formula,

P is 0, 1, 2 or 3.

In one embodiment, Formula (VI) has the following general structure:

In this formula,

P is 0, 1, 2 or 3.

In one embodiment, Formula (VI) has the following general structure:

In this formula,

P is 0, 1, 2 or 3.

In one embodiment, Formula (VI) has the following general structure:

In this formula,

P is 0, 1, 2 or 3.

In one embodiment, the compounds of the present invention have the structure shown below and include pharmaceutically acceptable salts, solvates, esters, prodrugs or isomers of the compounds:

In another aspect, the invention provides a method of preparing a compound described in each of the various embodiments described above, a pharmaceutical formulation or composition comprising one or more of the compounds, and one or more conditions associated with KSP kinesin activity, such as those discussed in detail below. Or a method of treating or preventing a disease.

As used above, and throughout the specification, unless otherwise indicated, the following terms should be understood to have the following meanings:

"Subject" includes both mammals and non-mammals.

“Mammal” includes humans and other mammals.

The term "substituted" means that one or more hydrogens on the specified atom are replaced with one selected from the group shown, provided that the normal valence of the designated atom is not exceeded and such substitution results in a stable compound. Combinations of substituents and / or variables are only acceptable if such combinations result in stable compounds. "Stable compound" or "stable structure" means that the compound is sufficiently strong to separate it from the reaction mixture to a degree of purity that is useful and formulated into an effective therapeutic agent.

The term "optionally substituted" means any substitution of the specified group, radical or residue. Any atom with unsatisfied valences in the context, schemes, examples, and tables herein is assumed to have hydrogen atom (s) to meet valences.

The following definitions apply, unless otherwise indicated, regardless of whether the term is used by itself or in combination with another term. Thus, the definition of "alkyl" applies not only to "alkyl" but also to "alkyl" sites such as "hydroxyalkyl", "haloalkyl", "alkoxy" and the like.

"Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and has from about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups have from about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups have from about 1 to about 6 carbon atoms in the chain. Side chain means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to the alkyl straight chain. "Lower alkyl" means about 1 to about 6 carbon atoms in the chain, which may be straight or branched. "Alkyl" may be unsubstituted or optionally substituted with one or more substituents as described herein. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl. Alkyl "includes“ alkylene ”which refers to a bifunctional group obtained by removing a hydrogen atom from an alkyl group as defined above. Non-limiting examples of alkylene include methylene (—CH ₂ —), ethylene (—CH ₂ CH). _2- ) and propylene (-C ₃ H _6- ; which may be straight or branched).

"Heteroalkyl" means an alkyl group as defined above having one or more carbon atoms, eg, one, two or three carbon atoms, replaced by one or more heteroatoms which may be the same or different, wherein The point of attachment to the rest of the molecule is through the carbon atom of the heteroalkyl radical. Such suitable heteroatoms include O, S, (and S (O), S (O) _2, etc.) and N. Non-limiting examples include ethers, thioethers, amines, 2-aminoethyl, 2-dimethylaminoethyl and the like.

"Alkenyl" refers to an aliphatic hydrocarbon group containing one or more carbon-carbon double bonds which may be straight or branched and have from about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have from about 2 to about 12 carbon atoms in the chain, and more preferably from about 2 to about 6 carbon atoms in the chain. Side chain means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to the straight alkenyl chain. "Lower alkenyl" means about 2 to about 6 carbon atoms in the chain, which may be straight or branched. "Alkenyl" may be unsubstituted or optionally substituted with one or more substituents as described herein. Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

"Alkynyl" means an aliphatic hydrocarbon group containing one or more carbon-carbon triple bonds, which may be straight or branched, and has from about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have from about 2 to about 12 carbon atoms in the chain; More preferably about 2 to about 4 carbon atoms in the chain. Side chain means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to the straight chain alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain, which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. "Alkynyl" may be unsubstituted or optionally substituted with one or more substituents as described herein.

"Aryl" means an aromatic monocyclic or multicyclic ring system having from about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. Aryl groups may be the same or different and may be optionally substituted with one or more "ring system substituents" as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.

"Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, wherein at least one ring atom is Elements other than carbon, such as nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. "Heteroaryl" may be the same or different and may be optionally substituted with one or more "ring system substituents" as defined herein. The prefix aza, oxa or thia before the heteroaryl terminology means that one or more nitrogen, oxygen or sulfur atoms are each present as ring atoms. The nitrogen atom of heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl , Pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolinyl, imidazo [1, 2-a] pyridinyl, imidazo [2,1-b] thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyri Dill, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl, and the like.

"Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which aryl and alkyl are as previously described. Preferred aralkyls include lower alkyl groups. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is via alkyl.

"Alkylaryl" means an alkyl-aryl- group in which alkyl and aryl are as previously described. Preferred alkylaryls include lower alkyl groups. Non-limiting examples of suitable alkylaryl groups are tolyl. The bond to the parent moiety is through aryl.

"Cycloalkyl" means a non-aromatic mono- or multicyclic ring system having from about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. Cycloalkyls may be the same or different and may be optionally substituted with one or more "ring system substituents" as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl, and the like.

"Cycloalkylalkyl" means a cycloalkyl moiety as defined above bonded to a parent core via an alkyl moiety (as defined above). Non-limiting examples of suitable cycloalkylalkyl include cyclohexylmethyl, adamantylmethyl, and the like.

"Cycloalkenyl" means a non-aromatic mono- or multicyclic ring system having from about 3 to about 10 carbon atoms, preferably from about 5 to about 10 carbon atoms, containing at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring carbons. Cycloalkenyl may be the same or different and may be optionally substituted with one or more "ring system substituents" as defined above. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and the like. A non-limiting example of a suitable farcyclic cycloalkenyl is norbornylenyl.

"Cycloalkenylalkyl" means a cycloalkenyl moiety as defined above linked to the parent nucleus through an alkyl moiety (as defined above). Non-limiting examples of suitable cycloalkenylalkyl include cyclopentenylmethyl, cyclohexenylmethyl, and the like.

"Halogen" means fluorine, chlorine, bromine or iodine. Preference is given to fluorine, chlorine and bromine.

.A "ring system substituent" refers to a ring system (eg, an aromatic, heteroaromatic, saturated or partially unsaturated alicyclic or heterocyclic ring system, for example, replacing available hydrogen on a carbon atom or heteroatom of the ring system). It means a substituent attached to). A "ring system substituent" can be referred to by itself or can be referred to as a variable or specific functional group or groups attached to a ring system. For example, in Formula 1, when R ² is —C (O) R ¹⁷ and R ¹⁷ is substituted heterocycloalkyl, the substituent attached to the heterocycloalkyl is a ring system substituent. When two or more ring system substituents are present on a given ring, these multiple substituents may be bonded to the same or different available ring carbon or heteroatom. Ring system substituents may be the same or different and are as described herein. Other non-limiting examples of ring system substituents are alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy , Hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, hetero Arylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, -C (= N-CN) -NH ₂ , -C (= NH) -NH ₂ , -C (= NH) -NH (alkyl), Y ₁ Y ₂ N-, Y ₁ Y ₂ N-alkyl-, Y ₁ Y ₂ NC (O)-, Y ₁ Y ₂ NSO ₂ -and -SO ₂ NY ₁ Y ₂ , wherein Y ₁ and Y ₂ may be the same or different and is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Ring system substituent" may also mean a single moiety that simultaneously replaces two hydrogens (one H on each carbon) available on two adjacent carbon atoms on the ring system. Examples of such residues are methylene dioxy, ethylenedioxy, -C (CH ₃ ) ₂ -and the like, which form, for example, the following residues:

.

"Heteroarylalkyl" (or "heteroaryl-alkyl-") means a heteroaryl moiety as defined above linked to the parent nucleus via an alkyl moiety (as defined above). Non-limiting examples of suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl, and the like.

"Heterocyclyl" (or "heterocycloalkyl") is a non-aromatic saturated monocyclic or multicynic containing from about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms. A click ring system, wherein one or more atoms in the ring system are alone or in combination of elements other than carbon, such as nitrogen, oxygen, or sulfur. There are no adjacent oxygen and / or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heterocyclyl means that each of at least one nitrogen, oxygen or sulfur atom is present as a ring atom. Any —NH in the heterocyclyl ring may be present protected such as, for example, —N (Boc), —N (CBz), —N (Tos) group, and the like; Such protection is also contemplated as part of the present invention. Heterocyclyl may be the same or different and may be optionally substituted with one or more "ring system substituents" as defined herein. The nitrogen or sulfur atom of the heterocyclyl may be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolinyl, 1,4-dioxanyl, tetrahydrofuranyl , Tetrahydrothiophenyl, azetidinyl, lactam, lactone and the like.

."Heterocyclyl" also includes rings in which = 0 replaces two available hydrogens on the same carbon atom (ie, heterocyclyl includes rings having carbonyl groups in the ring). Examples of such residues are pyrrolidones:

.

"Heterocyclylalkyl" (or "heterocycloalkylalkyl" or "heterocycloalkyl-alkyl-") means a heterocyclyl moiety as defined above linked to the parent nucleus via an alkyl moiety (as defined above). Non-limiting examples of suitable heterocyclylalkyl include piperidinylmethyl, piperazinylmethyl, and the like.

."Heterocyclenyl" (or "heterocycloalkenyl") is a non-aromatic monocyclic or multicyclic containing from about 3 to about 10 ring atoms, preferably from about 5 to about 10 ring atoms. Ring system, wherein one or more atoms in the ring system are solely or a combination of elements other than carbon, such as nitrogen, oxygen, or sulfur atoms, and represent one or more carbon-carbon double bonds or carbon-nitrogen double bonds. It contains. There are no adjacent oxygen and / or sulfur atoms present in the ring system. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl terminology means that one or more nitrogen, oxygen or sulfur atoms are each present as ring atoms. Heterocyclenyl may be optionally substituted with one or more ring system substituents, where "ring system substituents" are as defined above. The nitrogen or sulfur atom of the heterocyclenyl may be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Non-limiting examples of suitable heterocyclenyl groups include 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6- Tetrahydrofildine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazole, dihydrooxa Sol, dihydrooxadiazole, dihydrothiazole, 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo [2.2.1] heptenyl, dihydro Thiophenyl, dihydrothiopyranyl and the like. "Heterocyclenyl" may also mean a single moiety (eg, carbonyl) that simultaneously replaces two available hydrogens on the same carbon atom on the ring system. Examples of such residues are pyrrolidinone:

.

"Heterocyclenylalkyl" (or "heterocycloalkenylalkyl") means a heterocyclenyl moiety as defined above linked to the parent nucleus via an alkyl moiety (as defined above).

내에서, 2 및 5번으로 표시된 탄소에 직접 부착된 -OH는 없다.It should be noted that within the heteroatom containing ring system of the present invention, there are no hydroxyl groups on the carbon atoms adjacent to N, O or S as well as no N or S groups on the carbon adjacent to other heteroatoms. Thus, for example, ring

There is no -OH attached directly to the carbons labeled 2 and 5.

와 같은 토우토머(tautomer) 형은 본 발명의 특정 양태에서 등가인 것으로 고려된다.Also, for example, residues:

Tautomer types such as are considered equivalent in certain embodiments of the present invention.

"Alkynylalkyl" means an alkynyl-alkyl- group in which alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain lower alkynyl and lower alkyl groups. The bond to the parent moiety is via alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl.

"Heteroaralkyl" means a heteroaryl-alkyl- group where heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain lower alkyl groups. Non-limiting examples of suitable aralkyl groups include pyridylmethyl and quinolin-3-ylmethyl. The bond to the parent moiety is via alkyl.

"Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyl contains lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

"Acyl" means an H-C (O)-, alkyl-C (O)-or cycloalkyl-C (O)-group in which the various groups have been previously described. Binding to the parent moiety is through carbonyl. Preferred acyls contain lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl.

"Aroyl" means an aryl-C (O)-group in which the aryl group is as previously described. Binding to the parent moiety is through carbonyl. Non-limiting examples of suitable groups include benzoyl and 1-naphthoyl.

"Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is via ether oxygen.

"Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is via ether oxygen.

"Aralkyloxy" means an aralkyl-O- group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to the parent moiety is via ether oxygen.

"Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. Binding to the parent moiety is through sulfur.

"Arylthio" means an aryl-S- group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. Binding to the parent moiety is through sulfur.

"Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkylthio groups are benzylthio. Binding to the parent moiety is through sulfur.

"Alkylsilyl" means an alkyl-Si- group in which alkyl is as previously defined and the point of attachment to the parent moiety is on Si. Preferred alkylsilyls contain lower alkyl. An example of an alkylsilyl group is trimethylsilyl (-Si (CH ₃ ) ₃ ).

"Alkoxycarbonyl" refers to an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. Binding to the parent moiety is through carbonyl.

"Aryloxycarbonyl" refers to an aryl-O-C (O)-group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. Binding to the parent moiety is through carbonyl.

"Aralkoxycarbonyl" means an aralkyl-O-C (O)-group. Non-limiting examples of suitable aralkoxycarbonyl groups are benzyloxycarbonyl. Binding to the parent moiety is through carbonyl.

"Alkylsulfonyl" means an alkyl-S (O ₂ )-group. Preferred groups are those in which the alkyl group is lower alkyl. Binding to the parent moiety is through sulfonyl.

"Arylsulfonyl" means an aryl-S (O ₂ )-group. Binding to the parent moiety is through sulfonyl.

The term "substituted" means that one or more hydrogens on the designated atom are substituted with one selected from the group shown, provided that the normal valence of the designated atom is not exceeded in the presence of such a substitution, resulting in a stable compound. Combinations of substituents and / or variables are only acceptable if such combinations result in stable compounds. "Stable compound" or "stable structure" means a compound that is sufficiently strong that it is separated from the reaction mixture in useful purity and formulated into a useful therapeutic agent.

The term "optionally substituted" means any substitution with the specified group, radical or residue.

The term "purified", "purified form" or "isolated and purified form" for a compound refers to the physical state of the compound after separation from the synthetic process or from a natural source or combination thereof. Thus, the term “purified”, “purified form” or “isolated and purified form” for a compound is obtained from a purification process or procedures described herein or well known to those skilled in the art, Refers to the physical state of the compound having a purity sufficient to be described herein or characterized by standard analytical techniques well known to those skilled in the art.

In addition, it is assumed that any carbon and hetero atom having an unsatisfied valence in the context, schemes, examples, and tables herein has a sufficient number of hydrogen atom (s) to meet valency.

When a functional group in a compound is named “protected,” it means that the group has been modified to exclude undesirable side effects at the protected site when the compound reacts. Suitable protection groups can be recognized not only by those skilled in the art but also by referring to standard documents such as, for example, TW Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York. will be.

If any variable (eg aryl, heterocycle, R ^2, etc.) is present more than once in any component or in any of the inventions, its definition in each presence is independent of its definition in all other presences. .

As used herein, the term “composition” is intended to include not only products that include a specified amount of a particular component, but also any product that is produced directly or indirectly from a combination of specified components of a specified amount.

The term “pharmaceutical composition” also refers to one or more (eg, two) such as, for example, a further agent selected from the list of compounds of the invention and additional agents described herein, in combination with a pharmaceutically inert vehicle. It is intended to include both bulk compositions consisting of pharmaceutically active agents and individual dosage units. The bulk composition and each individual dosage unit may contain a fixed amount of the "one or more pharmaceutically active agents" described above. Bulk compositions are materials that are not formed in individual dosage units. Exemplary dosage units are oral dosage units such as tablets, pills, and the like. Similarly, the methods described herein for treating a patient by administering a pharmaceutical composition of the present invention are intended to include the administration of said bulk composition and individual dosage units.

Prodrugs and solvates of the compounds of the invention are also contemplated herein. A discussion of prodrugs can be found in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term “prodrug” means a compound (eg, a drug precursor) that is converted in vivo to produce a compound of Formula 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof. Conversion may occur by a variety of mechanisms (eg, metabolic or chemical processes), such as through blood hydrolysis. A discussion of the use of prodrugs can be found in T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

For example, when the compound of Formula 1, or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, the prodrug may have a hydrogen atom of the acid group, e.g., (C ₁ -C ₈ ) alkyl, (C ₂ -C ₁₂ ) alkanoyloxymethyl, 1- (alkanoyloxy) ethyl having 4 to 9 carbon atoms, 1-methyl-1- (alkanoyloxy) -ethyl having 5 to 10 carbon atoms , Alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl having 5 to 8 carbon atoms, carbon number N- (alkoxycarbonyl) aminomethyl having 3 to 9, 1- (N- (alkoxycarbonyl) amino) ethyl having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma- Butyrolactone-4-yl, di-N, N- (C ₁ -C ₂ ) alkylamino (C ₂ -C ₃ ) alkyl (eg β-dimethylaminoethyl), carbamoyl- (C ₁ -C ₂ ) Alkyl, N, N-di (C ₁ -C ₂ ) alkylcarbamoyl- (C ₁ -C ₂ Esters formed by substitution with groups such as alkyl) and piperidino-, pyrrolidino- or morpholino (C ₂ -C ₃ ) alkyl and the like.

Similarly, when the compound of formula 1 contains an alcohol functional group, the prodrug may contain a hydrogen atom of the alcohol group, for example, (C ₁ -C ₆ ) alkanoyloxymethyl, 1-((C ₁ -C _6). ) Alkanoyloxy) ethyl, 1-methyl-1-((C ₁ -C ₆ ) alkanoyloxy) ethyl, (C ₁ -C ₆ ) alkoxycarbonyloxymethyl, N- (C ₁ -C ₆ ) alkoxy Carbonylaminomethyl, succinoyl, (C ₁ -C ₆ ) alkanoyl, α-amino (C ₁ -C ₄ ) alkanyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl ( Wherein each α-aminoacyl group is independently selected from naturally occurring L-amino acids), P (O) (OH) ₂ , -P (O) (O (C ₁ -C ₆ ) alkyl) ₂ or And can be formed by substituting a group such as glycosyl (a radical produced by the removal of a hydroxyl group of a hemiacetal type of carbohydrate).

If the compound of formula 1 contains an amine functional group, the prodrug may contain hydrogen atoms in the amine group, for example R-carbonyl, RO-carbonyl, NRR'-carbonyl, wherein R and R 'are each Independently is (C ₁ -C ₁₀ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, benzyl, or R-carbonyl, or R-carbonyl is natural α-aminoacyl or natural α-aminoacyl ], -C (OH) C (O) OY ¹ [where Y ¹ is H, (C ₁ -C ₆ ) alkyl or benzyl], -C (OY ² ) Y ³ [where Y ² is (C ₁ -C ₄ ) alkyl and Y ³ is (C ₁ -C ₆ ) alkyl, carboxy (C ₁ -C ₆ ) alkyl, amino (C ₁ -C ₄ ) alkyl or mono-N- or di-NN- (C ₁ -C ₆ ) alkylaminoalkyl, -C (Y ⁴ ) Y ⁵ [wherein Y ⁴ is H or methyl and Y ⁵ is mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino Is substituted with a group such as morpholino, piperidin-1-yl or pyrrolidin-1-yl.

One or more compounds of the present invention may exist in solvated and unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and the present invention provides both solvated and unsolvated forms. It is intended to be included. "Solvate" means a physical association of a compound of the invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, solvates may be separated, for example when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvates" include both solution phases and separable solvates. Non-limiting examples of suitable solvates include ethanolate, methanolate, and the like. "Hydrate" is a solvate in which the solvent molecule is H ₂ O.

One or more compounds of the present invention may be optionally converted to solvates. The preparation of solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical Sci, 93 (3), 601-611 (2004) describe the preparation of solvates of antifungal fluconazole from ethyl acetate as well as from water. It is describing. Similar preparations of solvates, antisolvates, hydrates and the like are described in E. C. van Tonder et al, AAPS Pharm SciTech., 5 (1), article 12 (2004); And in A. L. Bingham et al, Chem. Commun., 603-604 (2001). Conventional, non-limiting procedures dissolve the compounds of the present invention in a desired amount of the desired solvent (organic or water or mixtures thereof) at temperatures above ambient temperature and form crystals which are then separated by standard methods. Cooling at a rate sufficient to For example, I.R. Analytical techniques such as spectroscopy indicate the presence of a solvent (or water) in the crystal as a solvate (or hydrate).

Compounds of the present invention may form salts that are also included within the scope of the present invention. References herein to compounds of the invention are understood to include references to salts thereof, unless otherwise indicated. As used herein, the term “salt (s)” refers to acid salts formed with inorganic and / or organic acids, and basic salts formed with inorganic and / or organic bases. In addition, when a compound of any of the compounds of the present invention contains both basic residues such as but not limited to pyridine or imidazole, and acidic residues such as but not limited to carboxylic acids, the zwitterionic (" Internal salts ") may be formed and included within the term" salt (s) "as used herein. Although other salts may also be useful, pharmaceutically acceptable (eg nontoxic, physiologically acceptable) salts are preferred. Salts of the compounds of the present invention can be formed, for example, by reacting a compound of the present invention with an equivalent amount of an acid or base in a medium or aqueous medium in which the salt is precipitated and then lyophilized.

Exemplary acid addition salts include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorrate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide , Lactate, malate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartarate, thiocyanate, toluenesulfonate (also tosyl Known as rate) and the like. In addition, acids generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are described, for example, in P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66 (1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D. C. on their website). These descriptions are incorporated herein by reference.

Exemplary basic salts are alkali metal salts such as ammonium salts, sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, organic bases such as dicyclohexylamine, t-butyl amine, such as organic amines. Salts and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups include lower alkyl halides such as methyl, ethyl and butyl chloride, bromide and iodide, dialkyl sulfates such as dimethyl, diethyl and dibutyl sulfate, long chain halides such as decyl, Lauryl and stearyl chloride, bromide and iodide), aralkyl halides such as benzyl and phenethyl bromide and the like.

All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the present invention, and all acid and base salts are considered to be the same as the free form of the corresponding compound for the purposes of the present invention.

Pharmaceutically acceptable esters of the compounds of the invention include the following groups: (1) carboxylic esters obtained by esterification of hydroxy groups, wherein the non-carbonyl moiety of the carboxylic acid moiety of the ester grouping is linear or Branched alkyl (e.g. acetyl, n-propyl, t-butyl or n-butyl), alkoxyalkyl (e.g. methoxymethyl), aralkyl (e.g. benzyl), aryloxyalkyl (e.g. phenoxymethyl), aryl (Eg, phenyl optionally substituted with halogen, C _1-4 alkyl or C _1-4 alkoxy or amino); (2) sulfonate esters such as alkyl- or aralkylsulfonyl (eg methanesulfonyl); (3) amino acid esters such as L-valyl or L-isorusilyl; (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters can be further esterified with, for example, C _1-20 alcohols or reactive derivatives thereof, or 2,3-di (C _6-24 ) acyl glycerol.

The compounds of the invention, and salts, solvates, esters and prodrugs thereof, may exist in their tautomeric forms (eg amides or imino ethers). All such tautomeric forms are contemplated herein as part of the present invention.

Compounds of formula (1) may contain asymmetric or chiral centers, and therefore may exist in different cubic forms. All stereoisomeric forms of the compounds of formula 1 and mixtures thereof including racemic mixtures form part of the present invention. In addition, the present invention includes all geometric and positional isomers. When the compound of formula 1 incorporates double bonds or fused rings, both cis- and trans-forms, and mixtures are included within the scope of the present invention.

Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physicochemical differences by methods well known to those skilled in the art such as, for example, chromatography and / or fractional crystallization. Enantiomers react an enantiomeric mixture with a suitable optically active compound (e.g., chiral alcohol or Mosher's acid chloride), separate the diastereomers and then convert the individual diastereomers into the corresponding pure enantiomers. It can be separated into diastereomeric mixtures by conversion (eg hydrolysis). In addition, some of the compounds of Formula 1 may be atropisomers (eg substituted biaryls) and are contemplated as part of the present invention. Enantiomers can also be separated by the use of chiral HPLC columns.

In addition, the compounds of formula 1 may exist in different tautomeric forms, and all such forms are possible to be included within the scope of the present invention. Also included are, for example, all keto-enol and imine-enamine types of compounds.

The present invention, such as those that may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may be present in the absence of asymmetric carbons), aromeric forms, atropisomer forms, and diastereomeric forms All stereoisomers of compounds (including salts, solvates, hydrates, esters and prodrugs of compounds, as well as salts, solvates and esters of prodrugs) of are also positional isomers (eg, geometric isomers, optical isomers, etc.) For example, 4-pyridyl and 3-pyridyl) are contemplated within the scope of the present invention. (For example, where the compound of formula 1 contains a double bond or fused ring, both cis- and trans-forms and mixtures are included within the scope of the present invention. Also, for example, all keto- of compounds Enol and imine-enamine forms are included within the present invention.) Individual stereoisomers of the compounds of the present invention are substantially free of, for example, other isomers, or, for example, racemates or all other Or with other selected stereoisomers. The chiral center of the present invention may have an S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salts,“ solvates ”,“ esters ”,“ prodrugs ”and the like are enantiomers, stereoisomers, rotamers, tautomers, regioisomers, salts of racemates or prodrugs, solvents of the compounds of the invention. The same applies to cargoes, esters and prodrugs.

The present invention also includes isotopically labeled compounds of the present invention wherein the same as those recited herein, but wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number generally found in nature. do. Such compounds are useful as therapeutic, diagnostic or research reagents. Examples of isotopes that may be incorporated into the compounds of the present invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, respectively. , ¹⁸ O, ¹⁷ 0, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl.

Certain isotopically labeled compounds of Formula 1 (eg, those labeled with ³ H and ¹⁴ C) are useful in compound and / or matrix tissue distribution assays. Tritium (ie ³ H) and carbon-14 (ie ¹⁴ C) isotopes are particularly preferred due to their easy preparation and detectability. In addition, substitution with heavy isotopes such as deuterium (eg ² H) may provide certain therapeutic benefits resulting from better metabolic stability (eg, increased in vivo half-life or reduced dose requirements). It may be desirable in some situations. Isotopically labeled compounds of Formula 1 are generally subjected to procedures similar to those described in the following schemes and / or examples, by substituting non-isotopically labeled reagents with suitable isotopically labeled reagents. Can be prepared accordingly.

Compounds of the invention, and polymorphic forms of salts, solvates, esters, and prodrugs of the compounds of the invention, are intended to be included in the invention.

Manufacturing Example

In general, the compounds of the present invention may be prepared by a variety of methods well known to those skilled in the art, for example, as outlined in the general scheme below and in the examples below. The examples should not be construed as limiting the scope of the invention. Still other mechanical pathways and similar structures will be apparent to those skilled in the art.

The available EC ₅₀ values for the exemplified compounds shown in the table below are shown according to the following ranges:

A-≤ 500 nM

B-> 500 nM

C-> 500 nM to ≤ 1000 nM

D-> 1000 nM

The following abbreviations are used in the procedures and schemes:

ACN acetonitrile

AcOH acetic acid

Aq Mercury

BOC tert-butoxycarbonyl

BOC-ON [2- (tert-butoxycarbonyloxyimino) -2-phenylacetonitrile]

BOC ₂ O BOC Anhydride

C ℃

Cpd Compound

CBZCl Benzyl Chloroformate

DCM dichloromethane

DEAD diethyl azodicarboxylate

DIAD diisopropylazodicarboxylate

DIEA diisopropylethylamine

DMA N, N-dimethylacetamide

DMAP 4-N, N-dimethylaminopyridine

DME Dimethoxyethane

DMF Dimethylformamide

DMSO Dimethyl Sulfoxide

EDCl 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

EI electron ionization

Eq equivalent

EtOAc ethyl acetate

EtOH Ethanol

g gram

h. time

¹ H proton

HATU N, N, N ', N'-tetramethyl-O- (7-azabenzotriazol-1-yl) uronium

       Hexafluorophosphate

Hex Hexane

HOBT 1-hydroxybenzotriazole

HPLC high pressure liquid chromatography

KSP Kinesin Spindle Protein

LAH Lithium Aluminum Hydride

LDA Lithium Diisopropylamide

LHMDS lithium hexamethyldisilylamide

M Mall

mmol mmol

mCPBA meta-chloroperoxybenzoic acid

Me methyl

MeCN acetonitrile

MeOH Methanol

min min

mg milligram

MHZ megahertz

mL milliliters

MPLC Medium Pressure Liquid Chromatography

NMR nuclear magnetic resonance

MS mass spectroscopy

NBS N-bromosuccinimide

NIS N-iodosuccinimide

NMM N-methylmorpholine

NMP 1-methyl-2-pyrrolidone

ON overnight

PCC pyridinium chlorochromate

PTLC Preparative Thin Layer Chromatography

Pyr pyridine

RT room temperature

sgc silica gel 60 chromatography

tBOC tert-butoxycarbonyl

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

t _R dwell time

Example

General Scheme 1:

General Scheme 2:

Example 101:

Part A:

To a suspension of sodium hydride (800 mg, 20 mmol) in THF (30 mL) was added a solution of triethyl phosphonoacetate (4 mL, 20 mmol) in THF (10 mL), and the reaction mixture was then stirred for 1 h at room temperature. Was stirred. A solution of 1-tetralone 101 A (2.92 g, 20 mmol) in THF (10 mL) was added and then the reaction mixture was refluxed for 16 h. The volatiles were removed in vacuo and the residue was re-dissolved in DCM and then washed with water. Zn and E- of compound 101 B (1.7 g, 7.83 mmol, 39%) were dried over magnesium sulfate, concentrated, purified by flash silica chromatography, and eluted with (0-100%) hexanes / ethyl acetate. Isomers were obtained. HPLC-MS t _R = 1.97-2.12 min (UV _{254 nm} ); Mass calculated for formula C ₁₄ H ₁₆ O ₂ 216.1, found LCMS m / z 217.1 (M + H).

Part B:

Isopropylmagnesium chloride (2M, 6.94 mL, 13.9 mmol) was added N, O-dimethylhydroxylamine hydrochloride (677 mg, 6.94 mmol) and compound 101 B (1.0 g, 4.63) in THF (20 mL) at -20 ° C. mmol) was added dropwise over 15 minutes. The reaction mixture was aged to −10 ° C., stirred for an additional 20 minutes and then quenched by addition of saturated ammonium chloride solution. Extracted with ethyl acetate, dried over magnesium sulfate, concentrated, purified by flash silica chromatography, gradient elution with (0-100%) hexanes / ethyl acetate, Compound 101 C (685 mg, 2.96 mmol, 64%) Z- and E-isomers were obtained. HPLC-MS t _R = 1.55-1.80 min (UV _{254 nm} ); Mass calculated for formula C ₁₄ H ₁₇ NO ₂ 231.1, found LCMS m / z 232.1 (M + H).

Part C:

Isopropylmagnesium chloride (2M, 4.5 mL, 9.0 mmol) was added dropwise to a stirred solution of 2,5-difluoroiodomethane (1.1 mL, 9.0 mmol) in THF (20 mL) at -78 ° C. The reaction mixture was aged to −40 ° C. and a solution of compound 101 C (685 mg, 2.97 mmol) in THF (10 mL) was added. After warming to room temperature, stirring for 16 hours yielded the formation of compound 4, which was confirmed by LCMS analysis. The reaction mixture was quenched by addition of saturated ammonium chloride solution, extracted with ethyl acetate, dried over magnesium sulfate, concentrated, purified by flash silica chromatography and gradient eluted with (0-100%) hexanes / ethyl acetate Z- and E-isomers of compound 101 D (481 mg, 1.69 mmol, 57%) were obtained. HPLC-MS t _R = 2.4-2.6 min (UV _{254 nm} ); Mass calculated for formula C ₁₈ H ₁₄ F ₂ O 284.1. Found LCMS m / z 285.1 (M + H).

Part D:

To a solution of compound 101 D (100 mg, 0.35 mmol) in THF (2 mL) was added hydrazine monohydrate (12 μL, 0.39 mmol), then the reaction mixture was heated in microwave at 150 ° C. for 20 minutes. The reaction mixture was concentrated and then purified by flash silica chromatography and gradient eluted with (0-100%) hexanes / ethyl acetate to afford compound 101 E (45 mg, 0.15 mmol, 43%). HPLC-MS t _R = 2.45 (UV _{254 nm} ); Mass calculated 298.1 for Formula C ₁₈ H ₁₂ F ₂ N ₂ , obsd. LCMS m / z 299.1 (M + H).

Part E:

A mixture of compound 101 E (20 mg, 0.07 mmol), acetyl chloride (14 μL, 0.2 mmol) and potassium carbonate (14 mg, 0.1 mmol) in THF (2 mL) was stirred at room temperature for 3 hours. LCMS analysis confirmed the formation of product. The reaction mixture was quenched by addition of 1N HCl, extracted with ethyl acetate, dried over magnesium sulfate, concentrated and purified by prep.HPLC to give compound 101 as off white solid.

The following compounds were synthesized using this procedure:

Example 201:

Part A:

A mixture of compound 101 E (120 mg, 0.4 mmol), 4-nitrophenylchloroformate (242 mg, 1.2 mmol) and potassium carbonate (83 mg, 0.6 mmol) in THF (10 mL) was stirred at room temperature for 3 hours. It was. LCMS analysis confirmed the formation of the product. The reaction mixture was quenched by addition of saturated NaHCO ₃ , extracted with ethyl acetate, dried over magnesium sulfate and concentrated to give crude compound 201 B as an off-white solid. HPLC-MS t _R = 2.18 (UV _{254 nm} ); Mass calculated for formula C ₂₄ H ₁₇ F ₂ N ₃ O ₅ , 465.1. Found LCMS m / z 466.1 (M + H).

Part B:

To a solution of compound 201 B (18 mg, 0.04 mmol) in DMF (1.5 mL) was added amine (0.49 mmol), then the reaction mixture was heated in microwave at 150 ° C. for 5 minutes. The reaction mixture was concentrated and then purified by prep.HPLC to give compound 201 as off-white solid.

The following compounds were synthesized using this procedure:

Example 3:

Part A:

A mixture of compound 10 (0.1 mmol), acid chloride (0.12 mmol) and DIEA (0.2 mmol) in THF (2 mL) was stirred at rt for 16 h. LCMS analysis confirmed that the product had formed. The reaction mixture was concentrated and then purified by prep. HPLC to give compound 11 as a white solid.

The following compounds were synthesized using this procedure:

Example 401:

Part A:

1-tetrarone (101 A, 1.33 mL, 10 mmol) in toluene (15 mL) sealed in a Schlenk tube, allyl alcohol (3.4 mL, 50 mmol), 2,2-dimethoxypropane (1.84 mL, 15 mmol) ), p-toluenesulfonic acid (345 mg, 2 mmol) and 3 ′ molecular sieve (3 g) were placed in a 200 ° C. oil bath. The reaction mixture was stirred at 200 ° C. for 15 hours and then cooled to room temperature. The reaction mixture was filtered through celite. The filtrate was concentrated. The residue was purified by column chromatography using 20% DCM in hexane as eluent to afford compound 401 B as a pale yellow oil (774 mg, 42% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04 (dd, J = 1.2, 7.6 Hz, 1H), 7.46 (dt, J = 1.6, 7.6 Hz, 1H), 7.30 (tt, J = 0.8, 7.6 Hz, 1 H), 7.23 (d, J = 8.0, 1H), 5.92-5.78 (m, 1H), 5.14-5.04 (m, 2H), 2.99 (dd, J = 4.8, 7.6 Hz, 2H), 2.80-2.72 (m, 1H), 2.60-2.50 (m, 1H), 2.32-2.20 (m, 2H), 1.92-1.80 (m, 1H).

Part B:

The reaction mixture of compound 401 B (46 mg, 0.25 mmol), 2-ethynyl-1,4-difluorobenzene (34 mg, 0.25 mmol) and sodium t-butoxide (38 mg, 0.4 mmol) was t- Stir in butanol (1 mL). Column chromatography using eluent of 10% EtOAc in hexanes gave compound 401 C (13 mg, 16% yield). HPLC-MS RT = 2.54 min, Mass calcd. For Formula C ₂₁ H ₁₈ F ₂ O 324.1, found LCMS m / z 325.1 (M + H).

Part C:

To a solution of compound 401 C (13 mg) in dioxane (0.2 mL) and water (50 uL) was added sulfuric acid (50 uL) with stirring. The reaction mixture was stirred in microwave at 150 ° C. for 15 minutes. The reaction mixture was concentrated. Column chromatography using eluent of 20% EtOAc in hexanes gave compound 401 D. HPLC-MS RT = 2.51 min. Mass calcd. For Formula C ₂₁ H ₁₃ F ₂ O 324.1, found LCMS m / z 325.1 (M + H).

Part D:

The reaction mixture of compound 401 D obtained from part C and hydrazine monohydrate (0.1 mL) in acetic acid (0.5 mL) was stirred in microwave at 160 ° C. for 15 minutes. Purification using reverse phase HPLC and lyophilization gave compound 401 as an HCl salt. HPLC-MS RT = 6.54 min, Mass calcd. For Formula C ₂₃ H ₂₂ F ₂ N ₂ O, 380.17. Found LCMS m / z 381.28 (M + H).

Part E:

To a solution of compound 401 in THF (0.2 mL) obtained from part D was added a solution of 9-BBN in THF (0.2 mL, 0.5 M). The reaction mixture was stirred at room temperature for 2 hours. Then, an aqueous NaOH solution (1 mL, 1 M) and an aqueous hydrogen peroxide solution (1 mL, 30%) were added. The reaction mixture was stirred at rt for 1 h. Purification using reverse phase HPLC and after lyophilization gave compound 402 as an HCl salt. HPLC-MS RT = 5.66 min, Mass calcd. For Formula C ₂₃ H ₂₄ F ₂ N ₂ O ₂ 398.18, found LCMS m / z 399.29 (M + H).

Part F:

To a solution of 2,6-lutidine (8.1 μL, 0.07 mmol) in compound 402 and DCM (0.5 mL) obtained from part E was added tricyclic anhydride (8.4 μL, 0.05 mmol). The reaction mixture was stirred at room temperature for 2 hours. Thereafter, ammonia in dioxane (0.5 M, 3 mL) was added. The reaction mixture was sealed in a Schlenk tube and then stirred at 58 ° C. overnight. Purification using reverse phase HPLC and after lyophilization gave compound 403 as an HCl salt. HPLC-MS RT = 3.89 min, Mass calcd. For Formula C ₂₃ H ₂₅ F ₂ N ₃ O, 397.20. Found LCMS m / z 398.23 (M + H).

The following compounds were synthesized using this procedure:

Example 501:

Part A:

To a solution of 2,3-dihydro-1H-quinolin-4-one (501 A, 1 g, 6.8 mmol) and DIEA (4.7 mL, 27 mmol) in DCM (30 mL) benzyl chloroformate (2.8 mL, 20 mmol) was added. The reaction mixture was stirred at rt overnight then concentrated. The residue was purified by column chromatography. Elution with 20% EtOAc in hexanes gave compound 501 B (1.585 g, 83% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.00 (dd, J = 1.2, 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.54-7.48 (m, 1H), 7.44-7.32 ( m, 5H), 7.21-7.16 (m, 1H), 5.29 (S ₁ 2H), 4.23 (t, J = 6.4, 2H), 2.81-2.76 (m, 2H).

Part B:

Compound 501 B (1.4 g, 5 mmol), allyl alcohol (1.7 mL, 25 mmol), 2,2-dimethoxypropane (0.922 mL, 7.5 mmol) in xylene (5 mL), p-toluenesulfonic acid (172 mg , 1 mmol) and 3 ′ molecular sieve (1.5 g) were loaded into a Schlenk tube. The Schlenk tube was sealed and then placed in a 200 ° C. oil bath. The reaction mixture was stirred at 200 ° C. for 15 hours and then cooled to room temperature. The reaction mixture was filtered through celite. The filtrate was concentrated. The residue was purified by column chromatography. Elution with 12% EtOAc in hexanes gave compound 501 C as a pale yellow oil (1.0 g, 62% yield). 1 H NMR (400 MHz, CDCl ₃ ) δ 8.04-7.98 (m, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.53-7.47 (m, 1H), 7.44-7.32 (m, 5H) , 7.21-7.15 (m, 1H), 5.86-5.72 (m, 1H), 5.31 (d, J = 12 Hz, 1H), 5.26 (d, J = 12.4 Hz, 1H), 5.08 (d, J = 16.4 Hz, 1H), 5.07 (d, J = 10.8 Hz, 1H), 4.37 (dd, J = 4.0, 13.6 Hz, 1H), 3.85 (dd, J = 9.2, 13.6 Hz, 1H), 2.76 -2.60 (m, 2H), 2.30-2.20 (m, 1H).

Part C:

THF (0.5 mL, 1.0 M) in a solution of compound 501 C (64.2 mg, 0.2 mmol) and ((2,5-difluorophenyl) ethynyl) trimethylsilane (84 mg, 0.4 mmol) in THF (0.4 mL) A solution of TBAF in) was added. The reaction mixture was stirred in the microwave at 130 ° C. for 30 minutes. The reaction mixture was quenched using aqueous NaHCO ₃ solution. The organics were extracted with EtOAc. Concentration of the EtOAc solution gave compound 501 D. HPLC-MS RT = 2.10 min, Mass calcd. For Formula C ₂₀ H ₁₇ F ₂ NO 325.1, found LCMS m / z 326.1 (M + H).

Part D:

To a solution of compound 501 D in dioxane (0.5 mL) and water (100 uL) was added with stirring sulfuric acid (100 uL). The reaction mixture was stirred in microwave at 150 ° C. for 30 minutes. The reaction mixture was quenched using aqueous NaHCO ₃ solution. The organics were extracted with EtOAc. EtOAc solution was concentrated. The residue was purified by flash chromatography using eluent of 25% EtOAc in hexanes to give compound 501 E. HPLC-MS RT = 2.02-2.34 min. Mass calcd. For Formula C ₂₀ H ₁₇ F ₂ NO 325.1, Observed LCMS m / z 326.1 (M + H).

Part E:

The reaction mixture of compound 501 E obtained from part D, DIEA (30 uL) and hydrazine monohydrochloride (10 mg) in EtOH (0.2 mL) was stirred in a microwave at 140 ° C. for 40 minutes. The reaction mixture was quenched using aqueous NaHCO ₃ solution. The organics were extracted with EtOAc. Concentration of the EtOAc solution gave compound 501 F. HPLC-MS RT = 1.22-1.33 min. Mass calcd. For Formula C ₂₀ H ₁₉ F ₂ N ₃ 339.1, obsd. LCMS m / z 340.1 (M + H).

Part F:

To a solution of compound 501 F in dioxane was added acetyl chloride (10 mg). The reaction mixture was stirred and then concentrated. Purification using reverse phase HPLC gave lyophilization to yield compound 501 as an HCl salt. HPLC-MS RT = 3.62 min, Mass calcd. For Formula C ₂₂ H ₂₁ F ₂ N ₃ O, 381.17. Found LCMS m / z 382.29 (M + H).

Example 601:

Part A:

Compound 501 B (1.4 g, 5 mmol), allyl alcohol (1.7 mL, 25 mmol), 2,2-dimethoxypropane (0.922 mL, 7.5 mmol) in xylene (5 mL), p-toluenesulfonic acid (172 mg , 1 mmol) and 3 ′ molecular sieve (1.5 g) were loaded into a Schlenk tube. The Schlenk tube was sealed and then placed in a 200 ° C. oil bath. The reaction mixture was stirred at 200 ° C. for 15 hours and then cooled to room temperature. The reaction mixture was filtered through celite. The filtrate was concentrated. The residue was purified by column chromatography. Elution with 12% EtOAc in hexanes gave compound 601 B as a pale yellow oil (1.0 g, 62% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04-7.98 (m, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.53- 7.47 (m, 1H), 7.44-7.32 (m, 5H ), 7.21-7.15 (m, 1H), 5.86-5.72 (m, 1H), 5.31 (d, J = 12 Hz, 1H), 5.26 (d, J = 12.4 Hz, 1H), 5.12-5.04 (m , 2H), 4.37 (dd, J = 4.0, 13.6 Hz, 1H), 3.85 (dd, J = 9.2, 13.6 Hz, 1H), 2.76-2.60 (m, 2H), 2.30-2.20 (m, 1H).

Part B:

Ozone was bubbled into a solution of Compound 601 B (94.5 mg, 0.3 mmol) in DCM (5 mL) at −78 ° C. for 15 minutes. Triphenylphosphine (262 mg, 1 mmol) was added to the solution. The reaction mixture was stirred for 3 hours while warming to room temperature. The reaction mixture was concentrated. The residue was purified by flash chromatography using 20% EtOAc in hexane as eluent to afford Compound 601 C (74 mg, 76% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.80 (s, 1 H), 7.99 (dd, J = 1.6, 7.6 Hz, 1 H), 7.85 (d, J = 8.8 Hz, 1 H), 7.55-7.49 (m, 1H), 7.44-7.32 (m, 5H), 7.19 (dt, J = 1.2, 7.6 Hz, 1H), 5.29 (s, 2H), 4.58 (dd, J = 4.8, 13.6 Hz, 1H) , 3.74 (dd, J = 11.2, 13.2 Hz, 1H), 3.34-3.26 (m, 1H), 2.99 (ddd, J = 0.8, 5.2, 18.4 Hz, 1H), 2.66 (dd, J = 7.2, 18.4 Hz, 1 H).

Part C:

Dibenzylamine (553 μL, 2.88 mmol) was added at 0 ° C. to a mixture of compound 601 C (780 mg, 2.4 mmol) and crushed 4 ′ molecular sieve (2.77 g) in chloroform (11 mL). The reaction mixture was stirred at 0 ° C. for 2 hours and then filtered to remove molecular sieve. To the filtrate solution in chloroform was added sodium triacetoxyborohydride (610 mg, 2.88 mmol) at room temperature. The reaction mixture was stirred at rt for 1 h and then quenched with aqueous HCl solution (1 M). The mixture was then basified with aqueous NaOH solution. The organics were extracted with DCM. The organic layers were combined and then concentrated. The residue was purified by flash chromatography using eluent of 10% EtOAc in hexanes to give compound 601 D (800 mg, 66% yield) as a yellow gel. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (dd, J = 1.6, 8.0 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.51-7.45 (m, 1H), 7.40- 7.12 (m, 16H), 5.24 (d, J = 12 Hz, 1H), 5.18 (d, J = 12.4 Hz, 1H), 4.03 (dd, J = 4.0, 14 Hz, 1H), 3.65 (d, J = 13.2 Hz, 2H), 3.63 (dd, J = 8.4, 13.6 Hz, 1H), 3.42 (d, J = 13.2 Hz, 2H), 2.84-2.72 (m, 1H), 2.61 -2.45 (m, 2H ), 2.08-1.98 (m, 1 H), 1.64-1.52 (m, 1 H).

Part D:

To a flask containing Compound 601 D (75.6 mg, 0.15 mmol) was added Petasis reagent in toluene (5% wt, 3 mL, 0.75 mmol) under an argon atmosphere. The reaction mixture was stirred for 4 h at 70 ° C. in toluene in the dark. The reaction mixture was quenched with EtOAc and acetone (1: 1) and then concentrated. The residue was purified by flash chromatography using 10% EtOAc in hexanes to give compound 601 E (66.2 mg, 88% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.66 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 1.6, 8.4 Hz, 1H), 7.31-7.10 (m, 16H), 6.99-6.93 (m, 1H), 5.38 (s, 1H), 5.12 (d, J = 12.4 Hz, 1H), 5.06 (d, J = 12.8 Hz, 1H), 4.60 (s, 1H), 3.82 (dd, J = 4.0, 13.2 Hz, 1H), 3.48 (d, J = 13.6 Hz, 2H), 3.36 (d, J = 13.6 Hz, 2H), 3.28 (dd, J = 3.2, 13.2 Hz, 1H ), 2.72-2.64 (m, 1H), 2.45-2.32 (m, 2H), 1.54-1.46 (m, 2H).

Part E:

A mixture of benzylhydrazine monohydrochloride (0.8 g, 5 mmol) and sodium hydroxide (0.6 g, 15 mmol) in THF (5 mL) was stirred at rt overnight. The reaction mixture was filtered. To the filtrate was added 2,5-difluorobenzaldehyde (601 F, 0.71 g, 5 mmol). The reaction mixture was stirred overnight at room temperature and then concentrated to give 601 G. HPLC-MS RT = 2.23 min. Mass calcd. For Formula C ₁₄ H ₁₂ F ₂ N ₂ 246.1, Observed LCMS m / z 247.2 (M + H).

Part F:

To a solution of compound 601 G (615 mg, 2.5 mmol) in EtOAc (5 mL) was added N-chlorosuccinimide (334 mg, 2.5 mmol). The reaction mixture was stirred at 60 ° C. for 3 hours and then concentrated. The residue was purified by flash chromatography using eluent of 10% EtOAc in hexanes to give compound 601 H (460 mg, 66% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40-7.28 (m, 6H), 7.10-6.95 (m, 2H), 6.31 (br s, 1H), 4.57 (s, 2H).

Part G:

To a solution of compound 601 E (20 mg, 0.04 mmol) and compound 601 H (11.2 mg, 0.04 mmol) in chloroform (1 mL) was added triethylamine (27.8 μL, 0.2 mmol). The reaction mixture was stirred at 60 ° C. overnight and then concentrated. The residue was purified by flash chromatography using eluent of 10% EtOAc in hexanes to give compound 601 I (15 mg, 50% yield). HPLC-MS RT = 2.37 min. Mass calcd. For Formula C ₄₈ H ₄₄ F ₂ N ₄ O ₂ , 746.3, found LCMS m / z 747.2 (M + H).

Part H:

A solution of compound 601 I (15 mg, 0.02 mmol) in MeOH / EtOAc (4 mL, 1/1) was carbon-phased in an H-cube at 40 bar H ₂ at a temperature of 40 ° C. and a flow rate of 0.4 mL / min. Passed through a cartridge of 10% palladium. Purification using reverse phase HPLC and after lyophilization gave compound 601 as an HCl salt. HPLC-MS RT = 4.60 min. Mass calcd. For Formula C ₂₆ H ₂₆ F ₂ N ₄ 432.21. Observation LCMS m / z 433.22 (M + H).

The following compounds were synthesized using this procedure:

Example 701:

Part A:

Wittig Salt (methyltriphenylphosphonium bromide, 2.0 equiv, 0.420 mmol, 150 mg) was weighed into a round bottom flask equipped with a stir bar. The flask was emptied, then purged with N ₂ (g) and sealed with a septum. Anhydrous THF (2 mL) was added, then the solution was cooled to -78 ° C, then LiHMDS (2.0 equiv, 0.420 mmol, 420 μL) was added. The ice bath was removed and the reaction was warmed for 15 minutes (to about −25 ° C.). The reaction vessel was cooled back to -78 ° C, then commercially available 2-benzyl-2,3-dihydroisoquinolin-4 (1H) -one (701 A, 1.0 equiv, 0.210 mmol, 50 mg in 2 mL THF) Solution was added. The reaction was allowed to warm for 15 hours. The reaction was quenched with MeOH, then concentrated under reduced pressure and purified by gradient elution of hexanes / EtOAc on silica gel to give compound 701 B (18 mg, 36% yield). HPLC-MS RT = 1.034 min (5 min method), Mass Calcd for Formula C ₁₇ H ₁₇ N, 235.14, found LCMS m / z 236.20 (M + H). ¹ H NMR (400 MHz, DMSO) δ 7.63 (1H, m), 7.42-7.20 (6H, m), 6.96 (1H, m), 6.76 (1H, d), 5.56 (1H, s), 4.90 (1H , s), 3.68 (2H, s), 3.62 (2H, s), 3.64 (2H, s).

Part B:

2-benzyl-4-methylene-1,2,3,4-tetrahydroisoquinoline (Compound 701 B, 1.0 equiv, 0.076 mmol, 18 mg) and (Z) -N-benzyl-2,5-difluoro Benzohydrazonoyl chloride (601 H, 43 mg, 0.153 mmol, 2.0 equiv) was weighed into 20 mL vials and then dissolved in anhydrous CHCl ₃ (1 mL). Triethylamine (5.0 equiv, 0.380 mmol, 50 μL) was added and the vial was purged with N ₂ (g), sealed with a cap and then heated at 70 ° C. for 18 hours. All volatiles were removed under reduced pressure, then the residue was dissolved in DMSO / acetonitrile (3: 1). The residue was purified using reverse phase HPLC to yield product 701. HPLC-MS RT = 5.801 min (10 min method), Mass Calcd for Formula C ₃₁ H ₂₇ F ₂ N ₃ , 479.2175, found LCMS m / z 480.2749 (M + H).

The pharmacological properties of the compounds of the present invention, including efficacy as inhibitors of KSP activity, can be confirmed by a number of pharmacological assays. Inhibitory activity of the compounds of the present invention on KSP can be assayed by using methods known in the art, such as in the examples above and as described below.

KSP Biochemical Assay

KSP biochemical enzyme assay was performed in 384-well plates. All reagents were thawed on ice. The compound was diluted to the desired concentration in 100% DMSO. 10 mg microtubules (Cytoskeleton) were reconstituted in 10 mL tubulin buffer (80 mM PIPES pH 6.8, 1 mM EGTA, 1 mM MgCl ₂ , 0.005% sodium azide) + 100ul 2 mM paclitaxel (cytoskeleton).

Each reactant contained 10 nM KSP motor domain (amino acids 15-368), 20 uM paclitaxel (cytoskeleton), 0.18 uM microtubules, 100 uM ATP (Roche) and kinesin buffer (20 mM ACES pH 7.0, 1 mM EGTA, 1 mM MgCl ₂ , 25 mM KCl, 1 mM DTT). For each reaction, 19 uL of mixture containing KSP kinetic domain, paclitaxel, microtubules and kinesin buffer was combined with 1 uL of diluted compound. The reaction was initiated by the addition of 5 uL ATP. The reaction was allowed to proceed for 1 hour at room temperature. The reaction was stopped by the addition of 50ul Biomol green (Biomol International). After an additional 30 minutes, the absorbance at OD620nm was measured using Envision.

IC50 Determination: Dose-response curves were plotted from inhibition data, each duplicated from 8 point serial dilutions of inhibitory compounds. The concentration of the compound was plotted against enzymatic activity (OD readout). The dose-response curve was then fitted to a standard sigmoidal curve and IC50 values were derived by nonlinear regression analysis to generate IC50 values.

KSP Cell Assay:

HCT116 colon cancer cells were grown in DMEM: F12 medium with 10% heat inactivated FBS at 37 ° C., 5% CO ₂ . Cells were plated at 7,500 cells per well in PDL coated 384-well tissue culture plates. After 6 hours the medium was removed and fresh medium containing the drug was added. Cells were incubated with drug for 16 hours. All further steps were performed at room temperature in the dark. Cells were fixed with 25 ul / well Prefer fixative solution + 250 nM Hoechst dye and incubated for 30 minutes. The fixative solution was removed and the cells washed with PBS. Cells were then permeated with 25ul / well 0.2% Triton-X in PBS and incubated for 10 minutes. Cells were washed with PBS and then incubated for 30 minutes with 25 ul / well of PBS containing 3% FBS. Cells were then stained overnight at 4 ° C. with 25ul / well antibody solution in PBS + 3% FBS. The antibodies used were Phos-Histone H3 (ser10) -Alexa Flur 488 conjugate and Phos-MPM2 Texas Red conjugate. The cells are washed with PBS and the images are immunofluorescence. The percentage of positive stained cells was calculated and EC ₅₀ values for the compounds of the invention tested were determined using Excel XLfit.

EC50 Determination: Dose-response curves were plotted from inhibition data, each generated in duplicate from 8 point serial dilutions of inhibitory compounds. The concentration of the compound was plotted against enzymatic activity (OD readout). Dose-response curves were then fitted to standard sigmoidal curves and EC50 values were derived by nonlinear regression analysis to generate EC50 values.

Exemplary compounds of the invention tested in the above cell assays exhibited EC _5O values in the range as reported in the table below.

How to use

As inhibitors of KSP activity, the compounds of the present invention are contemplated as being useful for treating a wide variety of diseases, conditions or disorders ("diseases").

In one embodiment, the present invention comprises administering one or more compounds or compositions of the invention or pharmaceutically acceptable salts, esters, isomers, tautomers or prodrugs thereof to a subject in need of inhibition of KSP kinesin activity. Thus, there is provided a method of inhibiting KSP kinesin activity in the subject (eg, cell, animal or human).

In one embodiment, the invention provides administration of one or more compounds or compositions of the invention or pharmaceutically acceptable salts, esters, isomers, tautomers or prodrugs thereof to a subject in need of selective inhibition of KSP kinesin activity. Including, selectively inhibiting KSP kinesin activity in the subject (eg, cell, animal or human).

In some embodiments, the disease that can be treated includes a disease that is susceptible to changes in mitosis by inhibiting KSP activity. As will be appreciated by those skilled in the art, mitosis may increase or decrease the activity of a component in various ways, such as in the mitotic pathway, or by disturbing equilibrium (eg, By inhibiting or activating).

In one embodiment, a therapeutically effective amount of one or more compounds of the invention, or a pharmaceutically acceptable salt or ester thereof, is administered to a subject in need of treatment or prevention of a disease associated with KSP activity. Provided are methods for treating or preventing a disease associated with KSP activity.

In one embodiment, the compounds of the present invention can be used to inhibit mitotic spindle formation, thus stopping the prolonged cell cycle in mitosis. "Inhibition" in this context means reducing or preventing mitotic spindle formation or causing mitotic spindle dysfunction. "Mitotic spindle formation" means that microtubules are organized into a bipolar structure by mitotic kinesin. "Mitotic spindle dysfunction" means mitotic arrest and unipolar spindle formation.

In one embodiment, the compounds of the present invention The compounds of the present invention may be useful for binding to KSP and / or inhibiting KSP activity. In one embodiment, the KSP is a human KSP. In one embodiment, such KSP activity is inhibited in vitro, in vivo (eg, in a patient in need thereof) or ex vivo.

In another embodiment, the compounds of the present invention can be used to bind KSP kinesin or to inhibit KSP kinesin activity from non-human organisms. In this context, "inhibition" means increasing or decreasing spindle pole separation, causing malformation, ie, splaying the mitotic spindle pole, or otherwise causing morphological fluctuations of the mitotic spindle.

Also included in the definition of KSP for the purposes of the present invention are variants and / or fragments of KSP (see US Pat. No. 6,437,115).

The compounds of the present invention can be used to treat diseases associated with or caused by abnormal cell proliferation. Such diseases include, but are not limited to, cancer (discussed further below), hyperplasia, heart thickening, autoimmune diseases, fungal diseases, arthritis, transplant rejection, inflammatory bowel disease, immune diseases, inflammation, surgery, angiogenesis, and the like. Cell proliferation induced after medical surgery, but not limited to, but not limited to. Treatment includes inhibiting cell proliferation. In some cases, it is recognized that the cells may not be abnormally proliferating and still require treatment. For example, during wound healing, cells may proliferate “normally,” but inhibition of cell proliferation may be desirable. Thus, in one aspect, the invention herein includes application to cells or subjects suffering from or at risk of suffering from these diseases, diseases or conditions.

The terms "treat cancer" and "treatment of cancer" refer to the effect of alleviating the cancer state by administering to a mammal suffering from the cancer state and killing to some extent cancer cells, and also the growth and / or metastasis of the cancer. Refers to the effect of causing inhibition.

Due to KSP inhibitory action, the compounds, compositions and methods provided herein are useful for treating a wide variety of cancers. Non-limiting examples of such cancers include solid tumors and hematological cancers such as skin, breast, brain, colon, gallbladder, thyroid, cervical carcinoma, testes, and cancers of the blood. Additional non-limiting examples of cancers suitable for treatment include:

Heart : sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibrosarcoma, lipoma and teratoma;

Lungs: tracheal carcinoma (squamous cell, undifferentiated small cell, undifferentiated giant cell, adenocarcinoma), alveolar (bronchiole) carcinoma, bronchial carcinoma, sarcoma, lymphoma, cartilage hyperoma, mesothelioma;

Gastrointestinal: mesothelioma (squamous cell carcinoma, adenocarcinoma, leiomyarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyoma), pancreas (coronary adenocarcinoma, insulinoma, glucagon, gastrinoma, carcinoid tumor, vipoma) ), Small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibromatosis, fibroid), large intestine (adenocarcinoma, thyroidoma, choriomas, leiomyoma);

Urogenital tract: Kidney (adenocarcinoma, Wilms' tumor (renal blastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testicles (testis, teratoma) , Embryonic carcinoma, teratocarcinoma, chorionic carcinoma, pore, interstitial cell carcinoma, fibroid, fibroadenoma, glandular tumor, lipoma);

Liver: liver cancer (hepatic cell carcinoma), cholangiocarcinoma, hepatoblastoma, hemangiosarcoma, hepatocellular carcinoma, hemangioma;

Bone: Osteosarcoma (bone sarcoma), Fibrosarcoma, Malignant fibrous histiocytoma, Cartilage sarcoma, Ewing's sarcoma, Malignant lymphoma (reticulocyte sarcoma), Multiple sclerosis, Malignant giant cell tumor chordoma, Osteochondrosis ( Osteochondral osteoplasia), benign glioma, chondroma, chodromyxofibroma, osteomyeloma and giant cell tumors;

Nervous system: skull (osteomas, hemangiomas, granulomas, osteomas, osteomyelitis), meninges (meningiomas, meningiosarcomas, glioma), brains (astrogliomas, stromal blastomas, glioma, ventricular cell tumors, seed cell tumors (pineal adenoma), polymorphisms Glioblastoma, oligodendrocyte glioma, neuromyoma, retinoblastoma, congenital tumor), spinal cord neurofibromatosis, meningioma, glioma, sarcoma);

Gynecology: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovary (ovarian carcinoma (severe cystic carcinoma, mucous cystic carcinoma, unclassified carcinoma), granulocytic cell tumor, ser Tortoli-Leydog cell tumor, ovarian germ cell tumor, malignant teratoma, vulvar (squamous cell carcinoma, intraepithelial tumor, adenocarcinoma, fibrosarcoma, malignant melanoma), vagina (transparent cell carcinoma), squamous cell carcinoma, Staphylosarcoma (germstone), uterine tube (sarcoma);

Blood disorders: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, acute and chronic lymphocytic leukemia, myeloproliferative diseases, multiple sclerosis, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma ( Malignant lymphoma), B-cell lymphoma, T-cell lymphoma, hair cell lymphoma, Burkett's lymphoma, promyelocytic leukemia;

Skin : malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, hemangioma, dermal fibroid, keloid, psoriasis;

Adrenal gland : neuroblastoma; And

Other tumors : pigmentary dry skin disease, keratinocytes and thyroid cell tumors.

As used herein, treatment of cancer includes the treatment of cancer cells, including cells suffering from any of the conditions, diseases or disorders described above.

The compounds of the present invention may also be useful for chemoprevention of cancer. Chemoprevention is defined as inhibiting the progression of invasive cancer by either blocking the onset of a mutagenic phenomenon or by blocking the progression of pre-malignant cells already suffering from seizures. Compounds of the invention may also be useful for inhibiting cancer recurrence.

Compounds of the invention may also be useful for inhibiting tumor angiogenesis and metastasis.

Compounds of the invention may also be useful as antifungal agents by modulating the activity of fungal members of the bimC kinesin subgroup, as described in US Pat. No. 6,284,480.

For each of the foregoing embodiments, the amount of one or more compounds of the invention administered is preferably an effective amount for the intended purpose. The phrase “effective amount” refers to a tissue that is considered by an administrator (eg, a researcher, doctor, or veterinarian), including alleviation of symptoms of the condition or disease being treated, and prevention, delay or arrest of the progression of one or more cell proliferative diseases, Compounds of the present invention that will elicit a biological or medical response of a cell, cell population (e.g., a population of abnormal proliferating cells, such as cancer cells or psoriasis cells), systems or subjects (e.g., animals or humans), and herein Means the amount of other pharmacological or therapeutic agents described. A "therapeutically effective amount" means an effective amount whose purpose includes a therapeutic purpose, such as in a person or non-human patient in need of treatment. Formulations or compositions, combinations and treatments of the invention can be administered by any suitable means of contacting these compounds with the site of action in the body of the subject being treated or in a targeted population of aberrant proliferating cells.

Suitable dosage ranges for the various aspects of the present invention are readily determined by those skilled in the art and depend on the intended use. Suitable dosage ranges include from about 0.001 to about 500 mg / kg body weight / day of a compound of the invention, or a pharmaceutically acceptable salt, ester or prodrug thereof, and the like. Another suitable dosage range is about 0.01 to about 25 mg / kg body weight / day. For administration of a pharmaceutically acceptable salt of the compound, the weights indicated above refer to the weight of the acid or base equivalents of the therapeutic compound derived from the salt.

It may be desirable to have KSP kinesin inhibitors that can specifically inhibit KSP kinesin activity at low concentrations, such as those that cause 50% or more inhibition levels at concentrations of 50 μM or less, 100 nM or less, or 50 nM or less. Such administration of a compound of the invention represents various aspects of the invention.

Composition

In some embodiments, one or more compounds of the invention are administered as pure chemicals. In another embodiment, the compound of the present invention is administered as a pharmaceutical composition. Accordingly, pharmaceutical compositions comprising one or more compounds of the present invention are within the scope of the present invention. Such pharmaceutical compositions of the present invention comprise one or more compounds of the invention (eg, doses of one, two, three or more different compounds of the invention) with one or more acceptable carriers and optionally other therapeutic agents. Include in combination. Each carrier (eg, including an adjuvant or vehicle) must be compatible with the other ingredients of the composition but acceptable in the sense that it is not intended for the intended purpose or, in the case of therapy, to be detrimental to the subject being treated. Thus, in another aspect, the invention also provides a medicament comprising one or more compounds of the invention, or a pharmaceutically acceptable salt, solvate, ester, prodrug or isomer thereof, and one or more pharmaceutically acceptable carriers. To provide a pharmaceutical composition.

To prepare pharmaceutical compositions from the compounds described herein, the inert, pharmaceutically acceptable carrier may be a solid or a liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. Powders and tablets may comprise about 5 to about 95% of the active ingredient. Suitable solid carriers such as magnesium carbonate, magnesium stearate, talc, sugars or lactose are known in the art. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of preparing the various compositions can be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18 ^th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania. Can be.

The term “pharmaceutical composition” also refers to a pharmaceutical composition comprising one or more (eg, two) pharmaceutically active agents such as, for example, a compound of the invention, and an additional agent selected from the list of additional agents described herein. It is intended to include both individual dosage units and bulk compositions that comprise together with the inert vehicle. The bulk composition and each individual dosage unit may contain a fixed amount of the "one or more pharmaceutically active agents" described above. Bulk compositions are materials that are not formed in individual dosage units. Exemplary dosage units are oral dosage units such as tablets, pills, and the like. Similarly, the methods described herein for treating a subject by administering a pharmaceutical composition of the present invention are also intended to include the administration of the bulk composition and individual dosage units described above.

In addition, the compositions of the present invention may be formulated in sustained release to provide a rate controlled release of one or more ingredients or active ingredients to optimize the therapeutic effect. Dosage forms suitable for sustained release include layered tablets molded into tablets or capsules containing controlled release polymer matrices impregnated with layers or active ingredients of varying disintegration rates and containing such impregnated or enclosed porous polymer matrices.

Liquid form preparations include solutions, suspensions, and emulsions. By way of example mention is made of water or water-propylene glycol solutions or oral solutions for parenteral injection, addition of sweetening and whitening agents for suspensions and emulsions. Liquid form preparations may also include solutions for nasal administration.

Aerosol formulations suitable for inhalation may include powdered solids and solutions which may be combined with a pharmaceutically acceptable carrier such as an inert compressed gas such as nitrogen.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral or parenteral (eg, subcutaneous, intramuscular, orbital, intracapsular, spinal, intrasternal, intravenous, etc.) administration. . Such liquid forms include solutions, suspensions and emulsions.

The compounds of the present invention may also be transdermally deliverable. Transdermal compositions may take the form of creams, lotions, aerosols and / or emulsions and may be included in transdermal patches of the matrix or reservoir type as in the art for this purpose.

In one embodiment, one or more compounds or compositions of the invention are formulated for subcutaneous administration.

In one embodiment, one or more compounds or compositions of the invention are formulated for oral administration.

In one embodiment, one or more compounds or compositions of the invention are formulated for parenteral administration.

In one embodiment, one or more compounds or compositions of the invention are formulated for intravenous administration.

In one embodiment, the pharmaceutical formulation is provided in unit dosage form. In this form, the preparation is subdivided into unit doses of suitable size containing the active ingredient in an appropriate amount, for example, an amount effective to achieve the desired purpose.

As specified herein, the amount of active compound in unit dosages of the formulation can be varied or adjusted to suit the intended purpose. Further non-limiting examples of such dose ranges range from about 1 mg to about 100 mg, alternatively from about 1 mg to about 50 mg, or alternatively from about 1 mg to about 25 mg, depending on the particular application.

The actual dose used may vary depending on the needs of the patient and the severity of the condition being treated. Determination of dosage regimens suitable for a particular situation is within the skill of the art. For convenience, the total daily dose may be divided and administered in portions throughout the day as needed.

Dosage and frequency of administration of the compounds of the invention and / or pharmaceutically acceptable salts or esters thereof may be adjusted at the discretion of the attending physician, taking into account factors such as the age, condition and physique of the patient, and the severity of the condition being treated. will be. Representatively recommended daily dose regimens for oral administration may range from 2 to 4 divided doses, from about 1 mg / day to about 500 mg / day, preferably from 1 mg / day to 200 mg / day.

In another aspect, the invention comprises a therapeutically effective amount of one or more compounds of the invention, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable carriers, adjuvants or vehicles, and optionally instructions for use. To provide a kit comprising an insert and / or label.

In another aspect, the invention provides a kit comprising an amount of one or more compounds of the invention, or a pharmaceutically acceptable salt or ester thereof, and an amount of one or more additional therapeutic agents listed above, wherein two or more The amount of ingredient is that amount which produces the desired therapeutic effect.

In another aspect, the invention provides one or more compounds of the invention, or a pharmaceutically acceptable salt, solvate, ester thereof, for the manufacture of a medicament for inhibiting KSP kinesin activity in a subject in need thereof. Or prodrugs.

In another aspect, the invention provides one or more compounds of the invention for the manufacture of a medicament for the treatment of one or more diseases by inhibition of KSP kinesin activity in a patient in need thereof. It provides the use of a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.

In another aspect, the invention provides one or more compounds of the invention, or a pharmaceutically acceptable salt, solvate, ester or precursor thereof, for the manufacture of a medicament for the treatment of any of the conditions, diseases or disorders described herein. Provide the use of the drug.

In another aspect, the present invention provides a pharmaceutical composition comprising (i) one or more compounds of the invention, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; And (ii) at least one second active ingredient described herein.

Combination therapy

Compounds of the invention (and compositions comprising one or more compounds of the invention) are also useful in combination with one or more therapeutic agents other than the compounds of the invention. Such therapeutic agents are selected depending on the intended purpose. Non-limiting examples of such agents include those effective in treating the following diseases or conditions, and / or minimizing one or more side effects of the therapeutic agent, and / or enhancing or changing the bioavailability of the therapeutic agent administered.

Combinations of compounds of the invention with other anticancer or chemotherapeutic agents are within the scope of the invention. Non-limiting examples of such agents can be found in Cancer Principles and Practice of Oncology by VT Devita and S. Hellman (editors), 6 ^th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. . One of ordinary skill in the art would be able to determine which combination of agents would be useful based on the cancer (or other indications) involved and the particular characteristics of the drug. The following description provides further non-limiting examples of such combinations. Those skilled in the art will readily be able to determine further suitable formulations.

Thus, anticancer agents suitable for use in combination with one or more compounds of the invention (or compositions comprising one or more compounds of the invention) include, but are not limited to: estrogen receptor modulators, androgen receptor modulators, Antibodies bound to retinoid receptor modulators, cytotoxic agents, microtubule inhibitors / stabilizers, topoisomerase inhibitors, antisense RNA and DNA oligonucleotides, antimetabolic agents, cytotoxic agents or radioisotopes, HMG -CoA reductase inhibitors, prenyltransferase inhibitors, farnesyl protein transferase inhibitors, angiogenesis inhibitors, kinase inhibitors, COX2 inhibitors, integrin blockers, PPAR agonists, and MDR inhibitors. Additional anticancer agents also include hypoxic activatable agents, proteasome inhibitors, ubiquitin inhibitors, HDM2 inhibitors, TNF activators, BUB-R inhibitors, CENP-E inhibitors, and interferons (eg, alpha interferon). Such anticancer agents may be small molecules or biological agents (eg, RNA antisense and antibodies). Compounds of the invention are also useful when co-administered with radiotherapy.

"Estrogen receptor modulator" refers to a compound that inhibits or inhibits estrogen from binding to a receptor, regardless of metabolism. Examples of estrogen receptor modulators are tamoxifen, raloxifene, idoxifen, LY353381, LY117081, toremifene, fulvestrant, 4- [7- (2,2-dimethyl-l-oxopropoxy-4-methyl-2 -[4- [2- (1-piperidinyl) ethoxy] phenyl] -2H-1-benzopyran-3-yl] -phenyl-2,2-dimethylphanoate, 4,4'-dihydroxy Benzophenone-2,4-dinitrophenyl-hydrazone, aid SH646, including but not limited to.

"Androgen receptor modulators" refer to compounds that interfere with or inhibit the binding of androgens to receptors, regardless of metabolism. Examples of androgen receptor modulators include finasteride and other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarosol and abiraterone acetate.

"Retinoid receptor modulators" refer to compounds that interfere with or inhibit the binding of the retinoid to the receptor, regardless of metabolism. Examples of such retinoid receptor modulators are bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, difluoromethylornithine, ILX23-7553, trans-N- (4'-hydroxyphenyl ) Retinamide, and N-4-carboxyphenyl retinamide.

Examples of cytotoxic agents include sertenev, sachettin, ifosfamide, tasornermin, ronidamine, carboplatin, altretamine, prednisostin, dibromodulsitol, rannimustine, potemustine, Nedaplatin, oxaliplatin, temozolomide (TEMODAR ^™ , available from Schering-Plough Corporation, Kenilworth, NJ), cyclophosphamide, heptaplatin, esturamustine, im Prosulfane Tosylate, Trophosphamide, Nimustine, Dibrospidium Chloride, Fumitepha, Lovaplatin, Satraplatin, Propyromycin, Cisplatin, Doxorubicin, Irofulben, Dexiphosphamide, Cis-Aminedichloro (2-Methyl-pyridine) platinum, benzylguanine, gluphosphamide, GPX100, (trans, trans, trans) -bis-mu- (hexane-1,6-diamine) -mu- [diamine-platinum (II) ] Bis [diamine (chloro) platinum (II)] te Lachloride, Diarizinylspermine, Arsenic Trioxide, 1- (11-dodecylamino-10-hydroxyundecyl) -3,7-dimethylxanthine, Zorubicin, Idarubicin, Daunorubicin , Bisantrene, mitoxone, pyrarubicin, pinapid, valerubicin, amrubicin, antineoclastone, 3'-deancino-3'-morpholino-13-deoxo-10-hydroxycarbox Minomycin, annamycin, galarubicin, elinapids, MEN10755, 4-demethoxy-3-deamino-3-aziridinyl-4-methylsulfonyl-dagnobiscin (reference WO 00/50032), Methotrexate, gemcitabine, and mixtures thereof.

Examples of microtubule inhibitors / microtubule-stabilizers include paclitaxel, vindesine sulfate, 3 ', 4'-didehydro-4'-dec-8'-norvincarleucoblastine, docetaxel, vincristine, vinblastine , Vinorelobine, lysine, dolastatin, mibobulin isethionate, auristatin, semadothin, RPR109881, BMS184476, vinflunin, cryptophycin, 2,3,4,5,6-pentafluoro- N- (3-fluoro-4-methoxyphenyl) benzene sulfonamide, anhydrobinblastin, N, N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl -L-proline-t-butylamide, TDX258, epothilones (see, eg, US Pat. Nos. 6,284,781 and 6,288,237) and BMS188797.

Some examples of topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubicatecan, 6-netoxypropionyl-3 ', 4'-0-exo-benzylidene-charthreucin, 9-methoxy- N, N-dimethyl-5-nitropyrazolo [3,4,5-kl] arridin-2- (6H) propanamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro -9-hydroxy-4-methyl-1H, 12H-benzo [de] pyrano [3 ', 4': b, 7] -indolizino [1,2b] quinoline-10,13 (9H, 15H) Dione, rurtotecan, 7- [2- (N-isopropylamino) ethyl]-(20S) camptothecin, BNP1350, BNPM 100, BN80915, BN80942, etoposide phosphate, teniposide, sopoic acid, 2 ' -Dimethylamino-2'-deoxy-etoposide, GL331, N- [2- (dimethylamino) ethyl] -9-hydroxy-5,6-dimethyl-6H-pyrido [4,3-b] Carbazole-1-carboxamide, asulacrine, (5a, 5aB, 8aa, 9b) -9- [2- [N- [2- (dimethylamino) ethyl] -N-methylamino] ethyl] -5 -[4-hydroxy-3,5-dimethoxyphenyl] -5,5a, 6,8,8a, 9-hexahydrofu (3 ', 4': 6,7) naphtho (2,3-d) -1,3-dioxol-6-one, 2,3- (methylenedioxy) -5-methyl-7-hydroxy -8-methoxybenzo [c] -phenanthridinium, 6,9-bis [(2-aminoethyl) amino] benzo [g] isoquinoline-5,10-dione, 5- (3-aminopropylamino) -7,10-dihydroxy-2- (2-hydroxyethylaminomethyl) -6H-pyrazolo [4,5,1-de] acridin-6-one, N- [1- [2- (Diethylamino) ethylamino] -7-methoxy-9-oxo-9H-thioxen-4-ylmethyl] formamide, N- (2- (dimethylamino) ethyl) acridin-4-car Voxamide, 6-[[2- (dimethylamino) ethyl] amino] -3-hydroxy-7H-indeno [2,1-c] quinolin-7-one, dimesna and camptosta.

Examples of antisense RNA and DNA oligonucleotides include G3139, ODN698, RVASKRAS, GEM231, and INX3001.

Gene therapy can be used to deliver any tumor control gene. Examples of such genes are p53 (see, eg, US Pat. No. 6,069,134), uPA / uPAR antagonists (see, “a uPA / of Adenovirus-Mediated Delivery”), which can be delivered via recombinant virus-mediated gene delivery. uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth and Dissemination in Mice, "Gene Therapy, August 1998; 5 (8): 1105-13), and gene therapy for interferon gamma (see J Immunol 2000; 164: 217-222). ), But is not limited thereto. For an overview of genetic strategies for treating cancer, see Hall et al (Am J Hum Genet 61: 785-789,1997) and Kufe et al (Cancer Medicine, 5th Ed, pp 876-889, BC Decker, Hamilton 2000 )].

Examples of anti-metabolites are 5-fluorouracil, enositabine, carmofur, tegapur, pentostatin, doxyfluridine, trimetrexate, fludarabine, capecitabine, gallosicarbine, cita Lavigne, oxphosphate, postavin sodium hydrate, raltitrexed, paltitrexide, emitepur, tiazopurin, decitabine, nolatrexed, pemetrexet, naljarabine, 2'-deoxy-2'- Methylidenecytidine, 2'-fluoromethylene-2'-deoxycytidine, N- [5- (2,3-dihydro-benzofuryl) sulfonyl] -N '-(3,4-dichlorophenyl Urea, N6- [4-deoxy-4- [N2- [2 (E), 4 (E) -tetradecadienoyl] glycylamino] -L-glycero-BL-manno-heptapyranosyl ] Adenine, Aplidine, Actinascidine, Troxacitabine, 4- [2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino [5,4-b] [1,4] thiazin-6-yl- (S) -ethyl] -2,5-thienoyl-L-glutamic acid, aminopterin, 5-fluorouracil, alanosine , 11-acetyl-8- (carbamoyloxymethyl) -4-formyl-6-methoxy-14-oxa-1,11-diazatetracyclo (7.4.1.0.0) -tetradeca-2,4 , 6-trien-9-yl acetic acid ester, swainsonine, rometrexole, dexrazoic acid, methioninase, 2'-cyano-2'-deoxy-N4-palmitoyl-1-BD-ara Vino furanosyl cytosine and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone.

Examples of monoclonal antibody targeted therapeutics include therapeutic agents having a cytotoxic or radioisotope attached to cancer cell specific or target cell specific monoclonal antibodies. Examples include Bexsar.

"HMG-CoA reductase inhibitor" refers to 3-hydroxy-3-methylglutaryl-CoA reductase. Examples of HMG-CoA reductase inhibitors that may be used include lovastatin (MEVACOR ^®; U.S. Patent No. 4,231,938, 1 - 4,294,926 No. and Reference No. 4319039 No.), simvastatin (ZOCOR ^®; U.S. Patent No. 4,444,784, 1 - 4.82085 million and No. 4,916,239 Pravastatin (PRAVACHOL ^® ; US Pat. Nos. 4,346,227, 4,537,859, 4,410,629, 5,030,447 and 5,180,589), Fluvastatin (LESCOL ^® ; US Pat. Nos. 5,354,772, 4,911,165, including, see U.S. Patent No. 5,273,995, No. 4,681,893, 1 - 5489691 and No. 5342952 No.); claim 4929437, 1 - 5189164, 1 - 5118853, 1 - 5,290,946 and No. reference 5,356,896 call) and atorvastatin (LIPITOR ^® It is not limited to this. Structural formulas of these and additional HMG-CoA reductase inhibitors that can be used in the methods of the present invention are described in M. Yalpani, "Cholesterol Lowering Drugs", Chemistry & Industry, pp. P87 and US Pat. Nos. 4,782,084 and 4,885,314 to 85-89 (5 February 1996). As used herein, the term HMG-CoA reductase inhibitor has all the pharmaceutically acceptable lactone and open-acid forms (such as when the lactone ring is open to form free acid), and HMG-CoA reductase inhibitory activity. Since the salt and ester forms of the compounds are included, the use of such salt, ester, open acid and lactone forms is also within the scope of the present invention.

"Prenyl-protein transferase inhibitors" include farnesyl-protein transferase (FPTase), geranylgeranyl-protein transferase type I (GGPTase-I), and geranylgeranyl-protein transferase type II ( Compound that inhibits any or any combination of prenyl-protein transferase enzymes, including GGPTase-II, also called Rab GGPTase.

Examples of prenyl-protein transferase inhibitors can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95/32987, US Pat. Nos. 5,420,245, 5,523,430, 5,532,359, 5,510,510, 5,589,485, 5,602,098, European Patent Publication No. 0 618 221, European Patent Publication No. 0 675 112, European Patent Publication No. 0 604181, European Patent Publication No. 0 696 593, WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO 95/12572, WO 95/10514, U.S. Pat.Nos. 5,661,152, WO 95/10515, WO 95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO 96/06138, WO 96/06193, WO 96/16443 , WO 96/21701, WO 96/21456, WO 96/22278, WO 96/24611, WO 96/24612, WO96 / 05168, WO 96/05169, WO 96/00736, US Patent Nos. 5,571,792, WO 96/17861 , WO 96/33159, WO 96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO 96/30363, WO 96/31111, WO 96/31477, WO 96/31478 , WO 96/31501, WO 97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO 97/17070, WO 97/23478, WO 97/26246, WO, 97/30053, WO 97/44350 , WO 98/02436, and US Pat. No. 5,532,359. Examples of the role of prenyl-protein transferase inhibitors in angiogenesis can be found in Cancer, Vol. 35, No. 9, pp. 1394-1401 (1999).

An example of farnesyl protein transferase inhibitor is SARASAR ^™ (4- [2- [4-[(11R) -3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo [5, 6] cyclohepta [1,2-b] pyridin-11-yl-]-1-piperidinyl] -2-oxoethyl] -1-piperidinecarboxamide (Schering- in Kenilworth, NJ, USA) Plau Corporation), Tipifarnib (Zarnestra ^® or R115777; Janssen Pharmaceuticals), L778,123 [Farnesyl Protein Transferase Inhibitor; Merck and Campanile, Whitehouse, NJ, USA Merck & Company, BMS 214662 [Farnesyl Protein Transferase Inhibitor; Bristol-Myers Squibb Pharmaceuticals, Princeton, NJ].

"Angiogenesis inhibitors" refer to compounds that inhibit the formation of new blood vessels regardless of metabolism. Examples of angiogenesis inhibitors include tyrosine kinase inhibitors, for example inhibitors of tyrosine kinase receptors Flt-1 (VEGFR1) and FIk-1 / KDR (VEGFR2), epithelial-derived, fibroblast-derived, or platelet origin. Inhibitors of growth factors, matrix metalloprotease (MMP) inhibitors, integrin blockers, interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors including nonsteroidal anti-inflammatory (NSAID) like aspirin and ibuprofen, and selective cyclo Oxygenase-2-inhibitor-like celecoxib and rofecoxib [PNAS, Vol. 89, p. 7384 (1992); JNCI, Vol. 69, p. 475 (1982); Arch. Opthalmol., Vol. 108, p. 573 (1990); Anal Rec, Vol. 238, p. 68 (1994); FEBS Letters, Vol. 372, p. 83 (1995); Clin. Orthop. Vol. 313, p. 76 (1995); J. MoI. Endocrinol., Vol. 16, p. 107 (1996); Jpn. J. Pharmacol., Vol. 75, p. 105 (1997); Cancer Res., Vol. 57, p. 1625 (1997); Cell, Vol. 93, p. 705 (1998); Intl. J. MoI. Med., Vol. 2, p. 715 (1998); J. Biol. Chem., Vol. 274, p. 9116 (1999)], steroidal anti-inflammatory agents (e.g. corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone, methylfred, betamethasone), carboxyxamidotriazole, combretastatin A-4, squalane, 6 -O-chloroacetyl-carbonyl) -fumagilol, thalidomide, angiostatin, troponin-1, angiotensin II antagonist [Fernandez et al., J. Lab. Clin. Med. 105: 141-145 (1985), and antibodies against VEGF [Nature Biotechnology, Vol. 17, pp. 963-968 (October 1999); Kim et al., Nature, 362, 841-844 (1993); WO 00/44777; And WO 00/61186.

Another example of an angiogenesis inhibitor is endostatin, ukrain, lanpirnase, IM862, 5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) oxyranyl] -1-oxa Spiro [2,5] oct-6-yl (chloroacetyl) carbamate, acetyldinanan, 5-amino-1-[[3,5-dichloro-4- (4-chlorobenzoyl) phenyl] methyl] -1H -1,2,3-triazole-4-carboxamide, CM101, squalane, combretastatin, RPI4610, NX31838, sulfated mannopentaose phosphate, 7,7- (carbonyl-bis [imino -N-methyl-4,2-pyrrolocarbonylimino [N-methyl-4,2-pyrrole] -carbonylimino] -bis- (1,3-naphthalene disulfonate), and 3- [ (2,4-dimethylpyrrole-5-yl) methylene] -2-indolinone (SU5416), including but not limited to.

Other therapeutic agents that modulate or inhibit angiogenesis and may be used with the compounds of the present invention include agents that modulate or inhibit coagulation and fibrinolysis systems. See Clin. Chem. La. Med. 38: 679-692 (2000). Examples of such agents that modulate or inhibit coagulation and fibrinolysis pathways are heparin [Thromb. Haemost. 80: 10-23 (1998)], low molecular weight heparin and carboxypeptidase U inhibitors (also known as active thrombin activatable fibrinolytic inhibitors [TAFIa]). See Thrombosis Res. 101: 329-354 (2001), but is not limited to such. Examples of TAFIa inhibitors are described in PCT Publication WO 03 / 013,526.

Examples of kinase inhibitors include agents that inhibit cell surface receptors and signal transduction cascades down to these surface receptors. Such agents inhibit cell proliferation and survival. These include inhibitors of EGFR (eg gefitinib and erlotinib), antibodies to EGFR (eg C225), inhibitors of ERB-2 (eg trastuzumab), inhibitors of IGFR, inhibitors of cytokine receptors, MET Inhibitors of PI3K, such as LY294002, serine / threonine kinases (WO 02/083064, WO 02/083139, WO 02/083140 and WO 02/083138), including but not limited to inhibitors of Akt as described. ), Inhibitors of Raf kinases (eg BAY-43-9006), inhibitors of MEEK (eg CI-1040 and PD-098059), inhibitors of mTOR (eg Wyeth CCI-779), and C-abl kinase Inhibitors such as GLEEVEC ^™ , manufactured by Novartis Pharmaceuticals. Additional kinase inhibitors include those that inhibit proteins involved in the cell cycle. These include aurora kinase inhibitors, CDK inhibitors (eg, flavopyridols, CYC202, BMS387032 and polo-like kinase inhibitors). They also include agents that interfere with cell cycle checkpoints to sensitize cancer cells to DNA damaging agents. Such agents include, for example, inhibitors of ART, ATM, Chk1 and Chk2.

The present invention also includes combinations with NSAIDs, which are selective COX-2 inhibitors. NSAIDs, which are selective inhibitors of COX-2 for this technique, are measured as the ratio of IC50 to COX-2 over COX-2 over COX-1 as assessed by cell or microsomal assays. Defined as those that have a specificity that inhibits 2 or more than 100-fold. Particularly useful inhibitors of COX-2 in the methods of treatment of the invention include 3-phenyl-4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone; And 5-chloro-3- (4-methylsulfonyl) phenyl-2- (2-methyl-5 pyridinyl) pyridine; Or a pharmaceutically acceptable salt thereof.

Compounds useful in the present invention it is described as specific inhibitors of COX-2 include the acceptable salts chemical parecoxib, CELIEBREX ^® and BEXTRA ^® or a pharmaceutical one, and the like.

A "integrin blocker" is a compound that selectively antagonizes, inhibits or opposes the binding of physiological ligands to α _v β ₃ integrins, selectively antagonizes, inhibits or inhibits the binding of physiological ligands to α _v β ₅ integrins. Or antagonizes, inhibits or opposes the binding of a physiological ligand to both opposing compounds, α _v β ₃ integrins and α _v β ₅ integrins, and antagonizes the activity of certain integrins expressed in capillary endothelial cells, Refers to a compound that inhibits or opposes. The term also refers to α _v β ₆ , α _v β ₈ , α ₁ β ₁ , α ₂ β ₁ , α ₅ β ₁ , α ₆ β ₁ , and α ₆ β ₄ integrins. The term also refers to α _v β ₃ , α _v β ₅ , α _v β ₆ , α _v β ₈ , α ₁ β ₁ , α ₂ β ₁ , α ₅ β ₁ , α ₆ β ₁ , and α ₆ β ₄ integrins Refers to any combination of antagonists.

Combinations with compounds other than anticancer compounds are also included in the methods of the invention. For example, the combination of a compound of the invention with a PPAR-γ (ie: PPAR-gamma) agonist and a PPAR-δ (ie: PPAR-delta) agonist is useful for the treatment of certain malignant tumors. PPAR-γ and PPAR-δ are nuclear peroxysome growth factor-activated receptors γ and δ, respectively. Its relationship with the expression and angiogenesis of PPAR-γ on endothelial cells is described in J. Cardiovasc. Pharmacol. 1998; 31: 909-913; J. Biol. Chem. 1999; 274: 9116-9121; Invest. Ophthalmol Vis. Sci. 2000; 41: 2309-2317. More recently, PPAR-γ agonists inhibit angiogenic responses to VEGF in vitro; Both troglitazone and rosiglitazone malate have been shown to inhibit the development of retinal angiogenesis in mice. Arch. Ophthamol. 2001; 119: 709-717. Examples of PPAR-γ agonists and PPAR-γ / α agonists include thiazolidinediones (eg DRF2725, CS-011, troglitazone, rosiglitazone and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2-[(5,7-dipropyl-3-trifluoromethyl- 1,2-benzisoxazol-6-yl) oxy] -2-methylpropionic acid, and 2 (R) -7- (3- (2-chloro-4- (4-fluorophenoxy) phenoxy) prop Foxy) -2-ethylchroman-2-carboxylic acid, including but not limited to.

The compounds of the invention can also be administered in conjunction with one or more inhibitors of inherent multidrug resistance (MDR), in particular MDR associated with the expression of high levels of the transporter protein. Such MDR inhibitors include inhibitors of p-glycoprotein (P-gp), for example, LY335979, XR9576, OC144-093, R101922, VX853 and PSC833 (Valspodar).

Additional anticancer agents may also be hypoxic activatable agents (e.g. tyrapazamine), proteasome inhibitors (e.g. lactacystin and bortezomib), ubiquitin inhibitors, HDM2 inhibitors, TNF activators, BUB-R inhibitors , CENP-E inhibitors, and interferon alpha.

Compounds of the present invention may also be used for treating acute, delayed, terminally-phased nausea or vomiting, and anticipated vomiting, which may result from the use of a compound of the present invention alone or in combination with radiation therapy. Can be used with nausea. For the prophylaxis or treatment of vomiting, the compounds of the present invention may be used in combination with one or more other anti-nausea agents, in particular neurokinin-1 receptor antagonists, 5HT3 receptors, ondansetron, granistron, trocetolone and jatisetron. Antagonists, GABAB receptor agonists such as baclofen, decadron (dexamethasone), canalogue, aristocort, nasalide, preferid, benecortene or US Pat. Nos. 2,789,118, 2,990,401, 3,048,581, Corticosteroids, phenolthiazines such as those described in US Pat. Nos. 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712 (e.g., crochlorperazine, flufenazine, thiolidazine and mesoridine ), Metoclopramide or dronabinol. In one embodiment, the anti-nausea agent selected from neurokinin-1 receptor antagonists, 5HT3 receptor antagonists and corticosteroids is administered as an adjuvant for the treatment or prevention of vomiting that may result from the administration of the compounds of the invention.

Examples of neurokinin-1 receptor antagonists that may be used with the compounds of the present invention are described in US Pat. Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, the contents of which are incorporated herein by reference. 5,459,270, 5,494,926, 5,496,833, 5,637,699, and 5,719,147. In one embodiment, the neurokinin-1 receptor antagonist for use with the compounds of the invention is directed to 2- (R)-(1- (R)-(3,5-bis (trifluoromethyl) phenyl) Methoxy) -3- (S)-(4-fluorophenyl) -4- (3- (5-oxo-1H, 4H-1,2,4-triazolo) methyl) morpholine, or a pharmaceutical thereof It is selected among the acceptable salts, which are described in US Pat. No. 5,719,147.

The compounds of the present invention can be administered with one or more immunologically-enhancing drugs such as, for example, levamisol, isoprinosine and zadcin.

As noted above, the present invention provides a combination comprising an amount of one or more compounds (or compositions comprising the compounds) of the invention, or a pharmaceutically acceptable salt or ester thereof, and an amount of one or more additional therapeutic agents listed above. Water, wherein the amount of compound / therapeutic agent is that amount that produces the desired therapeutic effect.

When administering a combination therapy to a patient in need of such administration, the therapeutic agents in the combination, or pharmaceutical compositions or compositions comprising the therapeutic agents, may be administered in any order such as, for example, continuously, simultaneously, together, in concert, etc. Can be. The amount of the various active agents in such combination therapy may be different amounts (different dosages) or the same amount (same dosage). Thus, for purposes of explanation, the compounds of the present invention and additional therapeutic agents may be present in fixed doses (dosage) in a single dosage unit (eg, capsules, tablets, etc.). 2 and a commercially available example of such single dosage unit containing an amount of two different active compounds is VYTORIN ^® - a (Merck Schering of Kenilworth, New Jersey, USA material Plow Pharmaceuticals Bucharest Carlsbad manufacturer).

When formulated at fixed dosages, such combination products utilize a compound of the invention within the dosage ranges described herein, as well as other pharmaceutically active agents or therapeutic agents within that dosage range. The compounds of the present invention can also be administered continuously with known therapeutic agents if the combination formulation is inappropriate. The present invention is not limited to the order of administration: The compounds of the present invention can be administered before or after administration of known therapeutic agents. Such techniques are within the skill of those skilled in the art and the attending physician.

Those skilled in the art will recognize that changes may be made to the above described aspects without departing from the broader spirit of the invention. Accordingly, it is to be understood that the invention is not limited to the specific embodiments described, but is intended to cover modifications that are within the spirit and scope of the invention, as defined in the appended claims.

Claims (56)

A compound of Formula 1, or a pharmaceutically acceptable salt, solvate, ester, prodrug or isomer thereof:
Formula 1

In Formula 1 above,
R ¹ , R ² , R ³ , p, R ²⁷ , R ²⁸ , E, ring A and ring B are independently selected from each other, where:
p is 0, 1, 2, 3 or 4;
Ring A (including indicated E and unsaturated) is a 4-8 membered cycloalkenyl or heterocycloalkenyl ring;
E is -O-, -S-, -S (O)-, -S (O) _2- , -C (R ⁴ ) (R ⁵ )-, -N (R ⁶ )-, -N (C ( Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-, -C (O) -N (R ¹¹ )- , -N (R ¹¹ ) -C (O)-, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) _2- , -C (O) -O- , -OC (O)-, -ON (R ⁶ )-, -N (R ⁶ ) -O-, -N (R ⁶ ) -N (R ¹² )-. -N = N-, -C (R ⁷ ) = N-, -C (O) -C (R ⁷ ) = N-, -C (O) -N = N-, -0-C (Y)- N (R ¹¹ )-, -N (R ¹¹ ) -C (Y) -O-, -N (R ¹¹ ) -C (Y) -N (R ¹² )-, -C (Y) -N (R ¹¹ ) -O-, -C (Y) -N (R ¹¹ ) -N (R ¹² )-, -0-N (R ¹¹ ) -C (Y)-and -N (R ¹² ) -N (R ¹¹ ) -C (Y)-, and
Where Y is (= 0), (= S), (= N (R ¹³ )), (= N (CN)), (= N (OR ¹⁴ )), (= N (R ¹⁵ ) ( R ¹⁶ )) and (═C (R ¹⁷ ) (R ¹⁸ )) independently;
Ring B is an aromatic or heteroaromatic ring, or a partially unsaturated alicyclic ring, or a partially unsaturated heterocyclic ring,
Wherein the ring is optionally substituted with one or more substituents which may be unsubstituted or may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, halo Alkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ ,- OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ ,- C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ Is independently selected from the group consisting of -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ ;
R ¹ is selected from the group consisting of aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl and heterocycloalkenyl,
Wherein each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or may be the same or different Optionally independently substituted with one or more substituents, each substituent being halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, hetero Aryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² ,- NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and from the group consisting of ^{-NR 23 C (O) NR 25} R 26 It is selected for neutral;
R ² is —C (Z) R ⁷ , -C (Z) NR ⁹ R ¹⁰ , -C (Z) OR ⁸ , -SO ₂ NR ⁹ R ¹⁰ , alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, Selected from the group consisting of cycloalkenyl, heterocycloalkyl and heterocycloalkenyl,
Where each Z is (= 0), (= S), (= N (R ¹³ )), (= N (CN)), (= N (OR ¹⁴ )), (= N (R ¹⁵ ) ( R ¹⁶ )) and (= C (R ¹⁷ ) (R ¹⁸ )), independently
Wherein each said alkyl, each said heteroalkyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl and each said heterocycloal Kenyl is optionally substituted with one or more substituents which may be unsubstituted or may be the same or different, and each substituent is oxo provided the aryl and heteroaryl are not substituted with oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl , Heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C ( O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ ,- S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C ( O) NR ²⁵ R ²⁶ is independently selected from the group consisting of;
R ²⁷ (when not combined with R ²⁸ ) is H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, hetero Cycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ ,- NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ independently Selected,
Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group;
R ²⁸ (when not combined with R ²⁷ ) is H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, hetero Cycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ ,- NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ independently Selected,
Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group; or
Alternatively, R ²⁷ and R ²⁸ are heterocycloalkyl rings containing 1 to 3 heteroatoms selected from the group consisting of cycloalkyl, cycloalkenyl, N, O and S together with the carbon atoms to which they are attached Or form a heterocycloalkenyl ring containing 1 to 3 heteroatoms selected from the group consisting of N, O and S,
Wherein the heterocycloalkyl ring and the heterocycloalkenyl ring are each independently substituted with one or more substituents which may be unsubstituted or the same or different, and each substituent is oxo, halogen, -CN, -NO ₂ , Alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, Heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O ) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O ) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ ;
Each R ³ (if present) is alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, Halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C ( O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (S) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ ,- SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ , -NR ²³ C (O) NR ²⁵ R ²⁶ and- Independently selected from the group consisting of NR ²³ -C (NH) -N (R ²⁶ ) ₂ ,
Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group, or
Alternatively, when p is 2, 3 or 4, the two R ³ groups bonded to the same ring carbon atom together with the carbon atom to which they are attached are spirocycloalkyl, spirocycloalkenyl, or -NH-, -NR Spiroheterocycloalkyl rings containing 1 to 3 ring heteroatoms independently selected from the group consisting of ^6- , -S-, -S (O)-, -S (O) ₂ -and -O-, or Spiro containing 1 to 3 ring heteroatoms independently selected from the group consisting of -NH-, -NR ^6- , -S-, -S (O)-, -S (O) _2-, and -O- To form a heterocycloalkenyl ring, or
Alternatively, R ² and R ³ together with the atoms to which they are attached, together with the carbon atoms to which they are attached, cycloalkyl, cycloalkenyl, -NH-, -NR ^6- , -S-, -S (O) -, A heterocycloalkyl ring containing 1 to 3 ring heteroatoms independently selected from the group consisting of -S (O) ₂ -and -O-, or -NH-, -NR ^6- , -S-, To form a heterocycloalkenyl ring containing 1 to 3 ring heteroatoms independently selected from the group consisting of -S (O)-, -S (O) ₂ -and -O-;
Each R ⁴ (unless combined with R ⁵ ) is H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl , Heterocycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ From the group consisting of R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ Independently selected,
Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group;
Each R ⁵ (when not combined with R ⁴ ) is H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl , Heterocycloalkenyl, halogen, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ From the group consisting of R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ Independently selected,
Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group; or
Alternatively, R ⁴ and R ⁵ are heterocycloalkyl rings containing 1 to 3 heteroatoms selected from the group consisting of cycloalkyl, cycloalkenyl, N, O and S together with the carbon atoms to which they are attached Or form a heterocycloalkenyl ring containing 1 to 3 heteroatoms selected from the group consisting of N, O and S,
Wherein the heterocycloalkyl ring and the heterocycloalkenyl ring are each independently substituted with one or more substituents which may be unsubstituted or the same or different, and each substituent is oxo, halogen, -CN, -NO ₂ , Alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, Heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O ) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O ) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ ;
Each R ⁶ is H, alkyl, -C (O) R ²⁴ , -C (O) OR ²⁰ , -C (S) R ²⁴ , heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, Independently selected from the group consisting of aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl,
Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (S) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N Independently from -CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ ;
Each R ⁷ is from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl Independently selected,
Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group;
Each R ⁸ is from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl Independently selected,
Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group;
Each R ⁹ (when not bonded to R ¹⁰ ) is H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl Is independently selected from the group consisting of heterocycloalkenyl,
Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group;
Each R ¹⁰ (when not bonded to R ⁹ ) is H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl Is independently selected from the group consisting of heterocycloalkenyl,
Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group; or
Alternatively, R ⁹ and R ¹⁰ together with the N atom to which they are attached form a heterocycloalkyl or heterocycloalkenyl ring containing 1 to 3 heteroatoms selected from the group consisting of N, O and S and,
Wherein the heterocycloalkyl ring and the heterocycloalkenyl ring are each independently substituted with one or more substituents which may be unsubstituted or the same or different, and each substituent is oxo, halogen, -CN, -NO ₂ , Alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, Heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O ) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O ) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ ;
Each R ¹¹ is from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl Independently selected,
Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group;
Each R ¹² is from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl Independently selected,
Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group;
Each R ¹³ is from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl Independently selected,
Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group;
Each R ¹⁴ is from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl Independently selected,
Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group;
Each R ¹⁵ (when not combined with R ¹⁶ ) is H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl Is independently selected from the group consisting of heterocycloalkenyl,
Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group;
Each R ¹⁶ (when not combined with R ¹⁵ ) is H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl Is independently selected from the group consisting of heterocycloalkenyl,
Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group; or
Alternatively, R ¹⁵ and R ¹⁶ together with the N atom to which they are attached form a heterocycloalkyl or heterocycloalkenyl ring containing 1 to 3 heteroatoms selected from the group consisting of N, O and S and,
Wherein the heterocycloalkyl ring and the heterocycloalkenyl ring are each independently substituted with one or more substituents which may be unsubstituted or the same or different, and each substituent is oxo, halogen, -CN, -NO ₂ , Alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, Heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O ) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O ) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ ;
Each R ¹⁷ (when not combined with R ¹⁸ ) is H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl , Heterocycloalkenyl, -CN, -OC (O) OR ²⁰ , -OR ¹⁹ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C ( O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC ( O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ , independently
Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group;
Each R ¹⁸ (when not bonded to R ¹⁷ ) is H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl , Heterocycloalkenyl, -CN, -OC (O) OR ²⁰ , -OR ¹⁹ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C ( O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC ( O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ , independently
Wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, Each of said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different, each independently Substituents of oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo Alkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group; or
Alternatively, R ¹⁷ and R ¹⁸ are heterocycloalkyl rings containing 1 to 3 heteroatoms selected from the group consisting of cycloalkyl, cycloalkenyl, N, O and S together with the carbon atoms to which they are attached Or form a heterocycloalkenyl ring containing 1 to 3 heteroatoms selected from the group consisting of N, O and S,
Wherein the heterocycloalkyl ring and the heterocycloalkenyl ring are each independently substituted with one or more substituents which may be unsubstituted or the same or different, and each substituent is oxo, halogen, -CN, -NO ₂ , Alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, Heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O ) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O ) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ ;
Each R ¹⁹ is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl;
Each R ²⁰ is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl;
Each R ²¹ (when not bonded to R ²² ) is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl;
Each R ²² (when not combined with R ²¹ ) is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl; or
Alternatively, R ²¹ and R ²² together with the N atom to which they are attached form a heterocycloalkyl or heterocycloalkenyl ring containing 1 to 3 heteroatoms selected from the group consisting of N, O and S and;
Each R ²³ is H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl. Independently selected from the group consisting of aryl, heteroaryl, cycloalkyl, halocycloalkyl;
Each R ²⁴ is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl;
Each R ²⁵ (when not bonded to R ²⁶ ) is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl;
Each R ²⁶ (when not combined with R ²⁵ ) is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl; or
Alternatively, R ²⁵ and R ²⁶ together with the N atom to which they are attached form a heterocycloalkyl or heterocycloalkenyl ring containing 1 to 3 heteroatoms selected from the group consisting of N, O and S do. The compound of claim 1, wherein ring A is a 4-7 membered cycloalkylene ring and E is —C (R ⁴ ) (R ⁵ ) —. The compound of claim 1, wherein ring A is a 5- to 7-membered heterocycloalkylene ring, and E is —O—, —S—, —S (O) —, —S (O) ₂ —, —N (R ⁶ )-, -N (C (Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-, -C ( O) -N (R ¹¹ )-, -N (R ¹¹ ) -C (O)-, -S (O) ₂ -N (R ¹¹ )-, -N (R ¹¹ ) -S (O) _2- , -C (O) -O-, -OC (O)-, -ON (R ⁶ )-, -N (R ⁶ ) -O-, -N (R ⁶ ) -N (R ¹² )-,- N = N-, -C (R ⁷ ) = N-, -C (O) -C (R ⁷ ) = N-, -C (O) -N = N-, -0-C (Y) -N (R ¹¹ )-, -N (R ¹¹ ) -C (Y) -O-, -N (R ¹¹ ) -C (Y) -N (R ¹² )-, -C (Y) -N (R ¹¹ ) -O-, -C (Y) -N (R ¹¹ ) -N (R ¹² )-, -QN (R ¹¹ ) -C (Y)-and -N (R ¹² ) -N (R ¹¹ )- A compound selected from the group consisting of C (Y)-. The compound of claim 1, wherein ring A is a 5-6 membered heterocycloalkylene ring, and E is —O—, —S—, —S (O) —, —S (O) ₂ —, —N (R ⁶ )-, -C (O) -N (R ¹¹ )-and -N (R ¹¹ ) -C (O)-. The compound of claim 1, wherein ring A is a 5- to 6-membered heterocycloalkylene ring, and E is —O—, —S—, —S (O) —, —S (O) ₂ — and —N (R ⁶ )-a compound selected from the group consisting of: The compound of claim 5, wherein R ⁶ is selected from the group consisting of H, alkyl, —C (O) R ²⁴ , —C (O) OR ^20, and —C (S) R ²⁴ . The compound of claim 1, wherein ring A is a 5-6 membered heterocycloalkylene ring, and E is selected from the group consisting of —O— and —N (R ⁶ ) —. The compound of claim 7, wherein R ⁶ is selected from the group consisting of H, alkyl, —C (O) R ²⁴ , —C (O) OR ^20, and —C (S) R ²⁴ . 9. The compound of claim 8, wherein ring A is a 5-membered heterocycloalkylene ring. 9. The compound of claim 8, wherein ring A is a 6 membered heterocycloalkylene ring. The compound of claim 1, wherein ring B is an unsubstituted aromatic ring or an aromatic ring substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl , Haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, Azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ ,- SO ₂ NR ²³ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ ,- C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ A compound selected independently. The compound of claim 1, wherein ring B is an unsubstituted benzo ring, or a benzo ring substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl , Haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, Azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ ,- SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ ,- C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ A compound selected independently. The compound of claim 1, wherein ring B is an unsubstituted or substituted heteroaromatic ring, or a heteroaromatic ring substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , Alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, hetero Cycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , —C (O) NR ²⁵ R ²⁶ , —NR ²³ C (N-CN) NR ²⁵ R ²⁶ and —NR ²³ C (O) NR ²⁵ R ²⁶ A compound independently selected from the group consisting of. 14. A ring according to claim 13, wherein ring B is a 5-6 membered heteroaromatic ring having 1 to 3 ring heteroatoms which may be the same or different and each heterocyclic atom is N, S, O, S (O) And S (O) ₂ . The compound of claim 1, wherein ring B is benzo, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thidiazolyl, pyridinyl , An unsubstituted or substituted moiety selected from the group consisting of pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl. The compound of claim 1, wherein R ¹ is unsubstituted aryl or aryl substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, halo Alkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O ) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ . The compound of claim 1, wherein R ¹ is phenyl substituted with 1 to 4 substituents which may be the same or different and each substituent is halo, —OH, —CN, —NO ₂ , —NR ²¹ R ²² and halo. A compound independently selected from the group consisting of alkyl. The compound of claim 1, wherein R ¹ is

Compound selected from the group consisting of. The compound of claim 1, wherein R ¹ is

A compound that is a residue selected from the group consisting of. The compound of claim 1, wherein R ¹ is

And R ²⁷ and R ²⁸ are each independently selected from the group consisting of H and alkyl. The compound of claim 1, wherein R ² is selected from the group consisting of —C (O) R ⁷ , —C (O) NR ⁹ R ^10, and —C (O) OR ⁸ . The compound of claim 1, wherein p is 0 and R ³ is absent. The compound of claim 1, wherein p is 1, 2, 3 or 4 and each R ³ is alkyl, heteroalkyl, alkenyl, heteroalkenyl, —CN, —NO ₂ , —OR ¹⁹ , —OC (O) OR ²⁰ , -NR ²¹ R ²² , -C (O) R ²⁴ , -C (S) R ²⁴ , -C (O) OR ²⁰ and -C (O) NR ²⁵ R ²⁶ are independently selected from the group consisting of Wherein each said alkyl, each said heteroalkyl, each said alkenyl and each said heteroalkenyl is optionally independently substituted with one or more substituents which may be unsubstituted or the same or different, and each Substituents are oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl , Heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C ( O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ^{2 0} , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and —NR ²³ C (O) NR ²⁵ R ²⁶ A compound independently selected from the group. 2. A compound according to claim 1, wherein p is 2, 3 or 4 and two R ³ groups bonded to the same ring A atom together with the carbon atom to which they are attached are spirocycloalkyl, spirocycloalkenyl, -NH-, -NR Spiroheterocycloalkyl rings containing 1 to 3 ring heteroatoms independently selected from the group consisting of ^6- , -S-, -S (O)-, -S (O) ₂ -and -O-, or Spiro containing 1 to 3 ring heteroatoms independently selected from the group consisting of -NH-, -NR ^6- , -S-, -S (O)-, -S (O) _2-, and -O- Compounds that form a heterocycloalkenyl ring. The compound of claim 1, wherein R ² and R ³ together with the carbon atoms to which they are attached are cycloalkyl, cycloalkenyl, —NH—, —NR ⁶ —, —S—, —S (O) —, —S (O ) Heterocycloalkyl ring containing 1 to 3 ring heteroatoms independently selected from the group consisting of ₂ -and -O-, or -NH-, -NR ^6- , -S-, -S (O)- And -S (O) ₂ -and -O- to form a heterocycloalkenyl ring containing 1 to 3 ring heteroatoms independently selected from the group consisting of. The compound of formula 2 (or formula (II)), or a pharmaceutically acceptable salt, solvate, ester, prodrug or isomer thereof:
Formula 2

In Formula 2 above,
R ¹ , R ² , R ²⁷ , R ²⁸ , E and ring B are independently selected from each other,
E is -O-, -S-, -S (O)-, -S (O) _2- , -C (R ⁴ ) (R ⁵ )-, -N (R ⁶ )-, -N (C ( Y) R ⁷ )-, -N (C (Y) OR ⁸ )-, -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-. The method of claim 26,
E is selected from the group consisting of -O-, -S-, -S (O)-, -S (O) _2- , -C (R ⁴ ) (R ⁵ )-and -N (R ⁶ )- ;
Ring B is benzo, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyri Unsubstituted or substituted residue selected from the group consisting of midinyl, pyrazinyl and triazinyl;
R ¹ is phenyl substituted with 1 to 4 substituents which may be the same or different and each substituent is independent from the group consisting of halo, —OH, —CN, —NO ₂ , —NR ²¹ R ²² and haloalkyl Is selected;
R ² is selected from the group consisting of —C (O) R ⁷ , —C (O) NR ⁹ R ¹⁰ and —C (O) OR ⁸ . The compound of claim 27, wherein R ¹ is

And R ²⁷ and R ²⁸ are each independently selected from the group consisting of H and alkyl. A compound of formula 3.1 (or formula III.1), or a pharmaceutically acceptable salt, solvate, ester, prodrug or isomer thereof:
Formula 3.1

In the above formula 3.1,
R ¹ , R ² , R ³ , R ²⁷ , R ²⁸ , p, E and ring B are independently selected from each other,
E is -O-, -S-, -S (O)-, -S (O) _2- , -C (R ⁴ ) (R ⁵ )-, -N (R ⁶ )-, -N (C ( Y) R ⁷ )-, -N (C (Y) OR ⁸ )-and -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-;
p is 0, 1 or 2. The method of claim 29,
E is selected from the group consisting of -C (R ⁴ ) (R ⁵ )-, -O-, -S-, -S (O)-, -S (O) ₂ -and -N (R ⁶ )-; ;
Ring B is an unsubstituted or substituted aromatic ring or an unsubstituted or substituted 5-6 membered heteroaromatic ring having 1 to 3 ring heteroatoms which may be the same or different, each ring heteroatom being N, Independently selected from the group consisting of S, O, S (O) and S (O) ₂ , wherein the substituents on the aromatic ring or the heteroaromatic ring (if present) are halogen, -CN, -NO ₂ , alkyl , Heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocyclo Alkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group consisting of;
R ¹ is unsubstituted aryl or aryl substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, halo Alkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , Independently selected from the group consisting of -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ ;
R ² is selected from the group consisting of —C (O) R ⁷ , —C (O) NR ⁹ R ¹⁰ and —C (O) OR ⁸ ;
p is O or 1;
Each R ³ (if present) is alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -C ( O) R ²⁴ , -C (S) R ²⁴ , -C (O) OR ²⁰ and -C (O) NR ²⁵ R ²⁶ , independently selected from the group consisting of: each of said alkyls, each said hetero Alkyl, each said alkenyl and each said heteroalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different and each substituent is oxo, halogen, -CN, -NO ₂ , Alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ Independent from the group The compound selected by. 32. The compound of claim 30, wherein ring B is benzo, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thidiazolyl, pyridinyl , Unsubstituted or substituted moiety selected from the group consisting of pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl;
R ¹ is phenyl substituted with 1 to 4 substituents which may be the same or different and each substituent is independently from the group consisting of halo, —OH, —CN —NO ₂ , —NR ²¹ R ²² and haloalkyl Selected;
R ² is selected from the group consisting of —C (O) R ⁷ , —C (O) NR ⁹ R ¹⁰ and —C (O) OR ⁸ ;
p is 0 or 1;
Each R ³ (if present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl and each Wherein said heteroalkenyl of is optionally substituted with one or more substituents which may be unsubstituted or the same or different and each substituent is oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, Alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N -CN) part of a group of NR ²⁵ R ²⁶ and ^{-NR 23 C (O) NR 25} R 26 Independently selected compound. The method of claim 31, wherein
R ¹ is

ego;
R ²⁷ and R ²⁸ are each independently selected from the group consisting of H and alkyl;
R ⁶ is selected from the group consisting of H, alkyl, -C (O) R ²⁴ , -C (O) OR ²⁰ and -C (S) R ²⁴ . The compound of formula 3.2 (or formula III.2), or a pharmaceutically acceptable salt, solvate, ester, prodrug or isomer thereof:
Formula 3.2

In the above formula 3.2,
R ¹ , R ² , R ³ , R ²⁷ , R ²⁸ , p, E and ring B are independently selected from each other,
E is -O-, -S-, -S (O)-, -S (O) _2- , -C (R ⁴ ) (R ⁵ )-, -N (R ⁶ )-, -N (C ( Y) R ⁷ )-, -N (C (Y) OR ⁸ )-and -N (C (Y) N (R ⁹ ) (R ¹⁰ ))-;
p is 0, 1 or 2. The method of claim 33, wherein
E is selected from the group consisting of -C (R ⁴ ) (R ⁵ )-, -O-, -S-, -S (O)-, -S (O) ₂ -and -N (R ⁶ )-; ;
Ring B is an unsubstituted or substituted aromatic ring or an unsubstituted or substituted 5- to 6-membered heteroaromatic ring having 1 to 3 ring heteroatoms which may be the same or different and each ring heteroatom is N, Independently selected from the group consisting of S, O, S (O) and S (O) ₂ , wherein the substituents on the aromatic ring or heteroaromatic ring (if present) are halogen, -CN, -NO ₂ , alkyl, Heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloal Kenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR Independently selected from the group consisting of ²⁵ R ²⁶ ;
R ¹ is unsubstituted aryl or aryl substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, haloal Kenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC ( O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C ( O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ ,- NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ are independently selected from the group consisting of;
R ² is selected from the group consisting of —C (O) R ⁷ , —C (O) NR ⁹ R ¹⁰ and —C (O) OR ⁸ ;
p is 0 or 1;
Each R ³ (if present) is alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -C ( O) R ²⁴ , -C (S) R ²⁴ , -C (O) OR ²⁰ and -C (O) NR ²⁵ R ²⁶ , independently selected from the group consisting of: each of said alkyls, each said hetero Alkyl, each said alkenyl and each said heteroalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different and each substituent is oxo, halogen, -CN, -NO ₂ , Alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ Independent from the group The compound selected by. The method of claim 34, wherein
Ring B is benzo, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyri Unsubstituted or substituted residue selected from the group consisting of midinyl, pyrazinyl and triazinyl;
R ¹ is phenyl substituted with 1 to 4 substituents which may be the same or different and each substituent is independent from the group consisting of halo, —OH, —CN, —NO ₂ , —NR ²¹ R ²² and haloalkyl Is selected;
R ² is selected from the group consisting of —C (O) R ⁷ , —C (O) NR ⁹ R ¹⁰ and —C (O) OR ⁸ ;
p is 0 or 1;
Each R ³ (if present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl and each Wherein said heteroalkenyl of is optionally substituted with one or more substituents which may be unsubstituted or the same or different and each substituent is oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, Alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N -CN) part of a group of NR ²⁵ R ²⁶ and ^{-NR 23 C (O) NR 25} R 26 Independently selected compound. 36. The method of claim 35 wherein
R ¹ is

ego;
R ²⁷ and R ²⁸ are each independently selected from the group consisting of H and alkyl;
R ⁶ is selected from the group consisting of H, alkyl, -C (O) R ²⁴ , -C (O) OR ²⁰ and -C (S) R ²⁴ . A compound of formula 4 (or formula IV), or a pharmaceutically acceptable salt, solvate, ester, prodrug or isomer thereof:
Formula 4

In Formula 4 above,
E is selected from the group consisting of -C (R ⁴ ) (R ⁵ )-, -O-, -S-, -S (O)-, -S (O) ₂ -and -N (R ⁶ )-; ;
Ring B is an unsubstituted or substituted aromatic ring, or an unsubstituted or substituted 5- to 6-membered heteroaromatic ring having 1 to 3 ring heteroatoms which may be the same or different, and each ring heteroatom is N Is independently selected from the group consisting of S, O, S (O) and S (O) ₂ , wherein the substituent on the aromatic ring or the heteroaromatic ring, if present, is halogen, -CN, -NO ₂ , Alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, hetero Cycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ is independently selected from the group consisting of;
R ¹ is unsubstituted aryl or aryl substituted with one or more substituents which may be the same or different and each substituent is halogen, —CN, —NO ₂ , alkyl, heteroalkyl, haloalkyl, alkenyl, halo Alkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , Independently selected from the group consisting of -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ ;
R ² is selected from the group consisting of —C (O) R ⁷ , —C (O) NR ⁹ R ¹⁰ and —C (O) OR ⁸ ;
p is 0, 1 or 2;
Each R ³ (if present) is alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO ₂ , -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -C ( O) R ²⁴ , -C (S) R ²⁴ , -C (O) OR ²⁰ and -C (O) NR ²⁵ R ²⁶ , independently selected from the group consisting of: each of said alkyls, each said hetero Alkyl, each said alkenyl and each said heteroalkenyl, is optionally substituted with one or more substituents which may be unsubstituted or the same or different and each substituent is oxo, halogen, -CN, -NO ₂ , Alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N-CN) NR ²⁵ R ²⁶ and -NR ²³ C (O) NR ²⁵ R ²⁶ Independent from the group The compound selected by. The method of claim 37,
E is selected from the group consisting of -O- and -N (R ⁶ )-;
Ring B is benzo, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyri Unsubstituted or substituted residue selected from the group consisting of midinyl, pyrazinyl and triazinyl;
R ¹ is phenyl substituted with 1 to 4 substituents which may be the same or different and each substituent is independent from the group consisting of halo, —OH, —CN, —NO ₂ , —NR ²¹ R ²² and haloalkyl Is selected;
R ² is selected from the group consisting of —C (O) R ⁷ , —C (O) NR ⁹ R ¹⁰ and —C (O) OR ⁸ ;
p is 0 or 1;
Each R ³ (if present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl and each Wherein said heteroalkenyl of is optionally substituted with one or more substituents which may be unsubstituted or the same or different and each substituent is oxo, halogen, -CN, -NO ₂ , alkyl, heteroalkyl, haloalkyl, Alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR ¹⁹ , -OC (O) OR ²⁰ , -NR ²¹ R ²² , -NR ²³ SO ₂ R ²⁴ , -NR ²³ C (O) OR ²⁰ , -NR ²³ C (O) R ²⁴ , -SO ₂ NR ²⁵ R ²⁶ , -C (O) R ²⁴ , -C (O) OR ²⁰ , -SR ¹⁹ , -S (O) R ¹⁹ , -SO ₂ R ¹⁹ , -OC (O) R ²⁴ , -C (O) NR ²⁵ R ²⁶ , -NR ²³ C (N -CN) part of a group of NR ²⁵ R ²⁶ and ^{-NR 23 C (O) NR 25} R 26 Independently selected compound. The compound of claim 38, wherein R ¹ is

ego;
R ²⁷ and R ²⁸ are each independently selected from the group consisting of H and alkyl;
R ⁶ is selected from the group consisting of H, alkyl, -C (O) R ²⁴ , -C (O) OR ²⁰ and -C (S) R ²⁴ . Compounds selected from the group consisting of: or pharmaceutically acceptable salts, solvates, esters, prodrugs or isomers thereof:

41. The compound of any one of claims 1-40, in isolated or purified form. 41. A therapeutically effective amount of one or more compounds according to any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, ester, prodrug or isomer thereof, and one or more pharmaceutically acceptable carriers. Pharmaceutical compositions comprising. The pharmaceutical composition of claim 42, further comprising one or more additional therapeutically active agents. The method of claim 43, wherein the one or more additional therapeutically active agents are estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, microtubule inhibitors / stabilizers, topoisomerase inhibitors, antisense RNA and DNA oligonucleotides, antimetabolic agents, antibodies coupled to cytotoxic agents, HMG-CoA reductase inhibitors, prenyltransferase inhibitors, farnesyl protein transferase inhibitors, angiogenesis inhibitors, kinase inhibitors, COX2 inhibitors, integrins Selected from blockers, PPAR agonists, MDR inhibitors, hypoxia activatable agents, proteasome inhibitors, ubiquitin inhibitors, HDM2 inhibitors, TNF activators, BUB-R inhibitors, CENP-E inhibitors, interferon and radiation Pharmaceutical compositions. 41. An effective amount of one or more compounds according to any one of claims 1 to 40, or a pharmaceutically acceptable salt, solvate, ester, prodrug or isomer thereof, is administered to a subject in need of inhibition of KSP kinesin activity. A method of inhibiting KSP kinesin activity in said subject. 41. An effective amount of one or more compounds according to any one of claims 1 to 40, or pharmaceutically acceptable salts, solvates, prodrugs, esters or isomers thereof, according to any one of the diseases associated with or caused by abnormal cell proliferation A method of treating a disease associated with or caused by abnormal cell proliferation in a subject, comprising administering to the subject in need thereof. The cell proliferation of claim 46, wherein the disease is caused by cancer, hyperplasia, cardiac hypertrophy, autoimmune disease, fungal disease, arthritis, transplant rejection, inflammatory bowel disease, immune disease, inflammation, tumor angiogenesis, and medical proliferation Method selected from the group consisting of: 47. The method of claim 46, wherein the cell proliferative disease is selected from solid tumor cancers and hematological cancers. 47. The method of claim 46, wherein the disease is a cancer selected from skin cancer, breast cancer, brain cancer, colon cancer, gallbladder cancer, thyroid cancer, cervical cancer, testicular cancer, and blood cancer. 47. The method of claim 46, wherein the disease is heart cancer, lung cancer, gastrointestinal cancer, genitourinary cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, blood cancer, skin cancer, adrenal cancer, pigmentary dry skin, keratin A cancer selected from thorny cell tumor and thyroid cell tumor. 47. The method of claim 46, wherein the cell proliferative disease is
Adenocarcinoma, Wilms' tumor (renal blastoma), lymphoma, leukemia, squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, prostate cancer, testicular cancer,
Liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, hemangiosarcoma, hepatocellular carcinoma, hemangioma;
Osteosarcoma (osteosarcoma), Fibrosarcoma, Malignant fibrous histiocytoma, Cartilage sarcoma, Ewing's sarcoma, Malignant lymphoma (reticulocyte sarcoma), Multiple sclerosis, Malignant giant cell tumor chordoma, Osteochondrosis (osteochondral cartilage) Sex oligodendrosis), benign glioma, chondroma, chodromyxofibroma, osteomyeloma and giant cell tumor,
Osteoma, Hemangioma, Granulomas, Staphylococcus, Transgenic osteomyelitis, Meningioma, Meningiosarcoma, Glioma, Glioblastoma, Pleural blastoma, Glioblastoma, Ventricular cell tumor, Seed cell carcinoma (pineal adenoma), Glioblastoma multiforme, Rare dendritic glioblastoma Retinoblastoma, congenital tumors, spinal neurofibromatosis, meningioma, glioma, sarcoma;
Endometrial carcinoma, cervical carcinoma, pre-tumor cervical dysplasia, acute cystic carcinoma, mucinous cystic carcinoma, unclassified carcinoma, granulocytic cell tumor, Sertoli-Leydog cell tumor, ovarian germ cell tumor, Malignant teratoma, squamous cell carcinoma, intraepithelial tumor, adenocarcinoma, fibrosarcoma, malignant melanoma, clear cell carcinoma, squamous cell carcinoma, staphylosarcoma (embryogenic hyper grape), uterine duct (sarcoma);
Myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, acute and chronic lymphocytic leukemia, myeloproliferative diseases, multiple sclerosis, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), B- Cell lymphoma, T-cell lymphoma, hair cell lymphoma, Burkett's lymphoma, promyelocytic leukemia;
Malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevus, lipoma, hemangioma, dermal fibroma, keloid, psoriasis and neuroblastoma. The method of claim 51, further comprising radiation therapy. 47. The method of claim 46, wherein the estrogen receptor modulator, androgen receptor modulator, retinoid receptor modulator, cytotoxic agent, microtubule inhibitor / stabilizer, topoisomerase inhibitor, antisense RNA and DNA oligonucleotide, antimetabolic agent, cell Antibody coupled to toxic agents, HMG-CoA reductase inhibitors, prenyltransferase inhibitors, farnesyl protein transferase inhibitors, angiogenesis inhibitors, kinase inhibitors, COX2 inhibitors, integrin blockers, PPAR agonists, MDR inhibitors, hypoxia activation Further comprising administering to the subject one or more additional therapeutically active agents selected from possible agents, proteasome inhibitors, ubiquitin inhibitors, HDM2 inhibitors, TNF activators, BUB-R inhibitors, CENP-E inhibitors, interferons and radiation. Way. 41. One or more compounds according to any one of claims 1-40, or a pharmaceutically acceptable salt, solvate thereof, for the manufacture of a medicament for inhibiting KSP kinesin activity in a subject in need thereof. Use of esters or prodrugs. 41. At least one compound according to any one of claims 1 to 40, for the manufacture of a medicament for the treatment of at least one disease by inhibiting KSP kinesin activity in a patient in need thereof. Or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. (I) A compound according to any one of claims 1 to 40 for the manufacture of a medicament for the treatment of one or more diseases by inhibiting KSP kinesin activity in a subject in need of treatment of the disease by inhibition of KSP kinesin activity. Or pharmaceutically acceptable salts, solvates, esters or prodrugs thereof; And (ii) estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, microtubule inhibitors / stabilizers, topoisomerase inhibitors, antisense RNA and DNA oligonucleotides, antimetabolic agents, cytotoxic agents Antibodies coupled to, HMG-CoA reductase inhibitors, prenyltransferase inhibitors, farnesyl protein transferase inhibitors, angiogenesis inhibitors, kinase inhibitors, COX2 inhibitors, integrin blockers, PPAR agonists, MDR inhibitors, hypoxia activatable agents The use of a combination comprising at least one second compound selected from proteasome inhibitors, ubiquitin inhibitors, HDM2 inhibitors, TNF activators, BUB-R inhibitors, CENP-E inhibitors, interferons and radiation.