RU2829459C1 - Compound aimed at protein and degradation thereof, and method for production and use thereof - Google Patents

Abstract

FIELD: medicine; pharmacology.

SUBSTANCE: invention relates to pharmacological preparations, namely to a compound of formula I, which is PTM-L-ULM. At the same time ULM has structure ULM-1, where in ULM-1: X'' is CH or N; Y'' is N; Q₁, Q₂, Q₃, Q₄ and Q₅ each independently represents CR₃''; R₃'' each independently represents hydrogen, halogen, C1-C6 alkyl, -O(C1-C6 alkyl); and alkyl is optionally substituted with 1–3 groups independently selected from halogen; m'' is equal to 2; R₁'' each independently represents hydrogen; R₂'' is hydrogen or C1-C6 alkyl, C1-C6 alkyl is optionally substituted with 1 group selected from -O-(C=O)-(C1-C6 alkyl); PTM is PTM-71, where in PTM-71: ring A is 6-member heteroaryl; R_d each independently represents hydrogen, halogen or C1-C6 alkyl; and alkyl is optionally substituted with one or more groups selected from halogen or hydroxyl; n is 1; R_e is hydrogen; R c is hydrogen, -O-(C1-C6 alkyl), -O-(3–8-membered heterocycloalkyl), C1-C6 alkyl; and alkyl, heterocycloalkyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen or -O-(C1-C6 alkyl); R_b is hydrogen, -O-(C1-C6 alkyl) or C1-C6 alkyl; and alkyl is optionally substituted with one or more groups independently selected from hydroxyl or halogen; R_a is hydrogen, 3–8 membered heterocycloalkyl, C3-C8 cycloalkyl; L is-(CH2)_j-, and one or more methylenes in -(CH2)_j- are optionally substituted with a group selected from -NR^3'-, -O-, -C(O)-, -C(O)NR^3'-, -NR^3'C(O)-, C3-C12 cycloalkylene or 3–12-membered heterocycloalkylene containing one or two N heteroatoms; R^3' each independently represents hydrogen or C1-C6 alkyl; j is equal to 3, 4, 5, 6, 7, 8, 9, 10; heteroaryl contains 1 heteroatom selected from N, O; 3–8-membered heterocycloalkyl contains 1 heteroatom selected from N, O. Invention also relates to individual compounds, a pharmaceutical composition based on said compounds and use thereof for treating IRAK4-mediated diseases.

EFFECT: obtaining alternative compounds for treating IRAK4-mediated diseases.

30 cl, 4 tbl, 71 ex

Description

Field of the invention: The present invention relates to the field of pharmacological preparations and, in particular, the present invention relates to compounds targeting IRAK4 proteins and causing their degradation, their pharmacological compositions and methods for producing them, as well as their use in drugs for the treatment and/or prevention of relevant diseases and conditions mediated by IRAK4, such as cancer, immune and inflammatory diseases.

BACKGROUND OF THE INVENTION: Interleukin-1 receptor kinase 4 (IRAK4) is a serine/threonine-specific protein kinase with biologically important kinase activity that plays an important role in the activation of the immune system. Studies have shown that IRAK4 is a key factor involved in the signaling pathways of IL-1β family receptors (including IL-1R, IL-18R, IL-33R, IL-36R) and Toll-like receptor (TLR). IRAK4-deficient mice and IRAK4-deficient patients do not respond to stimulation of TLR receptors (except TLR3) and IL-1β family receptors.

According to the presence or absence of MyD88, TLR/IL-1α and IL-1β-mediated signaling pathways can be divided into MyD88-dependent signaling pathways and MyD88-independent signaling pathways, in which IL-1R and TLR2, TLR4, TLR7/8, TLR9-mediated signaling pathways rely on MyD88 as a regulator to activate downstream inflammatory signaling pathways. Upon TLR/IL-1β ligand binding, MyD88 molecules are mobilized, MyD88 then mobilizes IRAK4 into the TLR/IL-1β complex via the N-terminal death domain, interacts with IRAK1 or IRAK2 and activates them, thereby transmitting signals further to the E3 ubiquitin ligase TNF receptor-associated factor (TRAF6), activating the serine/threonine kinase TAK1, and further activating the NF-κB and MAPK signaling pathways, thereby leading to the release of a variety of inflammatory cytokines and anti-apoptotic molecules. IRAK4-dependent TLR/IL-1β signaling pathway has been shown to be associated with a variety of diseases such as multiple sclerosis, atherosclerosis, myocardial infarction, myocarditis, Vogt-Koyanagi-Harada syndrome, systemic lupus erythematosus (SLE), obesity, type 1 diabetes mellitus, rheumatoid arthritis, spondyloarthritis (especially psoriatic spondylitis and ankylosing spondylitis), lupus erythematosus, psoriasis, vitiligo, giant cell arteritis, chronic inflammatory bowel disease and viral diseases such as HIV (human immunodeficiency virus), hepatitis virus; skin diseases such as psoriasis, atopic dermatitis, Kindler syndrome, bullous pemphigoid, allergic contact dermatitis, alopecia areata, acne inverse and acne vulgaris; Other inflammatory diseases such as allergy, Behcet's disease, gout, adult Still's disease, pericarditis and chronic inflammatory bowel diseases such as ulcerative colitis and Crohn's disease, transplant rejection and graft-versus-host disease; Gynecological diseases such as adenomyosis, dysmenorrhea, dyspareunia and endometriosis, especially pain associated with endometriosis and other symptoms associated with endometriosis such as dysmenorrhea, dyspareunia, dysuria and difficulty in defecation; Eye diseases such as retinal ischemia, keratitis, allergic conjunctivitis, keratoconjunctivitis sicca, macular degeneration and ocular pigment inflammation; Fibrotic diseases such as liver fibrosis, myocarditis, primary biliary cirrhosis, cystic fibrosis; chronic liver diseases such as fatty liver disease, especially non-alcoholic fatty liver disease (NAFLD) and/or non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH); cardiovascular diseases and neurological disorders such as myocardial reperfusion injury, myocardial infarction, hypertension and Alzheimer's disease, stroke, traumatic brain injury, amyotrophic lateral sclerosis (ALS) and Parkinson's disease; pruritus and pain (including acute, chronic, inflammatory and neuropathic pain) such as hyperalgesia, allodynia, premenstrual pain, endometriosis-related pain, postoperative pain, interstitial cystitis, CFS (complex local pain syndrome), trigeminal neuralgia, prostatitis, pain due to spinal cord injury, pain due to inflammation, low back pain, cancer pain, chemotherapy-related pain, HIV treatment-induced neuropathy, burn pain and chronic pain; neoplastic diseases such as some lymphomas: ABC-DLBCL (activated B-cell diffuse large B-cell lymphoma), mantle cell lymphoma and Waldenstrom's disease, as well as chronic lymphocytic leukemia, melanoma, pancreatic tumors and hepatocellular carcinoma, ras-dependent tumors, breast cancer, ovarian cancer, colorectal cancer, head and neck cancer, lung cancer and prostate cancer.

Regulation of the IRAK4-mediated signaling pathway is primarily mediated by its kinase function. However, several reports indicate that in some cell types, downstream signaling regulation of IRAK4 occurs other than through the kinase function of IRAK4. Cushing et al. reported that although IRAK4 phosphorylation was reduced in IL-1β-stimulated human skin fibroblasts, pharmacological inhibition of IRAK4 did not result in inhibition of IL-6 and TNF-α. Consistent with these results, the scaffolding function of IRAK4 is essential for IL1 signaling in IRAK4-deficient fibroblasts compared with wild-type cells, but its kinase effect is redundant. Meanwhile, Chiang and colleagues argued that the kinase activity of IRAK4 was not required for human B cells, T cells, dendritic cells, and monocytes, and gene excision using siRNA also demonstrated that IRAK4 has a supporting function in these cells. Several potent selective inhibitors of IRAK4 have been reported, such as CA-4948, BAY-1834845, BMS-986126, and PF-06650833. These inhibitors can selectively inhibit the kinase activity of IRAK4 and are mainly used for the prevention and treatment of autoimmune diseases, inflammatory diseases, and tumor diseases. However, on the one hand, IRAK4 has the function of a scaffold protein and an active kinase, but on the other hand, traditional small molecule inhibitors are prone to the development of drug resistance, so inhibition of the kinase activity of IRAK4 alone may not be sufficient to exhibit a therapeutic effect.

Proteolysis Targeting Chimera (PROTAC) is a different technology from traditional small molecule inhibitors. Traditional small molecule inhibitors usually need to act on the active site of the target protein in order to inhibit its activity. PROTAC is a heterogeneous bifunctional molecule, one end of which is a small molecule inhibitor that can recognize the target protein. Connected by a connecting chain, at the other end is an E3 ubiquitin ligase ligand that can recognize E3 ubiquitin ligase, due to which this bifunctional molecule recognizes the target protein and E3 ubiquitin ligase in the body and brings the target protein and E3 ubiquitin ligase closer to form a tertiary complex. After the target protein is ubiquitinated, it is degraded in the body via the ubiquitin-proteasome pathway. Compared with traditional small molecule inhibitors, on the one hand, PROTAC only needs to move the target protein closer to E3 ubiquitin ligase to induce substrate degradation, and this mode of action makes this technology applicable to some drug-resistant targets; on the other hand, after the target protein is degraded, PROTAC molecules can be released to continue participating in the degradation process of the next protein, so this degradation has a catalytic effect, and thus a lower dose of PROTAC can achieve effective degradation; on the other hand, traditional small molecule inhibitors are often susceptible to drug resistance due to point mutations, which cause the small molecule inhibitors to lose their inhibitory effect on the target. PROTAC can directly induce the degradation of the target protein, which can avoid drug resistance caused by point mutations to a certain extent. Thus, compared with traditional small molecule inhibitors, the use of PROTAC technology for the research and development of new small molecule drugs has great advantages and feasibility, and is expected to provide the next generation of promising new drugs. PROTAC technology has also been applied to modify various target drugs such as androgen receptor, estrogen receptor protein, BTK, etc. Several types of degraders targeting IRAK4 are disclosed in US 2019/0151295, US 2019/0192688, WO 2019/160915 and WO 2020/113233, and other degraders targeting IRAK4 remain to be developed.

ESSENCE OF THE INVENTION

The subject of the invention is a compound of formula I and/or its stereoisomer, enantiomer, diastereomer, deuterate, hydrate, solvate, prodrug and/or pharmaceutically acceptable salt:

Where:

RTM is a small molecule compound that can inhibit the protein kinase IRAK4 or bind the protein kinase IRAK4;

L is a connecting chain that connects RTM and ULM via a covalent bond;

ULM is a low molecular weight ligand of the E3 ubiquitin ligase complex, and ULM has the following structure:

where in ULM-1:

X'' represents CH or N;

Y'' represents CH, N, O or S;

each _Q1 , _Q2 , _Q3 , _Q4 and _Q5 is independently _CR3 ″ or N; each _R3 ″ is independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8-membered heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, -O(C1-C6 alkyl), -O-(C3-C8 cycloalkyl), -O-(3-8-membered heterocycloalkyl), N(C1-C6 alkyl) ₂ , NH(C3-C8 cycloalkyl), -NH(3-8-membered heterocycloalkyl), -O-(6-10-membered aryl) or -O-(5-10-membered heteroaryl); and alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with 1-3 groups independently selected from hydroxyl, halogen, cyano or amino; or R ₃ '' together with the atoms attached thereto forms cycloalkyl, heterocycloalkyl, heteroaryl or aryl; m'' is 1, 2 or 3;

each R ₁ '' is independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8-membered heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, or -O(C1-C6 alkyl); and the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with 1-3 groups independently selected from hydroxyl, halogen, cyano or amino;

R ₂ '' is absent, represents hydrogen, deuterium, C1-C6 alkyl or C3-C6 cycloalkyl, C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with 1-3 groups independently selected from hydroxyl, halogen, -O-(C=O)-(C1-C6 alkyl), cyano or amino.

In some embodiments of the present invention, in ULM-1,

X'' represents CH or N;

Y'' represents CH, N, O or S;

each Q ₁ , Q ₂ , Q ₃ , Q ₄ and Q ₅ independently represents CR ₃ '' or N;

each R ₃ "' is independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8-membered heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, -O(C1-C6 alkyl), -O-(C3-C8 cycloalkyl), -O-(3-8-membered heterocycloalkyl), N(C1-C6 alkyl) _1-2 , NH(C3-C8 cycloalkyl), -NH(3-8-membered heterocycloalkyl), -O-(6-10-membered aryl), -O-(5-10-membered heteroaryl); alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with 1-3 groups independently selected from hydroxyl, halogen or amino;

m'' is equal to 1, 2 or 3;

each R ₁ '' is independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8-membered heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, or -O(C1-C6 alkyl); the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with 1-3 groups independently selected from hydroxyl, halogen or amino; and

R ₂ '' is hydrogen, deuterium, C1-C6 alkyl or C3-C6 cycloalkyl, C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with 1-3 groups independently selected from hydroxyl, halogen or amino.

In some embodiments of the present invention, one or two of Q ₁ , Q ₂ , Q ₃ , Q ₄ and Q ₅ in ULM-1 are N, and in the remaining, each independently is CR ₃ ''.

In some embodiments of the present invention, each Q ₁ , Q ₂ , Q ₃ , Q ₄ and Q ₅ in ULM-1 is independently CR ₃ ''.

In some embodiments of the present invention, X'' in ULM-1 is N.

In some embodiments of the present invention, X'' in ULM-1 is CH.

In some embodiments of the present invention, Y'' in ULM-1 is N.

In some embodiments of the present invention, R ₁ '' in ULM-1, each independently, is hydrogen, deuterium, -F, -Cl, or C1-C6 alkyl, the alkyl optionally substituted with 1-3 halogens; preferably, R ₁ '' is hydrogen.

In some embodiments of the present invention, R ₂ '' in ULM-1 is hydrogen or C1-C6 alkyl, the alkyl optionally substituted with 1-3 halogens; preferably, R ₂ '' is hydrogen.

In some embodiments of the present invention, R ₃ '' in ULM-1, each independently, is hydrogen, deuterium, halogen, -O(C1-C6 alkyl) or C1-C6 alkyl, alkyl optionally substituted with 1-3 halogens; preferably, R ₃ '' is hydrogen, deuterium, F, Cl, methyl, methoxy, ethoxy, trifluoromethoxy, 2-hydroxypropyl-2-yl or trifluoromethyl.

In some embodiments of the present invention, ULM-1 is attached to L via Q ₁ , Q ₂ , Q ₃ , Q ₄ or Q ₅ .

In some embodiments of the present invention, the ULM has the following structure:

where Q ₁ , Q ₂ , Q ₃ , Q ₄ , Q ₅ , R ₁ '', R ₂ '' and m'' are defined as above for ULM-1.

In some embodiments of the present invention, the ULM has the following structure:

where R ₁ '', R ₂ '', R ₃ '' and m'' are defined as above for ULM-1.

In some embodiments of the present invention, the ULM has the following structure:

where R ₁ '', R ₂ '' and R ₃ '' are defined as above for ULM-1.

In some embodiments of the present invention, the ULM has the following structure:

where R ₃ '' are defined as above for ULM-1.

In some embodiments of the present invention, the ULM has the following structure:

where Q ₁ , Q ₂ , Q ₃ , Q ₅ , R ₁ '', R ₂ '' and m'' are defined as above for ULM-1. In some embodiments of the present invention, the ULM has the following structure:

where R ₁ '', R ₂ '', R ₃ '' and m'' are defined as above for ULM-1.

In some embodiments of the present invention, the ULM has the following structure:

where R ₁ '', R ₂ '', R ₃ '' are defined as above for ULM-1.

where R ₃ '' are defined as above for ULM-1.

In some embodiments of the present invention, the ULMs are selected from:

In some embodiments of the present invention, the ULMs are selected from:

In some embodiments of the present invention, the ULM has the following structure:

where Q ₁ , Q ₂ , Q ₃ , Q ₄ , Q ₅ , R ₁ '', R ₂ '' and m'' are defined as above for ULM-1.

In some embodiments of the present invention, the ULM has the following structure:

where R ₁ '', R ₂ '', R ₃ '' and m'' are defined as above for ULM-1.

In some embodiments of the present invention, the ULM has the following structure:

where R ₁ '', R ₂ '' and R ₃ '' are defined as above for ULM-1.

In some embodiments of the present invention, the ULM has the following structure:

where R ₃ '' are defined as above for ULM-1.

In some embodiments of the present invention, the ULM has the following structure:

where Q ₁ , Q ₂ , Q ₃ , Q ₅ , R ₁ '', R ₂ '' and m'' are defined as above for ULM-1.

In some embodiments of the present invention, the ULM has the following structure:

where R ₁ '', R ₂ '', R ₃ '' and m'' are defined as above for ULM-1.

In some embodiments of the present invention, the ULM has the following structure:

where R ₁ '', R ₂ '' and R ₃ '' are defined as above for ULM-1.

where R ₃ '' are defined as above for ULM-1.

In some embodiments of the present invention, the ULMs are selected from:

In some embodiments of the present invention, the ULMs are selected from:

In some embodiments of the present invention, a compound of formula I and/or a stereoisomer, enantiomer, diastereomer, deuterate, metabolite, hydrate, solvate, prodrug and/or pharmaceutically acceptable salt thereof is a compound of formula Ia and/or a stereoisomer, enantiomer, diastereomer, deuterate, metabolite, hydrate, solvate, prodrug and/or pharmaceutically acceptable salt thereof,

where Q ₁ , Q ₂ , Q ₃ , Q ₄ , Q ₅ , R ₁ '', R ₂ '', m'', X'' and Y'' are defined as specified above for ULM-1, and L, RTM are defined as specified herein.

In some embodiments of the present invention, the RTM has the following structure:

and/or is a pharmaceutically acceptable salt or stereoisomer thereof, where in RTM-1, RTM-1a or RTM-1b:

Z ₁ is hydrogen, deuterium, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or absent;

Z ₂ is hydrogen, deuterium, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

R ₁ is hydrogen, deuterium, optionally substituted alkyl, amino, halogen, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (aryl) alkyl- or optionally substituted (heterocycloalkyl) alkyl-;

_R2 is hydrogen, deuterium, halogen, amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (aryl)alkyl-, or optionally substituted (heterocycloalkyl)alkyl-, in each occurrence;

R ₃ is hydroxyl, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, or -NR _a R _b , in each occurrence;

R _a and R _b are independently hydrogen, deuterium, optionally substituted alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted (aryl)alkyl-, or optionally substituted (heterocycloalkyl)alkyl-, in each occurrence;

m is 0, 1, or 2, in each case; and

n is 0, 1, or 2, in each case; or

in some embodiments of the present invention, the RTM has the following structure:

and/or is a pharmaceutically acceptable salt or stereoisomer thereof, where in RTM-2, RTM-2a, RTM-2b or RTM-2c:

Z ₁ is optionally substituted heteroaryl;

Z ₂ is optionally substituted heterocycloalkyl, optionally substituted heteroaryl or a bond;

R ₁ is alkyl, piano, -NR _a R _b or optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heterocycloalkyl; wherein the substituents are independently alkyl, alkoxy, halogen, hydroxyl, hydroxyalkyl, amino, amino alkyl, nitro, cyano, haloalkyl, haloalkoxy, -OC(O)CH ₂ O-alkyl, -OP(O)(O-alkyl) ₂ or -CH ₂ OP(O)(O-alkyl) ₂ , in each occurrence;

R ₂ is independently optionally substituted alkyl or optionally substituted cycloalkyl, in each occurrence, wherein the substituents are independently halogen, alkoxy, hydroxyl, hydroxyalkyl, haloalkyl, or haloalkoxy, in each occurrence;

R ₃ is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxyl, hydroxyalkyl, or -NR _a R _b , in each occurrence;

R _a represents hydrogen or alkyl;

R _b is hydrogen, deuterium, alkyl, acyl, hydroxyalkyl, -S(O) ₂ alkyl, or optionally substituted cycloalkyl;

m or n is independently equal to 1 or 2; or

in some embodiments of the present invention, the RTM has the following structure:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein in RTM-3, RTM-3', RTM-3a or RTM-3a':

each X ₁ , X ₂ and X ₃ independently represents CR ² or N;

A is O, S, S(O) or S(O) ₂ ;

Z ₁ is optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted (heterocycloalkyl)alkyl-, optionally substituted (aryl) alkyl-, optionally substituted (heteroaryl) alkyl-, optionally substituted (cycloalkyl) alkyl-, optionally substituted aryl-O-, optionally substituted (heteroaryl) alkyl-, optionally substituted heterocycloalkyl-O-, optionally substituted cycloalkyl-O-, optionally substituted aryl-NR'-, optionally substituted heteroaryl-NR'-, optionally substituted heteroaryl-S-, optionally substituted heterocycloalkyl-NR'-, optionally substituted cycloalkyl-NR'-, optionally substituted heterocycloalkyl-S-, optionally substituted cycloalkyl-S-, optionally substituted (cycloalkyl)alkyl-NR'-, optionally substituted (aryl)alkyl-NR'-, optionally substituted (heterocycloalkyl)alkyl-NR'-, optionally substituted (heteroaryl)alkyl-NR', optionally substituted (cycloalkyl)alkyl-S-, optionally substituted (aryl)alkyl-S-, optionally substituted (heterocycloalkyl)alkyl-S-, optionally substituted (heteroaryl)alkyl-S-, optionally substituted (cycloalkyl)alkyl-O-, optionally substituted (aryl)alkyl-O-, optionally substituted (heterocycloalkyl)alkyl-O-, optionally substituted (heteroaryl)alkyl-O-; wherein the optional substituent is R ^x ;

Z ₂ is absent or optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted (heterocycloalkyl) alkyl-, optionally substituted (aryl) alkyl-, optionally substituted (heteroaryl) alkyl-, optionally substituted (cycloalkyl) alkyl-, optionally substituted aryl-O-, optionally substituted heteroaryl-O-, optionally substituted heterocycloalkyl-O-, optionally substituted cycloalkyl-O-, optionally substituted (cycloalkyl) alkyl-, optionally substituted (aryl) alkyl-, optionally substituted (heterocycloalkyl) alkyl-, optionally substituted (heteroaryl) alkyl-, optionally substituted (cycloalkyl) alkyl-NR''-, optionally substituted (heterocycloalkyl) alkyl-NR''-, optionally substituted (heteroaryl) alkyl-NR''-, optionally substituted (aryl) alkyl-NR''-, optionally substituted (cycloalkyl) alkyl-S-, optionally substituted (aryl) alkyl-S-, optionally substituted (heterocycloalkyl) alkyl-S-, optionally substituted (heteroaryl) alkyl-S-, optionally substituted (cycloalkyl) alkyl-O-, optionally substituted (aryl) alkyl-O-, optionally substituted (heterocycloalkyl) alkyl-O-, optionally substituted (heteroaryl) alkyl-O-; wherein the optional substituent is R ^y ;

Z ₃ is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted aryl-O-, optionally substituted heteroaryl-O-, optionally substituted cycloalkyl-O-, optionally substituted heterocycloalkyl-O-, optionally substituted (cycloalkyl)alkyl-, optionally substituted (aryl) alkyl-, optionally substituted (heterocycloalkyl)alkyl-, optionally substituted (heteroaryl) alkyl-, optionally substituted cycloalkyl-NR'''-, optionally substituted aryl-NR'''-, optionally substituted heteroaryl-NR'''-, optionally substituted heterocycloalkyl-NR'''-, optionally substituted (cycloalkyl) alkyl-NR'''-, optionally substituted (aryl) alkyl-NR'''-, optionally substituted (heteroaryl) alkyl-NR'''-, optionally substituted (heterocycloalkyl) alkyl-NR'''-, optionally substituted cycloalkyl-S-, optionally substituted aryl-S-, optionally substituted heteroaryl-S-, optionally substituted heterocycloalkyl-S-, optionally substituted (cycloalkyl) alkyl-O-, optionally substituted (aryl) alkyl-O-, optionally substituted (heteroaryl) alkyl-O-, optionally substituted (heterocycloalkyl) alkyl-O-, optionally substituted (cycloalkyl) alkyl-S-, optionally substituted (aryl) alkyl-S-, optionally substituted (heteroaryl) alkyl-S-, optionally substituted (heterocycloalkyl) alkyl-S-; where the optional substituent is R ^z ;

R ² is selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, cyano, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted cycloalkyl-O-, optionally substituted aryl, optionally substituted (aryl)alkyl-, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted (heterocycloalkyl)alkyl-, optionally substituted (heteroaryl)alkyl-, -NR ^a R ^b , -OR ³ and -SR ³ ; wherein the optional substituent is alkyl, alkoxy, halogen, haloalkyl, hydroxyl, hydroxyalkyl, -SH, -S(alkyl), cyano, amide, amino, carboxylic acid, glycine ester, alanine ester, oxo, aryl, cycloalkyl, heterocycloalkyl or heteroaryl;

each R', R'' and R''' is independently selected from hydrogen, deuterium, alkyl, hydroxyl, hydroxyalkyl, acyl or cycloalkyl;

each R ^x , R ^y and R ^z is independently selected from alkyl, alkenyl, alkynyl, halogen, hydroxyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, -SH, -S(alkyl), cyano, amide, carboxylic acid, carboxylate, ester, thioester, alkoxycarbonyl, -C(O)NH(alkyl), oxo, cycloalkyl, cycloalkyl-O-, (cycloalkyl)alkyl-, aryl, (aryl)alkyl-, heterocycloalkyl, heteroaryl, (heterocycloalkyl)alkyl-, (heteroaryl)alkyl-, -NR ^a R ^b , -OR ⁴ and -SR ⁴ ; wherein cycloalkyl, aryl, heteroaryl and heterocycloalkyl are optionally further substituted with one or more substituents selected from halogen, haloalkyl, amino, hydroxyl, alkyl, cyano, nitro, alkenyl, aminoalkyl, hydroxyalkyl or haloalkoxy;

each R ^a and R ^b is independently selected from hydrogen, deuterium, alkyl, aminoalkyl, acyl, amino acyl, halogen, haloalkyl, hydroxyl, haloalkoxy, hydroxyalkyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl-, (heterocycloalkyl)alkyl, (aryl)alkyl-, (heteroaryl)alkyl-; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from alkyl, halogen, alkenyl, cyano, hydroxyl, hydroxyalkyl, alkoxy, amino or nitro; or

R ^a and R ^b together with the N atoms to which they are attached form a 3- to 8-membered optionally substituted ring; and

each R ³ and R ⁴ is independently selected from hydrogen, deuterium, alkyl, aminoacyl, phosphate, phosphonate, alkyl phosphate, alkoxycarbonyl, cycloalkyl, (cycloalkyl)alkyl-, aryl, heteroaryl, heterocycloalkyl, (aryl)alkyl-, (heteroaryl)alkyl-, or (heterocycloalkyl)alkyl-; or,

in some embodiments of the present invention, the RTM has the following structure:

and/or its pharmaceutically acceptable salt or stereoisomer, where in RTM-4, RTM-4a, PTM-4b, RTM-4c, RTM-4a', RTM-4b', RTM-4c' and PTM-4d',

A is optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted (heterocycloalkyl)alkyl, optionally substituted (aryl)alkyl-, optionally substituted (heteroaryl)alkyl-, optionally substituted cycloalkyl-NR ^x -, optionally substituted heterocycloalkyl-NR ^x -, optionally substituted aryl-NR ^x -, optionally substituted heteroaryl-NR ^x -, optionally substituted nicloalkyl-O-, optionally substituted heterocycloalkyl-O-, optionally substituted aryl-O- or optionally substituted heteroaryl-O-; wherein the optional substituent is R ^x ;

B is hydrogen, deuterium, halogen, cyano, optionally substituted alkyl, alkenyl, optionally substituted alkoxy, -NR ^a R ^b , optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted (cycloalkyl)alkyl, optionally substituted (heterocycloalkyl)alkyl, optionally substituted (aryl) alkyl-, optionally substituted (heteroaryl) alkyl-, optionally substituted cycloalkyl-NR ^x -, optionally substituted heterocycloalkyl-NR ^x -, optionally substituted aryl-NR ^x -, optionally substituted heteroaryl-NR ^x -, optionally substituted cycloalkyl-O-, optionally substituted heterocycloalkyl-O-, optionally substituted heteroaryl-O-, optionally substituted aryl-O-; where the optional substituent is R ^y ;

Q is absent or is optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted (heterocycloalkyl)alkyl, optionally substituted (heteroaryl)alkyl, optionally substituted (aryl)alkyl-, optionally substituted (cycloalkyl)alkyl, -NR ³ R ⁴ , -OR ³ or -SR ³ ; wherein the optional substituent is R ^z ;

W represents N or CH;

R ₁ is hydrogen, deuterium, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted (heterocycloalkyl)alkyl, optionally substituted heterocycloalkyl, optionally substituted (aryl)alkyl-, optionally substituted (heteroaryl)alkyl-, optionally substituted alkoxyalkyl, optionally substituted aminoalkyl, or -(CH2) _{mR 2} ; wherein each optional substituent is independently selected from halogen, hydroxyl, alkoxy, amino, nitro, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl;

R ₂ is hydrogen, deuterium, -NR ^a R ^b , alkoxy, hydroxyl, optionally substituted heteroaryl or optionally substituted heterocycloalkyl; wherein the optional substituent is R ^y ;

each _R3 and _R4 is independently selected from optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted (aryl)alkyl-, optionally substituted (cycloalkyl)alkyl, optionally substituted (heteroaryl)alkyl, or optionally substituted (heterocycloalkyl)alkyl; wherein each optional substituent is independently selected from alkyl, halogen, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, nitro, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl-, (heteroaryl)alkyl-, (heterocycloalkyl)alkyl, heteroaryl, and (heteroaryl)alkyl;

each R ^a and R ^b is independently selected from hydrogen, deuterium, alkyl, aminoalkyl, acyl or heterocycloalkyl; or R ^a and R ^b together with the nitrogen atom to which they are attached form an optionally substituted ring;

R ^x is hydrogen, deuterium, alkyl, hydroxyl, hydroxyalkyl, acyl or cycloalkyl;

each R ^y and R ^z is independently selected from hydroxyl, hydroxyalkyl, halogen, alkyl, oxo, haloalkyl, alkoxy, alkenyloxy, amino, nitro, cyano, -SH, -S(alkyl), glycine ester, ester, thioester, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (aryl)alkyl- and (heteroaryl)alkyl; wherein the hydroxyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from alkyl, halogen, alkenyl, amino, nitro, cycloalkyl or (cycloalkyl)alkyl; or

R ^y and R ^z together with the atoms to which they are attached form an alkyl chain of 1-10 carbon atoms; of which 1-3 carbon atoms are optionally substituted with O, NH or S;

m is 1, 2, or 3; and n is 1 or 2; or

in some embodiments of the present invention, the RTM has the following structure:

or its prodrugs, nitrogen oxides, stereoisomers, solvates, pharmaceutically acceptable salts; where in RTM-5, RTM-5a, RTM-5b:

X is selected from O, S or NH;

A is selected from aryl or heteroaryl;

R is independently selected from hydrogen, deuterium, cyano, halogen, hydroxyl, nitro, ^{-NR3R4 ,} optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl; the optional substituent is independently selected from halogen, alkyl, haloalkyl, cyano, ^-NR5NR6 or -C(O) ^{OR7 ;}

R ¹ is independently selected from hydrogen, deuterium, halogen, alkyl, aryl, heterocycloalkyl, (heterocycloalkyl)alkyl-, heteroaryl, -Y-(aryl)alkyl- or -Y-cycloalkyl; cycloalkyl, aryl, heterocycloalkyl, (heterocycloalkyl)alkyl-, heteroaryl or (aryl)alkyl- are optionally substituted with hydroxyl, alkyl, haloalkyl, cyano or halogen;

Y is selected from the bond, -O-, -C(O)- or -NR ⁷ -;

R ² is independently selected from hydrogen, deuterium, carboxyl, cyano, hydroxyl, hydroxyalkyl, alkyl, aryl, heteroaryl, -S(O) ₂ R ⁵ or oxo;

R ³ and R ⁴ are independently selected from hydrogen, deuterium, hydroxyalkyl, aminoalkyl, optionally substituted alkyl, optionally substituted heterocycloalkyl, or optionally substituted aryl; the optional substituent is independently selected from halogen, halogen alkyl, or -C(O)OR ⁷ ;

each R ⁵ and R ⁶ is independently selected from hydrogen, deuterium, alkyl, -C(O)R ⁷ or -C(O)OR ⁷ ;

R ⁷ is selected from hydrogen and alkyl;

and each m, n, and p is independently selected from 1, 2, or 3; or

in some embodiments of the present invention, the RTM has the following structure:

and/or its pharmaceutically acceptable salt or stereoisomer, where in RTM-6, RTM-6a, RTM-6b, RTM-6c:

A is a triazole substituted with 0-2 R or

X represents N or CR ⁷ ;

R is hydrogen, deuterium, R ¹ , halogen, cyano, nitro, -OR ¹ -, -C(O)R ¹ , -C(O)OR ¹ , -C(O)NR ¹¹ R ¹ , -S(O) ₂ R ¹ , -NR ¹¹ C(O)R ¹ , -NR ¹¹ C(O)NR ¹¹ R ¹ , -NR ¹¹ C(O)OR ¹ , -NR ¹¹ S(O) ₂ R ¹ or -NR ¹¹ R ¹ ;

R ¹ is hydrogen, deuterium, 0-4 R ^1a substituted C1-C6 alkyl, C1-C6 haloalkyl, 0-4 R ^1a substituted C2-6 alkenyl, 0-3 R ^1a substituted C2-6 alkynyl, 0-3 R ^1a substituted C3-C10 cycloalkyl, 0-3 R ^1a substituted 6-10-membered aryl, 0-3 R ^1a substituted 5-10-membered heteroaryls containing 1-4 heteroatoms selected from N, O or S, or 0-3 R ^1a substituted 5-10-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S;

R ² is 0-4 R ^2a substituted 6-10 membered aryl, 1-4 R ^2a substituted 5-10 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, or 0-4 R ^2a substituted 5-10 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S;

R ^1a represents hydrogen, deuterium, oxo, F, Cl, Br, OCF ₃ , CN, NO ₂ , -(CH ₂ ) _r OR ^b , -(CH ₂ ) _r SR ^b , -(CH ₂ ) _r C( O)R ^b , -(CH ₂ ) _r C(O)OR ^b , -(CH ₂ ) _r OC(O)R ^b , -(CH ₂ ) _r NR ¹¹ R ¹¹ , -(CH ₂ ) _r C( O)NR ¹¹ R ¹¹ , -(CH ₂ ) _r NR ^b C(O)R ^c , -(CH ₂ ) _r NR ^b C(O)OR ^c , -NR ^b C(O)NR ¹¹ R ¹¹ , - S(O) _p NR ¹¹ R ¹¹ , -NR ^b S(O) _p R ^c , -S(O) ₂ R ^c , -S(O)R ^c , 0-2 R ^a substituted C1-C6 alkyl, C1-C6 haloalkyl, 0-3 R ^a substituted-(CH ₂ ) _r -3-14 membered carbocyclyl or 0-3 R ^a substituted -(CH ₂ ) _r -5-7-membered heterocycloalkyl or heteroaryl, each heterocycloalkyl or heteroaryl containing carbon atoms and 1-4 heteroatoms selected from N, O or S(O) _p ;

R ^2a represents hydrogen, deuterium, oxo, halogen, OCF ₃ , CN, NO ₂ , -(CH ₂ ) _r OR ^b , -(CH ₂ ) _r SR ^b , -(CH ₂ ) _r C(O)R ^b , -(CH ₂ ) _r C(O)OR ^b , -(CH ₂ ) _r OC(O)R ^b , -(CH ₂ ) _r NR ¹¹ R ¹¹ , -(CH ₂ ) _r C(O)NR ¹¹ R ¹¹ , -(CH ₂ ) _r NR ^b C(O)R ^c , -(CH ₂ ) _r NR ^b C(O)OR ^c , -NR ^b C(O)NR ¹¹ R ¹¹ , -S(O) _p NR ¹¹ R ¹¹ , -NR ^b S(O) _p R ^c , -S(O) ₂ R ^c , -S(O)R ^c , 0-2 R ^a substituted C1-C6 alkyl, C1-C6 haloalkyl, 0-1 R ^a substituted -(CH ₂ ) _r -3-14 membered carbocyclyl or 0-2 R ^a substituted -(CH ₂ ) _r -5-7 membered heterocycloalkyl or heteroaryl, each heterocycloalkyl or heteroaryl containing carbon atoms and 1-4 heteroatoms selected from N, O or S(O) _p ;

R ³ is 0-3 R ^3a substituted C1-C6 alkyl, C1-C6 haloalkyl, 0-3 R ^3a substituted C2-6 alkenyl, 0-3 R ^3a substituted C2-6 alkynyl, 0-3 R ^3a substituted C3-C10 cycloalkyl, 0-3 R ^3a substituted 6-10-membered aryl, 0-3 R ^3a substituted 5-10-membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, or 0-3 R ^3a substituted 5-10-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S;

R ^3a represents hydrogen, deuterium, oxo, F, Cl, Br, OCF ₃ , CN, NO ₂ , -(CH ₂ ) _r OR ^b , -(CH ₂ ) _r SR ^b , -(CH ₂ ) _r C( O)R ^b , -(CH ₂ ) _r C(O)OR ^b , -(CH ₂ ) _r OC(O)R ^b , -(CH ₂ ) _r NR ¹¹ R ¹¹ , -(CH ₂ ) _r C( O)NR ¹¹ R ¹¹ , -(CH ₂ ) _r NR ^b C(O)R ^c , -(CH ₂ ) _r NR ^b C(O)OR ^c , -NR ^b C(O)NR ¹¹ R ¹¹ , - S(O) _p NR ¹¹ R ¹¹ , -NR ^b S(O) _p R ^c , -S(O) ₂ R ^c , -S(O)R ^c , 0-2 R ^a substituted C1-C6 alkyl, C1-C6 haloalkyl, 0-3 R ^a substituted-(CH ₂ ) _r -3-14 membered carbocyclyl or 0-3 R ^a substituted -(CH ₂ ) _r -5-7-membered heterocycloalkyl or heteroaryl, each heterocycloalkyl or heteroaryl containing carbon atoms and 1-4 heteroatoms selected from N, O or S(O) _p ;

each R ⁴ and R ⁵ is independently selected from hydrogen, deuterium, 0-1 R ^f substituted C1-C4 alkyl, 0-3 R ^d substituted (CH ₂ )-phenyl, or -(CH ₂ )-5-7-membered heterocycloalkyl containing a carbon atom and heteroatoms selected from N, O, or S(O) _p ;

each R ⁶ and R ⁷ independently represents hydrogen, deuterium, oxo, F, Cl, Br, OCF ₃ , CN, NO ₂ , -(CH ₂ ) _r OR ^b , -(CH ₂ ) _r SR ^b , -(CH ₂ ) _r C(O)R ^b , -(CH ₂ ) _r C(O)OR ^b , -(CH ₂ ) _r OC(O)R ^b , -(CH ₂ ) _r NR ¹¹ R ¹¹ , -(CH ₂ ) _r C(O)NR ¹¹ R ¹¹ , -(CH ₂ ) _r NR ^b C(O)R ^c , -(CH ₂ ) _r NR ^b C(O)OR ^c , -NR ^b C(O)NR ¹¹ R ¹¹ , -S(O) _p NR ¹¹ R ¹¹ , -NR ^b S(O) _p R ^c , -S(O ⁾ _2Rc , -S(O) ^Rc , 0-2Ra ^substituted C1-C6 alkyl, C1-C6 haloalkyl, ^0-3Ra substituted -( _CH2 ) _r -3-14 membered carbocyclyl or ^0-3Ra substituted -( _CH2 ) _r -5-7 membered heterocycloalkyl or heteroaryl, each heterocycloalkyl or heteroaryl containing carbon atoms and 1-4 heteroatoms selected from N, O or S(O) _p , wherein ^R6 and ^R7 are not simultaneously hydrogen;

R ¹¹ is independently hydrogen, deuterium, R ^e , 0-1 R ^f substituted C1-C4 alkyl, 0-3 R ^d substituted CH ₂ -phenyl, or 0-3 R ^d substituted -(CH ₂ )-5-7-membered heterocyclyl containing carbon atoms and 1-4 heteroatoms selected from N, O, or S(O) _p , in various occurrences; or

R ¹¹ and another R ¹¹ on the same nitrogen atom, R ¹ or R ² together form an optionally substituted heterocycloalkyl;

R ^a represents hydrogen, deuterium, F, Cl, Br, OCF ₃ , CF ₃ , CHF ₂ , CN, NO ₂ , -(CH ₂ ) _r OR ^b , -(CH ₂ ) _r SR ^b , -(CH ₂ ) _r C(O)R ^b , -(CH ₂ ) _r C(O)OR ^b , -(CH ₂ ) _r OC(O)R ^b , -(CH ₂ ) _r NR ¹¹ R ¹¹ ; -(CH ₂ ) _r C(O)NR ¹¹ R ¹¹ , -(CH ₂ ) _r NR ^b C(O)R ^c , -(CH ₂ ) _r NR ^b C(O)OR ^c , -NR ^b C(O)NR ¹¹ R ¹¹ , -S(O) _p NR ¹¹ R ¹¹ , -NR ^b S(O) _p R ^c , -S(O) ₂ R ^c , ^c , 0-1 R ^f substituted C1-C6 alkyl, C1-C6 haloalkyl, -(CH ₂ ) _r -3-14 membered carbocyclyl or -(CH ₂ ) _r -5-7 membered heterocyclyl or heteroaryl, each heterocyclyl or heteroaryl contains carbon atoms and 1-4 heteroatoms selected from N, O or S(O) _p ; or two R ^a on adjacent carbon atoms or on the same carbon atom, together with the carbon atom to which they are attached, form a cyclic acetal of the formula -O-(CH ₂ ) _n -O- or -O-CF ₂ -O-, where n is selected from 1 or 2;

R ^b is hydrogen, deuterium, ^Re , 0-2 R ^d substituted C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 0-3 R ^d substituted (CH ₂ ) _r -phenyl;

R ^c is 0-1 R ^f substituted C1-C6 alkyl, C3-C6 cycloalkyl, or 0-3 R ^f substituted (CH ₂ ) _r -phenyl;

R ^d is hydrogen, deuterium, F, Cl, Br, OCF ₃ , CF ₃ , CN, NO ₂ , -OR ^e , -(CH ₂ ) _r C(O)R ^c , -NR ^e R ^e , NR ^e C(O)OR ^c , C1-C6 alkyl, or 0-3 R ^f -substituted (CH ² ) _r -phenyl;

R ^e is selected from hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, or 0-3 R ^f substituted (CH ₂ ) _r -phenyl;

R ^f is hydrogen, deuterium, halogen, NH ₂ , OH, or O(C1-C6 alkyl);

p is 0, 1, or 2;

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

or m is 0, 1, or 2; or

in some embodiments of the present invention, the RTM has the following structure:

or its pharmaceutically acceptable salt; and in RTM-7:

NO is a heteroaryl selected from pyrrolo[2,3-b]pyridyl, pyrrolo[2,3-b]pyrimidinyl, pyrazolo[3,4-b]pyridyl, pyrazolo[3,4-b]pyrimidinyl, imidazo[4,5-b]pyridyl or imidazo[4,5-b]pyrimidinyl, wherein the heteroaryl is bonded to the pyridyl in the compound via a nitrogen atom in the heteroaryl ring, and wherein the heteroaryl is substituted with 0-2 R _b ;

A is pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxadiazolyl or dihydroisoxolyl, each of which is independently substituted by R _a ;

R ₃ is a cyclic group selected from C2-C3 alkyl, C2-C3 fluoroalkyl, C3-C4 hydroxyalkyl, C3-C6 cycloalkyl, oxetane, tetrahydrofuryl, tetrahydropyran or pyrazole, wherein the cyclic group is substituted with 0-2 substituents independently selected from F, -OH, C1-C2 alkyl or -CH ₂ CHF ₂ ;

R _a represents: (i) hydrogen, deuterium, F, Cl, -OH, -CN, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 cyanoalkyl, C1-C6 hydroxyl alkyl, C1-C5 hydroxyl fluoroalkyl, C2-6 alkenyl, C1-C6 aminoalkyl, -(CH ₂ ) _1-3 NHR _y , -(CH ₂ ) _1-3 NHR _y R _y , -CH ₂ CH(OH)(phenyl), -CH ₂ (CH ₂ OH)(phenyl), -CH ₂ CH(OH)CH ₂ (phenyl), -CH ₂ CH(OH)CH ₂ O (methoxyphenyl), -CH ₂ CH(NH ₂ )(phenyl), -(CH ₂ CH ₂ O) ₄ H, -(CH ₂ ) _1-3 O(C1-C3 alkyl), -CH ₂ CH(OH)CH ₂ O(C1-C3 alkyl), -CH ₂ C(O)(C1-C3 alkyl), -CH ₂ C(O)NR _y R _y , -(CH ₂ ) ₁ -3NR _y C(O)(C1-C3 alkyl), -C(O)O(C1-C3 alkyl), -C(O)NH ₂ , -CH ₂ NR _y C(O)NH ₂ , -(CH ₂ ) _1-2 NR _y C(O)O(C1-C2 alkyl), -(CR _y R _y ) _1-5 OC(O)CH ₂ NR _y R _y , -CH ₂ CH ₂ S(O) ₂ CH ₃ , -CH ₂ S(O) ₂ (C1-C3 alkyl), -CH ₂ S(O) ₂ (phenyl) or -NH(aminocyclohexane); or

(ii) -( _CH2 ) _0-3NHRz or -( _CH2 ) _0-1C ( _O ) _Rz , where _Rz is C3-C6 cycloalkyl, azetidinyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrryl, pyrrolidonyl, morpholinyl, pyrrolidinyl, phenyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, dioxopyrimidinyl, benzo[d]imidazolyl, benzo[d]thiazolyl, 1,3-dioxocyclopentyl, _or 8-azabicyclo[3.2.1]octyl, each independently substituted with 0-4 substituents independently selected from the following: F, -OH, -CN, _NRyRy , C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C6 hydroxyalkyl, -CH(phenyl) ₂ , -O(C1-C4 alkyl), -C(O)(C1-C4 alkyl), -C(O)(C1-C4 deuterated alkyl), -C(O)(C1-5 hydroxyalkyl), -C(O))(C1-C3 fluoroalkyl), -C(O)(C3-C6 cycloalkyl), -C(O)O(C1-C4 alkyl), -C(O)NR _y R _y , -C(O)(phenyl), -C(O)(pyridyl), -C(O)CH ₂ (C3-C6 cycloalkyl), -NH(C1-C4 alkyl), -NH(C1-C3 fluoroalkyl), -NHC(O)CH ₃ , -NHC(O)O(C1-C3 alkyl), -NHC(O)O(CH3) ₃ , -S(O) ₂ (C1-C3 alkyl), -OS(O) ₂ (C1-C3 alkyl), methyloxadiazole or pyrimidinyl;

each R _b is independently selected from hydrogen, deuterium, Cl, -CN, -NH ₂ or -C(O)NH ₂ , wherein the heteroaryl is bonded to the pyridyl by a nitrogen atom in the heteroaryl; and

each R _y is independently hydrogen or C1-2 alkyl; or

in some embodiments of the present invention, the RTM has the following structure:

or its pharmaceutically acceptable salt; in RTM-8:

NO is a heteroaryl selected from imidazo[1,2-b]pyridazinyl or pyrazolo[1,5-a]pyrimidinyl, wherein the heteroaryl is linked to the pyridyl in the compound by a carbon atom in the heteroaryl ring, wherein the heteroaryl is substituted with 0-2 R _b ;

A is pyrazolyl, imidazolyl or triazolyl, each of which is substituted with 0-1 R _a ;

R ₃ : (i) -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CHF ₂ , -CH(CH ₃ )CH ₂ OH, oxetanyl, tetrahydrofuryl- or 0-2 F substituted C3-5 cyclopropyl;

(ii) pyrazolyl substituted with 0-2 substituents independently selected from the following: C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 fluoroalkyl, oxetanyl, tetrahydrofuryl or tetrahydropyranyl;

R _a is: (i) F, Cl, -OH, -CN, C1-C6 alkyl, C1-C4 fluoroalkyl, C1-C4 cycloalkyl or C1-C6 hydroxyalkyl; or

(ii) C3-C6 alkyl, azetidinyl, oxetanyl, tetrahydrofuryl-, tetrahydropyranyl, piperidinyl, piperazinyl, pyrryl, pyrrolidonyl, morpholinyl, pyrrolidyl, phenyl, pyrazolyl, imidazolyl, pyridyl or pyrimidinyl, each of which is independently substituted with 0-4 substituents selected from the following: F, -OH, -CN, NR _y R _y , C1-C3 alkyl, fluorinated C1-C3 alkyl, -CH(phenyl) ₂ , -O(C1-C4 alkyl), -C(O)(C1-C4 alkyl), -C(O)(C1-C4 deuterated alkyl), -C(O)(C3-C6 cycloalkyl), -C(O)O(C1-C4 alkyl), -C(O)NR _y R _y , -C(O)(phenyl), -C(O)(pyridyl), -C(O) _CH2 (C3-C6 cycloalkyl), -NHC(O)CH3, -NHC(O) _OCH3 , -NHC(O)O(CH3) ₃ , -S(O) ₂ (C1-C3 alkyl) or -OS(O)2(C1-C3 alkyl);

R _b is selected from F, Cl, -CN, -NH ₂ , -CH ₃ , -OCH ₃ or cyclopropyl;

R _y is hydrogen or C1-C3 alkyl; or

in some embodiments of the present invention, the RTM has the following structure:

or its pharmaceutically acceptable salt; in RTM-9:

NO is a heteroaryl selected from oxazolyl, pyrazolyl, imidazo[1,2-b]pyridazin-3-yl, or pyrazolo[1,5-a]pyrimidin-3-yl, wherein the heteroaryl is attached to the pyridyl moiety of the compound through a carbon atom in the heteroaryl ring, wherein the heteroaryl is substituted with 0-2 R _b ;

each R _b is independently selected from hydrogen, deuterium, F, Cl, -CN, -NH ₂ , C1-C3 alkyl, C1-2 fluoroalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, -NH(C1-C3 alkyl), -NH(C1-C4 hydroxyalkyl), cyanophenyl, pyridyl, or hydroxypyrrolidyl;

R1 is: (i) C3-C6 alkyl substituted with 1-4 substituents independently selected from F, -CN, -OH, _-OCH3 , -OCD3, -NHC(O)(C1-C3 alkyl), -S(O) ₂ (C1-C3 alkyl) or C1-C3 fluoroalkoxy;

(ii) -(CR _y R _y ) ₁ -3R _x or -(CH ₂ ) ₁ -3C(O)R _x , where R _x is phenyl, oxetanyl, tetrahydropyranyl, morpholinyl, piperidinyl, imidazolyl, pyridyl, thienyl or C4-6 cycloalkyl, each of which is substituted with 0-3 substituents independently selected from F, Cl, -OH, C1-C3 alkyl, C1-2 alkoxy or -S(O) ₂ NH ₂ ;

(iii) C4-6 cycloalkyl substituted with 0-2 substituents independently selected from -OH, C1-C4 hydroxyalkyl, C1-C3 alkoxy, -(CH ₂ ) _1-3 O(C1-C3 alkyl), -C(O)NH(C1-C4 alkyl), -C(O)NH(C3-C6 cycloalkyl), -N(C1-C3 alkyl) ₂ , -NHC(O)(C1-C3 alkyl), -NHC(O)O(C1-C3 alkyl) or -NHC(O)(C1-C4 hydroxyalkyl);

(iv) tetrahydrofuryl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl or triazolyl, each of which is substituted with 0-2 substituents independently selected from C1-C4 hydroxyalkyl, -S(O) ₂ (C1-C3 alkyl), _-CH2C (O)NH(C1-C3 alkyl), _-CH2C (O)NH(C1-C6 hydroxyalkyl), _-CH2C (O)NH(C1-C6 fluoroalkyl) or _-CH2C (O)NH(C1-C6 hydroxyl-fluoroalkyl); or

(v) 1-oxa-7-aza spiro[3,5]nonyl;

R _y is independently hydrogen, deuterium, F, or -OH; and R ₃ is: (i) C2-5 alkyl, C2-5 fluoroalkyl, C2-5 hydroxyalkyl, -(CH ₂ ) _{1-3R z} , or -CH(CH ₂ OH)CH ₂ R _z , wherein R _z is C4-6 cycloalkyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, or phenyl, each of which is substituted with 0-1 substituents independently selected from -OH or methyl;

(ii) C3-C6 cycloalkyl substituted with 0-3 substituents independently selected from F, Cl, -CN, -OH, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, -C(O)NH ₂ , -C(O)NH(C1-C3 alkyl) or -C(O)NH(C1-C3 fluoroalkyl);

(iii) oxetanyl, tetrahydrofuryl, tetrahydropyranyl, pyrrolidyl, piperidinyl, pyrazolyl, thiazolyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl or 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, each of which is substituted with 0-2 substituents independently selected from F, -OH, C1-C4 alkyl, C1-C3 hydroxyalkyl, C1-C4 fluoroalkyl, -CH ₂ (C3-C6 cycloalkyl), -(CH ₂ ) _1-3 (C1-C3 alkyl), -C(O)(C1-C3 fluoroalkyl), -S(O) ₂ (C1-C3 alkyl), C3-C6 cycloalkyl, C3-C6 fluorocycloalkyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, pyrimidinyl, fluoropyrimidinyl or methoxypyrimidinyl; or

(iv) phenyl substituted with 0-3 substituents independently selected from F, Cl, -CN, -OH, -C(O)NH ₂ , -C(O)NH(C1-C3 alkyl) or -C(O)NH (C1-C3 fluoroalkyl); or

in some embodiments of the present invention, the RTM has the following structure:

or its pharmaceutically acceptable salt or prodrug; and in RTM-10:

X represents CR ₄ or N;

Y is CR ₅ or N; provided that only one of X and Y is N;

R ₁ is

each R _1a , R _1b and R _1c independently represents hydrogen, deuterium, -OH, F, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, C1-C3 fluoroalkoxy or C3-C6 cycloalkyl; or two R _1a together with the carbon atoms to which they are attached may form a 3- to 4-membered spiro-cycloalkyl ring; or

R _1a and R _1b together with the carbon atoms to which they are attached may form a 3- to 4-membered cycloalkyl ring;

R _1a and R _1c together with the carbon atoms to which they are attached may form a 3- to 4-membered cycloalkyl ring;

R ₂ is hydrogen, deuterium, halogen, C1-C3 alkyl or C3-C6 cycloalkyl;

R ₃ is C1-C4 alkoxy, C1-C4 fluoroalkyl or C3-C6 cycloalkyl;

each R ₄ and R ₅ independently represents hydrogen, deuterium, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or C3-C6 cycloalkyl; or

in some embodiments of the present invention, the RTM has the following structure:

or a pharmaceutically acceptable salt thereof; wherein in RTM-11, RTM-11':

X represents N or CH;

m is equal to 1 or 2;

Ar is optionally substituted aryl or optionally substituted heteroaryl;

R ₁ is hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, hydroxyl-C1-C6 alkyl, C1-C6 alkyl-amino, amino-C1-C6 alkyl, amino-C1-C6 alkylamino, hydroxyl-C1-C6-alkyl amino, C3-C6 cycloalkylamino, amino-C3-C6-cycloalkylamino, amino-C3-C6-heterocycloalkylamino, aminocarbonyl, halogen or hydroxy-C1-C6-alkoxy; and

R ₂ is hydrogen or C1-C6 alkyl; or,

in some embodiments of the present invention, the RTM has the following structure:

or a stereoisomer or pharmaceutically acceptable salt thereof; wherein in RTM-12 or RTM-12':

R ¹ represents hydrogen or halogen;

R ³ is hydrogen, deuterium, halogen, -CN, -OH, C1-C3 alkyl, C2-3 alkenyl, C3-7 cycloalkyl, C1-C3 alkyl acyl, -(C0-3 alkyl) C(O)NR ⁶ R ⁷ , -(C2-3 alkenyl) C(O)NR ⁶ R ⁷ , -S(O) _1-2 NR ⁶ R ⁷ , -NR ⁸ R ⁹ , -OC1-C3 alkyl, 3- to 7-membered monocyclic saturated or partially saturated heterocycloalkyl, 5- to 6-membered monocyclic heteroaryl or 5- to 6-membered monocyclic aryl; wherein the alkyl, alkylacyl or alkenyl are optionally substituted with halogen, oxo, -CN, -OH, C1-C3 alkoxy or C1-C3 haloalkoxy; and each cycloalkyl, heterocycloalkyl, heteroaryl or aryl is independently optionally substituted with halogen, oxo, -CN, -OH, C1-C3 alkyl or C1-C3 haloalkyl;

R ₄ is hydrogen, deuterium, halogen, C1-C3 alkyl, C2-3 alkenyl, -(C0-3 alkyl) C(O)R ¹³ , -(C2-3 alkenyl) C(O)NR ¹⁰ R ¹¹ , -S(O) _1-2 NR ¹⁰ R ¹¹ , 3-7-membered monocyclic saturated or partially saturated heterocycloalkyl, -(C0-3 alkyl) C(O)NR ¹⁰ R ¹¹ , -C(O)NR ⁸ R ⁹ or -NR ⁸ R ⁹ ; wherein each alkyl, heterocycloalkyl or alkenyl is independently optionally substituted with halogen, oxo, -CN, -OH, C1-C3 alkoxy, C1-C3 haloalkoxy or optionally oxo-substituted 3-7 monocyclic saturated or partially saturated heterocycloalkyl ring;

R ⁵ is hydrogen, deuterium, -CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -O(C3-7 cycloalkyl), -O(C1-C3 alkyl)-3- to 8-membered cycloalkyl, -O(C0-3 alkyl)-3- to 8-membered saturated or partially unsaturated heterocycloalkyl, -O(C1-C3 alkyl) phenyl, -O(C1-C3 alkyl)-5- to 6-membered heteroaryl, 3- to 11-membered saturated or partially saturated heterocycloalkyl or 5- to 6-membered monocyclic heteroaryl; wherein each alkyl or alkoxy is independently optionally substituted with halogen, oxo, -CN, -OH, C3-7 cycloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or 3-11 membered saturated or partially saturated heterocycloalkyl optionally substituted with halogen, optionally substituted with -C(O)(C1-C3 alkyl) or C1-C3 alkyl; and cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is optionally substituted with halogen, oxo, -CN, -OH, C1-C6 alkoxy, -NR ⁸ R ⁹ , -C(O)C1-C3 alkyl), -(C0-3 alkyl) C(O)NR ¹⁰ R ¹¹ , -S(O) _1-2 NR ⁸ R ⁹ , -OP(O)(OC1-C3 alkyl) ₂ , C3-C10 cycloalkyl optionally substituted with -OH or halogen, 3-11-membered saturated or partially saturated heterocycloalkyl optionally substituted with oxo or C1-C3 alkyl, 5-6-membered monocyclic heteroaryl optionally substituted with halogen, oxo, -CN, -OH, C1-C3 alkyl or C1-C3 haloalkyl, or optionally substituted with halogen, oxo, -CN, -OH, -O(C1-C3 alkyl), -S(C1-C3 alkyl), -S(O) ₂ (C1-C3 alkyl), ^-NR8R9 , -C(O) ^NR8R9 , ^phenyl , C3 ^- C10 cycloalkyl, a saturated or partially saturated 3-11 membered heterocycloalkyl ring optionally substituted with oxo or C1-C3 alkyl, or C1-C4 alkyl substituted by a 5-6 membered monocyclic heteroaryl optionally substituted with oxo, halogen or C1-C3 alkyl;

A is a 3- to 11-membered heterocycloalkyl optionally substituted with halogen, oxo, -CN, -OH, C1-C6 alkyl, -(C0-3 alkyl)-C3-C6 cycloalkyl, -(C0-3 alkyl)-3-11-membered heterocycloalkyl, -NR ⁸ R ⁹ , -NR ¹² C(O)R ¹³ , -NR ¹² S(O) _1-2 R ¹³ , -C(O)(C1-C3 alkyl), -C(O)NR ¹⁰ R ¹¹ , -C(O)OR ¹³ , -S(O) _1-2 NR ¹⁰ R ¹¹ or -(C0-3 alkyl)-OR(O)(OC1-C3 alkyl) ₂ ; each alkyl, cycloalkyl or heterocycloalkyl is independently optionally substituted with halogen, oxo, -CN, -OR ¹³ , C1-C3 alkoxy, C1-C3 haloalkoxy, -C(O)(C1-C3 alkyl), -S(C1-C3 alkyl), or substituted C1-C3 alkyl optionally substituted with -OH, halogen, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or 3- to 8-membered heterocycloalkyl;

when A is a 5-membered azacycloalkyl, the nitrogen heteroatom is substituted;

R ⁶ and R ⁷ are independently hydrogen, deuterium, C1-C3 alkyl, or C3-C6 cycloalkyl, in each occurrence; wherein each alkyl or cycloalkyl is independently optionally substituted with halogen, oxo, -CN, -OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C1-C3 haloalkoxy;

each R ⁸ , R ⁹ , R ¹⁰ , or R ¹¹ is independently hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, -(C0-3 alkyl)phenyl, 3-11-membered saturated heterocycloalkyl, 5-6-membered monocyclic heteroaryl, -C(O)R ¹³ , -C(O)OR ¹³ , -S(O) _1-2 R ¹³ , or -C(O)NR ⁶ NR ⁷ , in each occurrence; or R ¹¹ and R ^10, together with the atoms to which they are attached, form a 5-8-membered heterocycloalkyl; wherein each alkyl, cycloalkyl, phenyl, heterocycloalkyl is independently optionally substituted with halogen, oxo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -OR ¹³ , -NR ⁶ NR ⁷ or 5-8-membered heteroaryl;

R ¹² is independently hydrogen, deuterium, C1-C6 alkyl or C3-C6 cycloalkyl, in each occurrence; each alkyl or cycloalkyl is independently optionally substituted with halogen, oxo, -CN, -OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy; and

R ¹³ is independently hydrogen, deuterium, C1-C6 alkyl or C3-C10 cycloalkyl, or a 3-11 membered saturated heterocycloalkyl, in each occurrence; wherein each alkyl, cycloalkyl or heterocycloalkyl is independently optionally substituted with halogen, oxo, -CN, -OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -OR ¹² or -NR ⁶ NR ⁷ ;

R16 is hydrogen, deuterium, halogen, -CN or C1-C3 alkyl optionally substituted with -NH ₂ , halogen or -CN; or

in some embodiments of the present invention, the RTM has the following structure:

or its stereoisomer or pharmaceutically acceptable salt; wherein in RTM-13:

R ₁ is C1-C6 alkoxy, oxetanyl, -NR _x R _y or 6-membered heteroaryl optionally substituted with R _z ;

R ₂ is hydrogen, deuterium, oxo, -CN, -OH, C1-C6 alkyl, -(C0-3 alkyl)-C3-C6 cycloalkyl, -(C0-3 alkyl)-3-11-membered heterocycloalkyl, -NR _a R _b , -NR _e C(O)R _f , -NR _e S(O) _1-2 R _f , -C(O)(C1-C3 alkyl), -C(O)NR _c R _d , -C(O)OR _f , -S(O) _1-2 R _c R _d , -(C0-3 alkyl)-OR(O)(OC1-C3 alkyl) ₂ ; each alkyl, cycloalkyl or heterocycloalkyl is independently optionally substituted with halogen, oxo, -CN, -OR _f , C1-C3 haloalkoxy, -C(O)(C1-C3 alkyl), -S(C1-C3 alkyl), or C1-C3 alkyl optionally substituted with -OH, halogen, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or 3- to 8-membered heterocycloalkyl;

ring A is a 5-membered or 6-membered heteroaryl, 6-membered saturated or partially saturated heterocycloalkyl and 9-membered bicyclic heteroaryl containing at least two heteroatoms selected from N, O or S; ring A is optionally substituted with R _m provided that ring A does not contain an optionally substituted 9-membered bicyclic heteroaryl of the following structure:

each R _a , R _b , R _c and R _d is independently hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, -(C0-3 alkyl)phenyl, 3-11-membered saturated heterocycloalkyl, 5-6-membered monocyclic heteroaryl, -C(O)R _f , -C(O)NR _g R _h , -C(O)OR _f or -S(O) _1-2 R _f , or R _c and R _d together with the atoms attached thereto form a 5-8-membered heterocycloalkyl; each alkyl, cycloalkyl, phenyl, heterocycloalkyl or heteroaryl is independently optionally substituted with halogen, oxo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -OR _f , C1-C3 haloalkoxy, -NR _g R _h or 5-6-membered monocyclic heteroaryl;

R _f is hydrogen, deuterium, C1-C6 alkyl or C3-C6 cycloalkyl; each alkyl or cycloalkyl is independently optionally substituted with halogen, oxo, -CN, -OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy;

R _f is hydrogen, deuterium, C1-6 alkyl, C3-C10 cycloalkyl or 3-11 membered saturated heterocycloalkyl; each alkyl, cycloalkyl or heterocycloalkyl is independently optionally substituted with halogen, oxo, -CN, -OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy, -OR _e or -NR _g R _h ;

each R _g and R _h is independently selected from hydrogen, deuterium, C1-C6 alkyl or C3-C6 cycloalkyl; each alkyl or cycloalkyl is independently optionally substituted with halogen, oxo, -CN, -OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy;

R _m is selected from halogen, oxo, -CN, -ORv, -S(O) _{1-2R v} , -OH, C1-C6 alkoxy, -NR _n R _p , -C(O)(C1-C3 alkyl), -(C0-3 alkyl) C(O)NR _r R _s , -S(O) _{1-2NR n} R _p , -OP(O)(OC1-C3 alkyl), C3-C10 cycloalkyl optionally substituted with -OH or halogen, saturated or partially saturated 3-11-membered heterocycloalkyl optionally substituted with halogen, oxo, -CN, -OH, C1-C4 alkoxy, -NR _n R _p , or C1-C4 alkyl optionally substituted with halogen or -OH, C1-C4 alkyl substituted with 3-11-membered saturated or partially saturated heterocycloalkyl substituted with 5-6-membered monocyclic heteroaryl optionally substituted with halogen, oxo, -CN, -OH, -O(C1-C3 alkyl), -S(C1-C3 alkyl), -S(O _{) 2} (C1-C3 alkyl), _-NRnRp , -C(O) _NRnRp , phenyl, C3-C10 cycloalkyl optionally substituted with _oxo , C1-C3 alkyl or optionally substituted with oxo, halogen or C1-C3 alkyl;

each R _n , R _p , R _r and R _s is independently selected from hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, -(C0-3 alkyl)phenyl, 3-11-membered saturated heterocycloalkyl, 5-6-membered monocyclic heteroaryl, -C(O)R _v , -C(O)OR _v , -C(O))NR _{t Ru} or -S(O) _1-2 R _v ; or R _r and R _s together with the atom to which they are attached form a heterocycloalkyl; each alkyl, cycloalkyl, phenyl, heterocycloalkyl or heteroaryl is independently optionally substituted with halogen, oxo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -OR _v , -NR _{t Ru} or 5-6-membered monocyclic heteroaryl;

each R _t and R _u is independently selected from hydrogen, deuterium, C1-C3 alkyl, C3-C6 cycloalkyl; each alkyl or cycloalkyl is independently optionally substituted with a substituent selected from halogen, oxo, -CN, -OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy;

R ^v is hydrogen, deuterium, C1-C3 alkyl, C3-C10 cycloalkyl or 3-11 membered saturated heterocycloalkyl; each alkyl, cycloalkyl or heterocycloalkyl is independently optionally substituted with halogen, oxo, -CN, -OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -OR _w or -NR _t R _u ;

R _w is selected from hydrogen, deuterium, C1-C6 alkyl and C3-C6 cycloalkyl; each alkyl or cycloalkyl is independently optionally substituted with halogen, oxo, -OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy;

each R _x and R _y is independently selected from C1-C6 alkyl; or R _x and R _y together with the atoms attached thereto form a 6-membered heterocycloalkyl optionally substituted with R _z ;

R _z represents halogen, oxo, -CN, -S(O) _1-2 R _v , -OH, C1-C6 alkoxy, -NR _n R _p , -C(O)(C1-C3 alkyl), -( C0-3 alkyl) C(O)NR _r R _s , -S(O) _1-2 NR _n R _p , -OP(O)(OC1-C3 alkyl) ₂ , C3-C10 cycloalkyl, optionally substituted with -OH or halogen, 3-11 membered saturated or partially saturated heterocycloalkyl, optionally substituted with oxo or C1-C3 alkyl, 5-6 membered monocyclic heteroaryl, optionally substituted with halogen, oxo, -CN, - OH, C1-C4 alkyl, -NR _n R _p , or C1-C4 alkyl, optionally substituted halogen or -OH, or C1-C4 alkyl, substituted with 3-11-membered saturated or partially saturated heterocycloalkyl, substituted 5-6-membered monocyclic heteroaryl, optionally substituted with halogen, oxo, -CN, -OH, -O(C1-C3 alkyl), -S(C1-C3 alkyl), -S(O) ₂ (C1-C3 alkyl), -NR _n R _p , -C(O)NR _n R _p , phenyl, C3-C10 cycloalkyl, optionally substituted with oxo, C1-C3 alkyl or optionally substituted with oxo, halogen or C1-C3 alkyl; or

in some embodiments of the present invention, the RTM has the following structure:

or its stereoisomer or pharmaceutically acceptable salt; wherein in RTM-14:

R ¹ is C1-C6 alkoxy, oxetanyl, -NR ^a R ^b or 6-membered heteroaryl optionally substituted with R ^c ;

R ² is methyl, hydroxymethyl or 2-hydroxypropyl-2-yl;

R ³ is methyl; or

R ² and R ³ together with the attached carbon atom form a 6-membered heterocycloalkyl optionally substituted with C1-C3 alkyl;

ring A is a 5-membered or 6-membered heteroaryl, 6-membered saturated or partially saturated heterocycloalkyl and 9-membered bicyclic heteroaryl containing at least two heteroatoms selected from N, O or S; ring A is optionally substituted with R ^d , provided that ring A does not contain an optionally substituted 9-membered bicyclic heteroaryl of the following structure:

each R ^a and R ^b is independently C1-C6 alkyl; or R ^a and R ^b, together with the atoms to which they are attached, form a 6-membered heterocycloalkyl optionally substituted with R ^c ;

R ^c is selected from halogen, oxo, -CN, -S(O) _{1-2R n} , -OH, C1-C6 alkoxy, -NR _e R _f , C(O)(C1-C3 alkyl), -(C0-3 alkyl)C(O)NR _g R _f , -S(O) _{1-2NR e} R _f , -OP(O)(OC1-C3 alkyl)2, C3-C10 cycloalkyl optionally substituted with -OH or halogen, 3-11-membered saturated or partially saturated heterocycloalkyl optionally substituted with oxo or C1-C3 alkyl; 5-6-membered monocyclic heteroaryl substituted with oxygen, halogen, -CN, -OH, C1-C4 alkoxy, -NR ^e R ^f , or C1-C4 alkyl optionally substituted with halogen or -OH; 3-11 saturated or partially saturated 3-11 membered heterocycloalkyl, optionally substituted with halogen, oxo, -CN, -OH, -O(C1-C3 alkyl), -S(C1-C3 alkyl), -S(O) ₂ (C1-C3 alkyl), -NR ^e R ^f , -C(O)NR ^e R ^f , phenyl, C3-C10 cycloalkyl, optionally substituted with oxo, C1-C3 alkyl, or 5-6 membered monocyclic heteroaryl, optionally substituted with oxo, halogen, C1-C3 alkyl;

R ^d is halogen, oxo, -CN, -OR ⁿ , -S(O) ₂ R ⁿ , -OH, C1-C6 alkoxy, -NR ^e R ^f , C(O)(C1-C3 alkyl), -(C0-3 alkyl) C(O)NR ^g R ^f , -S(O) _1-2 NR ^e R ^f , -OR(O)(OC1-C3 alkyl) ₂ , C3-C10 cycloalkyl optionally substituted with -OH or halogen, 3-11-membered saturated or partially saturated heterocycloalkyl optionally substituted with oxo or C1-C3 alkyl; 5-6 membered monocyclic heteroaryl substituted with oxo, halogen, -CN, -OH, C1-C4 alkoxy, -NR ^e R ^f , or C1-C4 alkyl, optionally substituted with halogen or -OH; 3-11 saturated or partially saturated 3-11 membered heterocycloalkyl, optionally substituted with halogen, oxo, -CN, -OH, -O(C1-C3 alkyl), -S(C1-C3 alkyl), -S(O) ₂ (C1-C3 alkyl), -NR ^e R ^f , -C(O)NR ^e R ^f , phenyl, C3-C10 cycloalkyl, optionally substituted with oxo or C1-C3 alkyl, or 5-6 membered monocyclic heteroaryl, optionally substituted with oxo, halogen or C1-C3 alkyl;

each R ^e , R ^f , R ^g and ^Rh is independently selected from hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, -(C0-3 alkyl)phenyl, 3-11-membered saturated heterocycloalkyl, 5-6-membered monocyclic heteroaryl, -C(O)R ⁿ , -C(O)OR ⁿ , -C(O)NR ^k R ^m , -S(O) _1-2 R ⁿ , or R ^g and ^Rh together with the atoms attached thereto form a 5-8-membered heterocycloalkyl; each alkyl, cycloalkyl, phenyl, heterocycloalkyl or heteroaryl is independently optionally substituted with halogen, oxo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -ORn, -NRkRm or 5-6-membered monocyclic heteroaryl;

each R ^k and R ^m is independently selected from hydrogen, deuterium, C1-C3 alkyl or C3-C6 cycloalkyl; each alkyl or cycloalkyl is independently optionally substituted with halogen, oxo, -CN, -OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy;

R ⁿ is selected from hydrogen, deuterium, C1-C6 alkyl, C3-C10 cycloalkyl or 3-11 saturated heterocycloalkyl; each alkyl, cycloalkyl or heterocycloalkyl is independently optionally substituted with halogen, oxo, -CN, -OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogenated C1-C3 alkoxy, -OR ^p or -NR ^g R ^h ;

R ^p is selected from hydrogen, deuterium, C1-C6 alkyl or C3-C6 cycloalkyl; each alkyl or cycloalkyl is independently optionally substituted with halogen, oxo, -CN, OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy; or

in some embodiments of the present invention, the RTM has the following structure:

or a stereoisomer or pharmaceutically acceptable salt thereof; wherein in RTM-15, RTM-15a, RTM-15b, RTM-15c, PTM-15d, RTM-15e, PTM-15f, PTM-15g or RTM-15h

A ¹ is CH ₂ or NH;

R ¹ represents hydrogen or halogen;

R ³ is hydrogen, deuterium, halogen, CN, OH, C1-C3 alkyl, C2-3 alkenyl, C3-7 cycloalkyl, C1-C3 alkyl acyl, -(C0-3 alkyl) C(O)NR ⁶ R ⁷ , -(C2-3-alkenyl) C(O)NR ⁶ R ⁷ , -S(O) _1-2 NR ⁶ R ⁷ , -NR ⁸ R ⁹ , -OC1-C3 alkyl, 3-7-membered monocyclic saturated or partially saturated heterocycloalkyl, 5-6-membered monocyclic heteroaryl ring or 5-6-membered monocyclic aryl; each alkyl, alkylacyl or alkenyl is independently optionally substituted with substituents selected from halogen, oxo, CN, OH, C1-C3 alkoxy or C1-C3 haloalkoxy; and each cycloalkyl, heterocycloalkyl, heteroaryl or aryl is independently optionally substituted with substituents selected from halogen, oxo, CN, OH, C1-C3 alkyl or C1-C3 haloalkyl;

R ⁴ is hydrogen, deuterium, halogen, C1-C3 alkyl, C2-3 alkenyl, -(C0-3 alkyl)C(O)R ¹³ , -(C2-3 alkenyl)C(O)NR ¹⁰ R ¹¹ , -S(O) _1-2 NR ¹⁰ R ¹¹ , 3-7 membered monocyclic saturated or partially saturated heterocycloalkyl, -C(O)NR ⁸ R ⁹ or -NR ⁸ R ⁹ , each alkyl, alkenyl or heterocycloalkyl independently optionally substituted with substituents selected from halogen, oxo, CN, OH, C1-C3 alkoxy, C1-C3 haloalkoxy, or an optionally oxo-substituted 3-7 membered monocyclic saturated or partially saturated heterocycloalkyl;

R ⁵ is hydrogen, deuterium, -CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -O(C3-7 cycloalkyl), -O(C1-C3 alkyl)-3-8-membered cycloalkyl, -O(C0-3 alkyl)-3-8-membered saturated or partially saturated heterocycloalkyl, -O(C1-C3 alkyl)-phenyl, -O(C1-C3 alkyl)-5-6-membered heteroaryl ring, a 3-11-membered saturated or partially saturated heterocycloalkyl or a 5-6-membered monocyclic heteroaryl ring, each alkyl and alkoxy independently optionally substituted with substituents selected from halogen, oxo, CN, OH, C1-C3 alkoxy, C1-C3 haloalkoxy, or 3-11-membered saturated or partially saturated heterocycloalkyl optionally substituted by the following substituents: (i) -C(O)(C1-C3 alkyl) optionally substituted by halogen, (ii) C1-C3 alkyl optionally substituted by halogen and cycloalkyl, heterocycloalkyl, phenyl or heteroaryl optionally substituted by the following groups: halogen, oxo, CN, OH, C1-C6 alkoxy, -NR ⁸ R ⁹ , -C(O)(C1-C3 alkyl), -(Co-3 alkyl) C(O)NR ¹⁰ R ¹¹ , -S(O)1-2NR ⁸ R ⁹ , -OP(O)(OC1-C3 alkyl) ₂ , C3-C10 cycloalkyl optionally substituted by OH or halogen, 3-11-membered saturated or partially saturated heterocycloalkyl optionally substituted with oxo or C1-C3 alkyl, 5-6-monocyclic heteroaryl optionally substituted with halogen, oxo, CN, OH, C1-C3 alkyl or C1-C3 haloalkyl, or C1-C4 alkyl optionally substituted with the following groups: halogen, oxo, CN, OH, -OC1-C3 alkyl, -SC1-C3 alkyl, -SO ₂ C1-C3 alkyl, -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , phenyl, C3-C10 cycloalkyl, 3-11-membered saturated or partially saturated heterocycloalkyl optionally substituted with oxo or C1-C3 alkyl, or 5-6-membered monocyclic heteroaryl optionally substituted with oxo, halogen or C1-C3 alkyl;

A is a 3-11-membered heterocycloalkyl optionally substituted with the following substituents: halogen, oxo, CN, OH, C1-C6 alkyl, -(C0-3 alkyl)-C3-C6 cycloalkyl, -(C0-3 alkyl)-3-11-membered heterocycloalkyl, -NR ⁸ R ⁹ , -NR ¹² C(O)R ¹³ , -NR ¹² S(O) _1-2 R ¹³ , -C(O)(C1-C3 alkyl), -C(O)NR ¹⁰ R ¹¹ , -C(O)OR ¹³ , - S(O) _1-2 NR ¹⁰ R ¹¹ or -(C0-3 alkyl)-OP(O)(OC1-C3 alkyl) ₂ , wherein each alkyl, cycloalkyl or heterocycloalkyl is independently optionally substituted with the following substituents: halogen, oxo, CN, OR ¹³ , C1-C3 haloalkoxy, -C(O)(C1-C3 alkyl), -SC1-C3 alkyl, or C1-C3 alkyl optionally substituted with the following substituents: OH, halogen, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or 3- to 8-membered heterocycloalkyl, and wherein when A is a 5-membered nitrogen-containing heterocycloalkyl, the nitrogen atom is substituted;

R ⁶ and R ⁷ are independently hydrogen, deuterium, C1-C3 alkyl or C3-C6 cycloalkyl, in each occurrence; wherein each alkyl or cycloalkyl is independently optionally substituted with the following substituents: halogen, oxo, -CN, -OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy;

R ⁸ , R ⁹ , R ¹⁰ or R ¹¹ are independently hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, -(C0-3 alkyl)phenyl, 3-11-membered saturated heterocycloalkyl, 5-6-membered monocyclic heteroaryl, -C(O)R ¹³ , -C(O)OR ¹³ , -C(O)NR ⁶ R ⁷ or -S(O) _1-2 R ¹³ , in each occurrence; or R ¹⁰ and R ¹¹ together form a 5-8-membered heterocycloalkyl, wherein the alkyl, cycloalkyl, phenyl, heterocycloalkyl or heteroaryl ring is each independently optionally substituted with the following substituents: halogen, oxo, CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -OR ¹³ , -NR ⁶ R ⁷ or a 5-6-membered monocyclic heteroaryl;

R ¹² is independently hydrogen, deuterium, C1-C6 alkyl or C3-C6 cycloalkyl, in each occurrence; each alkyl or cycloalkyl is independently optionally substituted with the following substituents: halogen, oxo, -CN, -OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy;

R ¹³ is independently hydrogen, deuterium, C1-C6 alkyl or C3-C10 cycloalkyl, or a 3-11 membered saturated heterocycloalkyl, in each occurrence; wherein each alkyl, cycloalkyl or heterocycloalkyl is independently optionally substituted with the following substituents: halogen, oxo, -CN, -OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -OR ¹² or -NR ⁶ NR ⁷ ; and

R ¹⁶ is hydrogen, deuterium, halogen, CN or C1-C3 alkyl optionally substituted with -NH ₂ , halogen or CN; or

in some embodiments of the present invention, the RTM has the following structure:

or a stereoisomer or pharmaceutically acceptable salt thereof; wherein in RTM-16, RTM-16a, RTM-16b, RTM-16c, PTM-16d, RTM-16e or PTM-16f:

each X, X', Y and Y' independently represents CH or N; Z represents C or N; provided that no more than three of X, X', Z, Y and Y' represent N;

R ¹ is C1-C6 alkyl or -(C1-C6 alkyl) _n -(C1-C6 cycloalkyl), wherein the alkyl or cycloalkyl is optionally substituted with deuterium, halogen, CN, OH or C1-C6 alkoxy;

R ² is hydrogen, methyl or optionally substituted cycloalkyl;

R ³ is hydrogen, deuterium, deuterium, halogen, nitrile, -(CH ₂ ) _t NR ^8a R ^8b , -(CH ₂ ) _t (6-10 membered aryl) or -(CH2) _t (5-10 membered heteroaryl) containing from 1 to 3 heteroatoms selected from N, O or S, wherein the aryl or heteroaryl is optionally substituted with from 1 to 3 of C1-C6 alkyl, deuterium, halogen, CN, OH, hydroxyl, C1-C6 alkyl or C1-C6 alkoxy, wherein the alkyl is optionally substituted with hydroxyl, halogen, CN or C1-C3 alkoxy;

each R ^4a and R ^4b independently represents hydrogen, deuterium, fluoro, OH, C1-C3 alkoxy or CH ₂ OR ⁷ , wherein R ⁷ together with R ¹ represents C1-C4 alkylene, and the C1-C4 alkylene is optionally substituted with halogen or alkyl;

each R ^5a and R ^5b independently represents hydrogen, deuterium, C1-C3 alkyl or C1-C3 alkoxy, the alkyl or alkoxy being optionally substituted with 1 to 3 of deuterium, halogen, OH or CN; or R ^5a and R ^5b, together with the atoms to which they are bonded, form a C3-C7 cycloalkyl or C3-C7 heterocycloalkyl, the cycloalkyl or heterocycloalkyl being optionally substituted with 1 to 3 of deuterium, halogen, OH, CN or C1-C3 alkyl;

R ⁶ is hydrogen or C1-C3 alkyl; or R ^5b and R ⁶ together with the atoms to which they are attached form C3-C7 cycloalkyl or C3-C7 heterocycloalkyl, the cycloalkyl or heterocycloalkyl being optionally substituted with 1 to 3 of deuterium, halogen, OH, CN or C1-C3 alkyl;

each R ^8a and R ^8b independently represents hydrogen, deuterium, -S(O) ₂ R ⁹ or -C(O)R ⁹ ;

R ⁹ is C1-C6 alkyl, C1-C6 cycloalkyl, 6-10-membered aryl or 5-10-membered heteroaryl containing from 1 to 3 heteroatoms, wherein the alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted with C1-C6 alkyl, halogen, CN, OH, C1-C6 alkoxy or C1-C6 hydroxyl in an amount of from 1 to 3;

n is 0 or 1;

t is 0, 1, 2, or 3; or

in some embodiments of the present invention, the RTM has the following structure:

or a stereoisomer or pharmaceutically acceptable salt thereof; wherein in RTM-17, RTM-17a, RTM-17b, RTM-17c, PTM-17d, RTM-17e or PTM-17f:

R ₁ is hydrogen or C1-C4 alkyl, wherein the alkyl is further optionally substituted with one or more substituents selected from halogen, hydroxyl, methoxy, amino, CF ₃ or C3-C6 cycloalkyl;

each R ² and R ³ is independently hydrogen, deuterium, deuterium, C1-C6 linear or branched alkyl, C3-C6 cycloalkyl, C1-C6 linear or branched perfluoroalkyl, C1-C6 linear or branched alkoxy, C1-C6 linear or branched perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxyl, aminocarbonyl, aryl, heteroaryl, (aryl) C1-C6 linear or branched alkyl, (heteroaryl) C1-C6 linear or branched alkyl, (heterocycloalkyl) C1-C6 linear or branched alkyl, (C1-C6 linear or branched alkyl) aryl, (C1-C6 linear or branched alkyl) heteroaryl, (C1-C6 linear or branched alkyl) heterocycloalkyl, (C1-C6 linear or branched alkoxy) carbonyl, (C1-C6 linear or branched alkyl) aminocarbonyl amino or (C1-C6 linear or branched alkyl) aminocarbonyl;

R ⁴ is selected from hydrogen, deuterium, deuterium, C1-C6 linear or branched alkyl, C1-C6 linear or branched perfluoroalkyl, aryl or alkaryl;

X is selected from -NH- or -CR _a R _b -, wherein (a) R _a and R _b are independently hydrogen, deuterium, deuterium, C1-C6 linear or branched alkyl, C3-C6 cycloalkyl, aryl, (aryl) C1-C6 linear or branched alkyl, heteroaryl, (C1-C6 linear or branched alkyl) heteroaryl, (heteroaryl) C1-C6 linear or branched alkyl, (heterocyclyl) C1-C6 linear or branched alkyl, or (b) R _a and R _b together form a chain comprising -(CR _c R _d ) _j -, wherein R _c and R _d are independently hydrogen, deuterium, deuterium, C1-C6 linear or branched alkyl, aryl, (C1-C6 linear or branched alkyl) aryl, heteroaryl, (C1-C6 linear or branched alkyl) heteroaryl, halogen, CN, CF ₃ , hydroxyl, CONH ₂ or SO ₂ CH ₃ ;

Y is -AR ⁵ ; wherein A is a bond, -(CH ₂ ) _k - or -(CD ₂ ) _k -; R ⁵ is C1-C6 linear or branched alkyl, C3-C6 cycloalkyl, aryl or -NR _a' R _b' , or an unsaturated, saturated or partially saturated 4-11 membered monocyclyl or bicyclyl containing 1-4 heteroatoms selected from oxygen, nitrogen or sulfur; wherein the alkyl, C3-C6 cycloalkyl, aryl or monocyclyl or bicyclyl is further optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, C1-C6 linear or branched alkyl, CN, hydroxyl, CF ₃ , -OR _e , -NR _e R _f , -S(O) _p R _e or C3-C6 cycloalkyl; wherein alkyl and cycloalkyl may be optionally substituted with one or more substituents selected from halogen, CN, hydroxyl, CONH2 or SO2CH3; wherein (a) Ra' and Rb' are independently hydrogen, deuterium, deuterium, C1-C6 linear or branched alkyl, C3-C6 cycloalkyl, aryl, (C1-C6 linear or branched alkyl)aryl, heteroaryl, or (C1-C6 linear or branched alkyl)heteroaryl, wherein the alkyl and cycloalkyl may be optionally substituted with one or more R _c', or (b) _Ra' and R _b' together form a chain containing -(CR _c' R _d' ) _j -, wherein R _c' and R _d' are independently hydrogen, deuterium, deuterium, C1-C6 linear or branched alkyl, aryl, (C1-C6 linear or branched alkyl)aryl, heteroaryl, (C1-C6 linear or branched alkyl)heteroaryl, halogen, CN, hydroxyl, _CF3 , CONH2, _{-ORe or -NReRf ,} or -S(O) _pRe ; wherein _Re and _Rf are independently hydrogen, deuterium, _deuterium , C1-C6 linear or branched alkyl or C3-C6 cycloalkyl, wherein alkyl and cycloalkyl may optionally be substituted with one or more substituents selected from halogen, CN, hydroxyl, _CF3 and _CONH2 ;

j is 2, 3, 4, or 5;

k is 1, 2, 3, or 4;

p is 0, 1, or 2;

n is 1 or 2; or

in some embodiments of the present invention, the RTM has the following structure:

or a stereoisomer or pharmaceutically acceptable salt thereof; wherein in RTM-18, RTM-18a, RTM-18b, RTM-18c, PTM-18d, RTM-18e or PTM-18f:

each X and X' independently represents CR ⁶ , N, or -N ⁺ O ^- ;

Y is independently N, -N ⁺ O ^- or CH; provided that at least one of X, X or Y is neither N nor -N+O", and no more than one of X, X' or Y is -N+O ^- ;

R ¹ is C1-C6 alkyl or 3-7-membered cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with 1-5 substituents selected from halogen, deuterium, -OR ⁵ , -SR ⁵ , -NR ^11a R ^11b , cyano, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkoxy;

R ² is 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl with 1-3 heteroatoms, 5-10 membered heteroaryl with 1-3 heteroatoms, or C6-12 aryl, wherein the cycloalkyl, heterocycloalkyl, heteroaryl or aryl are optionally substituted with 1 to 5 R ³ , and if the heteroatom of the heterocycloalkyl or heteroaryl is N, then N is optionally substituted with R ⁴ ;

R ³ independently represents deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, oxo, -SR ⁵ , -NR ^11a R ^11b , cyano or -OR ⁵ , wherein the alkyl, cycloalkyl or alkoxy is optionally and independently substituted with 1 to 5 groups selected from deuterium, halogen, -OR ^5, -SR ⁵ , -NR ^11a R ^11b , cyano, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkoxy; or two R ³ together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl or a 4- to 6-membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl being optionally substituted with 1-3 substituents selected from halogen, deuterium, -OR ⁵ , -SR ⁵ , -NR ^11a R ^11b , cyano, C1-C6 alkyl or C1-C6 alkoxy, the alkyl or alkoxy being optionally substituted with a substituent selected from halogen, deuterium, -OR ⁵ , -SR ⁵ , -NR ^11a R ^11b or cyano; wherein if the heteroatom in the heterocycloalkyl is N, then N is optionally substituted with R ⁴ ;

R ⁴ is hydrogen, deuterium, C1-C6 alkyl, -C(O)R ¹⁰ or -S(O) ₂ R ⁸ , wherein the alkyl is optionally substituted with OH, halogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy or cyano;

R ⁵ is hydrogen or C1-C6 alkyl, wherein alkyl is optionally substituted with halogen, deuterium, C1-C6 alkoxy, C1-C6 alkothyl, -NR ^11a R ^11b , cyano, C1-C6 alkyl or C3-C6 cycloalkyl;

R ⁶ is hydrogen, deuterium, halogen, cyano, -OR ⁵ , -SR ⁵ , -NR ^11a R ^11b , C1-C6 alkyl, C3-C6 cycloalkyl, 3-7-membered heterocycloalkyl, 5-6-membered heteroaryl or aryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl is optionally substituted with 1-3 substituents selected from halogen, -OR ⁵ , -SR ⁵ , -NR ^11a R ^11b , cyano, C1-C3 alkyl, -C(O)R ¹⁰ or oxo;

R ⁷ independently represents hydrogen, deuterium, methyl, cyano, OCF ₃ , OMe, CF ₃ or halogen;

R ⁸ is independently C1-6 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1-3 substituents selected from deuterium, halogen, OH, C1-C6 alkoxy, C1-C3 alkyl optionally substituted with -NR ^11a R ^11b or C1-C6 alkoxy, 3-6 membered cycloalkyl, -NR ^11a R ^11b or cyano;

R ¹⁰ is C1-C6 alkyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one to three substituents selected from deuterium, halogen, OH, C1-C6 alkoxy, C1-C3 alkyl optionally substituted with -NR ^11a R ^11b or C1-C6 alkoxy, 3- to 6-membered cycloalkyl, -NR ^11a R ^11b or cyano; and

each R ^11a and R ^11b independently represents hydrogen, deuterium, 3-6-membered cycloalkyl, or Cl-C6 alkyl, wherein the cycloalkyl or alkyl is optionally substituted with a substituent selected from deuterium, C1-C6 alkoxy, or cyano; if the alkyl is C2-6 alkyl, then the alkyl is optionally substituted with deuterium, C1-C6 alkoxy, cyano, halogen, or OH; or

in some embodiments of the present invention, the RTM has the following structure:

or a pharmaceutically acceptable salt thereof; wherein in RTM-19, RTM-19a, RTM-19b, RTM-19c, PTM-19d, RTM-19e, PTM-19f, PTM-19g, PTM-19h, PTM-19i, PTM-19J, PTM-19k, PTM-19l, PTM-19m, PTM-19n, PTM-19o, PTM-19p, PTM-19q, PTM-19r, PTM-19s, PTM-19t, PTM-19u, PTM-19v, PTM-19w, PTM-19x, PTM-19y, PTM-19z, PTM-19a', PTM-19b', PTM-19c' or RTM-19d':

R is alkyl, heteroalkyl, heteroaryl, aryl, halogen, amide or CN;

R ¹ is H, alkyl, heteroalkyl; or R and R ¹ together with the atom to which they are attached form a heterocycloalkyl;

^R2 is H, an aliphatic group, alkyl, heteroalkyl, aryl, amide or heterocycloalkyl;

R ³ independently represents H, alkyl, halogen, heteroalkyl, -O-alkyl, heterocycloalkyl, aryl, -O-heterocycloalkyl, hydroxyl, nitro, cyano, carboxylic acid, ester, acyl, amide, amino, sulfonyl, sulfonamide, alkyl-S-, sulfinyl, haloalkyl, alkyl phosphate, or alkyl phosphonate;

each R ⁴ , R ⁵ , R ⁶ and R ⁷ is independently H, alkyl, heteroalkyl, alkoxy, heterocycloalkyl, aryl, O-heterocycloalkyl, hydroxyl, haloalkyl, halogen, nitro, cyano, carboxyl, ester, acyl, amide, amino, sulfonyl, sulfonamide, alkyl-S-, sulfinyl;

each R ⁸ and R ⁹ is independently H, alkyl, heteroalkyl, aryl, heterocycloalkyl, sulfonyl, nitro, halogen, haloalkyl, ester, cyano, or amino;

R ¹⁰ is H, alkyl, heteroalkyl, alkoxy, ester, aryl, nitro, cyano, hydroxyl, haloalkyl, alkyl phosphate or alkyl phosphonate;

each R ¹¹ , R ¹² , R ¹³ and R ¹⁴ independently represents H, alkyl, heteroalkyl, aryl, heterocycloalkyl, sulfonyl, nitro, halogen, haloalkyl, ester, cyano or amino;

each R ¹⁵ and R ¹⁶ independently represents H, alkyl, heteroalkyl, aryl, heterocycloalkyl, or forms a heterocycloalkyl together with the N atom to which they are attached;

each x, y and z is independently an integer from 1 to 6; each Het-1 and Het-2 is independently a heteroaryl;

Het-3 is heterocycloalkyl; or

in some embodiments of the present invention, the RTM has the following structure:

and/or its pharmaceutically acceptable salt or stereoisomer, wherein in RTM-20, RTM-20a, RTM-20b or RTM-20c:

at least one of R ¹ and R ² is an aromatic moiety and the remaining portion of R ¹ or R ² is H, alkyl, haloalkyl, nitro, cyano, amide, amino, hydroxyl, carboxyl, carboxylic ester or acyl;

R ³ is H, alkyl, heteroalkyl, heterocycloalkyl, amide, aromatic or aromatic aliphatic;

R ⁴ is H, alkyl, heteroalkyl, or one of R ¹ and R ² forms a heterocycloalkyl with R ⁴ and the atoms to which they are attached;

R ⁵ is H or alkyl;

R ⁶ , R ⁷ , R ⁸ and R ⁹ are H, alkyl, heteroalkyl, alkoxy, ester, sulfonyl, halogen, acyl, amino, aryl, heterocycloalkyl, nitro, cyano, hydroxyl, haloalkyl, alkyl phosphate or alkyl phosphonate; and

ring A is heterocycloalkyl; or

in some embodiments of the present invention, the RTM has the following structure:

or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide or prodrug thereof; wherein RTM is RTM-21, RTM-21a or RTM-21b:

X represents O or S;

Y represents O or S;

Z represents N or CR ⁹ ;

Het-1 is heteroaryl;

R ¹ and R ² independently represent H, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, or form a heterocycloalkyl together with the nitrogen atom to which they are attached;

^R3 , ^R4 , ^R5 , ^R6 and ^R9 are independently H, cycloalkyl, alkyl, halogen, heteroalkyl, -O-alkyl, heterocycloalkyl, aryl, -O-heterocycloalkyl, hydroxyl, nitro, cyano, carboxyl, ester, acyl, aminoamide, sulfonyl, sulfonamide, alkyl-S-, sulfinyl or haloalkyl;

R ⁷ is H, alkyl, heteroalkyl, heterocycloalkyl or aryl;

R ⁸ is independently alkyl, halogen, heteroalkyl, -O-alkyl, heterocycloalkyl, aryl, -O-heterocycloalkyl, hydroxyl, nitro, cyano, carboxyl, ester, acyl, amide, amino, sulfonyl, sulfonamide, alkyl-S-, sulfinyl or haloalkyl; and

m takes values from 0 to the possible substitution number on Het-1; or

in some embodiments of the present invention, the RTM has the following structure:

or a stereoisomer or pharmaceutically acceptable salt thereof; wherein in RTM-22, RTM-22a, RTM-22b, RTM-22c, PTM-22d, RTM-22e, PTM-22g or PTM-22h:

ring A is cycloalkyl;

ring B is selected from aryl or heteroaryl;

R ¹ is selected from C1-10 alkyl, C3-C10 cycloalkyl, halogen, aryl or heteroaryl;

R ² and R ³ are independently selected from hydrogen or C1-C6 alkyl;

R ⁴ is C1-C6 alkyl, cyano, halogen or hydrogen; or

in some embodiments of the present invention, the RTM has the following structure:

or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide or prodrug thereof; wherein in RTM-23:

Het-1 is heteroaryl;

R ¹ is hydrogen or alkyl;

R ² is alkoxy or -N(R ^c ) ₂ ;

R ³ is C1-C6 alkyl, C1-C3 haloalkyl or halogen;

m is 0, 1 or 2;

R ⁴ is C1-C6 alkyl;

k is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;

A represents N or CR ^h ;

R ^h represents hydrogen, deuterium, R ³ or

R ⁵ is hydrogen, deuterium, alkyl, phosphonoxyalkyl, phosphonoalkyl or acyl;

each R ₆ and R ₇ independently represents hydrogen, deuterium, alkyl or halogen;

X represents O or NR ⁹ ;

R ⁹ is R ^a , C(O)C1-C6 alkyl, C(O)N(R ^c ) ₂ , C(O)OR ^a ;

Y represents N or CH;

the linker is a bond, -(C(R ¹⁰ ) ₂ ) _n -O-, -C(O)-(C(R ¹⁰ ) ₂ ) _p -, or (C(R ¹⁰ ) ₂ ) _p -N(R ^a )-;

R ¹⁰ represents R ^a or R ^b ;

n is 1, 2, 3, 4, 5, or 6;

p is 0, 1, or 2;

R ^a represents hydrogen, deuterium, D, C1-C6 alkyl or C3-C6 cycloalkyl;

R ^b is hydroxyl, -CR ^a , or halogen;

R ^c is R ^a , or two R _c together with the nitrogen atoms attached thereto form a C3-7 heterocycloalkyl, and the heterocycloalkyl optionally further comprises one or two heteroatoms selected from N, S or O; or

in some embodiments of the present invention, the RTM has the following structure:

or a pharmaceutically acceptable salt thereof; wherein in RTM-24, RTM-24a, RTM-24b, RTM-24c, RTM-24d, RTM-24e, PTM-24f, PTM-24g, PTM-24h, PTM-24i, PTM-24J, RTM-24k, RTM-24l, RTM-24m, PTM-24n, PTM-24o, PTM-24p, PTM-24q, PTM-24r, RTM-24s, RTM-24t, PTM-24u, RTM-24v, PTM-24w, PTM-24x or PTM-24y:

ring A is a 3-7 membered saturated or partially

unsaturated carbocycle or 4-7-membered saturated or partially

unsaturated heterocycloalkyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

n is an integer between 0 and 4;

R ¹ independently represents -R, halogen, -CN, -NO ₂ , -OR, -CH ₂ OR, -SR, -N(R) ₂ , -SO ₂ R, -SO ₂ N(R) ₂ , -SOR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , -C(O)N(R)-OR, -NRC(O)OR, -NRC(O)N(R) ₂ , Cy or -NRSO ₂ R; or R ¹ is selected from one of the following formulas:

or two R ¹ together with the atoms to which they are attached form an optionally substituted 4-7 membered fused, spiro-fused or bridged bicyclyl containing 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each Cy is selected from the following optionally substituted rings: a 3-7-membered saturated or partially unsaturated carbocycle or a 4-7-membered saturated or partially unsaturated heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R is independently hydrogen or selected from the following optionally substituted groups: C1-C6 alkyl, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or two R, together with the nitrogen atoms to which they are attached, form a 4-7-membered saturated, partially unsaturated heterocyclic or heteroaryl ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur in addition to the nitrogen atom;

ring B is a 4-8-membered partially unsaturated carbocyclic fused ring, a benzo-fused ring, or a 4-7-membered partially unsaturated heterocyclic fused ring containing 1-2 heteroatoms selected from nitrogen, oxygen, or sulfur, 5-6-membered heteroaromatic fused rings with 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring B may optionally be substituted with one or more selected from oxo, thiocarbonyl, or imino;

m is from 1 to 4;

p is from 0 to 2;

W is N or -C(R ³ )-;

R ^z represents R, CN, NO ₂ , halogen, -C(O)N(R) ₂ , -C(O)OR, -C(O)R, -N(R) ₂ , -NH-[Ar ], -N(R)C(O)OR, -NRC(O)N(R) ₂ , -OR or -SO ₂ N(R) ₂ ;

[Ar] represents an optionally substituted phenyl or heteroaromatic ring;

R ³ represents hydrogen, deuterium, halogen, -CN, C1-C4 aliphatic group, C1-C4 haloaliphatic group, -OR, -C(O)R or -C(O)N(R) ₂ ;

L ¹ is a bond or a divalent hydrocarbon chain C1-C6 in which one or two methylene units of the chain are optionally and independently replaced by -NR-, -N(R)C(O)-, -C(O)N(R)-, -N(R)SO ₂ -, -SO ₂ N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)-, -C(O) O-, -S-, -SO- or -SO ₂ -;

each L ² independently represents a bond or a divalent hydrocarbon chain C1-C6 in which one or two methylene units of the chain are optionally and independently replaced by -NR-, -N(R)C(O)-, -C(O)N(R)-, -N(R)SO ₂ -, -SO ₂ N(R)-, -O-, -C(O)-, -OC(O)-, -C(O) O-, -S-, -SO-, or -SO ₂ -;

each R ⁴ is independently halogen, -CN, -NO2, -OR, -SR, -N(R) ₂ , -SO ₂ R, -SO ₂ N(R) ₂ , -SOR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -C(O)N(R)OR, -N(R)C(O)OR, -N(R)S(O) ₂ N(R) ₂ , -NRSO ₂ R or is selected from the following optionally substituted groups: C1-C6 aliphatic, phenyl, 4-7-membered saturated or partially unsaturated heterocyclyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or two ^-L2 ( ^R4 ) ^pR4 groups together with the atoms to which they are attached form an optionally substituted 4-7-membered fused, spiro-fused or bridged bicyclyl containing 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or

in some embodiments of the present invention, the RTM has the following structure:

or a stereoisomer or pharmaceutically acceptable salt thereof; wherein in RTM-25, RTM-25a, RTM-25b, RTM-25c, PTM-25d, RTM-25e, PTM-25f, PTM-25g or PTM-25h:

Q represents CH, C-CN or N;

X is CL ² (R ⁴ ) _p R ⁸ and Y is N; or X is N and Y is CR ^x ;

ring A is a 3-7-membered saturated or partially unsaturated carbocycle or a 4-7-membered saturated or partially unsaturated heterocycloalkyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R ¹ and R ^1' independently represents -R ² , halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -S(O) ₂ R, -S(O) ₂ N(R) ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) ₂ , -C(O)N(R)OR, -N(R)C(O)OR, -N(R)C(O)N(R) ₂ , Cy, or -N(R)S(O) ₂ R;

or R ¹ is selected from one of the following formulas:

two R ¹ groups, together with the atoms to which they are attached, form an optionally substituted 4- to 7-membered fused,

spiro-fused or mono-fused bicyclyl containing 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each Cy is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated carbocycle or a 4-10 membered saturated or partially unsaturated heterocycle containing 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R is independently hydrogen or an optionally substituted group selected from the following: C1-C6 alkyl, phenyl, 4-7-membered saturated or partially unsaturated heterocycles containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-6-membered heteroaromatic rings containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or two R, together with the nitrogen atom to which they are attached, form a 4-7-membered saturated, partially unsaturated heterocyclic or heteroaromatic ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, in addition to the nitrogen atom;

each ^R2 is independently an optionally substituted group selected from the following: C1-C6 alkyl, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6-membered heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R ⁴ is independently halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -S(O) ₂ R, -S(O) ₂ N(R) ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) ₂ , -N(R)C(O)R, -N(R)C(O)N(R) ₂ , -C(O)N(R)OR, -N(R)C(O)OR, -N(R)S(O) ₂ N(R) ₂ , -N(R)S(O) ₂ R or an optionally substituted group selected from the following: C1-C6 alkyl, phenyl, 4-7-membered saturated or partially unsaturated heterocyclyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

R ^x represents hydrogen, deuterium, -R ² , -CN, -NO ₂ , halogen, -C(O)N(R) ₂ , -C(O)OR, -C(O)R, -N(R) ₂ , -NH[Ar], -OR, or -S(O) ₂ N(R) ₂ ;

R ^z represents hydrogen, deuterium, -R ² , -CN, -NO ₂ , halogen, -C(O)N(R) ₂ , -C(O)OR, -C(O)R, -N(R) ₂ , -NH[Ar], -OR, or -S(O) ₂ N(R) ₂ ;

[Ar] is a phenyl or heteroaromatic ring substituted with m

L ¹ is a covalent bond or a divalent hydrocarbon chain C1-C6 in which one or two methylene units of the chain are optionally and independently replaced by -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) ₂ -;

L ² is a covalent bond or a divalent hydrocarbon chain C1-C6 in which one or two methylene units of the chain are optionally and independently replaced by -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) ₂ -;

m is an integer 0-4;

n is an integer 0-4; and

p is an integer 0-2; and

in some embodiments of the present invention, the RTM has the following structure:

or a stereoisomer or pharmaceutically acceptable salt thereof; wherein in RTM-26, RTM-26a, RTM-26b, RTM-26c, PTM-26d, RTM-26e, PTM-26f, PTM-26g, PTM-26h, PTM-26i, PTM-26g, PTM-26k, PTM-26l, RTM-26m or PTM-26n:

Q represents CH or N;

ring A is a 3-7-membered saturated or partially unsaturated carbocycle or a 4-7-membered saturated or partially unsaturated heterocycloalkyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R ¹ is independently -R ² , halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -S(O) ₂ R, -S(O) ₂ N(R) ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) ₂ , -C(O)N(R)OR, -N(R)C(O)OR, -N(R)C(O)N(R) ₂ , Cy, or -N(R)S(O) ₂ R;

or R1 is selected from one of the following formulas:

two R ¹ groups, together with the atoms to which they are attached, form an optionally substituted 4- to 7-membered fused,

spiro-fused or mono-fused bicyclyl containing 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each Cy is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated carbocycle or a 4-10 membered saturated or partially unsaturated heterocycle containing 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R is independently hydrogen or an optionally substituted group selected from the following: C1-C6 alkyl, phenyl, 4-7-membered saturated or partially unsaturated heterocycles containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-6-membered heteroaromatic rings containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or two R, together with the nitrogen atom to which they are attached, form a 4-7-membered saturated, partially unsaturated heterocyclic or heteroaromatic ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, in addition to the nitrogen atom;

each R ² is an optionally substituted group independently selected from the following: C1-C6 alkyl, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6-membered heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each of R ⁵ and R ⁶ independently represents hydrogen or - -L ² (R ⁴ ) _p R ^x ; or

R ⁵ and R ⁶ together with the attached atoms form a 4-7 membered partially unsaturated heterocyclic or aromatic ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R ⁴ is independently halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -S(O) ₂ R, -S(O) ₂ N(R) ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) ₂ , -N(R)C(O)R, -N(R)C(O)N(R) ₂ , -C(O)N(R)OR, -N(R)C(O)OR, -N(R)S(O) ₂ N(R) ₂ , -N(R)S(O) ₂ R or an optionally substituted group selected from the following: C1-C6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

R ⁷ - represents hydrogen, deuterium, -R ² , -CN, -NO ₂ , halogen, -C(O)N(R) ₂ , -C(O)OR, -C(O)R, -N(R) ₂ , -NH[Ar], -OR or -S(O) ₂ N(R) ₂ ;

R ^z represents hydrogen, deuterium, -R ² , -CN, -NO ₂ , halogen, -C(O)N(R) ₂ , -C(O)OR, -C(O)R, -N(R) ₂ , -NH[Ar], -OR, or -S(O) ₂ N(R) ₂ ;

[Ar] is optionally substituted phenyl or a 5-6 membered heteroaryl ring containing 1-4 heteroatoms independently selected from N, O or S;

L ¹ is a covalent bond or a divalent hydrocarbon chain C1-C6 in which one or two methylene units of the chain are optionally and independently replaced by -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) ₂ -;

L ² is a covalent bond or a divalent hydrocarbon chain C1-C6 in which one or two methylene units of the chain are optionally and independently replaced by -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) ₂ -;

m is an integer 0-4;

n is an integer 0-4; and

p is an integer 0-2; and

in some embodiments of the present invention, the RTM has the following structure:

or a stereoisomer or pharmaceutically acceptable salt thereof; wherein in RTM-27, RTM-27a, RTM-27b, RTM-27c, PTM-27d, RTM-27e, PTM-27f, PTM-27g or PTM-27h:

ring A is a 3-7-membered saturated or partially unsaturated carbocycle or a 4-7-membered saturated or partially unsaturated heterocycloalkyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R ¹ is independently -R, halogen, -CN, -NO ₂ , -OR, -SR, -N(R), -S(O) ₂ R, -S(O) ₂ N(R) ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) ₂ , -C(O)N(R)OR, -N(R)C(O)OR, -N(R)C(O)N(R) ₂ , Cy, or -N(R)S(O) ₂ R;

or R ¹ is selected from one of the following formulas:

two R ¹ groups, together with the atoms to which they are attached, form an optionally substituted 4- to 7-membered fused,

spiro-fused or mono-fused bicyclyl containing 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each Cy is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated carbocycle or a 4-10 membered saturated or partially unsaturated heterocycle containing 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R is independently hydrogen or an optionally substituted group selected from the following: C1-C6 alkyl, phenyl, 4-7-membered saturated or partially unsaturated heterocycles containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-6-membered heteroaromatic rings containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or two R, together with the nitrogen atom to which they are attached, form a 4-7-membered saturated, partially unsaturated heterocyclic or heteroaromatic ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, in addition to the nitrogen atom;

R ^z is -R, -CN, -NO ₂ , halogen, -C(O)N(R) ₂ , -C(O)OR, -C(O)R, -N(R) ₂ , -OR, or -S(O) ₂ N(R) ₂ ;

Ring B is a 4-8 membered unsubstituted partially unsaturated carbocyclic fused ring;

L represents a covalent bond or a divalent hydrocarbon chain C1-C6 in which one or two methylene units of the chain are optionally and independently replaced by -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) ₂ -;

n is an integer 0-4; or

in some embodiments of the present invention, the RTM has the following structure:

or a pharmaceutically acceptable salt thereof; wherein in RTM-28, RTM-28a, RTM-28b, RTM-28c, RTM-28d or RTM-28e:

ring A is a 3- to 7-membered saturated or partially unsaturated carbocycle or a 4- to 7-membered saturated or partially unsaturated heterocycloalkyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; n is from 0 to 4;

R ¹ independently represents -R, halogen, -CN, -NO ₂ , -OR, -CH ₂ OR, -SR, -N(R) ₂ , -SO ₂ R, -SO ₂ N(R) ₂ , -SOR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , -C(O)N(R)-OR, -NRC(O)OR, -NRC(O)N(R) ₂ , Cy or -NRSO ₂ R; or R ¹ is selected from one of the following formulas:

or two R ¹ together with the atoms to which they are attached form an optionally substituted 4-7 membered fused, spiro-fused or bridged bicyclyl containing 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each Cy is selected from the following optionally substituted rings: a 3-7-membered saturated or partially unsaturated carbocycle or a 4-7-membered saturated or partially unsaturated heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R is independently hydrogen or selected from the following optionally substituted groups: C1-C6 alkyl, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or two R, together with the nitrogen atoms to which they are attached, form a 4-7-membered saturated, partially unsaturated heterocyclic or heteroaryl ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur in addition to the nitrogen atom;

each R ^x and R ^y independently represents R, CN, NO ₂ , halogen, -SR, -OR, -N(R) ₂ , -SO ₂ R, -SO ₂ N(R) ₂ , -SOR, -C(O)R, -C(O)OR, -C(O)N(R) ₂ , -N(R)C(O)R, -NRC(O)N(R) ₂ or -NRSO ₂ R;

Rx and Ry together with the atoms to which they are attached form a ring B substituted by m

ring B is a 4-8-membered partially unsaturated carbocyclic fused ring, a benzo-fused ring or a 4-7-membered partially unsaturated heterocyclic fused ring containing 1-2 heteroatoms selected from nitrogen, oxygen or sulfur, 5-6-membered heteroaromatic fused rings containing 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein ring B may be optionally substituted with one or more selected from oxo, thiocarbonyl or imino;

m is an integer between 0 and 4;

p is an integer between 0 and 2;

W is N or -C(R ³ )-;

R ^z represents R, CN, NO ₂ , halogen, -C(O)N(R) ₂ , -C(O)OR, -C(O)R, -N(R) ₂ , -N(R) C(O)OR, -NRC(O)N(R) ₂ , -OR or -SO ₂ N(R) ₂ ;

R ³ represents hydrogen, deuterium, halogen, -CN, C1-C4 aliphatic group, C1-C4 haloaliphatic group, -OR, -C(O)R or -C(O)N(R) ₂ ;

L ¹ is a bond or a divalent hydrocarbon chain C1-C6 in which one or two methylene units of the chain are optionally and independently replaced by -NR-, -N(R)C(O)-, -C(O)N(R)-, -N(R)SO ₂ -, -SO ₂ N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)-, -C(O) O-, -S-, -SO- or -SO ₂ -;

each L ² independently represents a covalent bond or a divalent hydrocarbon chain C1-C6 in which one or two methylene units of the chain are optionally and independently replaced by -NR-, -N(R)C(O)-, -C(O)N(R)-, -N(R)SO ₂ -, -SO ₂ N(R)-, -O-, -C(O)-, -OC(O)-, -C(O) O-, -S-, -SO-, or -SO ₂ -;

each R ⁴ is independently halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -SO ₂ R, -SO ₂ N(R) ₂ , -SOR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -C(O)N(R)OR, -N(R)C(O)OR, -N(R)S(O) ₂ N(R) ₂ , -NRSO ₂ R or selected from the following optionally substituted groups: C1-C6 alkyl, phenyl, 4-7-membered saturated or partially unsaturated heterocyclyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur,

or two ^-L2 ( ^R4 ) _pR4 groups, together with the atoms to which they are attached, form an optionally substituted 4-7-membered fused, spiro-fused, or bridged bicyclyl containing 0-2 heteroatoms independently selected from nitrogen, oxygen ^, or sulfur; or

in some embodiments of the present invention, the RTM has the following structure:

or its pharmaceutically acceptable salt; and in RTM-29:

ring A is a 3-7-membered saturated or partially unsaturated carbocycle or a 4-7-membered saturated or partially unsaturated heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

Ring B is or ;

moreover is a ring moiety fused to a pyrimidine ring, # is -L ² (R ⁴ ) _p -R ^X ;

R ¹ and R ^1' are independently -R ² , halogen, -CN, -NO ₂ , -OR, -CH ₂ OR, -SR, -N(R) ₂ , -SO ₂ R, -SO ₂ N(R) ₂ , -SOR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , -C(O)N(R)-OR, -NRC(O)OR, -NRC(O)N(R) ₂ , Cy or -NRSO ₂ R; or R ¹ is selected from one of the following formulas:

or two R ¹ together with the atoms to which they are attached form an optionally substituted 4-7 membered fused, spiro-fused or bridged bicyclyl containing 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each Cy is selected from the following optionally substituted rings: a 3-7 membered saturated or partially unsaturated carbocycle or a 4-10 membered saturated or partially unsaturated heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R is independently hydrogen or selected from the following optionally substituted groups: C1-C6 alkyl, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or

two R, together with the nitrogen atoms to which they are attached, form a 4-7 membered saturated, partially unsaturated heterocyclic or heteroaryl ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, in addition to the nitrogen atom;

each R ² is an optionally substituted group independently selected from the following: C1-C6 alkyl, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6-membered heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R ⁴ is independently halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -S(O) ₂ R, -S(O) ₂ N(R) ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) ₂ , -N(R)C(O)R, -N(R)C(O)N(R) ₂ , -C(O)N(R)OR, -N(R)C(O)OR, -N(R)S(O) ₂ N(R) ₂ , -N(R)S(O) ₂ R or an optionally substituted group selected from the following: C1-C6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

R ^x represents hydrogen, deuterium, -R ² , -CN, -NO ₂ , halogen, -C(O)N(R) ₂ , -C(O)OR, -C(O)R, -N(R) ₂ , -NH[Ar], -OR, or -S(O) ₂ N(R) ₂ ;

R ^z represents hydrogen, deuterium, -R2, -CN, -NO2, halogen, -C(O)N(R)2, -C(O)OR, -C(O)R, -N(R)2, -NH[Ar], -OR, or -S(O) ₂ N(R) ₂ ;

[Ar] is phenyl substituted with m R1' or a heteroaromatic ring containing 1-4 heteroatoms selected from N, O or S;

L ¹ is a covalent bond or a divalent hydrocarbon chain C1-C6 in which one or two methylene units of the chain are optionally and independently replaced by -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

L ² is a covalent bond or a divalent hydrocarbon chain C1-C6 in which one or two methylene units of the chain are optionally and independently replaced by -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) ₂ -;

m is an integer 0-4;

n is an integer 0-4; and

p is an integer 0-2; and

in some embodiments of the present invention, the RTM has the following structure:

or a pharmaceutically acceptable salt thereof; wherein in RTM-30: Y is N or CRS;

ring A is a 3-7-membered saturated or partially unsaturated carbocycle or a 4-7-membered saturated or partially unsaturated heterocycloalkyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

R ¹ and R ^1' are independently -R ² , halogen, -CN, -NO ₂ , -OR, -CH ₂ OR, -SR, -N(R) ₂ , -SO ₂ R, -SO ₂ N(R) ₂ , -SOR, -C(O)R, -CO2R, -C(O)N(R) ₂ , -C(O)N(R)-OR, -NRC(O)OR, -NRC(O)N(R) ₂ , Cy or -NRSO ₂ R; or R ¹ is selected from one of the following formulas:

or two R ¹ together with the atoms to which they are attached form an optionally substituted 4-7 membered fused, spiro-fused or bridged bicyclyl containing 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each Cy is selected from the following optionally substituted rings: a 3-7 membered saturated or partially unsaturated carbocycle or a 4-10 membered saturated or partially unsaturated heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R is independently hydrogen or selected from the following optionally substituted groups: C1-C6 alkyl, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or two R, together with the nitrogen atoms to which they are attached, form a 4-7-membered saturated, partially unsaturated heterocyclic or heteroaryl ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, in addition to the nitrogen atom;

each R ² is an optionally substituted group independently selected from the following: C1-C6 alkyl, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6-membered heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R ⁴ is independently halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -S(O) ₂ R, -S(O) ₂ N(R) ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) ₂ , -N(R)C(O)R, -N(R)C(O)N(R) ₂ , -C(O)N(R)OR, -N(R)C(O)OR, -N(R)S(O) ₂ N(R) ₂ , -N(R)S(O) ₂ R or an optionally substituted group selected from the following: C1-C6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R ^x , R ^{y ,} and R ^z independently represents hydrogen, deuterium, -R ² , -CN, -NO ₂ , halogen, -C(O)N(R) ₂ , -C(O)OR, -C(O)R, -N(R) ₂ , -NH[Ar], -OR, or -S(O) ₂ N(R) ₂ ;

R ^x and R ^y together with the atoms to which they are attached form a 4- to 7-membered partially unsaturated carbocycle or partially unsaturated heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S;

[Ar] is phenyl substituted with ^mR1 , or 5-6-membered heteroaryl containing 1-4 heteroatoms selected from N, O or S;

L ¹ is a covalent bond or a divalent hydrocarbon chain C1-C6 in which one or two methylene units of the chain are optionally and independently replaced by -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) ₂ -;

m is an integer 0-4;

n is an integer 0-4; or

in some embodiments of the present invention, the RTM has the following structure:

or its pharmaceutically acceptable salt; in RTM-31:

ring A is a 5-6 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; the heteroaromatic ring is optionally substituted;

X is absent or is -O-, -S-, -SO ₂ -, -SO-, -C(O)-, -CO ₂ -, -C(O)N(R)-, -OC(O)N(R)-, -NRC(O)-, -NRC(O)N(R)-, -NRSO ₂ - or -N(R)-; or X is (CRR) _m -O-, -(CRR) _m S-, -(CRR) _m SO ₂ -, -(CRR) _m SO-, -(CRR) _m C(O)-, -(CRR) _m CO ₂ -, -(CRR) _m C(O)N(R)-, -(CRR) _m OC(O)N(R)-, -(CRR) _m NRC(O)-, -(CRR) _m NRC(O)N(R)-, -(CRR) _m NRSO ₂ - or -(CRR) _m N(R)-;

Y is optionally substituted C1-6 alkyl;

Z is absent, a divalent _C3-10 aryl, a divalent 3-8-membered saturated or partially unsaturated carbocycle, a divalent 3-7-membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a divalent 5-6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of the foregoing groups is optionally substituted; or Z is -O-, -S-, _-SO2- , -SO-, -C(O)-, _-CO2- , -C(O)N(R)-, -OC(O)N(R)-, -NRC(O)-, -NRC(O)N(R)-, _-NRSO2- or -N(R)-;

W represents CR or N;

each R is independently hydrogen, deuterium, C1-6 alkyl, C3-C10 aryl, a 3-8-membered saturated or partially unsaturated carbocycle, a 3-7-membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6-membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of the foregoing groups is optionally substituted; or two R on the same atom, together with the atom to which they are attached, form a C3-C10 aryl, a 3- to 8-membered saturated or partially unsaturated carbocycle, a 3- to 7-membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5- to 6-membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of the foregoing groups is optionally substituted;

each R ¹ is independently -R, halogen, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R, or -N (R) ₂ ;

each R ² is -R, halogen, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R, or -N(R) ₂ ;

each R ⁴ is -R, halogen, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO2R, or -N(R) ₂ ;

each m is independently equal to 1 or 2; or

n is 0, 1, 2, 3, 4, or 5; or

in some embodiments of the present invention, the RTM has the following structure:

and/or its pharmaceutically acceptable salt; in RTM-32, RTM-32a or RTM-32b:

ring A is a 5-membered heterocyclyl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; the heterocyclyl or heteroaromatic ring is optionally substituted;

ring B is a 6-membered aryl or 6-membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; the aryl or heteroaromatic ring is optionally substituted;

ring C is a 5-membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; the heterocyclyl or heteroaromatic ring is optionally substituted;

X is absent or is -CH=CH-, C≡C, -O-, -S-, -SO ₂ -, -SO-, -C(O)-, -CO ₂ -, -C(O)N(R)-, -OC(O)N(R)-, -NRC(O)-, -NRC(O)N(R)-, -NRSO ₂ - or -N(R)-;

Y is absent or is a divalent C3-10 aryl, a divalent 3-8-membered saturated or partially unsaturated carbocycle, a divalent 3-7-membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a divalent 5-6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of the above groups is optionally substituted;

each R is independently hydrogen, C1-6 alkyl, C3-C10 aryl, a 3-8-membered saturated or partially unsaturated carbocycle, a 3-7-membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6-membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of the foregoing groups is optionally substituted; or

each R is independently -OR ^c , -SR ^c , -SO ₂ R ^c , -SOR ^c , -C(O)R ^c , -CO ₂ R ^c , -C(O)N(R)R ^c , -OC(O)N(R)R ^c , -NRC(O)R ^c , -NRC(O)N(R)R ^c , -NRSO ₂ R ^c or -N(R)R ^c ;

two R on the same atom, together with the atom to which they are attached, form a C3-C10 aryl, a 3- to 8-membered saturated or partially unsaturated carbocycle, a 3- to 7-membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5- to 6-membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of the foregoing groups is optionally substituted;

R ^a represents H or optionally substituted C1-6 alkyl;

R ^b represents H or optionally substituted C1-6 alkyl;

each R ^c is independently H or optionally substituted C1-6 alkyl;

n is 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, or 4; and r is 0, 1, or 2; or

in some embodiments of the present invention, the RTM has the following structure:

or its pharmaceutically acceptable tautomers, solvates, salts and stereoisomers, including mixtures thereof in all ratios; and in RTM-33:

each R ¹ and R ³ independently represents H, (CH ₂ ) _p CON(R5) ₂ , OA, Hal, COOH, COOA, (CH ₂ ) _p NHCOA (CH ₂ ) _p Het1, (CH ₂ ) _p NR2R5 or OH;

R2 refers to H or a linear or branched alkyl containing 1, 2 or 3 C atoms, wherein one or two H atoms of the alkyl may be substituted by OR6, NR5R6, NHCOR5, CONR5R6;

R4 stands for H or A;

R5 is H or linear or branched alkyl containing 1, 2 or 3 carbon atoms;

R6 is H or linear or branched alkyl containing 1, 2 or 3 carbon atoms;

Z is absent or represents divalent Ar or divalent Het;

L refers to ( _CH2 ) _n , where one or two _CH2 groups may be replaced by O or CH=CH-, and/or one or two H atoms may be replaced by OR2, NR2R5 or Het1;

divalent Ar refers to 1,2-, 1,3- or 1,4-phenylene optionally substituted with 1-5 groups independently selected from Hal, CN, _-CF3 , _-OCF3 , OH, O-A, _SO2 -A, COOH, COOA, -CO-A, O-phenyl, _SO2 -phenyl, _SO2 - _CF3 , Het2 or A;

divalent Het refers to unsaturated, saturated, or 5- or 6-membered heteroaryl containing from 1 to 2 N, O, or S atoms, it may be unsubstituted or monosubstituted, disubstituted, or trisubstituted with Hal, CN, _-CF3 , _-OCF3 , O-A, SO2 _- A, COOH, COOA, -CO-A, O-phenyl, SO2 _- phenyl, SO2 _{- CF3} , Het2, or A;

A refers to a linear or branched alkyl containing from 1 to 10 C atoms, wherein from 1 to 5 H atoms may be replaced by F, or one or two non-adjacent CH2 groups may be replaced by O;

Het1 means morpholinyl, piperidinyl or pyrrolidinyl;

Het2 means morpholinyl, piperidinyl or pyrrolidinyl;

Hal stands for F, Cl, Br, I;

n represents 1, 2, 3, 4, 5 or 6;

p represents 0, 1, or 2; or

in some embodiments of the present invention, the RTM has the following structure:

or its pharmaceutically acceptable salt; in RTM-34:

is a 3-7-membered nitrogen-containing heterocycloalkyl or heteroaryl containing 0-2 additional heteroatoms independently selected from nitrogen, oxygen or sulfur;

each Ra is independently -R, halogen, -haloalkyl, -OR, -SR, -CN, _-NO2 , -SO2R, -SOR, -C(O)R, _-CO2R , -C(O)N( _R ) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , _-NRSO2R , or -N(R) ₂ ;

ring X is C3-C10 aryl; 5-6 membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; fused C3-C10 aryl; fused 5-10 membered saturated or partially unsaturated cycloalkyl; fused 5-10 membered heterocycloalkyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; or fused 5-10 membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of the foregoing groups is optionally substituted;

R ¹ is -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R, or -N(R) ₃ ;

R ² is -R, -halogen, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R or -N(R) ₂ ;

R ³ is -R or -haloalkyl;

R ⁴ is -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R or -N(R) ₃ ;

Z represents N or CR;

each R is independently hydrogen, deuterium, C1-6 alkyl, C3-C10 aryl, a 3-8-membered saturated or partially unsaturated carbocycle, a 3-7-membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6-membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of the foregoing groups is optionally substituted; or two R on the same atom, together with the atom to which they are attached, form a C3-C10 aryl, a 3- to 8-membered saturated or partially unsaturated carbocycle, a 3- to 7-membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5- to 6-membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of the foregoing groups is optionally substituted; and

p is 0, 1, 2, 3, 4, or 5;

when ring X is phenyl, Z is N, R ¹ is R ² is H, R ³ is n-propyl, and R ⁴ is n-propyl and H, then is not ; or

in some embodiments of the present invention, the RTM has the following structure:

or a pharmaceutically acceptable salt thereof; wherein in RTM-35 or RTM-35a:

B is CH, N or S; D is CH or N; E is CH or N; F is CH or N; G is CH or N; and J is C or N, wherein when B is S, D is CH, E is N, F is CH, G is N, J is C;

X is O, S, _CH2 or N;

M is 0 or 1; n is 0, 1 or 2;

ring A is pyridyl, pyrazolyl, thienyl, furanyl or phenyl,

R ₁ is independently selected from (C1-4)alkyl, pyrimidinyl, piperidinyl or phenyl, each of which is optionally substituted with (C1-4)alkyl, OH, halogen, O(C1-4)alkyl, methylpiperidinyl substituted with S(O) ₂ R _c , C(O)N(Rb) ₂ or C(O)O(C1-C4)alkyl;

R ₂ is absent or represents H;

R ₃ is independently selected from: (C1-C4) alkyl, pyranyl, cyclopentyl, cyclohexyl, cycloheptyl, thiopyranyl, pyrazolyl, piperidinyl, morpholinyl, piperazinyl, each of which is optionally substituted with one or more independently selected from halogen, OH, oxo, N(Rb) ₂ , oxopyrrolidyl or morpholinyl;

or R ₂ and R ₃ together with the nitrogen atom to which they are attached form piperazinyl or morpholinyl, each of which is optionally substituted with oxo;

R ⁴ independently represents H or methyl;

R _b is independently selected from H and (C1-4)alkyl; and

R _c is methyl; or

in some embodiments of the present invention, the RTM has the following structure:

or its pharmaceutically acceptable salt or stereoisomer; and in RTM-37:

X represents NH or O;

b is 0 or 1;

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

R ₁ and R ₂ independently represent H or C1-C4 alkyl; or R ₁ and R ₂ together with the nitrogen atom to which they are attached form a monocyclic or bicyclic heterocyclyl containing 3-8 carbon atoms, in addition to the above-mentioned nitrogen, the heterocyclyl optionally also containing one or two heteroatoms selected from N, O or S, the alkyl and heterocyclyl are optionally substituted with one or more substituents selected from R _a ;

R ₃ is C1-C4 alkyl in which two adjacent alkyls can be joined together to form a bridge ring of 3-6 carbon atoms;

R ₄ is absent, represents halogen or O(C1-C4) alkyl;

R ₅ is halogen, CN, C1-C4 alkyl, O(C1-C4) alkyl, C2-4 alkenyl, aryl, heteroaryl or a non-aromatic ring, alkyl, alkenyl, aryl, heteroaryl and the non-aromatic ring are optionally substituted with one or more R _b ;

R ₆ is absent, represents halogen, O(C1-C4) alkyl;

R _a is independently selected from halogen, oxo, hydroxyl, CF ₃ , O(C1-C4)alkyl, SO ₂ (C1-C4)alkyl, C(O)O(C1-C4)alkyl, C(O)heterocycloalkyl or heterocycloalkyl, wherein the alkyls may be aggregated together to form a bridge ring with another alkyl, and wherein the alkyl and heterocycloalkyl are optionally substituted with R _b ; and

R _b is independently selected from OH, halogen, CHF ₂ , (C1-C4) alkyl, CF ₃ , COOH, SO ₂ (C1-C4) alkyl, C(O)O(C1-C4) alkyl, O(C1-C4) alkyl, aryl, heterocycloalkyl, CN, C(O)N(Rc) ₂ , N(Rc) ₂ ; Rc and alkyl are optionally substituted with OH, O(C1-C4) alkyl, alkyl and heterocycloalkyl;

Rc is independently H, SO ₂ (C1-C4) alkyl, or (C1-C4) alkyl; or

in some embodiments of the present invention, the RTM has the following structure:

and/or its pharmaceutically acceptable salt or stereoisomer, wherein in RTM-38, RTM-38a or RTM-38b:

X represents CH or N;

a is 0 or 1; b is 0 or 1; m is 0, 1, or 2;

ring A is C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl or heterocycle optionally substituted with 1-3 substituents independently selected from R ₁ ;

R ₁ is selected from: H, oxo, (C=O) _a O _b (C1-10) alkyl, (C=O) _a O _b -aryl, (C=O) _a O _b (C2-10) alkenyl, (C=O) _a O _b (C2-10) alkynyl, CO ₂ H, halogen, OH, O _b (C1-6) fluoroalkyl, (C=O) _a NR ₅ R ₆ , CN, (C=O) _a O _b (C3-C8) cycloalkyl, S(O) _m NR ⁵ R ⁶ , SH, S(O) _m - (C1-10) alkyl or (C=O) _a O _b -heterocycloalkyl, alkyl, aryl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from R _a ;

R ² and R ³ are independently selected from: H, (C=O) _a O _b (C1-10)alkyl, (C=O) _a O _b -aryl, C2-10 alkenyl, C2-10 alkynyl, (C=O) _a O _b heterocycloalkyl, CO ₂ H, CN, O _b (C1-6) fluoroalkyl, O _a (C=O) _b NR ₅ R ₆ , CHO, (N=O)R ₅ R ₆ , S(O) _m NR ₅ R ₆ , SH, S(O) _m (C1-C10) alkyl, (C=O) _a O _b -C3-C8 cycloalkyl optionally substituted with one or more substituents selected from R ₁ ; or

R ₂ and R ₃ together with the nitrogen to which they are attached may form a monocyclic or bicyclic heterocyclyl, each ring having 3-7 members, and in addition to nitrogen, the ring optionally further comprises one or two heteroatoms selected from N, O or S; the monocyclic or bicyclic heterocyclyl is optionally substituted with one or more substituents selected from R ₁ ;

R ₄ is selected from C1-C6 alkyl or C3-C6 cycloalkyl and is optionally substituted with R _a ;

R ₅ and R ₆ are independently selected from: H, oxo, (C=O) _a O _b -(C1-10) alkyl, (C=O) _a O _b -aryl, (C=O) _a O _b (C2-10) alkenyl, (C=O) _a O _b -(C2-C10) alkynyl, CO ₂ H, O _b (C1-C6) fluoroalkyl, (C=0) a N(Ra) ₂ , CN, (C=0) _a O _b -(C3-C8)) cycloalkyl, S(O) _m N(Ra) ₂ , SH, S(O) _m (Cl-10) alkyl and (C=O) _a O _b -heterocycloalkyl; alkyl, aryl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from R _a ;

R _a is independently selected from R _b , OH, C1-C6 alkoxy, halogen, cyclopropyl, CO ₂ H, CN, O _a (=O) _b (C1-C6) alkyl, oxo, or N(R _b ) ₂ ;

R _b is independently selected from H or C1-C6 alkyl; or

in some embodiments of the present invention, the RTM has the following structure:

or a pharmaceutically acceptable salt or stereoisomer thereof; wherein in RTM-39 or RTM-39a:

X independently represents CH or N;

Y represents H or methyl;

a is 0 or 1; b is 0 or 1; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4;

ring A is C3-8 picloalkenyl, aryl or heterocycle optionally substituted with 1-3 substituents independently selected from R ₁ ;

R1 is selected from: H, oxo, (C=O) _aOb (C1-10) _alkyl , (C=O) _{aOb -} aryl, ( _{C=O)aOb(C2-10)alkenyl, (C=O)aOb ( C2-10} ) _alkynyl , _CO2H , halogen, OH, _Ob (C1-6) ^{fluoroalkyl, (C=O)aNR5R6 ,} CN, ( ^C =0)aOb(C3-C8)cycloalkyl, S _{(O)mNR5R6, SH, S(O)m-} ⁽ _C1-10 )alkyl or (C=O) _{aOb -} heterocycloalkyl, alkyl, aryl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from Ra;

R ₂ and R ₃ are independently selected from: H, (C=O) _a O _b (C1-10)alkyl, (C=O) _a O _b -aryl, C2-10 alkenyl, C2-10 alkynyl, (C=O) _a O _b heterocycloalkyl, CO ₂ H, CN, O _b (C1-6) fluoroalkyl, O _a (C=O) _b NR ₅ R ₆ , CHO, (N=O)R ₅ R ₆ , S(O) _m NR ₅ R ₆ , SH, S(O) _m (C1-C10) alkyl, (C=O) _a O _b -C3-C8 cycloalkyl optionally substituted with one or more substituents selected from R1; or

R ₂ and R ₃ may form monocyclic or bicyclic heterocyclic rings together with the nitrogen to which they are attached, each ring having 3-7 members, and in addition to nitrogen, the ring optionally further comprises one or two heteroatoms selected from N, O or C; the monocyclic or bicyclic heterocyclic ring is optionally substituted with one or more substituents selected from Ri;

R ₄ is selected from C1-C6 alkyl, hydroxyl, methoxy, CF ₃ or F, the alkyl optionally substituted with hydroxyl;

R5 and R6 are independently selected from: H, oxo, ( _{C=O)aOb-(C1-10)alkyl, (C=O)aOb-aryl, (C=O)aOb ( C2-10 )} alkenyl, (C= _O ) _aOb- (C2-C10)alkynyl, _CO2H , _Ob (C1-C6)fluoroalkyl, (C=O)aN(Ra)2, CN, (C=O) _aOb- (C3-C8)) _cycloalkyl , S(O)mN(Ra)2, SH, S(O)m(C1-10)alkyl and (C=O) _{aOb -} heterocycloalkyl; alkyl, aryl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from Ra;

Ra is independently selected from Rb, OH, C1-C6 alkoxy, halogen, cyclopropyl, _CO2H , CN, Oa(=O)b(C1-C6)alkyl, oxo, or N(Rb)2;

Rb is independently selected from H or C1-C6 alkyl; or

in some embodiments of the present invention, the RTM has the following structure:

or its pharmaceutically acceptable salt; and in RTM-42:

X represents N or CH;

Y is selected from ^-NR2- , _-CH2- , -CHR- or -O-, when Y is -CHR-, R and ^R3 together with the carbon to which they are attached optionally form a 4-6 membered cycloalkyl, cycloalkenyl or heterocycloalkyl, wherein the 4-6 membered cycloalkyl, cycloalkenyl or heterocycloalkyl is optionally substituted with 1-3 substituents, wherein the substituent is independently selected from C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, _CF3 , heterocycloalkyl, halogen, ^-COOR8 , ^-NHR8 , -SRS, ^{-OR8 ,} _-SO2R8 , ^-COR8 , ^-NHCOR8 or ^-CONHR8 ; or when Y is ^-NR2 , ^R2 and ^R3 together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl, the 4-6 membered heterocycloalkyl being optionally substituted with 1-3 substituents independently selected from C1-C3 alkyl, C3-6 cycloalkyl, phenyl, CF3, heterocycloalkyl, halogen, ^-COOR8 , ^-NHR8 , ^-SR8 , ^-OR8 , _-SO2R8 , ^-COR8 , ^-NHCOR8 or ^{-CONHR8 ;}

R ¹ is selected from hydrogen, deuterium, C1-10 alkyl, C3-C6 cycloalkyl, aryl, heterocycloalkyl, halogen, -COOR ⁷ , -NHR ⁷ , -SR ⁷ , -OR ⁷ , -SO ₂ R ⁷ , -COR ⁷ , -NHCOR ⁷ or -CONHR ⁷ ; wherein alkyl, cycloalkyl, aryl and heterocycloalkyl are optionally substituted with 1-3 substituents independently selected from C1-C4 alkyl, C3-C6 cycloalkyl, CN, phenyl, _CF3 , heterocycloalkyl, halogen, ^-COOR8 , ^-NHR8 , ^-SR8 , ^{-OR8 ,} _-SO2R8 , ^-COR8 , ^-NHCOR8 or ^-CONHR8 , wherein ^-NHR8 is optionally substituted with -N(C1-C4 alkyl)N2 or -N(C3-C6 cycloalkyl) _NH2 ;

R ² is selected from hydrogen, deuterium, C1-10 alkyl or C3-C8 cycloalkyl;

R ³ is selected from hydrogen, deuterium, C1-10 alkyl, C3-C8 cycloalkyl, aryl, heterocycloalkyl or -COOR ⁷ ; wherein alkyl, cycloalkyl, aryl and heterocycloalkyl are optionally substituted with 1-3 substituents independently selected from C1-C4 alkyl, C3-6 cycloalkyl, phenyl, CF ₃ , heterocycloalkyl, halogen, -COOR ⁸ , -NHR ⁸ , -SR ⁸ , -OR ⁸ , -SO ₂ R ⁸ , -COR ⁸ , -NHCOR ⁸ or -CONHR ⁸ ;

R ⁶ is selected from C1-10 alkyl, C3-C8 cycloalkyl, aryl, heterocycloalkyl, -COOR ⁷ , -SO ₂ R ⁷ , -COR ⁷ ; wherein the alkyl, cycloalkyl, aryl and heterocycloalkyl are optionally substituted with 1-3 substituents independently selected from C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, CF ₃ , heterocycloalkyl, halogen, -COOR ⁸ , -NHR ⁸ , -SR ⁸ , -OR ⁸ , -SO ₂ R ⁸ , -COR ⁸ , -NHCOR ⁸ or -CONHR ⁸ ;

R ⁷ is selected from hydrogen, deuterium, C1-10 alkyl, C3-C8 cycloalkyl, aryl or heteroaryl; wherein alkyl, cycloalkyl, aryl and heterocycloalkyl are optionally substituted with 1-3 substituents independently selected from C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, CF ₃ , heterocycloalkyl, halogen, -COOR ⁸ , -NHR ⁸ , -SR ⁸ , -OR ⁸ , -SO ₂ R ⁸ , -COR ⁸ , -NHCOR ⁸ or -CONHR ⁸ ;

R ⁸ is selected from hydrogen, deuterium, C1-C6 alkyl or C3-C6 cycloalkyl; or in some embodiments of the present invention, the RTM has the following structure:

or its pharmaceutically acceptable salt; and in RTM-43:

A' represents C=O, C(R) ₂ or NR;

L is selected from C3-C10 aryl, a 3-8-membered saturated or partially unsaturated carbocycle, a divalent 3-7-membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, each of which is optionally substituted;

X represents CR;

Y represents NR or S;

Z represents CR or N;

R ¹ is C3-C10 aryl, a 3-8-membered saturated or partially unsaturated carbocycle, a 3-7-membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6-membered monocyclic heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, each of which is optionally substituted;

R ² is -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R, or -N(R) ₂ ;

each R is independently hydrogen, deuterium, C1-C6 alkyl, C3-C10 aryl, a 3-8-membered saturated or partially unsaturated carbocycle, a 3-7-membered heterocyclyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, each of which is optionally substituted; or two R on the same atom, together with the atom bonded thereto, form a C3-C10 aryl, a 3- to 8-membered saturated or partially unsaturated cycloalkyl, a 3- to 7-membered heterocycloalkyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5- to 6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, each of which is optionally substituted; or

in some embodiments of the present invention, the RTM has the following structure:

or its pharmaceutically acceptable salt; and in RTM-44:

X represents CR or N;

X' is CR or N; wherein at least one of X or X' is N;

Y represents CR or N;

R ¹ is C1-C6 alkyl, C3-C10 aryl, 3-8-membered saturated or partially unsaturated cycloalkyl, 3-7-membered heterocycloalkyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, each of which is optionally substituted;

R ² is C1-C6 alkyl, C3-C10 aryl, 3-8-membered saturated or partially unsaturated cycloalkyl, 3-7-membered heterocycloalkyl containing 1-4 heteroatoms independently selected from nitrogen and oxygen, or 5-6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, each of which is optionally substituted; or

R ² is (CR ² ) _m -C3-C10 aryl, (CR ² ) _m -3-8-membered saturated or partially unsaturated cycloalkyl, (CR ² ) _m -3-7-membered heterocycloalkyl, the heterocycloalkyl has 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or (CR ² ) _m -5-6-membered monocyclic heteroaryl, the heteroaryl has 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, each of which is optionally substituted;

each R ³ is independently -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , NRC(O)R, -NRC(O)N(R) ₂ , -NR SO ₂ R, or -N(R) ₂ ;

each R is independently hydrogen, deuterium, C1-C6 alkyl, C3-C10 aryl, 3-8-membered saturated or partially unsaturated cycloalkyl, 3-7-membered heterocycloalkyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, each of which is optionally substituted; or two R on the same atom together with the atom bonded to them form a C3-C10 aryl, a 3- to 8-membered saturated or partially unsaturated cycloalkyl, a 3- to 7-membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5- to 6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, each of which is optionally substituted;

m is equal to 1 or 2;

n is 0, 1, 2, or 3; or

in some embodiments of the present invention, the RTM has the following structure:

or its pharmaceutically acceptable salt; in RTM-45:

each X and X' independently represents CR or N;

A is O, S, _SO2 , SO, -NRC(O), _-NRSO2 , or -N(R), or A is absent;

R ³ is -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R, or -N(R) ₂ ; or

when A is -NRC(O), _-NRSO2 , or -N(R); then R and ^R3 , together with the atoms to which each is bonded, form a 3-7-membered heterocyclic alkyl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6-membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, each of which is optionally substituted;

ring Z is a 3-7 membered heterocyclic alkyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, each of which is optionally substituted;

R ¹ is -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R or -N(R) ₂ ; R ^a is absent or is -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R or -N(R) ₂ ;

ring Y is an optionally substituted 5-6 membered monocyclic heteroaryl containing 2-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

R ² is -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R, or -N(R) ₂ ;

R ^b is absent or is -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R or -N(R) ₂ ;

each R is independently hydrogen, deuterium, C1-C6 alkyl, C3-C10 aryl, 3-8-membered saturated or partially unsaturated cycloalkyl, 3-7-membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, each of which is optionally substituted; or two R on the same atom, together with the atom to which they are attached, form a C3-C10 aryl, a 3- to 8-membered saturated or partially unsaturated cycloalkyl, a 3- to 7-membered heterocycloalkyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5- to 6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which is optionally substituted;

wherein when X is N and A is absent, then R3 is not H; or in some embodiments of the present invention, RTM has the following structure:

or its pharmaceutically acceptable derivatives, solvates, tautomers, salts, hydrates and stereoisomers, including mixtures thereof in all proportions; in RTM-46:

R'' is H, C1-C6 alkyl, C3-C10 aryl, 3-8-membered saturated or partially unsaturated cycloalkyl, 3-7-membered heterocycloalkyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, each of which is optionally substituted;

R ¹ is absent or represents A or QR;

R ^a is absent or represents OR ³ , CF ₃ , Hal, NO ₂ ;

R ^b is absent or represents A or COR;

^R2 is independently C1-6 alkyl, C3-C10 aryl, 3-8-membered saturated or partially unsaturated cycloalkyl, 3-7-membered heterocycloalkyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, each of which is optionally substituted;

each Q is independently a linear or branched alkylene containing 1-6 carbon atoms, in which 1-5 hydrogen atoms may be independently replaced by groups selected from OR ³ , Hal, N(R ³ ) ₂ , and in which 1 or 2 -CH2- groups may be independently replaced by CO, SO, SO ₂ or NR ³ , or Q is a 4-8-membered saturated, unsaturated heterocycloalkyl or heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each A is independently a linear or branched alkyl containing 1-10 carbon atoms, in which 1-7 hydrogen atoms may be independently replaced by groups selected from -OR ³ , Hal, NHSO ₂ A, SO ₂ A, SOA, N(R ³ ) ₂ , and in which 1, 2 or 3 non-adjacent -CH ₂ - groups may be independently replaced by -CO-, NR ³ or -O-,

each Hal represents F, Cl, Br or I,

each R'' is independently hydrogen, C1-C6 alkyl, C3-C10 aryl, 3-8-membered saturated or partially unsaturated alkyl, 3-7-membered heterocycloalkyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, each of which is optionally substituted;

each R ³ is H or C1-C6 alkyl in which one hydrogen atom may be replaced by a group selected from OH, O-(C1-C6 alkyl) or Hal;

n is 0 or 1; or

in some embodiments of the present invention, the RTM has the following structure:

or its pharmaceutically acceptable salt; and in RTM-47:

Z represents

X represents CH or N;

Y represents CH or N;

R ^a , R ^c and R1 each independently represent H, Hal or A1;

R ^b is H or C1-12 alkyl;

A1 is C1-12 branched or linear alkyl in which 1-7 H atoms are optionally replaced by Hal, OR ^b , COOR ^b , CN or N(R ^b ) ₂ , and in which 1-5 -CH ₂ - groups are optionally replaced by O, CO, NR ^b or S, SO, SO ₂ , 1,2-, 1,3- or 1,4-phenylene, -CH=CH- or And

Hal stands for F, Cl, Br, I; or

in some embodiments of the present invention, the RTM has the following structure:

or its pharmaceutically acceptable salt; and in RTM-48:

R ⁰ represents hydrogen or C1-C4 alkyl, wherein C1-C4 alkyl is optionally monosubstituted or polysubstituted by the same or different groups selected from hydroxyl and halogen;

R ¹ is hydrogen, deuterium, halogen, cyano, C(O)OH, C(O)OR ^a , C(O)NH ₂ , C(O)N(H)R ^a , C(O)N(R ^a )R ^b , C(O)R _d , hydroxyl or C1-C6 alkyl, C1-C6 alkyl optionally monosubstituted or polysubstituted with the same or different groups selected from the following: hydroxy, halogen, cyano, C(O)OH, C(O)OR ^a , S(O) ₂ C1-C6 alkyl, NH ₂ , NHR ^a , N(R ^a )R ^b , C1-C6 alkoxy optionally monosubstituted or polysubstituted with the same or different groups selected from halogen, C3-C8 cycloalkyl-O-, optionally monosubstituted or polysubstituted with the same or different groups selected from halogen, heterocycloalkyl a, optionally monosubstituted or polysubstituted by the same or different groups selected from R ^c , or is C1-C6 alkoxy, wherein C1-C6 alkoxy is optionally monosubstituted or polysubstituted by the same or different groups selected from the following: hydroxy, halogen, cyano, C(O)OH, C(O)OR ^a , S(O) ₂ C1-C6 alkyl, NH ₂ , NHR ^a , N(R ^a )R ^b , C3-C8 cycloalkyl, optionally monosubstituted or polysubstituted by the same or different groups selected from halogen, C1-C6 alkoxy, optionally monosubstituted or polysubstituted by the same or different groups selected from halogen, C3-C8 cycloalkyl-O-, optionally monosubstituted or polysubstituted by the same or different groups selected from halogen, heterocycloalkyl optionally monosubstituted or polysubstituted by the same or different groups selected from R ^c , aryl optionally monosubstituted or polysubstituted by the same or different groups selected from R ^c , 5- or 6-membered heteroaryl optionally monosubstituted or polysubstituted by the same or different groups selected from R ^c , or is C3-C8-cycloalkyl-O- or heterocycloalkyl-O- which is optionally monosubstituted or polysubstituted by the same or different groups selected from the following: hydroxyl, halogen, cyano or C1-C6 alkyl, or is aryl-O- or 5-membered or 6-membered heteroaryl-O-, wherein aryl-O- and 5-membered or 6-membered heteroaryl-O- may be optionally monosubstituted or polysubstituted by the same or different groups selected from the following: hydroxyl, halogen, cyano, C(O)OH, C(O)OR ^a , C1-C6 alkyl or C1-C6 alkoxy, or is C3-C8 cycloalkyl or heterocycloalkyl which may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: hydroxyl, halogen, cyano and C1-C6 alkyl, or is C2-6 alkenyl or C2-6 alkynyl, or is aryl, 5- to 10-membered heteroaryl, aryl-C1-C4 alkyl or 5-membered or 6-membered heteroaryl-C1-C4 alkyl, wherein aryl and heteroaryl may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: halogen, hydroxyl, cyano, C(O)OH, C(O)OR ^a , C1-C6 alkyl, C3-C8 cycloalkyl or C1-C6 alkoxy;

R ^a is C1-C6 alkyl, C3-C10 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally monosubstituted or polysubstituted with the same or different groups selected from the following: halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 alkoxy, heterocycloalkyl, -C(O)0C1-C6 alkyl or S(O) _2C1 -C6 alkyl;

R ^b is C1-C6 alkyl or C3-C10 cycloalkyl;

or R ^a and R ^b together with the nitrogen atom form a 5- or 6-membered heterocyclyl, wherein the 5- or 6-membered heterocyclyl may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: hydroxyl, halogen, cyano or C1-C6 alkyl;

R ^c is hydroxyl, halogen, cyano, C1-C3 alkyl or C1-C3 alkoxy;

R _d is hydrogen, deuterium, C1-C6 alkyl or C3-C10 cycloalkyl;

R ² is hydrogen, deuterium, C1-C6 alkyl or C3-C6 cycloalkyl;

R ¹³ is hydrogen or C1-C6 alkyl;

W is a 5-membered heteroaryl that contains one to three heteroatoms selected from N, O or S and may be optionally monosubstituted

R ³ and may be optionally monosubstituted or polysubstituted by the same or different R ⁴ , or W is pyridyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl or 1,3,5-triazinyl, each of which may be optionally monosubstituted by R ³ and optionally mono- or multiply substituted by the same or different R ⁴ ;

R ³ is hydrogen, deuterium, halogen, cyano, C(O)R ^a , NH ₂ , NHR ^a , N(R ^a )R ^b , N(H)C(O)R ^a or C1-C6 alkyl, wherein C1-C6 alkyl may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: hydroxyl, halogen, cyano, C(O)R ^a , C(O)OH, C(O)OR ^a , S(O) ₂ -C1-C6 alkyl, NH ₂ , NHR ^a , N(R ^a )R ^b , C1-C6 alkoxy, C3-C8 cycloalkyl-O-, wherein C1-C6 alkoxy and C3-C8 cycloalkyl-O- may be optionally monosubstituted or polysubstituted with the same or different halogens; or C1-C6-alkyl is optionally monosubstituted or polysubstituted by the same or different groups selected from the following: C3-C6-cycloalkyl and heterocycloalkyl, wherein C3-C6-cycloalkyl and heterocycloalkyl may be optionally monosubstituted, disubstituted and trisubstituted by the same or different groups selected from the following: halogen, cyano, C1-C3-alkyl and C1-C3-alkoxy, or C1-C6-alkyl is optionally monosubstituted or polysubstituted by the same or different groups selected from the following: aryl and 5-membered or 6-membered heteroaryl, aryl and 5-membered or 6-membered heteroaryl may be optionally monosubstituted, disubstituted or trisubstituted by the same or different groups selected from the following: halogen, cyano, C1-C3-alkyl and C1-C3-alkoxy, or

R ³ is C1-C6 alkoxy, wherein C1-C6 alkoxy may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: hydroxyl, halogen, cyano, C(O)OR ^a , S(O) ₂ -C1-C6-alkyl, N(R ^a )R ^b , C3-C8-cycloalkyl, C1-C4-alkoxy, C3-C8-cycloalkyl-O-, or is C3-C6-cycloalkyl, heterocycloalkyl or C5-C11-spiroalkyl, wherein cycloalkyl, heterocycloalkyl and spiroalkyl may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: hydroxyl, halogen, cyano, C(O)R ^a , C(O)OH, C(O)OR ^a , C1-C6-alkyl and C1-C4-alkoxy; or is aryl or 5- to 10-membered heteroaryl, wherein aryl and heteroaryl may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: halogen, hydroxyl, cyano, C(O)OR ^a , S(O) ₂ -C1-C6 alkyl, NO ₂ , NH ₂ , NHR ^a , N(R ^a )R ^b , N(H)C(=O)R ^a , C3-C8 cycloalkyl, C1-C3 alkoxy and C1-C3 alkyl, wherein C1-C3 alkyl may be optionally monosubstituted or polysubstituted with the same or different halogens;

R ⁴ is halogen, hydroxyl, cyano or C1-C6 alkyl, wherein C1-C6 alkyl may be optionally mono-substituted or poly-substituted by the same or different groups selected from halogen; C1-C6 alkoxy, wherein C1-C6 alkoxy may be optionally mono-substituted or poly-substituted by the same or different groups selected from halogen; C2-6 alkenyl; C2-6 alkynyl; C3-C10 cycloalkyl; 3-10-membered heterocycloalkyl and aryl, wherein aryl may be optionally mono- or multi-substituted by the same or different R, or

R ⁴ is aryl or heteroaryl which may optionally be monosubstituted or polysubstituted by the same or different R, or

R ⁴ represents C(O)R ^a , C(O)NH ₂ , C(O)N(H)R ^a , C(O)N(R ^a )R ^b , C(O)OR ^a , NH ₂ , NHR ^a , N(R ^a )R ^b , N(H)C(O)R ^a , N(R ^a )C(O)R ^a , N(H)C(O)NH ₂ , N(H) C(O)NHR ^a , N(H)C(O)N(R ^a )R ^b , N(R ^a C(O)) NH ₂ , N(R ^a )C(O)NHR ^a , N(R ^a )C(O)N(R ^a )R ^b , N(H)C(O)OR ^a , N(R ^a )C(O)OR ^a , NO ₂ , N(H)S(O)R ^a , N(R ^a )S(=O)R ^a , N(H)S(O) ₂ R ^a , N(R ^a )S(O) ₂ R ^a , N=S(O)(R ^a )R ^b , OC(O )R ^a , OC(O)NH ₂ , OC(O)NHR ^a , OC(O)N(R ^a )R ^b , SH, SR ^a , S(O)R ^a , S(O) ₂ R ^a , S(O) ₂ NH ₂ , S(O) ₂ NHR ^a , S(O) ₂ N(R ^a )R ^b or S(O)(=NR ^a )R ^b ;

R is halogen, cyano, C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, aryl, heteroaryl, C(O)R ^a , C(O)NH ₂ , C(O)N(H)R ^a , C(O)N(R ^a )R ^b , C(O)OR ^a , NH ₂ , NHR ^a , N(R ^a )R ^b , N(H)C(O)R ^a , N(R ^a )C(O)R ^a , N(H)C(O)NH ₂ , N(H)C(O)NHR ^a , N(H)C(O)N(R ^a )R ^b , N(R ^a )C(O)NH ₂ , N(R ^a )C(O)NHR ^a , N(R ^a )C(O)N(R ^a )R ^b , N(H)C(O)OR ^a , N(R ^a )C(O)OR ^a , NO ₂ , N(H)S(O)R ^a , N(R ^a )S(O)R ^a , N(H)S(O) ₂ R ^a , N(R ^a )S(O) ₂ R ^a , N=S(O)(R ^a )R ^b , OH, -C6-alkoxy, OC(O)R ^a , OC(O)NH ₂ , OC(O)NHR ^a , OC(O)N(R ^a )R ^b , SH, SR ^a , S (O)R ^a , S(O) ₂ R ^a , S(O) ₂ NH ₂ , S(O) ₂ NHR ^a , S(C-) ₂ N(R ^a )R ^b or S(O)(=NR ^a )R ^b ;

n represents 0 or 1;

Y represents a group selected from

or ,

where * represents the point at which the group is attached to the rest of the molecule;

R ⁵ is hydrogen, deuterium, C1-C6 alkyl or C3-C10 cycloalkyl, wherein C1-C6 alkyl may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: hydroxyl, halogen, cyano, C(O)OH, C(O)OR ^a , S(O) ₂ -C1-C6 alkyl, N(R ^a )R ^b , C1-C4 alkoxy or C3-C8 cycloalkyl;

R ⁶ is hydrogen or C1-C6 alkyl, wherein C1-C6 alkyl may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: hydroxyl, halogen, cyano, C3-C10 cycloalkyl, C(O)R ^a , C(O)OH, C(O)OR ^a , S(O) ₂ -C1-C6 alkyl, N(R ^a )R ^b , C1-C4 alkoxy or C3-C8 cycloalkyl-O-, or is C3-C10 cycloalkyl, wherein C3-C10 cycloalkyl may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: hydroxyl, halogen, cyano or C1-C6 alkyl, wherein C1-C6 alkyl may be optionally substituted with hydroxyl, or is heterocycloalkyl, wherein heterocycloalkyl may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: halogen, cyano, C1-C3-alkyl or C1-C3-alkoxy, or is aryl or 5-membered or 6-membered heteroaryl, wherein aryl and 5-membered or ⁶ -membered heteroaryl may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: halogen, cyano, C1-C3-alkyl, C1-C3-alkoxy, S(O) _2NH2 , S(O) _2NHRa and S( _O ) _2N ( ^Ra ) ^Rb ;

R ^7a represents hydrogen, deuterium, halogen, N(R ^a )R ^b , C1-C6 alkyl or C3-C10 cycloalkyl, wherein C1-C6 alkyl may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: hydroxyl, halogen, cyano, C(O)OH, C(O)OR ^a , S(O) ₂ -C1-C6 alkyl, N(R ^a )R ^b , C1-C4 alkoxy, C3-C8 cycloalkyl and heterocycloalkyl;

R ^7b represents hydrogen, deuterium, halogen or C1-C6-alkyl, wherein C1-C6-alkyl may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: hydroxyl, halogen, cyano, C(O)OH, C(O)OR ^a , S(O) ₂ -C1-C6 alkyl, N(R ^a )R ^b , C1-C4-alkoxy, C3-C8-cycloalkyl or heterocycloalkyl; or

R ^7a and R ^7b together with the carbon atom form C3-C6-cycloalkyl, C3-C6-cycloalkyl may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: hydroxyl, halogen, cyano and C1-C6-alkyl, or

R ^7a and R ^7b together represent oxo;

R ^7c represents hydrogen, deuterium, halogen, N(R ^a )R ^b , C1-C6-alkyl or C3-C10-cycloalkyl, wherein C1-C6-alkyl may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: hydroxyl, halogen, cyano, C(O)OH, C(O)OR ^a , S(O) ₂₂ -C1-C6-alkyl, N(R ^a )R ^b , C1-C4-alkoxy, C3-C8-cycloalkyl or heterocycloalkyl;

R ^7d represents hydrogen, deuterium, halogen or C1-C6-alkyl, wherein C1-C6-alkyl may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: hydroxyl, halogen, cyano, C(O)OH, C(O)OR ^a , S(O) ₂ -C1-C6 alkyl, N(R ^a )R ^b , C1-C4 alkoxy, C3-C8-cycloalkyl or heterocycloalkyl; or

R ^7c and R ^7d together with the carbon atom form C3-C6-cycloalkyl, and C3-C6-cycloalkyl may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: hydroxyl, halogen, cyano or C1-C6-alkyl, or

R ^7c and R ^7d together are oxo;

R ^8a represents hydrogen, deuterium, halogen, N(R ^a )R ^b , C1-C6 alkyl or C3-C10 cycloalkyl, wherein C1-C6 alkyl may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: hydroxyl, halogen, cyano, C(O)OH, C(O)OR ^a , S(O) ₂ C1-C6 alkyl, N(R ^a )R ^b , C1-C4 alkoxy, C3-C8 cycloalkyl or heterocycloalkyl;

R ^8b represents hydrogen, deuterium, halogen or C1-C6 alkyl, wherein C1-C6 alkyl may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: hydroxyl, halogen, cyano, C(O)OH, C(O)OR ^a , S(O) ₂ C1-C6 alkyl, N(R ^a )R ^b , C1-C4 alkoxy, C3-C8 cycloalkyl or heterocycloalkyl; or

R ^8a and R ^8b together with the carbon atom form C3-C6-cycloalkyl, and C3-C6-cycloalkyl may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: hydroxyl, halogen, cyano or C1-C6-alkyl;

R ^8c represents hydrogen, deuterium, halogen, N(R ^a )R ^b , C1-C6 alkyl or C3-C10 cycloalkyl, wherein C1-C6 alkyl may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: hydroxyl, halogen, cyano, C(O)OH, C(O)OR ^a , S(O) ₂ C1-C6 alkyl, N(R ^a )R ^b , C1-C4 alkoxy, C3-C8 cycloalkyl or heterocycloalkyl;

R ^8d represents hydrogen, deuterium, halogen or C1-C6 alkyl, wherein C1-C6 alkyl may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: hydroxyl, halogen, cyano, C(O)OH, C(O)OR ^a , S(O) ₂ -C1-C6 alkyl, N(R ^a )R ^b , C1-C4 alkoxy, C3-C8 cycloalkyl or heterocycloalkyl; or

R ^8c and R ^8d together with the carbon atom form C3-C6-cycloalkyl, and the C3-C6-cycloalkyl may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: hydroxyl, halogen, cyano or C1-C6-alkyl, or

R ^8c and R ^8d together represent oxo;

o represents 0, 1, or 2;

p represents 0, 1, or 2;

q represents 0, 1, or 2;

r is 0, 1, or 2;

s represents 0, 1, or 2;

where o, p, q, r and s do not simultaneously represent 0;

Z is selected from C(=O), CR ⁹ R ¹⁰ , NR ¹¹ , O, S, S(O) or S(O) ₂ ;

R ⁹ is hydrogen or C1-C6 alkyl,

R ¹⁰ is hydrogen, deuterium, halogen, cyano, C(O)R ^a , C(O)OH, C(O)OR ^a , C(O)NH ₂ , C(O)N(H)R ^a , C(O)N(R ^a )R ^b , N(H)C(O)R ^a , N(R ^b )C(O)R ^a , S(O) ₂ R ^a , hydroxyl, N(R ^a )R ^b or C1-C6 alkyl, C1-C6 alkyl may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: hydroxyl, halogen, cyano, C(O)R ^a , C(O)OH, C(O)OR ^a , S(O) ₂ C1-C6 alkyl, N(R ^a )R ^b , C1-C4 alkoxy and C3-C8 cycloalkyl-O-, or is C1-C6-alkoxy, wherein C1-C6-alkoxy may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: hydroxyl, halogen, cyano, C(O)OH, C(O)OR ^a , S(O) ₂ C1-C6 alkyl, N(R ^a )R ^b , C3-C8-cycloalkyl, C1-C4-alkoxy, C3-C8-cycloalkyl-O-, heterocycloalkyl, aryl or 5- or 6-membered heteroaryl, wherein aryl and 5-membered or 6-membered heteroaryl may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: halogen, cyano, C1-C3 alkyl and C1-C3 alkoxy, or is aryl-O- or 5-membered or 6-membered heteroaryl-O-, wherein aryl-O- and 5-membered or 6-membered heteroaryl-O- may be optionally monosubstituted or polysubstituted by the same or different groups selected from the following: hydroxyl, halogen, cyano, C(O)OH, C(O)OR ^a , C1-C3 alkyl or C1-C3 alkoxy, or is C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C4 alkyl, heterocycloalkyl or heterocycloalkyl-C1-C4 alkyl, which may be optionally monosubstituted or polysubstituted by the same or different groups selected from the following: hydroxyl, halogen, cyano, C(O)R ^a , C(O)OH, C(O)OR ^a , C1-C6 alkyl or C1-C6 alkoxy, wherein C1-C6 alkoxy may be optionally monosubstituted or polysubstituted by the same or different halogens or oxo; or is C2-6 alkenyl or C2-6 alkynyl, or is aryl, 5- to 10-membered heteroaryl, aryl-C1-C4 alkyl or 5- or 6-membered heteroaryl-C1-C4 alkyl, wherein aryl and heteroaryl may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: halogen, hydroxyl, cyano, C(O)OH, C(O)OR ^a , NHR ^a , N(R ^a )R ^b , C1-C3 alkyl, C3-C8 cycloalkyl or C1-C3 alkoxy;

or R ⁹ and R ¹⁰ together with the carbon atom form a C3-C8 cycloalkyl or a 4-6-membered heterocycloalkyl, wherein the C3-C8 cycloalkyl or 4-6-membered heterocycloalkyl may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: hydroxyl, halogen, cyano, C1-C6 alkyl, C(O) ^Ra or oxo;

R ¹¹ represents hydrogen, deuterium, C(O)R ^a , C(O)OR ^a , C(O)NH ₂ , C(O)N(H)R ^a , C(O)N(R ^a )R ^b , S(O) ₂ R ^a , S(O) ₂ N(R ^a )R ^b or C1-C6 alkyl, C1-C6 alkyl may be optionally monosubstituted or polysubstituted with the same or different groups selected from the following: hydroxyl, halogen, cyano, C(O)R ^a , C(O)OR ^a , C(O)NH ₂ , C(O)N(H)R ^a , C(O)N(R ^a )R ^b , S(O) ₂ C1-C6 alkyl, N(R ^a )R ^b , C3-C8 cycloalkyl, C1-C4 alkoxy or C3-C8-cycloalkyl-O-, wherein C3-C8-cycloalkyl, C1-C4-alkoxy and C3-C8-cycloalkyl-O- may be optionally mono- or polysubstituted with the same or different selected groups from hydroxyl and halogen; or is C3-C8 cycloalkyl, heterocycloalkyl or heterocycloalkyl-C1-C4 alkyl which may be optionally mono- or polysubstituted by the same or different groups selected from the following: hydroxy, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, wherein alkyl and alkoxy may be optionally monosubstituted or polysubstituted by the same or different groups selected from halogen and oxo, or is C2-6 alkenyl or C2-6 alkynyl, or is aryl, 5- to 10-membered heteroaryl, aryl-C1-C4 alkyl, or 5-membered or 6-membered heteroaryl-C1-C4 alkyl, wherein aryl and heteroaryl may be optionally monosubstituted or polysubstituted by the same or different groups selected from the following: halogen, hydroxyl, cyano, C(O)OH, C(O)OR ^a , C1-C3 alkyl, C3-C8 cycloalkyl or C1-C3 alkoxy; or

in some embodiments of the present invention, the RTM has the following structure:

or a pharmaceutically acceptable salt, solvate, or solvate salt thereof; wherein in RTM-49:

Cy is a monocyclic C3-7 cycloalkyl which is optionally substituted with one or more independently selected R ³ , or a 4-7-membered monocyclic heterocycloalkyl containing one or two heteroatoms independently selected from N, S or O and optionally substituted with one or more groups independently selected from R ³ ;

R ¹ is H, SO ₃ H, P(O)(OH) ₂ , C1-C4 alkyl, C(O)-(4- to 7-membered monocyclic heterocycloalkyl containing one or two heteroatoms independently selected from N, S and O), or C(O)C1-C6 alkyl, C1-C6 alkyl optionally substituted with one or more independently selected R ⁴ groups;

R ² is H or C1-C4 alkyl;

each R ³ is independently selected from: OH, oxo, halogen, or C1-C4 alkyl;

each R ⁴ is independently selected from: -NR ^5a R ^5b , -C(O)OH, 4- to 7-membered monocyclic heterocycloalkyl containing one or two heteroatoms independently selected from N, S and O and optionally substituted with one or more independently selected C1-C4 alkyl, or -NHC(O)-C1-C4 alkyl-NH ₂ ; and

R ^5a and R ^5b independently represent H or C1-C4 alkyl; or

in some embodiments of the present invention, the RTM has the following structure:

or a pharmaceutically acceptable salt thereof; wherein in RTM-50, RTM-50, RTM-50 or RTM-50:

ring A is selected from phenyl or 5- or 6-membered heteroaryl;

ring B is selected from phenyl or 5- or 6-membered heteroaryl;

n is 0, 1 or 2;

p is 0, 1, or 2;

one of W and X is N, and the other of W and X is C; Y is N or CR ² ;

R ¹ is selected from C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C6 cycloalkyl, 3-6 membered saturated heterocycloalkyl, halogen, -CN, -C(R ^1a )=NR(OR ^1a ), -C(R ^1a )=N(R ^1a ), -C(O)R ^1a , -C(O) ₂ R ^1a , -C(O)NR ^1a , -NO ₂ , -N(R ^1a ) ₂ , -N(R ^1a )C(O)R ^1a , -NR ^1a C(O) ₂ R ^1a , -N(R ^1a )C(O) N(R) N(R ^1a ) ₂ , -N(R ^1a )S(O) ₂ R ^1a , -OR ^1a , -OC(O)R ^1a , -OC(O) N(R ^1a ) ₂ , -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -S(O) N( R ^1a ) ₂ or -S(O) ₂ N(R ^1a ) ₂ , wherein C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C6 cycloalkyl, 3-6-membered saturated heterocycloalkyl is optionally substituted with one or more than R ¹⁰ ; or two R ¹ substituents together with the atoms to which they are attached form a C5-7-cycloalkyl or saturated 5- to 7-membered heterocyclyl, wherein the C5-7-cycloalkyl or saturated 5- to 7-membered heterocyclyl is optionally substituted with one or more R ¹⁵ ;

R ^1a is independently selected from H, C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 6-membered monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl, in each occurrence wherein each of the C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 6-membered monocyclic cycloalkyl, and 3- to 6-membered monocyclic heterocycloalkyl is independently optionally substituted with one or more R ¹⁰ ;

R ¹⁰ is independently selected from C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 6-membered cycloalkyl, 3-6-membered heterocycloalkyl, halogen, -CN, -C(R ^10a )=NR( OR ^10a ), -C(R ^10a )=N(R ^10a ), -C(O) R ^10a , -C(O) ₂ R ^10a , -C(O) N(R ^10a ) ₂ , -NO ₂ , -N(R ^10a ) ₂ , -N(R ^10a ) C(O) R ^10a , -N( R ^10a ) C(O) ₂ R ^10a , -N(R ^10a ) C(O) N(R ^10a ) ₂ , -N(R ^10a ) S(O) ₂ R ^10a , -OR ^10a , -OC(O) R ^10a , -OC(O) N(R ^10a ) ₂ , -SR ^10a , -S(O) R ^10a , -S(O) ₂ R ^10a , -S(O) N(R ^10a ) ₂ and -S(O) ₂ N(R ^10a ) ₂ , in each case;

R ^10a is independently selected from H and C1-C6 alkyl, at each occurrence, wherein the C1-C6 alkyl is optionally substituted with one or more halogens;

R ¹⁵ is independently selected from C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, halogen, -CN, -C(R ^15a )=NR(OR ^15a ), -C(R ^15a )=N(R ^15a ), -C (O)(R ^15a ), -C (O) ₂ (R ^15a ), -C (O) N(R ^15a ) ₂ , -NO ₂ , -N(R ^15a )C (O)( _R ^15a ), ^{-N(R 15a )C (O) 2 (R 15a ), N(R 15a )} _C ^{( O} ) N(R ^15a ) ₂ , N(R ^15a )S(O) ₂ (R ^15a ), -OR ^15a , -OC(O)R ^15a , -OC(O) N(R ^15a ) ₂ , -SR ^15a , -S(O)R ^15a , -S(O) ₂ (R ^15a ), -S(O) N(R ^15a ) 2 and -S(O) ₂ N(R ^15a ) ₂ , in each case;

R ^15a is independently selected from H and C1-C6 alkyl, at each occurrence, wherein the C1-C6 alkyl is optionally substituted with one or more halogens;

R is selected from H, C1-C8 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, halogen, -CN, -C(R ^2a )=NR(OR ^2a ), -C(R ^2a )=N(R ^2a ), -C (O)(R ^2a ), -C (O) ₂ (R ^2a ), -C (O) N(R ^2a ) ₂ , -NO ₂ , -N(R ^{2a )} C (O)( _R ^2a ), -N(R ^2a )C (O) ₂ (R ^2a ), N(R ^2a )C (O) N(R ^2a ) ₂ , N(R ^2a )S(O) ₂ ( ^R2a ), ^-OR2a , -OC(O) ^R2a , -OC(O)N( ^R2a ) ₂ , ^-SR2a , -S(O) ^R2a , -S(O) ₂ ( ^R2a ), -S(O)N( ^R2a ) ₂ and -S(O) _2N ( ^R2a ) ₂ , wherein C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-7-membered cycloalkyl and 3-7-membered heterocycloalkyl are optionally substituted with one or more R;

R ^2a is independently selected from H and C1-C6 alkyl, at each occurrence, wherein C1-C6 alkyl at each occurrence is optionally and independently substituted with one or more R ²⁰ ;

R ²⁰ is independently selected from C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3-7 membered saturated heterocycloalkyl, halogen, -CN, -C(R ^20a )=NR(OR ^20a ) , -C(R ^20a )=N(R ^20a ), -С (O)(R ^20a ), -С (O) ₂ (R ^20a ), -C (O) N(R ^20a ) ₂ , -NO ₂ , -N(R ^20a ) ₂ , -N(R ^20a )C (O)(R ^20a ), -N (R ^20a )C (O) ₂ (R ^20a ), N(R ^20a )C (O) N(R ^20a ) ₂ , N(R ^20a )S(O) ₂ (R ^20a ), -OR ^20a , -OC(O)R ^20a , -OC(O) N(R ^20a ) ₂ , -SR ^20a , -S(O)R ^20a , -S(O) ₂ (R ^20a ), -S(O) N(R ^20a ) ₂ and -S(O) ₂ N(R ^20a ) ₂ , in each case, wherein C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl and 3-7 membered saturated heterocycloalkyl are optionally and independently substituted with one or more R, in each case;

R ^20a is independently selected from H and C1-C4 alkyl, in each occurrence, wherein the C1-C4 alkyl is optionally substituted with R;

R ²⁵ is selected from halogen and -OR ^25a ;

R ^25a is selected from H and C1-C6 alkyl;

R is selected from C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C6 cycloalkyl, 3-6-membered saturated heterocycloalkyl, halogen, -CN, -C(R ^3a )=NR(OR ^3a ), -C(R ^3a )=N(R ^3a ), -C (t))(R ^3a ), -C (O) ₂ (R ^3a ), -C (O) N(R ^3a ) ₂ , -NO ₂ , -N(R ^3a ) ₂ , -N(R ^3a )C (O)(R ^3a ), -N(R ^3a )C (C-) ₂ (R ^3a ), N(R ^3a )C (O) N(R ^3a ) ₂ , N(R ^3a )S(C-) ₂ (R ^3a ), -OR ^3a , -OC(C-)R ^3a , -OC(O) N(R ^3a ) ₂ , -SR ^3a , -S(O)R ^3a , -S(C-) ₂ (R ^3a ), -S(O) N(R ^3a ) ₂ and -S(O) ₂ N(R ^3a ) ₂ , wherein C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C6 cycloalkyl and 3-6-membered saturated heterocycloalkyl are optionally substituted with one or more R;

R ^3a is independently selected from H, C1-C6 alkyl, 3-6-membered cycloalkyl, and 3-6-membered heterocycloalkyl, at each occurrence, wherein the C1-C6 alkyl, 3-6-membered cycloalkyl, and 3-6-membered heterocycloalkyl are optionally and independently substituted with one or more R, at each occurrence;

R is independently selected from C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, halogen, -CN, -C(R ^30a )=NR(OR ^30a ), -C(R ^30a )=N(R ^30a ), -C (O)( _R ^30a ), -C (O) ₂ (R ^30a ), -C (O) N(R ^30a ) ₂ , -NO ₂ , -N(R ^30a ) _C (O)(R ^30a ), -N(R ^30a )C (O) ² (R ^30a ), N(R ^30a )C (O) N(R ^30a ) ₂ , N(R ^30a )S(O) ₂ (R ^30a ), -OR ^30a , -OC(O)R ^30a , -OC(O) N(R ^30a ) ₂ , -SR ^30a , -S(O)R ^30a , -S(O) ₂ (R ^30a ), -S(O) N(R ^30a ) 2 and -S(O) ₂ N(R ^30a ) ₂ , at each occurrence, wherein C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl are optionally and independently substituted with one or more R at each occurrence;

R ^30a is independently selected from H and C1-C4 alkyl, at each occurrence, wherein the C1-C4 alkyl is optionally substituted with one or more R;

R ³⁵ is independently selected from halogen and -OR ^35a , at each occurrence;

R ^35a is independently selected from H and C1-C6 alkyl at each occurrence;

R ⁴ is selected from H, halogen, C1-C4 alkyl, N(R ^4a ) ₂ and -OR ^4a ; And

R ^4a is independently selected from H and C1-C6 alkyl, at each occurrence; or

in some embodiments of the present invention, the RTM has the following structure:

and/or its pharmaceutically acceptable salt, wherein in RTM-51, RTM-51a, RTM-51b or RTM-51c:

ring A is selected from phenyl and 5- or 6-membered heteroaryl; ring B is selected from phenyl and 5- or 6-membered heteroaryl; ring C is 3- to 6-membered cycloalkyl,

N is 1, 2 or 3;

P is 0, 1 or 2;

one of W and X is N, and the other of W and X is C; Y is N or CR ² ;

R ¹ is selected from C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, -CN, -C(R ^1a )=NR(OR ^1a ), -C(R ^1a )=N(R ^1a ), -C (O)(R ^1a ), -C (O) ₂ (R ^1a ), -C (O) N(R ^1a ) ₂ , -NO ₂ , -N(R ^1a ) ₂ , -N(R ^1a )C (O)(R ^1a ), -N(R ^1a )C (O) ₂ (R ^1a ), N(R ^1a )C (O) N( R ^1a ) ₂ , N(R ^1a )S(O) ₂ (R ^1a ), -OR ^1a , -OC(O)R ^1a , -OC(O) N(R ^1a ) ₂ , -SR ^1a , -S(O)R ^1a , -S(O) ₂ (R ^1a ), -S(O) N(R ^1a ) 2 or -S( O) ₂ N(R ^1a ) ₂ , wherein C1-C6 alkyl, C2-6 alkenyl and C2-6 alkynyl are optionally substituted with one or more R ¹⁰ ;

R ^1a is independently selected from H or C1-C6 alkyl, at each occurrence, wherein C1-C6 alkyl is optionally and independently substituted with one or more R ¹⁰ , at each occurrence;

R ¹⁰ is independently selected from halogen, -CN, -C(R ^10a )=NR(OR ^10a ), -C(R ^10a )=N(R ^10a ), -C (O)(R ^10a ), -C (O ) ₂ (R ^10a ), -C (O) N(R ^10a ) ₂ , -NO ₂ , -N(R ^10a ) ₂ , -N(R ^10a )C (O)(R ^10a ), -N(R ^10a )C (O) ₂ (R ^10a ), N(R ^10a )C (O)N(R ^10a ) ₂ ,N(R ^10a )S(O) ₂ (R ^10a ), -OR ^10a , -OC(O)R ^10a , -OC(O) N(R ^10a ) ₂ , -SR ^10a , -S(O)R ^10a , -S(O) ₂ (R ^10a ), -S(O)N(R ^10a ) ₂ and -S(O) ₂ N( R ^10a ) ₂ , in each case;

R ^10a is independently selected from H or C1-C6 alkyl, in each occurrence, wherein C1-C6 alkyl is optionally substituted with one or more halogens;

R ² is selected from H, C1-C6 alkyl, C 2-6 alkenyl, C2-6 alkynyl, 3-7-membered cycloalkyl, 3-7-membered heterocycloalkyl, halogen, -CN, -C(R ^2a )=NR(OR ^2a ), -C(R ^2a )=N(R ^2a ), -C (O)(R ^2a ), -C (O) ₂ (R ^2a ), -C (O) N(R ^2a ) ₂ , -NO ₂ , -N(R ^{2a )} C (O)( _R ^2a ), -N(R ^2a )C (O) ₂ (R ^2a ), N(R ^2a )C (O) N(R ^2a ) ₂ , N(R ^2a )S(O) ₂ ( ^R2a ), ^-OR2a , -OC(O) ^R2a , -OC(O)N( ^R2a ) ₂ , ^-SR2a , -S(O) ^R2a , -S(O) ₂ ( ^R2a ), -S(O)N( ^R2a ) ₂ and -S(O) _2N ( ^R2a ) ₂ , wherein C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-7-membered cycloalkyl and 3-7-membered heterocycloalkyl are optionally substituted with one or more ^R20 ;

R ^2a is independently selected from H or C1-C6 alkyl, at each occurrence, wherein C1-C6 alkyl is optionally substituted with one or more R ²⁰ , at each occurrence;

R ²⁰ is independently selected from C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3-7 membered saturated heterocycloalkyl, halogen, -CN, -C(R ^20a )=NR(OR ^20a ) , -C(R ^20a )=N(R ^20a ), -С (O)(R ^20a ), -С (O) ₂ (R ^20a ), -C (O) N(R ^20a ) ₂ , -NO ₂ , -N(R ^20a ) ₂ , -N(R ^20a )C (O)(R ^20a ), -N (R ^20a )C (O) ₂ (R ^20a ), N(R ^20a )C (O) N(R ^20a ) ₂ , N(R ^20a )S(O) ₂ (R ^20a ), -OR ^20a , -OC(O)R ^20a , -OC(O) N(R ^20a ) ₂ , -SR ^20a , -S(O) R ^20a , -S(O) ₂ (R ^20a ), -S(O) N(R ^20a ) ₂ and -S(O) ₂ N(R ^20a ) ₂ , in each case, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl and 3-7 membered saturated heterocycloalkyl are optionally substituted by one or more R ²⁵ , in each case;

R ^20a is independently selected from H and C1-C6 alkyl, at each occurrence, wherein the C1-C6 alkyl is optionally substituted with R ²⁵ ;

R ²⁵ is selected from halogen and -OR ^25a ;

R ^25a is selected from H and C1-C6 alkyl;

R is selected from C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C6 cycloalkyl, 3-6-membered saturated heterocycloalkyl, halogen, -CN, -C(R ^3a )=NR(OR ^3a ), -C(R ^3a )=N(R ^3a ), -C (O)(R ^3a ), -C (O) ₂ (R ^3a ), -C (O) N(R ^3a ) ₂ , -NO ₂ , -N(R ^3a ) ₂ , -N(R ^3a )C (O)(R ^3a ), -N(R ^3a )C (O) ₂ (R ^3a ), N(R ^3a )C (O) N(R ^3a ) ₂ , N(R ^3a )S(O) ₂ (R ^3a ), -OR ^3a , -OC(O)R ^3a , -OC(O) N(R ^3a ) ₂ , -SR ^3a , -S(O)R ^3a , -S(O) ₂ (R ^3a ), -S(O) N(R ^3a ) ₂ and -S(O) ₂ N(R ^3a ) ₂ , wherein C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C6 cycloalkyl and 3-6-membered saturated heterocycloalkyl are optionally substituted with one or more R ³⁰ ;

R ^3a is independently selected from H, C1-C6 alkyl, 3-6-membered cycloalkyl, and 3-6-membered heterocycloalkyl, at each occurrence, wherein the C1-C6 alkyl, 3-6-membered cycloalkyl, and 3-6-membered heterocycloalkyl are optionally substituted with one or more R ³⁰ , at each occurrence;

R ³⁰ is independently selected from C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, halogen, -CN, -C(R ^30a )=NR(OR ^30a ), -C(R ^30a )=N(R ^30a ), -C (O)(R ^30a ), -C (O) ₂ (R ^30a ), -C (O) N(R ^30a ) ₂ , -NO ₂ , -N(R ^30a _{)C (O)(R 30a ), -N(R 30a )C (O) 2 (} ^{R 30a ) ,} N(R ^30a )C (O) N(R ^30a ) ₂ , N(R ^30a )S(O) ₂ (R ^30a ), -OR ^30a , -OC(O)R ^30a , -OC(O) N(R ^30a ) ₂ , -SR ^30a , -S(O)R ^30a , -S(O) ₂ (R ^30a ), -S(O) N(R ^30a ) ₂ and -S(O) ₂ N(R ^30a ) ₂ , in each occurrence, wherein C1-C6 alkyl, C 2-6 alkenyl, C2-6 alkynyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl are optionally substituted with one or more R ³⁵ ;

R ^30a is independently selected from H or C1-C4 alkyl, at each occurrence, wherein C1-C4 alkyl is optionally substituted with one or more R ³⁵ ;

R ³⁵ is independently selected from halogen or -OR ^35a , in each occurrence;

R ^35a is independently selected from H or C1-C6 alkyl, at each occurrence; or

in some embodiments of the present invention, the RTM has the following structure:

or a pharmaceutically acceptable salt thereof; wherein in RTM-52, RTM-52a, RTM-52b, RTM-52C, PTM-52d, RTM-52e or PTM-52f:

ring A is phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from O, S or N, wherein ring A is optionally substituted with further optionally substituted alkyl;

ring B is phenyl, 5-6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, S and N, or 5-6-membered heteroaryl containing 1-3 heteroatoms selected from O, S and N, wherein ring B is optionally substituted with further optionally substituted alkyl,

R ³ is selected from hydrogen, deuterium, alkyl optionally substituted with alkoxy, amino, N-(alkyl)amino, N,N-(dialkyl)amino, phenyl, heterocycloalkyl, heteroaryl, wherein each phenyl, heterocycloalkyl and heteroaryl is independently optionally substituted with one or two groups selected from alkyl, and alkoxy is optionally substituted with tri(alkyl)silyl;

R ⁴ is selected from heteroaryl or aryl, each independently optionally substituted, or R ⁴ and R ³ together with the nitrogen atom to which they are bonded form an optionally substituted 3-7 membered heterocycloalkyl, or R ⁴ is an alkylene chain containing 1-3 carbon atoms that are optionally substituted with one or two groups independently selected from alkyl or cycloalkyl, each optionally substituted with hydroxyl or alkoxy, or R ⁴ is absent;

R ⁵ is selected from C(O)NR ⁵¹ , NR ⁵² or O, or R ⁵ is absent, provided that if R ⁴ is absent, R ⁵ is absent;

R ⁶ is an alkylene or alkenylene chain containing one or two double bonds, wherein the alkylene or alkenylene chain contains 2-10 carbon atoms, wherein the alkylene or alkenylene chain is optionally substituted with one or two groups independently selected from alkyl or cycloalkyl, each optionally substituted with hydroxyl or alkoxy, and wherein one or two carbon atoms in the alkylene chain are optionally substituted with O, S, SO, SO ₂ or NR ⁶¹ , wherein two carbon atoms in the alkylene chain are optionally linked by an alkylene chain of two or three carbon atoms to form a 5-7-membered ring;

R ⁷ is selected from NR ⁷¹ or O, or R ⁷ is absent;

R ⁵¹ is selected from hydrogen or alkyl;

R ⁵² is selected from hydrogen, deuterium, alkyl and -C(O)OR ⁸¹ ;

R ⁶¹ is selected from hydrogen, deuterium, alkyl and -C(O)OR ⁸¹ ;

R ⁷¹ is selected from hydrogen, deuterium, alkyl and -C(O)OR ⁸¹ ;

R ⁸¹ is alkyl; or

in some embodiments of the present invention, the RTM has the following structure:

and in RTM-53 or RTM-53a:

R ₁ is selected from CN, C1-C6 alkyl or 3-6 membered heterocycloalkyl, wherein C1-C6 alkyl and 3-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R _a ;

R ₂ is selected from C1-C6 alkyl and 3-6-membered heterocycloalkyl, wherein C1-C6 alkyl and 3-6-membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R ^b ;

R ³ is selected from H, F, Cl, Br, I, OH, NH ₂ , CN, C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, C3-C6 cycloalkyl, wherein C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, C3-C6 cycloalkyl are optionally substituted with 1, 2 or 3 R _c ;

ring A is selected from 3-10 membered heterocycloalkyl, and the 3-10 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R _d ;

L ₁ is selected from O and N(R ₄ );

L ₂ is selected from a single bond, CH ₂ and CH ₂ CH ₂ ;

R ₄ is selected from H and Me;

each R _a is independently selected from F, Cl, Br, I, OH, NH ₂ , CN and COOH;

each R ^b is independently selected from F, Cl, Br, I, OH, NH ₂ , COOH and Me;

each R _c is independently selected from F, Cl, Br, I, OH, NH ₂ or CN;

each R _d is independently selected from F, Cl, Br, I, OH, NH ₂ or CN;

3-6-membered heterocycloalkyl contains 1, 2 or 3 heteroatoms or groups of heteroatoms independently selected from -O-, -S-, -NH-, N;

3- to 10-membered heterocycloalkyl contains 1, 2, or 3 heteroatoms or groups of heteroatoms independently selected from -O-, -S-, -NH-, N, -C(O)NH-; or

in some embodiments of the present invention, the RTM has the following structure:

or its pharmaceutically acceptable salt; and in RTM-54:

m is 0, 1, 2, or 3;

ring A is selected from 5-6-membered heteroaryl;

ring B is selected from 3-7-membered cycloalkyl, 4-6-membered heterocycloalkyl; L is selected from O or NH;

R ₁ is selected from H, or is selected from C1-C3 alkyl or C1-C3 heteroalkyl, which are optionally substituted with 1, 2 or 3 R;

R ₂ is selected from OH, NH ₂ , CN, halogen, or is selected from C1-C3 alkyl, C1-C3 heteroalkyl or 4-6-membered heterocycloalkyl, which are optionally substituted with 1, 2 or 3 R;

R is selected from F, Cl, Br, I, OH, NH ₂ , CN, methyl, ethyl, CF ₃ ;

"hetero" from C1-C3 heteroalkyl, 4-6-membered heterocycloalkyl or 5-6-membered heterocycloalkenyl are independently selected from: N, O, S, NH, -C(O)NH-; the number of the above heteroatoms or heteroatomic groups is independently selected from 1, 2, 3 or 4, respectively; or

in some embodiments of the present invention, the RTM has the following structure:

or its pharmaceutically acceptable salt; and in RTM-55:

n is selected from 1 or 2;

m is selected from 0, 1, 2, or 3;

R ₁ is selected from H, CN, OH or is selected from optionally substituted by R;

R ₂ is selected from: H, F, Cl, Br or I;

R ₃ is selected from OH, NH ₂ , CN, halogen, or is selected from C1-C3 alkyl or C1-C3 heteroalkyl, which are optionally substituted with 1, 2 or 3 R; or

two R ³ together with the atom to which they are attached form a 3-6 membered ring;

L is selected from a single bond, -CH ₂ - or -CH ₂ CH ₂ -;

L ₁ is selected from O or NH;

ring A is selected from 4-6-membered heterocycloalkyl;

R is selected from F, Cl, Br, I, OH, NH ₂ , CN, or is selected from C1-C3 alkyl or C1-C3 heteroalkyl, which are optionally substituted with 1, 2 or 3 R'; and R' is selected from F, Cl, Br, I, OH, NH ₂ , CN or CF ₃ ; "hetero" from C1-C3 heteroalkyl and 4-6-membered heterocycloalkyl, respectively, are independently selected from N, O, S, NH; each number of the above heteroatoms or groups of heteroatoms is independently selected from 1, 2, 3 or 4; or

in some embodiments of the present invention, the RTM has the following structure:

or a pharmaceutically acceptable salt thereof; wherein in RTM-56 or RTM-56a:

R ₁ is H;

X is O or NR _a , where R _a is H or C1-C6 alkyl;

Y is CR _b R _c or NR _d , wherein R _b and R _c are each independently H, halogen, C1-C6 alkyl, C1-C6 alkoxy or amino, and R _d is H or C1-C6 alkyl; or R _b and _Ra , the carbon atom bonded to R _b , and the nitrogen atom bonded to ^Ra , together form a C3-C10 heterocycloalkyl; or R _d and _{Ra ,} together with the nitrogen atoms to which they are bonded, form a C3-C10 heterocycloalkyl;

R ² is -CH ₂ CH ₂ R _e or NR _f R _g , wherein R _e is H, halogen, C1-C6 alkyl, or OR _h , each R _f and R _g independently is C1-C6 alkyl or C3-C8 cycloalkyl, and _Rh is H or C1-C6 alkyl, or _Rh , R _d , the oxygen atom bonded to _Rh , and the nitrogen atom bonded to R _d together form a C3-C10 heterocycloalkyl;

_R3 and _R4 independently represent H, halogen, nitro, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, aryl or heteroaryl;

m is 1, 2, 3, or 4; and

n is 1 or 2; or

in some embodiments of the present invention, the RTM has the following structure:

or a pharmaceutically acceptable salt thereof; wherein in RTM-57 or RTM-57a:

R ¹ is C1-C6 alkyl or thioalkyl;

X is O or NR_a, where R_a represents H or C1-C6 alkyl;

Y is _CRbRc or _NRd , wherein each _Rb and _Rc is independently H, halogen, C1-C6 alkyl _, C1-C6 alkoxy, amino, or _Rd is H or C1-C6 alkyl; if X is ^NRa and Y is _CRbRc , _Rb together with _Ra , the carbon atom bonded to _Ra , and the nitrogen atom bonded to _Ra form an unsubstituted _C3 -C10 heterocycloalkyl; or if X is _NRa and Y is _NRd , _Rd together with _Ra and the nitrogen atoms to which they are bonded form an unsubstituted C3-C10 heterocycloalkyl;

R ₂ is -CH ₂ CH ₂ R _e or NR _f R _g , where R _e is H, halogen, or OR _h , and each R _f and R _g is independently unsubstituted C1-C6 alkyl, and _Rh is H or unsubstituted C1-C6 alkyl; if Y is NR _d , R ² is -CH ₂ CH ₂ R _e , and R _e is OR _h , _Rh together with R _d , the oxygen atom bonded to Rh, and the nitrogen atom bonded to R _d form an unsubstituted C3-C10 heterocycloalkyl; and

R ₃ is an unsubstituted 6-membered heteroaryl containing one or two nitrogen atoms; or

in some embodiments of the present invention, the RTM has the following structure:

or its pharmaceutically acceptable salt; and in RTM-58:

R ¹ is a 5-6 membered monocyclic aromatic heterocycloalkyl, an 8-14 membered fused polycyclic aromatic heterocycloalkyl, or C6-14 aryl, each of which is optionally substituted with 1 to 3 substituents selected from the following:

(1) halogen atom;

(2) C1-C6 alkyl optionally substituted with 1 to 3 groups selected from halogen or hydroxyl;

(3) C6-14 aryl optionally substituted with 1 to 3 halogens;

(4) 5-6-membered monocyclic aromatic heterocycloalkyl or 8-14-membered fused polycyclic aromatic heterocycloalkyl, each of which is optionally substituted with 1 to 3 substituents selected from the following:

(i) amino, optionally monosubstituted or disubstituted with C1-C6 alkyl, wherein C1-C6 alkyl is optionally substituted with 1 to 3 substituents selected from the following: (a) a halogen atom or (b) C3-C10 cycloalkyl;

(ii) a halogen atom;

(iii) C1-C6 alkoxy;

(iv) cyano;

(v) C1-C6 alkyl optionally substituted with 1 to 3 substituents selected from: (a) azido, (b) amino optionally monosubstituted or disubstituted with C1-C6 alkyl, wherein C1-C6 alkyl is optionally substituted with 1 to 3 substituents selected from a halogen atom or C3-C10 cycloalkyl, (c) hydroxyl, (d) a halogen atom;

(vi) formyl;

(vii) carboxyl;

(viii) carbamoyl;

(ix) C3-C10 cycloalkyl; or

(x) 3-8-membered monocyclic non-aromatic heterocycloalkyl;

(5) 3- to 8-membered monocyclic non-aromatic heterocycloalkyl, 9- to 14-membered fused polycyclic non-aromatic heterocycloalkyl, or 7- to 14-membered spiro heterocycloalkyl, each of which is optionally substituted with 1 to 3 substituents selected from the following:

(i) C1-C6 alkyl optionally substituted with 1 to 3 substituents selected from: (a) hydroxyl, (b) amino optionally monosubstituted or disubstituted with C1-C6 alkyl, (c) cyano, or (d) C6-14 aryl;

(ii) oxo;

(iii) hydroxyl;

(iv) carbamoyl; or

(v) thio group;

(6) C3-C10 cycloalkylsulfonyl;

(7) C1-C6 alkyl carbonyl;

(8) 5-6-membered monocyclic aromatic heterocyclic sulfonyl; or

(9) halogenated thio group;

R ² is

(1) C1-C6 alkyl optionally substituted with 1 to 3 substituents selected from the following:

(1) C1-C6 alkoxycarbonyl, (ii) C1-C6 alkylsulfonyl, (iii) carbamoyl, (iv) cyano, (v) 3-8-membered monocyclic non-aromatic heterocycloalkyl optionally substituted with 1 to 3 oxo groups, or (vi) a halogen atom;

(2) C3-C10 cycloalkyl optionally substituted with 1 to 3 hydroxyls; or

(3) 3-8-membered monocyclic non-aromatic heterocycloalkyl;

R ₃ and R ₄ independently represent

(1) a hydrogen atom; or

(2) C1-C6 alkyl optionally substituted with 1 to 3 substituents selected from amino, wherein amino is optionally monosubstituted or disubstituted with C1-C6 alkyl;

R ₅ and R ₆ independently represent

(1) hydrogen atom;

(2) hydroxyl;

(3) C1-C6 alkyl optionally substituted with 1 to 3 substituents selected from: (i) hydroxyl; (ii) amino optionally monosubstituted or disubstituted with substituents selected from: (a) C1-C6 alkyl optionally substituted with 1 to 3 halogen atoms; (b) C3-C10 cycloalkyl optionally substituted with 1 to 3 halogen atoms; (c) a 3- to 8-membered monocyclic non-aromatic heterocycloalkyl; (d) C1-C6 alkylsulfonyl; (e) C1-C6 alkyl-carbonyl or (f) C3-C10 cycloalkylcarbonyl; (iii) halogen atoms; (iv) C1-C6 alkylthio; (v) C1-C6 alkylsulfinyl or (vi) C1-C6 alkylsulfonyl;

(4) C1-C6 alkoxy;

(5) amino, optionally monosubstituted or disubstituted with substituents selected from the following: (i) C1-C6 alkyl, (ii) C1-C6 alkyl, (iii) C1-C6 alkylsulfonyl;

(6) 3-8-membered monocyclic non-aromatic heterocycloalkyl;

(7) carboxyl; or

(8) carbamoyl, optionally monosubstituted or bis-substituted with C1-C6 alkyl; or

R ⁵ and R ⁶ combine to optionally form: (1) a 3-8 membered monocyclic non-aromatic heterocyclyl or (2) a C3-C10 cycloalkyl;

X represents CR ⁷ R ⁸ , NRS, O or S;

R ⁷ and R ⁸ independently represent: (1) a hydrogen atom; (2) cyano; (3) C1-C6 alkyl optionally substituted with 1 to 3 hydroxyls; or (4) hydroxyl;

R ⁷ and R ⁸ are combined for non-compulsory education:

(1) C3-C10 cycloalkyl optionally substituted with 1 to 3 substituents selected from: (i) oxo or (ii) hydroxyl;

(2) 3-8-membered monocyclic non-aromatic heterocyclyl optionally substituted with 1 to 3 C7-16 (aryl)alkyl- groups;

R ⁹ represents:

(1) hydrogen atom;

(2) C1-C6 alkyl optionally substituted with 1 to 3 substituents selected from: (i) hydroxyl; (ii) C1-C6 alkoxy optionally substituted with 1 to 3 C6-14 aryl groups; or (iii) amino optionally monosubstituted or disubstituted with C1-C6 alkyl;

(3) C2-6 alkenyl; or

(4) C7-16 (aryl) alkyl-, optionally substituted with 1 to 3 C1-C6 alkoxy groups; or

in some embodiments of the present invention, the RTM has the following structure:

or its pharmaceutically acceptable salt; and in RTM-59:

R ¹ is optionally substituted with heteroaryl or C6-14 aryl;

R ² , R ³ , R ⁴ , R ⁵ and R ⁶ independently represent hydrogen or substituents; or

in some embodiments of the present invention, the RTM has the following structure:

or a pharmaceutically acceptable oxide, pharmaceutically acceptable solvate and/or pharmaceutically acceptable salt thereof, wherein in RTM-60, RTM-60a, RTM-60b, RTM-60c, PTM-60d, RTM-60e, PTM-60f, PTM-60g, PTM-60h, PTM-60i, PTM-60J, PTM-60k, PTM-601, PTM-60m, PTM-60n, PTM-60o, PTM-60p, PTM-60q, PTM-60r, PTM-60s, PTM-60t, PTM-60u or PTM-60v:

ring A is a substituted or unsubstituted saturated, unsaturated or partially unsaturated 5- to 6-membered heterocycloalkyl, provided that the heterocycloalkyl is not thiazolyl;

Su ¹ is a 5-membered heteroaryl;

Su ² is C3-12 cycloalkyl optionally fused with 5-

up to 6-membered heteroaryl or from 5- to 7-membered heteroaryl;

L ¹ represents a bond or C1-C3 alkylene, and one of the CH ₂ groups is optionally substituted with O or NH;

X represents N, ^NR3 , O, or S;

Y represents CR ⁴ or N;

if X is N, then k is 2 and ring A is a 6-membered heteroaryl; if X is ^NR3 , S, or O, then k is 1 and ring A is a 5-membered heteroaryl;

R ¹ is selected from H, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-7-membered heterocycloalkyl, substituted or unsubstituted C6-12 aryl, substituted or unsubstituted 5-7-membered heteroaryl, halogen, CN, -NO ₂ , -OR ¹⁰ , -SR ¹⁰ , -NRUR ¹² , -C(O)R ¹⁴ , -C(O)NR ¹¹ R ¹² , -NR ¹³ C(O)R ¹⁴ , -OC(O)R ¹⁴ , -C(O) ₂ R ¹¹ , -NR ¹³ C(O)NR ¹¹ R ¹² , -NR ¹³ S(O) ₂ R ¹⁴ , -S(O) ₂ NR ¹¹ R ¹² , -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ ; provided that R ¹ is not -NH ₂ ;

R ² is selected from H or substituted or unsubstituted C1-C3 alkyl;

R ³ is selected from H, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-4 alkenyl, substituted or unsubstituted C2-4 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkenyl, substituted or unsubstituted 3-7-membered heterocycloalkyl, substituted or unsubstituted C5-12 aryl, substituted or unsubstituted 5-7-membered heteroaryl, -CN, -C(O)R ⁶ and -C(O)NR ^7a R ^7b ;

R ⁴ is selected from H, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C2-4 alkenyl, substituted or unsubstituted C2-4 alkynyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkenyl, substituted or unsubstituted 3-7-membered heterocycloalkyl, substituted or unsubstituted C5-12 aryl, substituted or unsubstituted 5-7-membered heteroaryl, -OH, -OR ⁶ , -CN, -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ^7a R ^7b , COOH or halogen;

R ⁶ is selected from substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-7-membered heterocycloalkyl, substituted or unsubstituted C6-12 aryl, substituted or unsubstituted 5-7-membered heteroaryl;

each R ^7a and R ^7b is independently selected from H or substituted or unsubstituted C1-C3 alkyl; or R ^7a and R ^7b together with the N to which they are attached form a substituted or unsubstituted 3-7-membered heterocycloalkyl;

each R ⁸ is independently selected from C1-C4 alkyl, C1-C4 haloalkyl, halogen, CN or -NO ₂ ;

each R ⁹ is independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, 3-7-membered heterocycloalkyl, phenyl, 5-7-membered heteroaryl, halogen, CN, -NO ₂ , -OR ¹⁰ , -SR ¹⁰ , -NR ¹¹ R ¹² , -C(O)R ¹⁴ , -C(O)NR ¹¹ R ¹² , -NR ¹³ C(O)R ¹⁴ , -OC(O)R ¹⁴ , -C(O) ₂ R ¹¹ , -NR ¹³ C(O)NR ¹¹ R ¹² , -NR ¹³ S(O) ₂ R ¹⁴ , -S(O) ₂ NR ¹¹ R ¹² , -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ ;

R ¹⁰ is selected from H, C1-C4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-C8 cycloalkyl, 3-7-membered heterocycloalkyl, phenyl and 5-7-membered heteroaryl;

R ¹¹ and R ¹² independently represent H, C1-C4 alkyl, C3-C8 cycloalkyl, 3-7-membered heterocycloalkyl, phenyl and 5-7-membered heteroaryl; or R ¹¹ and R ¹² together with the N to which they are attached form a 3-7-membered heterocycloalkyl;

R ¹³ is selected from H or C1-C4 alkyl;

R ¹⁴ is selected from C1-C4 alkyl, C3-C8 cycloalkyl, 3-7-membered heterocycloalkyl, phenyl or 5-7-membered heteroaryl;

m is 0, 1, or 2; and

n is 0, 1, or 2; or

in some embodiments of the present invention, the RTM has the following structure:

and its pharmaceutically acceptable tautomer, salt and stereoisomer, including mixtures thereof in all ratios; and in RTM-61:

R ¹ is absent or represents A or Q-Het,

Z represents where X is O, S or N, Y

represents C or N, T represents C or N, or Z represents pyridinyl or pyridazinyl;

R ^a is absent or represents OR ³ , CF ₃ , Hal, NO ₂ ;

R ^b is absent or selected from A or COHet;

R ² is H, Het, Q-Het, Cyc, A or OA,

Het is a 4-9 membered monocyclic or fused spiro- or bridged bicyclyl which is saturated, unsaturated or aromatic and contains 1-3 groups independently selected from N, O, S, CO, SO or _SO2 , and wherein one or two H atoms may be replaced by A, OA, COA, CN, Hal, _NO2 , ^OR3 , SOA or _SO2A ;

Cys is a 4-8 membered saturated carbocycle which optionally contains SO, SO ₂ , CO and is optionally monosubstituted or disubstituted with groups selected from CO(NR ³ ) ₂ and COHet, OR ³ , Hetl, A, CH ₂ Het1, NH ₂ , NHCOA, OCH ₂ Cyc1, SO ₂ A or -SA(=NH)(=O),

Q is a linear or branched alkylene containing 1-6 carbon atoms, wherein 1-5 H atoms may be substituted with groups independently selected from OR ³ , Hal, N(R ³ ) ₂ , and wherein 1 or 2 CH groups may be substituted with groups independently selected from CO, SO, SO ₂ and NR ³ , or Q is a 4-8-membered divalent heterocyclyl, which is saturated, unsaturated or aromatic and contains 1-3 heteroatoms independently selected from N, O and S;

A is a linear or branched alkyl containing 1-10 carbon atoms, wherein 1-7 H atoms may be substituted with groups independently selected from -OR ³ , Ha1, NHSO ₂ A, SO ₂ A, SO A, N(R ³ ) ₂ , and wherein 1, 2 or 3 non-adjacent CH ₂ groups may be substituted with groups independently selected from -CO-, NR ³ and/or -O-;

Ha1 is F, Cl, Br or I,

R ³ is H or C1-C6 alkyl, wherein one H atom may be substituted by a group selected from OH, O-C1-C6 alkyl or Hal,

Het1 is a 5- or 6-membered saturated monocyclic heterocyclyl containing 1-3 N- and/or O- atoms, optionally monosubstituted with A;

Cyc1 is a cycloalkyl containing 3-7 atoms; or

in some embodiments of the present invention, the RTM has the following structure:

or its pharmaceutically acceptable salt; and in RTM-62:

A is phenyl or 5-10 membered heteroaryl optionally substituted by one or more R ¹ groups;

L is selected from O or NR ² ;

G is C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl or phenyl optionally substituted with one or more R ³ groups;

Z is phenyl or 5-10 membered heteroaryl optionally substituted with one or more R ⁴ groups;

each R ¹ is independently selected from C1-C6 alkyl, 4-6-membered heterocycloalkyl, hydroxyl, halogen, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkoxy, amino, (C1-C6 alkyl) ₂ -amino, carboxyl, or C1-C6 alkylsulfonyl;

R ² is selected from hydrogen or C1-C6 alkyl;

each R ³ is independently selected from hydroxyl, oxo, C1-C6 alkyl, 4-6-membered heterocycloalkyl, 5-10-membered heteroaryl, hydroxyl C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylacylamino, C1-C6 alkylcarbonyl, or C1-C6 alkylaminoacyl;

each R ⁴ is independently selected from the group consisting of C1-C6 alkyl, cyano, C3-C6 cycloalkyl, 4-6-membered heterocycloalkyl, phenyl, 5-10-membered heteroaryl, oxo, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, 4-6-membered heterocycloalkylcarbonyl, or R ^4a R ^4b NC(O)-;

each R ^4a and R ^4b is independently selected from hydrogen, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, 4-6-membered heterocycloalkyl C1-C6 alkyl, 5-10-membered heteroaryl C1-C6 alkyl, or 4-6-membered heterocycloalkyl;

wherein in R ¹ , R ³ , R ⁴ , R ^4a and R ^4b cycloalkyl, heterocycloalkyl, aryl and heteroaryl, as an independent group or as part of a group, are optionally substituted with one or more substituents independently selected from C1-C6 alkyl or oxo; wherein heterocycloalkyl and heteroaryl contain one or more heteroatoms selected from nitrogen, oxygen and sulfur; or

in some embodiments of the present invention, the RTM has the following structure:

or a pharmaceutically acceptable salt thereof; wherein in RTM-63, RTM-63a or RTM-63b:

ring A is an aromatic ring or an aromatic heterocyclyl;

n is equal to the integer O-4;

X is selected from N or O;

Ro is selected from C1-C4 alkyl, heterocyclyl, _-OCH3 , _-CF3 , _-CHF2 , -CN, _-CONH2 , halogen, -(CH2) _m - ^Ra , -O-(CH2) _m - ^Ra ;

m is equal to an integer 1-4;

R ^a represents a nitrogen-containing heterocyclyl, wherein the nitrogen-containing heterocyclyl may be optionally substituted with one or more substituents selected from halogen, -OH, -CH ₃ , -OCH ₃ ;

R ² and R ³ are independently selected from hydrogen atoms, heterocyclyl, -CH ₂ CH ₂ -N(R ^b ) ₂ , R ² and R ³ may be joined by nitrogen atoms to form a heterocyclyl, wherein the above-mentioned heterocyclyl may be further substituted with one or more R _c ;

R ^b is selected from a hydrogen atom, C1-4 alkyl or acetyl;

R _c is selected from -CF ₃ , -CHF ₂ , -OH, -NH ₂ or formyl; or

in some embodiments of the present invention, the RTM has the following structure:

or its pharmaceutically acceptable salt; and in RTM-64:

R ₁ is hydrogen, deuterium, halogen, hydroxyl, nitro, trifluoromethyl, cyano, NH(CO)R ₄ , C1-C8 alkyl, C1-C8 alkoxy or C3-C6 cycloalkyl;

R ₂ is hydrogen, deuterium, halogen, or NR ₅ R ₆ ;

R ₃ is hydrogen, deuterium, halogen or amino;

R ₄ is C1-C8 alkyl, C3-C6 cycloalkyl, C5-C10 aryl or C5-C10 arylheterocycloalkyl; wherein aryl heterocycloalkyl may optionally contain one or more other heteroatoms selected from O, S or N; wherein aryl or arylheterocycloalkyl may be optionally substituted, from monosubstitution to pentasubstitution, with the same or different substituents selected from: halogen, trifluoromethyl, cyano, nitro or hydroxyl;

R ₅ and R ₆ may be the same or different and represent hydrogen, deuterium, C1-C8 alkyl, or R ⁵ and R ⁶ together with the nitrogen to which they are attached form a 5- to 7-membered heterocycloalkyl which may optionally contain one or more other heteroatoms selected from O, S or N, and the heterocycloalkyl may be optionally substituted, from monosubstitution to pentasubstitution, with the same or different substituents selected from: da, halogen, hydroxyl, nitro, cyano or amino forms; or

in some embodiments of the present invention, the RTM has the following structure:

or its pharmaceutically acceptable salt; and in RTM-65:

V is hydrogen, deuterium, halogen, or substituted or unsubstituted C1-5 linear or branched alkyl, wherein the substituted alkyl may be substituted with one or more substituents selected from hydroxyl, halogen, nitro, or -CN;

X represents -NHR ¹ ;

R ¹ is a substituted or unsubstituted 6-10-membered aryl or a substituted or unsubstituted 5-10-membered heteroaryl containing one or more heteroatoms selected from N, O or S, wherein the substituted aryl or substituted heteroaryl may be substituted with the following: unsubstituted C1-10 linear or branched alkyl, or C1-10 linear or branched alkyl substituted with one or more substituents selected from: halogen, methoxy and dimethylamine or halogen, or amino, or a 5-10-membered heterocycloalkyl containing one or more heteroatoms selected from N, O or S, or the substituted aryl or substituted heteroaryl is fused to a C3-C10 ring or a 5-10-membered ring containing one or more heteroatoms selected from N, O or S;

Y represents -(C=O)NHR ² , -NH(C=O)R ² or -NH(C=O)NHR ² ;

R ² is a substituted or unsubstituted 6-10 membered aryl or a substituted or unsubstituted 5-10 membered heteroaryl containing one or more heteroatoms selected from N, O or S, wherein the substituted aryl or substituted heteroaryl may be substituted with one or more substituents selected from the following: halogen, -CH ₂ -R ³ , C _1-10 linear or branched alkyl substituted or unsubstituted with halogen, C 1-2 alkoxy unsubstituted or substituted with halogen, C 6-C 10 cycloalkyl unsubstituted or substituted with halogen, substituted or unsubstituted 5-10 membered heterocycloalkyl containing one or more heteroatoms selected from N, O or S, unsubstituted or substituted 5-10 membered heteroaryl containing one or more heteroatoms selected from N, O or S, and unsubstituted or substituted amino, wherein substituted heteroaryl, substituted heterocycloalkyl and substituted amino may be substituted with unsubstituted or substituted C1-C3 linear or branched alkyl, wherein substituted C1-C3 linear or branched alkyl may be substituted with dimethylamino;

R ³ is a 5- to 10-membered heterocycloalkyl containing one or more heteroatoms selected from N, O or S, which may be substituted with one or more substituents selected from: methyl, ethyl, dimethylamino and halogen, or be unsubstituted; or

in some embodiments of the present invention, the RTM has the following structure:

or its pharmaceutically acceptable salt; and in RTM-66:

each R ¹ and R ² is independently selected from: a) C1-10 alkyl which is optionally substituted with Z ¹ ; b) C3-C10 cycloalkyl which is optionally substituted with Z ¹ ; c) 5-10 membered heteroaryl which is optionally substituted with Z ¹ ; d) 6-10 membered aryl which is optionally substituted with Z ¹ ; e) 4-7 membered monocyclic heterocycloalkyl which is optionally substituted with Z ¹ ; f) 6-12 membered bicyclic heterocycloalkyl which is optionally substituted with Z ¹ ; or g) -N(R ¹² )(R ¹² ), -S(O) ₂ R ¹² , -S(O) ₂ N(R ¹² )(R ¹² ), or -H;

each ^R3 and ^R4 is independently selected from: a) H, halogen, _-NO2 , -CN, ^-OR12 , -C(O) ^-R12 , -C(O)-N( ^R12 )( ^R12 ), -N(R12)( ^R12 ), -N( ^R12 )C(O) ^-R12 , -N( ^R12 )C(O) ^OR12 , -N( ^R12 )S(O) ₂ ( ^R12 ), -N( ^R12 )C(O)-N( ^R12 )( ^R12 ), -S(O) ^{2R12 ,} or -S( _{O)2N (} ^R12 )( ^R12 );

b) C1-9 alkyl which is optionally substituted with Z ¹ ;

c) C2-9 alkynyl which is optionally substituted with Z ¹ ;

d) C2-9 alkenyl which is optionally substituted with Z ¹ ;

e) 5-10 membered heteroaryl which is optionally substituted with Z ¹ ;

f) 6-10 membered aryl which is optionally substituted with Z ¹ ;

g) 4-12 membered heterocycloalkyl which is optionally substituted with Z ¹ ; or

h) C3-C10 cycloalkyl which is optionally substituted with Z ¹ ;

each ^R5 , ^R6 and ^R7 is independently selected from: a) H, halogen, _-NO2 , -CN, ^-OR12 , -C(O) ^-R12 , -C(O)-N( ^R12 )( ^R12 ), -N( ^R12 )( ^R12 ), -N( ^R12 )C(O) ^-R12 , -N( ^R12 )C(O) ^OR12 or -N( ^R12 )S(O) ₂ ( ^R12 );

b) C1-5 alkyl which is optionally substituted with Z ¹ ; or

c) cyclopropyl, oxetanyl or acetanyl, which is optionally substituted with Z ¹ ;

Z ¹ independently represents oxo, halogen, -NO ₂ , -N3, -CN, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C1-C8 haloalkyl, aryl, heteroaryl, heterocycloalkyl, -OR ¹² , -C(O)-R ¹² , -C(O)0-R ¹² , -C(O)-N(R ¹² )(R ¹² ), -N(R ¹² )(R ¹² ), -N(R ¹² ) ₂ (R ¹² )+, -N(R ¹² )C(O)-R ¹² , -N(R ¹² )C(O)OR ¹² , -N(R ¹² )C(O)N(R ¹² )(R ¹² ), -N(R ¹² )S(O) ₂ (R ¹² ), -NR ¹² S(O) ₂ N(R ¹² )(R ¹² ), -NR ¹² S(O) ₂ 0(R ¹² ), -OC(O)R ¹² , -OC(O)OR ¹² , -OC(O)-N(R ¹² )(R ¹² ), -Si(R ¹² )3, -SR ¹² , -S(O)R ¹² , -S(O)(NH)R ¹² , -S(O) ₂ R ¹² or -S(O) ₂ N(R ¹² )(R ¹² );

wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, heteroaryl or heterocycloalkyl is optionally substituted with Z ^1a ; each Z ^1a is independently oxo, halogen, -NO ₂ , -CN, -N3, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C1-C8 haloalkyl, aryl, heteroaryl, heterocycloalkyl, -OR ¹² , -C(O)R ¹² , -C(O)OR ¹² , -C(O)N(R ¹² )(R ¹² ), -N(R ¹² )(R ¹² ), -N(R ¹² ) ₂ (R ¹² )+, -N(R ¹² )-C(O)R ¹² , -N(R ¹² )C(O)O(R ¹² ), -N(R ¹² )C(O)N(R ¹² )(R ¹² ), -N(R ¹² )S(O) ₂ (R ¹² ), -N(R ¹² )S(O) ₂ -N(R ¹² )(R ¹² ), -N(R ¹² )S(O) ₂ O(R ¹² ), -OC(O)R ¹² , -OC(O)OR ¹² , -OC(O)-N(R ¹² )(R ¹² ), -Si(R ¹² )3, -SR ¹² , -S(O)R ¹² , -S(O)(NH)R ¹² , -S(O) ₂ R ¹² or -S(O) ₂ N(R ¹² )(R ¹² );

wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, heteroaryl or heterocycloalkyl is optionally substituted with Z ^1b ;

each R ¹² is independently H, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl;

wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl is optionally substituted with Z ^1a ; each Z ^1b is independently oxo, hydroxyl, halogen, -NO ₂ , -N3, -CN, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C1-C8 haloalkyl, aryl, heteroaryl, heterocycloalkyl, -O(C1-9 alkyl), -O(C2-6 alkenyl), -O(C2-6 alkynyl), -O(C3-15 cycloalkyl), -O(C1-C8 haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocycloalkyl), -NH ₂ , -NH(C1-9 alkyl), -NH(C2-6 alkenyl), -NH(C2-6 alkynyl), -NH(C3-15 cycloalkyl), -NH(C1-C8 haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocycloalkyl), -N(C1-9 alkyl) ₂ , -N(C3-15 cycloalkyl) ₂ , -N(C2-6 alkenyl) ₂ , -N(C2-6 alkynyl) ₂ , -N(C3-15 cycloalkyl) ₂ , -N(C1-C8 haloalkyl) ₂ , -N(aryl) ₂ , -N(heteroaryl) ₂ , -N(heterocycloalkyl) ₂ , -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(C2-6 alkenyl), -N(C1-9 alkyl)(C2-6 alkynyl), -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(C1-C8 haloalkyl), -N(C1-9 alkyl)(aryl), -N(C1-9 alkyl)(heteroaryl), -N(C1-9 alkyl)(heterocycloalkyl), -C(O)(C1-9 alkyl), -C(O)(C2-6 alkenyl), -C(O)(C2-6 alkynyl), -C(O)(C3-15 cycloalkyl), -C(O)(C1-C8 haloalkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocycloalkyl), -C(O)O(C1-9 alkyl), -C(O)O(C2-6 alkenyl), -C(O)O(C2-6 alkynyl), -C(O)O(C3-15 cycloalkyl), -C(O)O(C1-C8 haloalkyl), -C(O)O(aryl), -C(O)O(heteroaryl), -C(O)O(heterocycloalkyl), -C(O)NH ₂ , -C(O)NH(C1-9 alkyl), -C(O)NH(C2-6 alkenyl), -C(O)NH(C2-6 alkynyl), -C(O)NH(C3-15 cycloalkyl), -C(O)NH(C1-C8 haloalkyl), -C(O)NH(aryl), -C(O)NH(heteroaryl), -C(O)NH(heterocycloalkyl), -C(O)N(C1-9 alkyl) ₂ , -C(O)N(C3-15 cycloalkyl) ₂ , -C(O)N(C2-6 alkenyl) ₂ , -C(O)N(C2-6 alkynyl) ₂ , -C(O)N(C3-15 cycloalkyl) ₂ , -C(O)N(C1-C8 haloalkyl) ₂ , -C(O)N(aryl) ₂ , -C(O)N(heteroaryl) ₂ , -C(O)N(heterocycloalkyl) ₂ , -NHC(O)(C1-9 alkyl), -NHC(O)(C2-6 alkenyl), -NHC(O)(C2-6 alkynyl), -NHC(O)(C3-15 cycloalkyl), -NHC(O)(C1-C8 haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocycloalkyl), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C2-6 alkenyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(C1-C8 haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocycloalkyl), -NHC(O)NH(C1-9 alkyl), -NHC(O)NH(C2-6 alkenyl), -NHC(O)NH(C2-6 alkynyl), -NHC(O)NH(C3-15 cycloalkyl), -NHC(O)NH(C1-C8 haloalkyl), -NHC(O)NH(aryl), -NHC(O)NH(heteroaryl), -NHC(O)NH(heterocycloalkyl), -SH, -S(C1-9 alkyl), -S(C2-6 alkenyl), -S(C2-6 alkynyl), -S(C3-15 cycloalkyl), -S(C1-C8 haloalkyl), -S(aryl), -S(heteroaryl), -S(heterocycloalkyl), -NHS(O)(C1-9 alkyl), -N(C1-9 alkyl)(S(O)(C1-9 alkyl), -S(O)N(C1-9 alkyl) ₂ , -S(O)(C1-9 alkyl), -S(O)(NH)(C1-9 alkyl), -S(O)(C2-6 alkyl), -S(O)(C2-6 alkynyl), -S(O)(C3-15 cycloalkyl), -S(O)(C1-C8 haloalkyl), -S(O)(aryl), -S(O)(heteroaryl), -S(O)(heterocycloalkyl), -S(O) ₂ (C1-9 alkyl), -S(O) ₂ (C2-6 alkenyl), -S(O) _{2 (C2-6 alkynyl), -S(O) 2} (C3-15 cycloalkyl), -S( _O ) ₂ (C1-C8 haloalkyl), -S(O) ₂ (aryl), -S(O) ₂ (heteroaryl), -S(O) ₂ (heterocycloalkyl), -S(O) ₂ NH(C1-9 alkyl) or -S(O) ₂ N(C1-9 alkyl) ₂ ;

wherein any alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl is optionally substituted with one or more halogen, C1-9 alkyl, C1-C8 haloalkyl, -OH, -NH ₂ , -NH(C1-9 alkyl), -NH(C3-15 cycloalkyl), -NH(C1-C8 haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocycloalkyl), -N(C1-9 alkyl) ₂ , -N(C3-15 cycloalkyl) ₂ , -NHC(O)(C3-15 cycloalkyl), -NHC(O)(C1-C8 haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocycloalkyl), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(C1-C8 haloalkyl), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)O (heterocycloalkyl), -NHC(O)NH(C1-9 alkyl), -S(O)(NH)(C1-9 alkyl), S(O) ₂ (C1-9 alkyl), -S(O) ₂ (C3-15 cycloalkyl), -S(O) ₂ (C1-C8 haloalkyl), -S(O) ₂ (aryl), -S(O) ₂ (heteroaryl), -S(O) ₂ (heterocycloalkyl), -S(O) ₂ NH(C1-9 alkyl), -S(O) _2N (C1-9 alkyl) ₂ , -O(C3-15 cycloalkyl), -O(C1-C8 haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocycloalkyl) or -O(C1-9 alkyl); provided that: when _R1 is C3 alkyl, ^R2 is F or hydroxyl substituted with C5 alkyl, ^R3 , ^R5 , ^R6 , ^R7 are H, and when ^R4 is CN, ^R1 is substituted with ^Z1 ; or

in some embodiments of the present invention, the RTM has the following structure:

and in RTM-67, RTM-67a, RTM-67b or RTM-67 with:

ring A is a monocyclic heteroaryl;

R ₁ is hydrogen or monocyclic or bicyclic heteroaryl optionally substituted with 1-3 R ₁₀ ;

R ₂ is hydrogen, deuterium, R ₀ , cyano, , , , haloalkyl, -C(O)NH ₂ , -C(O)NHR ₀ , -C(O)NH-R ₀ -OH, -C(O)NH-R ₀ -N(alkyl) _1-2 , -C(O)NH-R ₀₀ -OR ₀ , -C(O)N(R ₀ ) ₂ , -C(O)NH-cycloalkyl, -C(O)NH-heterocycloalkyl, -C(O)NH-(pyrazolyl optionally substituted with R ₀ ), -C(O)-R ₀ , -C(O)-cycloalkyl, -S(O) ₂ NH ₂ , -S(O) ₂ NH-R ₀ , -S(O) ₂ NH-cycloalkyl, -R ₀ -NH ₂ , -R ₀₀ -OH, -R ₀₀ -OR ₀ , R ₀₀ -(morpholin-4-yl)phenyl, phenyl, oxadiazolyl or tetrazolyl optionally substituted with R ₀ , oxadiazolyl optionally substituted with R ₀ , R ₀₀ -OH or R ₀ -OR ₀ ;

R ₃ is hydrogen, deuterium, R ₀ , haloalkyl, cycloalkyl, heterocycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, -C(O)N(R ₀ ) ₂ , -R ₀₀ cycloalkyl, -R ₀₀ -heterocycloalkyl, -R ₀₀ -phenyl, -R ₀₀ -OH, -R ₀₀ -OR ₀ , and cycloalkyl, heterocycloalkyl, phenyl and pyridyl are optionally substituted with R ₀ , halogen, -C(O)-OR ₀ , -C(O)-R ₀ , -OH, -OR ₀ , -S(O) ₂ -R, -O-haloalkyl, -OR ₀₀ -(morpholin-4-yl), -R ₀ -OH, -R ₀₀ -OR, morpholin-4-yl or -R ₀₀ - (morpholin-4-yl);

R ₁ ⁰ is hydrogen, deuterium, R ₀ , halogen, cyano, haloalkyl, cycloalkyl, -OR ₀ optionally substituted with amino, -O-haloalkyl, -R ₀ -OH, -R ₀₀ -OR ₀ or -R ₀₀ optionally substituted with amino;

R ₀ is alkyl;

R ₀₀ is alkyl or alkylene; or

in some embodiments of the present invention, the RTM has the following structure:

where in RTM-68:

Z ₁ is absent or represents a substituted or unsubstituted C1-C6 alkylene, a substituted or unsubstituted C3-C6 cycloalkylene, a substituted or unsubstituted C2-C6 alkenylene, or a substituted or unsubstituted C2-C6 alkynylene;

Z ₂ is a carbonyl,

R ₁ is or ;

each _R2 and each _R3 is absent or independently substituted or unsubstituted C1-C10 alkyl, substituted C3-C10 cycloalkyl, halogen, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C12 hydroxyalkyl, substituted or unsubstituted C1-C12 sulfhydrylalkyl, substituted or unsubstituted C3-C12 hydroxycycloalkyl, substituted or unsubstituted C3-C12 sulfhydrylcycloalkyl, piano, nitro, substituted or unsubstituted 3-12-membered heterocyclic alkyl, _-AR10 or -N( _R11 ) _R12 ;

R ₄ is substituted or unsubstituted C6-C20 aryl, or substituted or unsubstituted 5-20-membered heteroaryl;

R ₅ is substituted or unsubstituted C1-C10 alkyl, or substituted or unsubstituted C3-C10 cycloalkyl;

R ₆ is substituted or unsubstituted C1-C10 alkyl, or substituted or unsubstituted C3-C10 cycloalkyl;

R ₇ is hydrogen, deuterium, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, or R ₁₃ -C(O)-;

each R ₈ and R ₉ independently represents substituted or unsubstituted C1-C10 alkyl, or R ₈ and R ₉ together with the S atom to which they are attached form a 3-12-membered heterocyclic alkyl;

R ₁₀ is hydrogen, deuterium, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-12-membered heterocycloalkyl, or -R ₁₄ -R ₁₅ ;

each R ₁₁ and R ₁₂ independently represents hydrogen, deuterium, substituted or unsubstituted C1-C10 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;

R ₁₃ is substituted or unsubstituted C1-C10 alkyl, or substituted or unsubstituted C3-C10 cycloalkyl;

R ₁₄ is substituted or unsubstituted C1-C6 alkylene;

R ₁₅ is substituted or unsubstituted C3-C12 cycloalkyl, or substituted or unsubstituted C3-C12 heterocycloalkyl;

wherein any "substituted" refers to one or more (preferably 1, 2, 3 or 4) hydrogen atoms in the group substituted with a substituent selected from the group consisting of: C2-C8 acyl, C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, hydroxyl, sulfhydryl, amino, nitro, halogen, 3-12 membered heterocycloalkyl, cyano, C1-C10 haloalkyl, C3-C8 halocycloalkyl, C2-C4 ester, C2-C4 amide, C1-C4 carboxyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C12 aryl, 5-12 membered heteroaryl, -N(R ₁₆ )R ₁₁ ;

each R ₁₆ and R ₁₇ independently represents hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, or 3-10-membered heterocycloalkyl;

each heterocycloalkyl, heteroaryl and heteroalkyl ring independently has 1-3 (preferably 1, 2 or 3) heteroatoms selected from N, O and S;

A represents S or O;

a is equal to 0 or 1,

b is 0, 1, 2, or 3; or

in some embodiments of the present invention, the RTM has the following structure:

or a pharmaceutically acceptable salt thereof; wherein in RTM-69, RTM-69a, RTM-69b, RTM-69c, PTM-69d, RTM-69e, PTM-69f, PTM-69g, PTM-69h, PTM-69i:

each X and X' is independently CR ₈ , N, or -N ⁺ -O ^- ; Y is independently N, -N ⁺ -O ^- , or CR _8' ; provided that at least one of X, X, or Y is neither N nor -N ⁺ -O ^- , and no more than one of X, X, or Y is -N ⁺ -O ^- ;

R ₁ is C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CR _3a R _3b ) _m - (3- to 7-membered cycloalkyl), -(CR _3a R _3b ) _m - (3- to 7-membered heterocycloalkyl) containing 1-3 heteroatoms, -(CR _3a R _3b ) _m - (5- to 10-membered heteroaryl) containing 1-3 heteroatoms, or -(CR _3a R _3b ) _m -C6-C12 aryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl is optionally substituted with one to five substituents selected from halogen, deuterium, -OR ₅ , -SR ₅ , -NR _11a R _11b , cyano, C1-C6 alkyl, C3-C6 cycloalkyl or -C1-C6 alkoxy;

R ² is -(CR _3a R _3b ) _m -(3- to 10-membered cycloalkyl), -(CR _3a R _3b ) _m -(3- to 10-membered heterocycloalkyl) containing 1-3 heteroatoms, -(CR _3a R _3b ) _m -(5- to 10-membered heteroaryl) containing 1-3 heteroatoms, or -(CR _3a R _3b ) _m -C6-C12 aryl; wherein the cycloalkyl, heterocycloalkyl, heteroaryl or aryl is optionally substituted with 1-5 R ₄ ; wherein if the heteroatom of the heterocycloalkyl and heteroaryl is N, then N is optionally substituted with R _4' ; or R ² is C1-C6 alkyl, wherein the alkyl is optionally substituted with NH ₂ , OH or cyano;

R _3a and R _3b are independently hydrogen or C1-C3 alkyl, in each instance; R ₄ is independently a bond, deuterium, halogen, cyano, C1-C6 alkyl, C2-6 alkenyl, oxo, -OR ₅ , -SR ₅ , -S(O)R ₉ , -S(O) ₂ R ⁹ , -NR _11a R _11b , -C(O)R ₁₀ , -(CR _3a R _3b ) _n -(3- to 7-membered cycloalkyl), -(CR _3a R _3b ) _n -(4- to 10-membered heterocycloalkyl) containing 1-3 heteroatoms, -(CR _3a R _3b ) _n -(5- to 10-membered heteroaryl) containing 1-3 heteroatoms, or -(CR _3a R _3b ) _n -C6-C12 aryl, in each occurrence; wherein each alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl is optionally and independently substituted with from 1 to 5 substituents selected from deuterium, halogen, OR ₅ , -SR ₅ , -NR _11a R _11b , cyano, C1-C6 alkyl, C3-C6 cycloalkyl or -C1-C6 alkoxy; or two R _4, together with the carbon atoms to which they are attached, form a 3- to 6-membered cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with from 1 to 3 substituents selected from halogen, deuterium, OR ₅ , -SR ₅ , -NR _11a R _11b , cyano, C1-C6 alkyl or C1-C6 alkoxy; wherein the alkyl or alkoxy is optionally substituted with a substituent selected from halogen, deuterium, OR ₅ , -SR ₅ , -NR _11a R _11b or cyano; wherein if the heteroatom of the heterocycloalkyl a is N, then N is optionally substituted with R _4' ;

R _4' is independently C1-C6 alkyl, C2-6 alkenyl, -C(O)R ₁₀ , -S(O) ₂ R ₉ , -(CR _3a R _3b ) _n -(3-7 membered cycloalkyl), -(CR _3a R _3b ) _n -(4-10 membered heterocycloalkyl) or C(O)(CH ₂ ) _t CN; wherein each alkyl, alkenyl, cycloalkyl or heterocycloalkyl is optionally and independently substituted with 1-5 substituents selected from deuterium, halogen, OH, cyano or C1-C6 alkoxy; or R ₄ and R _4', together with the respective atoms to which they are attached, form a 3- to 6-membered cycloalkyl or a 4- to 6-membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl being optionally substituted with 1-3 substituents selected from halogen, deuterium, OR ₅ , -SR ₅ , -NR _11a R _11b , cyano, C1-C6 alkyl or C1-C6 alkoxy, the alkyl or alkoxy being optionally substituted with halogen, deuterium, OR ₅ , -SR ₅ , -NR _11a R _11b or cyano;

each R _4a and R _4b is independently hydrogen, deuterium, deuterium, F, OH, -OR ₅ , methyl, ethyl, vinyl, cyclopropyl or propyl optionally substituted with 1-5 deuteriums, fluorines, methoxy or OH;

R _4c and R _4d are independently halogen, OH, deuterium, C1-C6 alkyl, C2-6 alkenyl, -OR ₅ , -(CR _3a R _3b ) _n -(3- to 6-membered cycloalkyl), -(CR _3a R _3b ) _n -(4- to 6-membered heterocycloalkyl), NH ₂ , at each occurrence, wherein each alkyl, cycloalkyl and heterocycloalkyl is optionally and independently substituted with 1-5 substituents selected from deuterium, halogen, OH, cyano or C1-C6 alkoxy; or R _4c and R _4d , together with the carbon atoms to which they are attached, form a 4- to 7-membered heterocycloalkyl or a 3- to 7-membered cycloalkyl, the heterocycloalkyl and cycloalkyl being optionally and independently substituted with 1-3 fluoros, C1-C3 alkyls, or C1-C3 fluoroalkyls; or

R _4c and R _4a , together with the atoms to which they are attached, form a 4- to 7-membered heterocycloalkyl or a 3- to 7-membered cycloalkyl, each heterocycloalkyl and cycloalkyl independently optionally substituted with 1-3 fluoros, C1-C3 alkyls, or C1-C3 fluoroalkyls;

R ₅ is independently hydrogen or C1-C6 alkyl, wherein the alkyl is optionally substituted with halogen, deuterium, C1-C6 alkoxy, C1-C6 alkylthio, -NR _11a R _11b , cyano, C1-C6 alkyl or C3-C6 cycloalkyl; or two R ₅ together with the oxygen atoms to which they are attached form a 5- or 6-membered heterocycloalkyl;

R ₆ is hydrogen, deuterium, -C(O)NHR ₇ , CO ₂ R ₇ or cyano;

R ₇ is hydrogen or C1-C6 alkyl;

R ₈ independently represents hydrogen, deuterium, halogen, cyano, OR ₅ , -SR ₅ , -NR _11a R _11b , C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C6 cycloalkyl, 3-10-membered heterocycloalkyl, or 5-6-membered heteroaryl or aryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl is optionally substituted with 1 to 3 halogens, C3-C6 cycloalkyls, C3-C6 heterocycloalkyls containing 1 or 2 N heteroatoms, OR ₅ , -SR ₅ , -NR _11a R _11b , cyano, C1-C3 alkyl, -C(O)R ₁₀ or oxo;

R _8' is hydrogen, deuterium, deuterium, halogen, cyano, OR ₅ , -SR ₅ or -NR _11a R _11b ;

R ₉ is -(CR _3a R _3b ) _p -(C1-C3 alkyl), -(CR _3a R _3b ) _p -(4- to 6-membered cycloalkyl), -(CR _3a R _3b ) _p -(4- to 6-membered heterocycloalkyl) or -(CR _3a R _3b ) _p -(C5-C9 aryl), wherein each alkyl, cycloalkyl, heterocycloalkyl or aryl is optionally substituted with fluoro or C1-C3 alkyl;

R ₁₀ is C1-C6 alkyl, wherein the alkyl is optionally substituted with deuterium, halogen, OH, C1-C6 alkoxy or cyano;

each R _11a and R _11b independently represents hydrogen or C1-C6 alkyl, wherein the alkyl is optionally substituted with deuterium, C1-C6 alkoxy or cyano; if it is C2-6 alkyl, then the alkyl is optionally substituted with deuterium, C1-C6 alkoxy, cyano, halogen or OH;

m is equal to 0, 1, 2 or 3 independently;

n is equal to 0, 1, 2 or 3 independently;

p is independently 0 or 1; and

t is 1, 2, or 3; or

in some embodiments of the present invention, the RTM has the following structure:

or a pharmaceutically acceptable salt thereof; wherein in RTM-70, RTM-70a, RTM-70b or RTM-70 with:

each X ₁ and X ₃ independently represents CH or N; X ₂ represents CR ² or N; provided that one of X ₁ , X ₂ or X ₃ represents N;

A represents O, N or S;

Y represents N, _CH2 or O;

ring Z is aryl, heteroaryl or heterocycloalkyl;

R ₁ is independently halogen, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl, in each occurrence; the substituent is alkyl, alkoxy, aminoalkyl, halogen, hydroxyl, hydroxyalkyl, or -NR _a R _b ;

R ² is hydrogen, deuterium, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, or -NR _a R _b ; wherein the substituent is alkyl, amino, halogen, or hydroxyl;

R ₃ is alkyl or hydroxyl, in each case;

R _a and R _b are independently hydrogen, deuterium, alkyl, acyl, heteroaryl or heterocycloalkyl;

m and n are each independently 0, 1, or 2;

p is 0 or 1; or

in some embodiments of the present invention, the RTM has the following structure:

where in RTM-71:

ring A is a 6- to 10-membered aryl or 5- to 10-membered heteroaryl;

each R _d is independently hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl or 5-10 membered heteroaryl; and the alkyl, cycloalkyl and heteroaryl are optionally substituted with one or more groups selected from halogen, hydroxyl or amino;

n is 1, 2, 3, or 4;

R _e represents hydrogen or C1-C6 alkyl;

R _c is hydrogen, deuterium, -O-(C1-C6 alkyl), -O-(C3-C8 cycloalkyl), -O-(3- to 8-membered heterocycloalkyl), -O-(6- to 10-membered aryl), -O-(5- to 10-membered heteroaryl), -N(C1-C6 alkyl) ₂ , -NH(C3-C8 cycloalkyl), -NH(C3-C8 heterocycloalkyl), -NH(6- to 10-membered aryl), -NH(5- to 10-membered heteroaryl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C6-C10 aryl or 5- to 10-membered heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, amino, halogen, -O-(C1-C6 alkyl) and cyano;

R _b is hydrogen, deuterium, -O-(C1-C6 alkyl), -O-(C3-C8 cycloalkyl), -O-(C3-C8 heterocycloalkyl), -O-(6-10 membered aryl), -O-(5-10 membered heteroaryl), -N(C1-C6 alkyl)1-2, -NH(C3-C8 cycloalkyl), -NH(C3-C8 heterocycloalkyl), -NH(6-10 membered aryl), -NH(5-10 membered heteroaryl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C6-C10 aryl or 5-10 membered heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more groups, independently selected from hydroxyl, amino, halogen and cyano;

R _a represents hydrogen, deuterium, 3-8-membered heterocycloalkyl, C3-C8 cycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, C1-C6 alkyl, ; alkyl is optionally substituted with one or more groups independently selected from halogen, hydroxyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, S(O)1-2(C1-C6 alkyl), S(O)1-2(C3-C6 cycloalkyl), unsubstituted or mono- or polysubstituted with halogen C3-C6 cycloalkyl, unsubstituted or mono- or disubstituted with methyl monocyclic saturated heterocycloalkyl having 4-6 ring atoms and containing heteroatoms or heterogroups selected from O, S, SO or SO ₂ ; and cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more groups selected from hydroxyl, halogen, amino, cyano, C1-C6 alkyl, -O(C1-C6 alkyl), halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl and amino C1-C6 alkyl; wherein * represents the linkage site at which the group is attached to the remainder of the molecule; or

or a stereoisomer, or a pharmaceutically acceptable salt thereof; and in RTM-72:

R ¹ is: (a) C2-C3 hydroxyalkyl substituted with 0-4 R ^1a , wherein R ^1a is selected from F, Cl, -OH, -CHF ₂ , -CN, -CF ₃ , -OCH ₃ and cyclopropyl;

(b) C1-C3 alkyl substituted with -O(C1-C3) alkyl and 0-4 R ^1a , wherein R ^1a is selected from F, Cl, -OH, -CHF ₂ , -CN, -CF ₃ and cyclopropyl;

(c) C4-8 alkyl substituted with 0-7 R ^1a , wherein R ^1a is selected from F, Cl, -OH, -CHF ₂ , -CN, -CF ₃ , -OCH ₃ , cyclopropyl or -OR(O)(OH) ₂ ;

(d) -(CH ₂ ) ₂ -4NHC(O)(C1-C6 alkyl), -(CH ₂ ) ₂ CH(CH ₃ )NHC(O)(C1-C6 alkyl), -(CH ₂ ) ₂ CH (CH ₃ )NHC(O) O(C1-C6 alkyl), -(CH ₂ ) ₂ CH(CH ₃ )NHC(O)(CH ₂ ) _0-1 NH(C1-C6 alkyl) or -(CH ₂ ) ₂ CH(CH ₃ )NHC(O)(CH ₂ ) _0-1 N(C1-C6 alkyl) ₂ , -(CH ₂ ) ₂ CH(CH ₃ ) NHC(O)(CH ₂ ) _0-1 (C3-C6 cycloalkyl), -(CH ₂ ) ₂ CH(CH ₃ )NHC(O)( _CH2 ) _0-1 (C3-C6 fluorocycloalkyl), -(CH ₂ ) ₂ CH(CH ₃ )NHC(O)(C1-C6 hydroxyalkyl), -(CH ₂ ) ₂ CH(CH ₃ )NHC(O)N( C1-C6 alkyl)(phenyl) or -(CH ₂ ) ₂ CH(CH ₃ )NHC(O)(CH ₂ ) _0-1 R, where R is phenyl, morpholinyl, pyrrodiyl, thiazolyl or tetrahydropyran;

(e) cyclohexyl, cyclopentyl, cyclopropyl or cyclobutyl which are substituted with 0-2 substituents independently selected from the following: -OH, _-OCH3 , oke o, _-NH2 , nitro, C1-C6 alkyl, C1-C6 hydroxyalkyl, -C(O) _NH2 , -C(O)NH(C1-C3 alkyl), -C(O)NH(C1-C6 hydroxyalkyl), -C(O)NH(C3-C6 cycloalkyl), -C(O)NH(C3-C6 fluorocycloalkyl), -C(O)NH(C3-C6 cyanocycloalkyl), -NHC(O)(C1-C3 alkyl), -NHC(O)(pyrndyl), -NHC(O)(morpholinyl), -NHC(O)(hydroxylbicyclo(2,2,2)heptyl), -NHC(O)NH(C1-C4 alkyl), -NHC(O)O(C1-C3 alkyl), -NHS(O) ₂ CH ₃ , -NHS(O) ₂ NH ₂ , -NHS(O) ₂ (C1-C3 alkyl), -S(C1-C3 alkyl), thiazolyl, methylpyrazolyl or C1-C3 alkyl substituted with -OH or piclopropyl;

(f) -(CH ₂ ) ₂ phenyl, wherein phenyl is substituted by -C(O)NH ₂ , -C(O)NH(C1-C3 alkyl) or -S(O) ₂ NH ₂ ;

(g) piperidinyl, azetidinyl, azapiclopentane, piperazinyl, optionally which are optionally substituted with -C(O)(C1-C3 alkyl); or

(h)

R ² is phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazolyl, thiazolyl, triazolyl, benzoxazolyl, pyrazolepyridyl, pyrrolopyridyl, benzothiazolyl, thiazolpyridyl, pyrazolopyrimidinyl, benzoxadiazolyl, benzothiadiazolyl, quinolyl, cinnolinyl, quinazolinyl, quinoxapyl, 1,5-diazanaphthyl, 1,6-diazanaphthyl, pyridopyrazinyl or pyridopyrimidinyl, and each independently substituted with 0-2 substituents independently selected from the following: F, Cl, -OH, -CN, C1-C3 alkyl, -CH ₂ C(O)OCH ₃ , -O(C1-C3 alkyl), -NH ₂ , -NH(C1-C3 alkyl), -NH(cyclopropyl), -C(O)NH ₂ , -NHC(O)(C1-C3 alkyl), -NH(tetrahydropyralyl), hydroxypyrrolidyl, oxo, -O(piperidinyl) or pyridyl;

R ₃ is: (a) C1-C6 alkyl substituted with 0-4 substituents independently selected from the following: F, -CH ₃ , -CF ₃ , phenyl, tetrahydrofuranyl, morpholinyl, or C3-C6 cyclopentyl;

(b) C1-C6 hydroxyalkyl substituted with 0-3 groups selected from F, phenyl, fluorophenyl, difluorophenyl or dichlorophenyl;

(c) -( _CH2 ) _0-2 (C3-C7 cycloalkyl) substituted with 0-2 substituents independently selected from the following: F, Cl, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, -O(C1-C3 alkyl), _-OCF3 , -C(O) _NH2 , -C(O)NH(C1-C3 alkyl), -C(O)NH(C1-C3 hydroxyalkyl), -C(O)NH(C3-C5 cycloalkyl), -C(O)N(C1- _C3 alkyl) ₂ , -S(O) _2CH3 , _-CF2H , _-NH2 , -C(O) _CH2CH3 or _pyrazolyl ;

(d) oxetanyl, tetrahydropyranyl or fluorotetrahydropyranyl;

(e) thiazolyl substituted with 0-2 groups selected from C1-C3 hydroxyalkyl;

(f) phenyl substituted with 0-2 substituents independently selected from the following: -OH, -CN, -O(C1 _- C3 alkyl), C1-C3 hydroxyalkyl, -C(O) _NH2 , -S(O) _2NH2 , -NHS(O) ₂ (C1-C3 alkyl), pyrazolyl, imidazolyl or methyltetrazolyl; or

in some embodiments of the present invention, the RTM has the following structure:

or its pharmaceutically acceptable salt; and in RTM-73:

NO is a heteroaryl selected from the following: pyrazolyl, indolyl, pyrrolo[2,3-b]pyridyl, pyrrolo[2,3-b]pyrimidyl, pyrazolo[3,4-b]pyridyl, pyrazolo[3,4-b]pyrimidyl, 2,3-Dihydro-1H-pyrrolo[2,3-b]pyridyl, imidazolo[4,5-b]pyridyl or purinyl, wherein the heteroaryl is optionally substituted with R _a or R _b ;

R _a represents hydrogen, deuterium, F, Cl, Br, -CN, -OH, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, -NH ₂ , -NH(C1-C4 alkyl), -N(C1-C4 alkyl) ₂ , -NH(C1-C4 hydroxyalkyl), -NH(C1-C4 fluoroalkyl), -NH(C1-C6 hydroxyl-fluoroalkyl), -C(O)NH ₂ ,-CH ₂ NHC(O)(C1-C6 alkyl), -CH ₂ NHC(O)(C1-C6 hydroxyalkyl), -CH ₂ NHC(O)NH(C1-C6 alkyl), -CH ₂ KHC(O)KHCH ₂ (phenyl), -CH ₂ NHC(O)N(C1-C4 alkyl) ₂ , -CH ₂ NHC(O)O(C1-C4 alkyl), -CH ₂ NHC(O)(C3-C6 cycloalkyl), -CH ₂ NHC(O)(tetrahydrofuranyl), -CH ₂ NHC(O)CH ₂ (C3-C6 cycloalkyl), -CH ₂ NHC(O)CH ₂ (tetrahydropyranyl), -CH ₂ NHC(O)CH ₂ (phenyl), -NHC(O)(C1-C4 alkyl), pyrrolidinyl, hydroxypyrrolyl or pyridazinyl;

R _b represents hydrogen or -NH ₂ ;

R ₁ represents: (i) C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 hydroxyl-alkyl, C1-C8 hydroxyl-fluoroalkyl, -(C1-C6 alkylene)O(C1-C4 alkyl), -(C1 -C6 alkylene)O(C1-C4 fluoroalkyl), -(C1-C6 fluoroalkylene)O(C1-C4 alkyl), -(C1-C6 fluoroalkylene)O(C1-C4 deuterated alkyl), -(C1-C6 fluoroalkylene)O(C1-C4 fluoroalkyl), -(C1-C6 fluoroalkylene)C( C3-C6 cycloalkyl) ₂ (OH), -(C1-C4 alkylene)NHC(O)(C1-C4 alkylene)OC(O)(C1-C3 alkyl), -(C1-C6 alkylene)NHS(O) ₂ (C1-C4 alkyl), -(C1-C6 alkylene)P(O)(C1-C4 alkoxy) ₂ , -(C1-C6 fluoroalkylene)NH(C1-C4 alkyl), -( C1-C6 alkylene)C(O)NH(C1-C4 alkyl), -(C1-C6 fluoroalkylene)C(O)NH(C1-C4 alkyl), -(C1-C6 fluoroalkylene)C(O)NH(C1-C4 hydroxyalkyl) or -(C1-C6 fluoroalkylene)OP(O)(OH) ₂ ;

(ii) -(C1-C3 alkylene)R _x , -(C1-C3 fluoroalkylene)R _x , -(C1-C3 alkylene)C(O)R _x , -(C1-C3 alkylene)C(O)NHR _x , -(C1-C3 fluoroalkylene)C(O)NHR _x or -CH ₂ CF=(tetrahydropyranyl), wherein R _x is selected from the following cyclyls: C3-C6 cycloalkyl, tetrazolyl, 1,1-dioxidotetrahydrothiophenyl, 1,1-dioxidothiomorpholino, oxadiazolyl, piperidyl, piperazinyl, pyrrolidyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, imidazolyl, morpholinyl, phenyl and triazinyl, wherein each cyclyl is optionally substituted with 0-3 substituents independently selected from the following: F, -OH, _-CH3 , -( _CH2 ) _2OH , _-OCH3 , -C(O) _CH2CN , -S(O) _2CH3 , -S(O _{) 2NH2} , -NHC(O)CH3, -N(S( _{O)2CH3 ) 2} , _{-CH2CH2 ( acetaminophenyl} ) _{, -CH2CH2} (methoxyphenyl), _-CH2CH2 ( _{aminosulfonylphenyl} ), oxetanyl, _phenyl or morpholinyl;

(iii) C3-C6 cycloalkyl or C4-C6 cycloalkenyl, each substituted with 0-3 substituents independently selected from the following: F, -OH, -CN, C1-C3 alkyl, C1-C3 alkoxy, S(C1-C3 alkyl), nitro, S(O) ₂ (C1-C3 alkyl), C1-C4 hydroxyalkyl, -C(C1-C3 alkyl)(OH)(C3-C6 cycloalkyl), -CH ₂ C(O)NH(C1-C3 alkyl), -NHC(O)(C1-C3 alkyl), -NHC(O)(C1-C4 hydroxyalkyl), -C(O)NH(C1-C3 alkyl), -C(O)NH(C1-C3 deuterated alkyl), -C(O)NH(C3-C6 cycloalkyl), -NHC(O)O(C1-C3 alkyl), -NHS(O) ₂ (C1-C3 alkyl), pyridyl, imidazolyl, pyrazolyl, methylimidazolyl, methylpyrazolyl or thiazolyl;

(iv) tetrahydrofuranyl, piperidyl, pyrazolyl, phenyl, pyridyl or pyrimidyl, each substituted with 0-1 substituent selected from the following: -OH, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C4 hydroxyalkyl, C1-C3 alkoxy, -C(O)(C1-C4 alkyl), -S(O) ₂ (C1-C4 alkyl), -S(O) ₂ NH(C1-C4 alkyl), -NH(C1-C3 alkyl), -O(C1-C3 alkylene)N(C1-C3 alkyl) ₂ , -CH ₂ (morpholinyl), azetidinyl, tetrahydropyranyl, morpholinyl, oxetanyl, piperazinyl, piperidinyl, methylpiperazinyl, methoxypiperidinyl, pyridyl, pyrimidyl, methylsulfonylasetidine or -C(O)(methylsulfonylasetidine); or

(v) pyrrolo[2,3-c]pyridyl, bicyclic [2.2.1]hept-1-ol, tetrahydrobenzo[d]thiazol-2-amine, or 1,3-diazaspiro[4.5]dec-2,4-dione; and

R ² is: (i) C1-C7 alkyl or C2-6 alkenyl, each independently substituted with 0-3 substituents independently selected from F, -OH or -CN; -(C1-C4 alkylene)O(C1-C4 alkyl), -(C1-C4 alkylene)O(C1-C4 fluoroalkyl), -(C1-C6 alkylene)NH ₂ , -(C1-C6 alkylene)S(O) ₂ (C1-C3 alkyl), -(C1-C6 fluoroalkylene)NH(C1-C3 alkyl) or -(C1-C6 alkylene)NHC(O)(C1-C4 fluoroalkyl);

(ii) -(C1-C4 alkylene)R _y , wherein R _y is C3-C6 alkyl, azetidine, oxetane, oxazolyl, pyridyl, tetrahydropyranyl, each of which is independently substituted with 0-3 substituents selected from the following: F, -OH, C1-C3 alkyl, C1-C3 hydroxyalkyl, -C(O)(C1-C3 alkyl), -C(O)(C1-C3 fluoroalkyl), -C(O)(C1-C3 cyanoalkyl), -C(O)O(C1-C3 alkyl), -C(O)NH ₂ , -C(O)NH(C1-C3 alkyl), -C(O)(dafluorophenyl), -NH ₂ , -NH(C1-C3 alkyl), -NH(C1-C3 fluoroalkyl), -NH(oxetane), -NHC(O)(C1-C3 alkyl), -NHC(O)(C1-C3 fluoroalkyl), -NHC(O)(C3-C6 cycloalkyl), -NHC(O)(fluorophenyl), -S(O) ₂ (C1-C3 alkyl), imidazolyl, phenyl, pyrimidyl, fluoropyrimidyl, chlorophimidyl or methoxypyrimidyl;

(iv) adamantyl, hydroxyadamantyl, benzo[d]imidazolyl, benzo[d]oxazolyl, benzo[d]triazolyl, benzo[d]thiazolyl, bicyclo[1.1.1]pentyl or hydroxybico[2.2.1]heptyl; or

(v) phenyl, pyrazolyl, thiazolyl, thiadiazolyl or indazolyl, each independently substituted with 0-2 substituents selected from the following: F, -Cl, -OH, -CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 fluoroalkyl, C1-cyanoalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, -(C1-C3 alkylene)O(C1-C3 alkyl), -(C1-C3 alkylene)O(C1-C3 fluoroalkyl), -C(O)NH ₂ , -C(O)NH(C1-C3 alkyl), -NHC(O)(C1-C3 alkyl), -NHC(O)S(O) ₂ (C1-C3 alkyl), -S(O) ₂ NH ₂ , -S(O) ₂ (C1-C3 alkyl), pyrazolyl, methylpyrazolyl, imidazolyl, triazolyl, methyltetrazolyl, ethyltetrazolyl, phenyl, pyrimidyl, fluoropyrimidyl or tetrahadropyranyl; or

in some embodiments of the present invention, the RTM has the following structure:

or its pharmaceutically acceptable salt; and in RTM-74:

ring A is aryl or heterocycloalkyl;

R ₁ is H, alkyl or heteroalkyl;

R ² is H, alkyl, heteroalkyl or heterocycloalkyl;

each Z ¹ , Z ² , Z ³ and Z ⁴ independently represents N or CR ₃ , wherein at least one of Z ¹ , Z ² , Z ³ and Z ⁴ is N;

R ₄ is halogen, heterocycloalkyl, aryl, -O-aryl or -NH-aryl; or in some embodiments of the present invention, the PTM has the following structure:

or its pharmaceutically acceptable salt; and in RTM-75:

is _C3-10 aryl, a 3-8-membered saturated or partially unsaturated carbocycle, a 3-7-membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6-membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R ^a is independently -R, halogen, -haloalkyl, -OR, -SR, -CN, _-NO2 , -SO2R, -SOR, -C(O)R, _-CO2R , -C(O)N( _R ) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , _-NRSO2R , or -N(R) ₂ ;

R ^b is -R, halogen, -haloalkyl, -OR, -SR, -CN, _-NO2 , -SO2R, -SOR, -C(O)R, _-CO2R , -C(O)N( _R ) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , _-NRSO2R , or -N(R) ₂ ; or R ^b is absent;

ring X is C3-10 aryl; a 5-6 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a fused C3-10 aryl; a fused 5-10 membered saturated or partially unsaturated carbocycle; a fused 5-10 membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or a fused 5-10 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of the above is optionally substituted;

R ¹ is -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R, or -N(R) ₂ ;

R ² is -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R or -N(R) ₂ ; R ₃ is -R or -haloalkyl;

R ⁴ is -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R or -N(R) ₂ ; each R is independently hydrogen, deuterium, C _1-6 aliphatic, C3-C10 aryl, a 3-8-membered saturated or partially unsaturated carbocyclic ring, a 3-7-membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6-membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of the above is optionally substituted; or

two R on the same atom, together with the atom to which they are attached, form - C3-C10 aryl, a 3-8-membered saturated or partially unsaturated carbocyclic ring, a 3-7-membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6-membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of the foregoing is optionally substituted; and

p is 0, 1, 2, 3, 4, or 5; or

in some embodiments of the present invention, the RTM has the following structure:

or its stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof; wherein in RTM-76:

Y is selected from O, S, SO, SO ₂ or NR ¹ ;

Z is selected from S, O or NR ² ;

A is a substituted or unsubstituted aryl or heteroaryl;

B is cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more R ³ groups;

R ¹ is selected from hydrogen or alkyl;

R ² is selected from hydrogen, deuterium, alkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxycarbonylalkyl, aminoacylalkyl, alkylaminoacylalkyl, dialkylaminoacylalkyl, (heterocycloalkyl)alkyl-, (aryl)alkyl-, or (heteroaryl)alkyl-;

each R ³ is independently selected from alkyl, heterocycloalkyl, halogen, hydroxyl, R ^3a R ^3b N-, carboxyl, haloalkyl, hydroxyalkyl, alkoxy, heterocycloalkoxyl, (heterocycloalkyl)alkyloxy, hydroxyalkoxyl, or R ^3a R ^3b NC(O)-, wherein the heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, alkyl, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, and dialkylamino, at each occurrence; each R ^3a and R ^3b is independently selected from hydrogen, deuterium, alkyl, cycloalkyl, hydroxyalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from halogen, alkyl, haloalkyl, hydroxyl, alkoxy, amino, alkylamino and dialkylamino; or

in some embodiments of the present invention, the RTM has the following structure:

or its stereoisomers, tautomers, solvates or pharmaceutically acceptable salts; wherein in RTM-77, RTM-77a, RTM-77b, RTM-77c, PTM-77d, RTM-77e, PTM-77f, PTM-77g, PTM-77h, PTM-77i:

R ¹ is selected from H, (C1-C8)alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, -C1-C4 alkyl-O-C1-C4 alkyl, -O-C1-C4 alkyl, C3-C8 cycloalkyl (C1-C8)alkyl, heterocycloalkyl (C1-C8)alkyl, 6-10-membered aryl, aryl (C1-C8)alkyl, heteroaryl (C1-C8)alkyl or heteroaryl, wherein alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted;

R ² is selected from C1-C8 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, -C1-C4 alkyl-O-C1-C4 alkyl, -O-C1-C4 alkyl, 6-10-membered aryl or heteroaryl, wherein alkyl, cycloalkyl, aryl, heteroaryl are optionally substituted;

each R ⁵ , R ⁶ , R ⁷ and R ⁸ is independently selected from H, halogen, C1-C4 alkyl, C1-C4 halogenalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, -C1-C4 alkyl-O-C1-C4 alkyl, -O-C1-C4 alkyl, aryl, aryl(C1-C4)alkyl, heteroaryl, CN, CO ₂ R', CONR'R", NR'R", NO ₂ , OR', SR', C(O)R', OC(O)R, N(R")C(O)R', N(R")CO ₂ R', N(R")C(O)NR'R", S(O) _m NR'R", S(O) _m R and N(R")S(O) _m R', wherein the alkyl, cycloalkyl, aryl and heteroaryl optionally substituted, wherein the subscript m is an integer 1 or 2;

each R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ is independently selected from H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, -C1-C4 alkyl-O-C1-C4 alkyl, -O-C1-C4 alkyl, aryl, aryl(C1-C4)alkyl, heteroaryl, CN, CO ₂ R', CONR'R", NR'R", NO ₂ , OR', SR', C(O)R', OC(O)R', N(R")C(O)R', N(R")CO ₂ R', N(R")C(O)NR'R", S(O) _m NR'R", S(O) _m R and N(R")S(O) _m R', alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted, wherein the subscript m is an integer of 1 or 2;

X selected from H, OR', NR'R", OC(O)R, CO ₂ R, CONR'R", OCONR'R", N(R")C(O)R, C(O)R, N(R")CO ₂ R' or N(R")C(O)NR'R";

Y is C(O), S(O), S(O) ₂ or -CH ₂ -;

each R' and R" is independently selected from H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, -C1-C4 alkyl-O-C1-C4 alkyl, -O-C1-C4 alkyl, aryl, aryl(C1-C4)alkyl, wherein alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted; or

R' and R" together with the N atoms bonded to them form a 5-, 6-, or 7-membered ring.

Preferably, in some embodiments of the present invention, the RTM has the following structure:

or a pharmaceutically acceptable salt thereof; wherein in RTM-70, RTM-70a, RTM-70b or RTM-70:

each X ₁ and X ₃ independently represents CH or N; X ₂ represents CR ² or N; provided that one of X ₁ , X ₂ or X ₃ represents N;

A represents O or S;

Y represents N, _CH2 or O;

ring Z is 6-10 membered aryl, 5-6 membered heteroaryl, or 3-8 membered heterocycloalkyl;

R ₁ is independently halogen, optionally substituted pyridyl, optionally substituted pyrazolyl, optionally substituted pyrrolidyl, or optionally substituted piperidinyl, in each occurrence; the substituent is alkyl, alkoxy, aminoalkyl, halogen, hydroxyl, hydroxyalkyl, or -NR _a R _b ;

R ² is hydrogen, deuterium, optionally substituted piperidinyl, optionally substituted pyrrolidyl, optionally substituted morpholinyl, optionally substituted piperazinyl, optionally substituted azetidinyl, optionally substituted pyrazolyl, optionally substituted furanyl, optionally substituted azabicyclo[3.2.1]octane or cyclopropyl; wherein the substituent is alkyl, amino, halogen or hydroxyl;

R ₃ is alkyl or hydroxyl, in each case;

R _a and R _b are independently hydrogen, deuterium, alkyl, acyl, heteroaryl or heterocycloalkyl;

m and n are each independently 0, 1, or 2;

p is 0 or 1.

Preferably, in some embodiments of the present invention, the RTM is selected from

Preferably, in some embodiments of the present invention, the RTM has the following structure:

Preferably, in some embodiments of the present invention, the compound of formula I and/or its stereoisomer, enantiomer, diastereomer, deuterate, metabolite, hydrate, solvate, prodrug and/or pharmaceutically acceptable salt thereof is a compound of formula IA and/or its stereoisomer, enantiomer, diastereomer, deuterate, metabolite, hydrate, solvate, prodrug and/or pharmaceutically acceptable salt thereof,

where X ₁ , X ₂ , X ₃ , A, Y, p, R ₁ , R ₃ , m, Z, n are as defined in RTM-70, and L, ULM are as defined in this document.

Preferably, in some embodiments of the present invention, the compound of formula I and/or its stereoisomer, enantiomer, diastereomer, deuterate, metabolite, hydrate, solvate, prodrug and/or pharmaceutically acceptable salt thereof is a compound of formula IA-1 and/or its stereoisomer, enantiomer, diastereomer, deuterate, metabolite, hydrate, solvate, prodrug and/or pharmaceutically acceptable salt thereof,

wherein A, Y, p, _R1 , _R2 , _R3 , m, n are as defined in RTM-70a, and L, ULM are as defined in this document.

Preferably, in some embodiments of the present invention, the compound of formula I and/or its stereoisomer, enantiomer, diastereomer, deuterate, metabolite, hydrate, solvate, prodrug and/or pharmaceutically acceptable salt thereof is a compound of formula IA-2 and/or its stereoisomer, enantiomer, diastereomer, deuterate, metabolite, hydrate, solvate, prodrug and/or pharmaceutically acceptable salt thereof,

wherein A, Y, R ₁ , R ₂ , n are as defined in PTM-70b, and L, ULM are as defined herein.

Preferably, in some embodiments of the present invention, the compound of formula I and/or its stereoisomer, enantiomer, diastereomer, deuterate, metabolite, hydrate, solvate, prodrug and/or pharmaceutically acceptable salt thereof is a compound of formula IA-3 and/or its stereoisomer, enantiomer, diastereomer, deuterate, metabolite, hydrate, solvate, prodrug and/or pharmaceutically acceptable salt thereof,

wherein A, Y, R ₁ , R ₂ , n are as defined in RTM-70c, and L, ULM are as defined in this document.

Preferably, in some embodiments of the present invention, the RTM has the following structure:

or a pharmaceutically acceptable salt thereof; wherein in PTM-69h or PTM-69i:

each X and X' independently represents CRs or N; Y independently represents N or CR _8' ; provided that at least one of X, X' or Y is not N;

R ₁ is C1-C6 alkyl or C3-C6 cycloalkyl, wherein alkyl and cycloalkyl are optionally substituted with a substituent selected from halogen, deuterium, -OH, cyano, C1-C3 alkyl, C3-C6 cycloalkyl or C1-C6 alkylthio;

R _3a and R _3b are independently hydrogen or C1-C3 alkyl, in each instance;

R ₄ is independently halogen, C1-C6 alkyl, C2-6 alkenyl, -OR ₅ , -(CR _3a R _3b ) _n -(3-6 membered cycloalkyl), -(CR _3a R _3b ) _n -(4-6 membered heterocycloalkyl), -NR _11a R _11b , at each occurrence, wherein each alkyl, cycloalkyl, heterocycloalkyl is optionally and independently substituted with 1-5 substituents selected from halogen, OH, cyano, C(O)(CH ₂ ) _t CN or C1-C6 alkoxyl; or two R ₄ together with the carbon atoms to which they are attached form cyclopropyl, cyclopentyl or cyclobutyl, wherein cyclopropyl, cyclopentyl and cyclobutyl are optionally substituted with 1-3 substituents selected from F, Cl, OH, methyl, ethyl, propyl, C1-C3 fluoroalkyl, C1-C3 difluoroalkyl, C1-C3 hydroxyalkyl, methoxy and ethoxy;

each R _4a and F _4b is independently hydrogen, deuterium, deuterium, F, OH, -OR ₅ , methyl, ethyl, vinyl, cyclopropyl or propyl optionally substituted with 1-5 deuteriums, fluorines, methoxy or OH;

R _4c and R _4d are independently halogen, OH, deuterium, C1-C6 alkyl, C2-6 alkenyl, -OR ₅ , -(CR _3a R _3b ) _n -(3-6 membered cycloalkyl), -(CR _3a R _3b ) _n -(4-6 membered heterocycloalkyl), NH ₂ , at each occurrence, wherein each alkyl, cycloalkyl and heterocycloalkyl is optionally and independently substituted with 1-5 substituents selected from deuterium, halogen, OH, cyano or C1-C6 alkoxy; or

R _4c and R _4d , together with the carbon atoms to which they are attached, form a 4- to 7-membered heterocycloalkyl or a 3- to 7-membered cycloalkyl, wherein the heterocycloalkyl and cycloalkyl are optionally and independently substituted with 1-3 fluorines, C1-C3 alkyls, or C1-C3 fluoroalkyls; or

R _4c and R _4a , together with the atoms to which they are attached, form a 4- to 7-membered heterocycloalkyl or a 3- to 7-membered cycloalkyl, each heterocycloalkyl and cycloalkyl independently optionally substituted with 1-3 fluoros, C1-C3 alkyls, or C1-C3 fluoroalkyls;

R ₅ is independently hydrogen or C1-C6 alkyl, wherein the alkyl is optionally substituted with F;

R ₈ independently represents hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 5-6-membered heteroaryl or aryl, wherein the alkyl, alkenyl, alkynyl, heteroaryl or aryl is optionally substituted with one, two or three halogens, -NR _11a R _11b , C3-C6 cycloalkyl, C3-C6 heterocycloalkyl containing one or two N heteroatoms, C1-C3 alkyl or oxo;

R ₈ represents hydrogen, deuterium, deuterium, halogen or cyano;

R ₁₀ is C1-C6 alkyl, wherein the alkyl is optionally substituted with deuterium, F or cyano;

each R _11a and R _11b independently represents hydrogen or C1-C6 alkyl, wherein the alkyl is optionally substituted with OH;

n is equal to 0 or 1 independently;

p is independently 0 or 1; and

t is 1, 2, or 3.

In some embodiments of the present invention, in PTM-69h or PTM-69i, R ₁ is C1-C6 alkyl optionally substituted with 1-3 deuteriums, fluorines, chloros, or C1-C3 alkoxyls; preferably, R ₁ is methyl, ethyl, propyl, or isopropyl, wherein each R ₁ is optionally substituted with deuterium, fluorine, or methoxy.

In some embodiments of the present invention, in PTM-69h or PTM-69i, R ₃ a and R _3b are independently hydrogen or methyl, at each occurrence.

In some embodiments of the present invention, in PTM-69h or PTM-69i, R ₄ is independently fluoro, chloro, hydroxyl, or C1-C3 alkyl optionally substituted with 1-5 deuteriums, fluorines, chloros, hydroxyls, or C1-C3 alkoxy, in each occurrence, or two R _4, together with the carbon atoms to which they are attached, form cyclopropyl, cyclobutyl, and cyclopentyl, the cyclopropyl, cyclobutyl, and cyclopentyl being optionally substituted with 1-3 fluorines, chloros, hydroxyls, methyls, ethyls, propyls, C1-C3 hydroxyalkyls, C1-C3 fluoroalkyls, C1-C3 difluoroalkyls, C1-C3 trifluoroalkyls, methoxy, or ethoxy; preferably R ₄ independently represents fluorine, hydroxyl, methyl, ethyl, propyl, in each occurrence, wherein methyl, ethyl or propyl is optionally substituted with 1, 2 or 3 fluorines, hydroxyls or methoxy, or two R ₄ together with the carbon atoms to which they are attached form cyclopropyl, cyclobutyl and cyclopentyl, cyclopropyl, cyclobutyl and cyclopentyl being optionally substituted with 1 to 3 fluorines, chloroes, hydroxyls, methyls, fluoromethyls, difluoromethyls, trifluoromethyls, ethyls, propyls, C1-C3 hydroxyalkyls, methoxy or ethoxy.

In some embodiments of the present invention, in PTM-69h or PTM-69i, R ₈ is independently hydrogen, deuterium, halogen, or C1-C6 alkyl, wherein the alkyl is optionally substituted with fluoro; preferably, R ₈ is independently hydrogen, deuterium, fluoro, or methyl.

In some embodiments of the present invention, in PTM-69h or PTM-69i, R ₈ is independently C2-6 alkenyl or C2-6 alkynyl, wherein alkenyl and alkynyl are optionally substituted with C3-C6 cycloalkyl, C3-C6 heterocycloalkyl containing 1 or 2 N heteroatoms; preferably, R ₈ is independently vinyl, ethynyl and optionally substituted with cyclohexanyl, piperidinyl or piperazinyl.

In some embodiments of the present invention in PTM-69i, R _4a is hydrogen, deuterium, methyl, ethyl, or propyl, optionally substituted with fluoro, deuterium, or methoxy.

In some embodiments of the present invention in PTM-69i, R _4b is hydrogen or fluoro.

In some embodiments of the present invention, in PTM-69i, R _4c is hydroxyl.

In some embodiments of the present invention, in PTM-69i, R _4d is fluoro, methoxy or hydroxyl, or methyl optionally substituted with one, two or three fluorines, or ethyl optionally substituted with one, two or three fluorines.

In some embodiments of the present invention in PTM-69i, R _4c and R _4a , or R _4c and R _4d , together with the carbon atoms to which they are attached, form cyclopropyl, optionally substituted with 1-3 fluoros, C1-C3 alkyls, or C1-C3 fluoroalkyls.

Preferably, in some embodiments of the present invention, the RTM is selected from

Preferably, in some embodiments of the present invention, the RTM is selected from

More preferably, in some embodiments of the present invention, the RTM is selected from

Preferably, in some embodiments of the present invention, the compound of formula I and/or its stereoisomer, enantiomer, diastereomer, deuterate, metabolite, hydrate, solvate, prodrug and/or pharmaceutically acceptable salt thereof is a compound of formula IB and/or its stereoisomer, enantiomer, diastereomer, deuterate, metabolite, hydrate, solvate, prodrug and/or pharmaceutically acceptable salt thereof,

wherein X, X', Y, _R1 , _R4 , _R3a , _R3b , _R8 , n are as defined in PTM-69h and L, ULM are as defined herein.

Preferably, in some embodiments of the present invention, the compound of formula I and/or its stereoisomer, enantiomer, diastereomer, deuterate, metabolite, hydrate, solvate, prodrug and/or pharmaceutically acceptable salt thereof is a compound of formula IB-1 and/or its stereoisomer, enantiomer, diastereomer, deuterate, metabolite, hydrate, solvate, prodrug and/or pharmaceutically acceptable salt thereof,

wherein X, X', Y, R ₁ , R _4a , R _4b , R _4c , R _4d , R _3a , R _3b , R ₈ , n are as defined in PTM-69i, and L, ULM are as defined herein.

Preferably, in some embodiments of the present invention, the RTM has the following structure:

where in RTM-71:

ring A is a 6- to 10-membered aryl or 5- to 10-membered heteroaryl;

R _d independently represents hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl or 5-10 membered heteroaryl; alkyl, cycloalkyl and heteroaryl are optionally substituted with one or more groups selected from halogen, hydroxyl or amino;

n is 1, 2, 3, or 4;

R _e represents hydrogen or C1-C6 alkyl;

R _c is hydrogen, deuterium, -O-(C1-C6 alkyl), -O-(C3-C8 cycloalkyl), -O-(3- to 8-membered heterocycloalkyl), -O-aryl, -O-heteroaryl, -N(C1-C6 alkyl) _1-2 , -NH(C3-C8 cycloalkyl), -NH(3- to 8-membered heterocycloalkyl), -NH-aryl, -NH-heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl; alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, amino, halogen, cyano or -O-(C1-C6 alkyl);

R _b represents hydrogen, deuterium, -O-(C1-C6 alkyl), -O-(C3-C8 cycloalkyl), -O-(3- to 8-membered heterocycloalkyl), -O-aryl, -O-heteroaryl, -N(C1-C6 alkyl) _1-2 , -NH(C3-C8 cycloalkyl), -NH(3- to 8-membered heterocycloalkyl), -NH-aryl, -NH-heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl; alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, amino, halogen and cyano;

R _a represents hydrogen, deuterium, 3-8-membered heterocycloalkyl, C3-C8 cycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, C1-C6 alkyl, alkyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, S(O) _1-2 (C1-C6 alkyl), S(O) _1-2 (C3-C6 cycloalkyl), unsubstituted or mono- or polysubstituted with halogen C3-C6 cycloalkyl, unsubstituted or mono- or disubstituted with methyl monocyclic saturated heterocycloalkyl having 4-6 ring atoms and containing heteroatoms or heterogroups selected from O, S, SO or _SO2 ; cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, amino, cyano, C1-C6 alkyl, -O(C1-C6 alkyl), halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl or amino C1-C6 alkyl.

More preferably, in some embodiments of the present invention, the RTM has the following structure:

where in RTM-71:

ring A is phenyl or pyridyl;

each R _d is independently hydrogen, deuterium, halogen, cyano, C1-C6 alkyl or C3-C6 cycloalkyl, alkyl and cycloalkyl are optionally substituted with one or more groups selected from halogen, hydroxyl or amino;

n is 1 or 2;

R _e represents hydrogen;

R _c is hydrogen, deuterium, -O(C1-C6 alkyl), -N(C1-C6 alkyl) _1-2 , C1-C6 alkyl, -O(C3-C6 cycloalkyl), -N(C3-C6 cycloalkyl), -O(3-6-membered heterocycloalkyl), -N[(3-6-membered heterocycloalkyl), alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more groups independently selected from hydroxyl, amino, halogen, cyano or -O-(C1-C6 alkyl);

R _b is hydrogen or C1-C6 alkyl, and the alkyl is optionally substituted with one or more groups independently selected from hydroxyl, amino, halogen or cyano;

Ra is hydrogen, deuterium, 3-8 membered heterocycloalkyl, C3-C8 cycloalkyl, C1-C6 alkyl, alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, S(O)1-2(C1-C6 alkyl), S(O)1-2(C3-C6 cycloalkyl), unsubstituted or mono- or polysubstituted with halogen C3-C6 cycloalkyl, unsubstituted or mono- or disubstituted with methyl monocyclic saturated heterocycloalkyl having 4-6 ring atoms and containing heteroatoms or heterogroups selected from O, S, SO or SO ₂ ; cycloalkyl and heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more groups selected from hydroxyl, halogen, amino, cyano, C1-C6 alkyl, -O(C1-C6 alkyl), halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl or amino C1-C6 alkyl.

In some embodiments of the present invention, in RTM-71, ring A is pyridyl.

In some embodiments of the present invention, in PTM-71, each R _d is independently hydrogen, deuterium, halogen, or C1-C6 alkyl optionally substituted with one or more groups selected from halogen or hydroxyl; preferably, R _d is hydrogen, deuterium, F, methyl, difluoromethyl, trifluoromethyl, or 2-hydroxypropyl.

In some embodiments of the present invention, in RTM-71, R _e is hydrogen.

In some embodiments of the present invention, in RTM-71, R _c is C1-C6 alkyl, the alkyl optionally substituted with one or more groups independently selected from hydroxyl and halogen; preferably, R _c is difluoromethyl or 2-hydroxypropyl.

In some embodiments of the present invention in PTM-71, R _c is -O(C1-C6 alkyl), the alkyl is optionally substituted with one or more groups independently selected from hydroxyl, halogen or -OCH ₃ ; preferably, R _c is methoxy, ethoxy, isopropoxy, -OCH ₂ CH ₂ OCH ₃ , difluoromethoxy or trifluoromethoxy.

In some embodiments of the present invention, in RTM-71, R _c is -O-(3-6 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N or O); preferably

In some embodiments of the present invention, in RTM-71, R _b is hydrogen or methyl.

In some embodiments of the present invention, in RTM-71, R _a is hydrogen.

In some embodiments of the present invention, in RTM-71, R _a is a 3-8-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O or S, the heterocycloalkyl is optionally substituted with one or more groups selected from hydroxyl, halogen, amino, cyano, C1-C6 alkyl, -O(C1-C6 alkyl), halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, amino C1-C6 alkyl; preferably R _a is a 3- to 8-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N or O, the heterocycloalkyl is optionally substituted with one or more groups selected from hydroxyl, halogen, amino, cyano, C1-C6 alkyl, -O(C1-C6 alkyl), halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, amino C1-C6 alkyl; more preferably R _a is piperidinyl or piperazinyl, piperidinyl and piperazinyl are optionally substituted with one or more groups selected from hydroxyl, halogen, amino, cyano, C1-C6 alkyl, -O(C1-C6 alkyl), halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, amino C1-C6 alkyl; most preferably represents piperidinyl, optionally substituted with one or more groups selected from hydroxyl, amino, methyl, methoxy, hydroxymethyl, trifluoromethyl.

In some embodiments of the present invention, in RTM-71, R _a is cyclohexane, and the cyclohexane is optionally substituted with one or more groups selected from hydroxyl, halogen, amino, cyano, C1-C6 alkyl, -O(C1-C6 alkyl), halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, amino C1-C6 alkyl, preferably optionally substituted with one or more groups selected from hydroxyl, amino, methyl, methoxy, hydroxymethyl, trifluoromethyl.

In some embodiments of the present invention in RTM-71, R _a is hydrogen or C1-C6 alkyl, C1-C6 alkyl optionally substituted with one or more groups selected from F, hydroxyl, methoxy, fluoromethoxy, -S(O) ₂ CH ₃ , -S(O) ₂ -cyclopropyl, cyclopropyl and oxetanyl.

In some embodiments of the present invention, the RTM has the following structure:

wherein R _a , R _b , R _c , R _d and R _e are as defined in RTM-71 above.

In some embodiments of the present invention, the RTM has the following structure:

wherein R _a , R _b , R _c , R _d , R _e and n are as defined in RTM-71 above.

Preferably, in some embodiments of the present invention, the RTM has the following structure:

where R _b , R _c , R _d and R _e are as defined in RTM-71 above.

Preferably, in some embodiments of the present invention, the RTM has the following structure:

where R _b , R _c , R _d and R _e are as defined in RTM-71 above.

Preferably, in some embodiments of the present invention, the RTM has the following structure:

where R _b , R _c , R _d and R _e are as defined in RTM-71 above.

Preferably, in some embodiments of the present invention, the RTM has the following structure:

where R _b , R _c , R _d and R _e are as defined in RTM-71 above.

Preferably, in some embodiments of the present invention, the RTM is selected from

More preferably, in some embodiments of the present invention, the RTM is selected from

Preferably, in some embodiments of the present invention, the RTM is selected from

Preferably, in some embodiments of the present invention, the compound of formula I and/or its stereoisomer, enantiomer, diastereomer, deuterate, metabolite, hydrate, solvate, prodrug and/or pharmaceutically acceptable salt thereof is a compound of formula IC and/or its stereoisomer, enantiomer, diastereomer, deuterate, metabolite, hydrate, solvate, prodrug and/or pharmaceutically acceptable salt thereof,

wherein ring A, R _a , R _b , R _c , R _d , R _e and n are as defined in RTM-71, and L, ULM are as defined in this document.

Preferably, in some embodiments of the present invention, the compound of formula I and/or its stereoisomer, enantiomer, diastereomer, deuterate, metabolite, hydrate, solvate, prodrug and/or pharmaceutically acceptable salt thereof is a compound of formula IC-1 and/or its stereoisomer, enantiomer, diastereomer, deuterate, metabolite, hydrate, solvate, prodrug and/or pharmaceutically acceptable salt thereof,

wherein R _a , R _b , R _c , R _d and R _e are as defined in RTM-71, and L, ULM are as defined in this document.

Preferably, in some embodiments of the present invention, the compound of formula I and/or its stereoisomer, enantiomer, diastereomer, deuterate, metabolite, hydrate, solvate, prodrug and/or pharmaceutically acceptable salt thereof is a compound of formula IC-2 and/or its stereoisomer, enantiomer, diastereomer, deuterate, metabolite, hydrate, solvate, prodrug and/or pharmaceutically acceptable salt thereof,

where R _b , R _c , R _d , R _e are as defined in RTM-71, and L, ULM are as defined in this document.

Preferably, in some embodiments of the present invention, the compound of formula I and/or its stereoisomer, enantiomer, diastereomer, deuterate, metabolite, hydrate, solvate, prodrug and/or pharmaceutically acceptable salt thereof is a compound of formula IC-3 and/or its stereoisomer, enantiomer, diastereomer, deuterate, metabolite, hydrate, solvate, prodrug and/or pharmaceutically acceptable salt thereof,

where R _b , R _c , R _d , R _e are as defined in RTM-71, and L, ULM are as defined in this document.

In some embodiments of the present invention, L is a bond.

In some embodiments of the present invention, L is -(CH ₂ ) _j -, one or more methylenes in -(CH ₂ ) _j - are optionally substituted with groups selected from -NR ^3' -, -O-, -S-, -S(O)-, -S(O)NR ^3' -, -NR ^3' S(O), -S(O) ₂ -, -S(O) ₂ NR ^3' -, -NR ^3' S(O) ₂ -, -NR ^4' S(O) ₂ NR ^3' -, -CR ^1' R ^2' -, -C(O)-, -C(O)O-, -OC(O)-, -NR ^3' C(O)O -, -OC(O)NR ^3' -, -C(O)NR ^3' -, -NR ^3' C(O)-, -NR ^4' C(O)NR ^3' -, -P(O)-, -P(O)O-, -OP(O)-, -OP(O)O-, vinylidene, ethynylene, C3-C12 cycloalkylene, 3-12 membered heterocyloalkylene containing 1 or more heteroatoms selected from N, O or S, 6-10 membered arylene or 5-10 membered heteroarylene; wherein each vinylidene, cycloalkylene, heterocycloalkylene, arylene and heteroarylene is independently optionally substituted with one or more substituents selected from halogen, -OR ^3' , -NR ^3' R ^4' , oxo, nitro, cyano, C1-C6 alkyl, -S(C1-C6 alkyl), C3-C10 cycloalkyl, 3-10 membered heterocyloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -C(O)R ^1' , -C(O)OR ^3' , -OC(O)R ^1' , -C(O)NR ^3' , -NR ^3' C(O)R ^1' , -S(O)R ^1' , -S(O)NR ^3' , -S(O) ₂ R ^1' , -S(O) ₂ NR ^3' , -NR ^3' S(O) ₂ R ^1' , -NR ^4' S(O) ₂ NR ^3' , -OC(O)NR ^3' and -NR ^4' C(O)NR ^3' , and each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from halogen, -OH, -NR ³ R ^4' , oxo, nitro, cyano, C1-C6 alkyl, C3-C10 cycloalkyl, 3-10-membered heterocyloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl; each R ^1' and R ^2' independently represents halogen, -OH, -NR ^3' R ^4' , C1-C6 alkyl, chlorinated C1-C6 alkyl, hydroxyl C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -NH(C1-C6 alkyl)2, C3-C10 cycloalkyl, -O(C3-C10 cycloalkyl), -NH(C3-C10 cycloalkyl), 3-10-membered heterocyloalkyl, -O(3-10-membered heterocyloalkyl), -NH(3-10-membered heterocyloalkyl), 6-10-membered aryl, -O(6-10-membered aryl), -NH(6-10-membered aryl), 5-10-membered heteroaryl, -O(5-10-membered heteroaryl), -NH(5-10 membered heteroaryl); each R ^3' , R ^4' is independently hydrogen, deuterium, C1-C6 alkyl, C3-C10 cycloalkyl, 3-10 membered heterocyloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; j is 1,2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20,21,22, 23,24 or 25.

Preferably, in some embodiments of the present invention, L is -( _CH2 ) _j- , one or more methylenes in -( _CH2 ) _j- are optionally substituted with groups selected from ^-NR3'- , -O-, ^-CR1'R2'- , -C( ^O )-, -S(O)-, -S(O) _2- , -C(O)O-, -OC(O)-, -C(O) ^{NR3'- , -NR3'C} (O)- _, -S(O ⁾ 2NR3'- ^{, -NR3'S} (O) _2- , vinylidene, ethynylene, phenyl, 8-10 membered bicycloarylene, 3-7 membered saturated or partially unsaturated cycloalkylene, 4-11 membered saturated or partially unsaturated spirocycloalkylene, 4-11 membered saturated or partially unsaturated fused cycloalkylene, 8- to 10-membered bicyclic saturated or partially unsaturated cycloalkylene, 4- to 7-membered saturated or partially unsaturated heterocycloalkylene containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 4- to 11-membered saturated or partially unsaturated spiroheterocycloalkylene containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 4- to 11-membered saturated or partially unsaturated fused heterocycloalkylene containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 8- to 10-membered bicyclic saturated or partially unsaturated heterocycloalkylene containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5- to 6-membered heteroarylene containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10 membered bicyclic heteroaryl containing 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; wherein each vinylidene, ethynylene, cycloalkylene, heterocycloalkylene, phenyl, spiroheterocycloalkylene, fused heterocycloalkylene, spirocycloalkylene, fused cycloalkylene and heteroarylene is independently optionally substituted with one or more substituents selected from halogen, oxo, ^{-NR3'R4 '} , -OR3 ^' , nitro, -CN, C1-C6 alkyl, C3-C10 cycloalkyl and 3-10-membered heterocyloalkyl, alkyl, cycloalkyl, heterocycloalkyl are optionally substituted with one or more substituents selected from halogen, -OH, _-NH2 , -CN, C1-C4 alkyl, C3-C6 cycloalkyl; each R ^1' and R ^2' is independently halogen, -OH, -NH ₂ , C1-C4 alkyl, C1-C4 chloroalkyl, C1-C4 hydroxyalkyl, -O(C1-C4 alkyl), -NH(C1-C4 alkyl), -NH(C1-C4 alkyl), C3-C6 cycloalkyl, -O(C3-C6 cycloalkyl), -NH(C3-C6 cycloalkyl), 3- to 6-membered heterocycloalkyl, -O(3- to 6-membered heterocycloalkyl), -NH(C3-C6 cycloalkyl); each R ^3' and R ^4' is independently hydrogen, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, and j is 2, 3,4, 5, 6, 7, 8, 9, 10, 11, or 12.

Preferably, in some embodiments of the present invention, L is -(CH ₂ ) _j -, one or more methylenes in -(CH ₂ ) _j - are optionally substituted with groups selected from -NR ^3' -, -O-, -CR ^1' R ^2' -, -C(O)-, -S(O)-, -S(O) ₂ -, -C(O)O-, -OC(O)-, -C(O)NR ^3' -, -NR ^3' C(O), -S(O) ₂ NR ^3' -, -NR ^3' S(O) ₂ -, vinylidene, ethynylene, phenyl, 8-10 membered bicyclic arylene, 3-7 membered saturated or partially unsaturated monocyclic cycloalkylene, 4-11 membered saturated or partially unsaturated spirocycloalkylene, 4-11 membered saturated or a partially unsaturated fused cycloalkylene, an 8- to 10-membered bicyclic saturated or partially unsaturated cycloalkylene, a 4- to 7-membered saturated or partially unsaturated heterocycloalkylene containing 1-2 heteroatoms independently selected from nitrogen or oxygen, a 4- to 11-membered saturated or partially unsaturated spiroheterocycloalkylene containing 1-2 heteroatoms independently selected from nitrogen or oxygen, a 4- to 11-membered saturated or partially unsaturated fused heterocycloalkylene containing 1-2 heteroatoms independently selected from nitrogen or oxygen, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocycloalkylene containing 1-2 heteroatoms independently selected from nitrogen or oxygen, a 5- to 6-membered heteroarylene containing 1-4 heteroatoms independently selected from nitrogen or oxygen, or 8-10 membered bicyclic heteroaryl containing 1-5 heteroatoms independently selected from nitrogen or oxygen; wherein each vinylidene, ethynylene, cycloalkylene, heterocycloalkylene, phenyl, spiroheterocycloalkylene, fused heterocycloalkylene, fused cycloalkylene, spirocycloalkylene and heteroarylene is independently optionally substituted with one or more substituents selected from halogen, oxo, -ΝR ^3' R ^4' , -OR ^3' , nitro, -CN, C1-C6 alkyl, C3-6 cycloalkyl, 3- to 6-membered heterocyloalkyl, alkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, -OH, -NH ₂ , -CN, C1-C4 alkyl, C3-C6 cycloalkyl, each R ^1' and R ^2' independently being halogen, -OH, -NH ₂ , C1-C4 alkyl, C1-C4 chloroalkyl, C1-C4 hydroxyalkyl, -O(C1-C4 alkyl), -NH(C1-C4 alkyl), -NH(C1-C4 alkyl), C3-C6 cycloalkyl, -O(C3-C6 cycloalkyl), -NH(C3-C6 cycloalkyl), 3- to 6-membered heterocycloalkyl, -O(3- to 6-membered heterocycloalkyl), -NH(C3-C6 cycloalkyl); R ^3' and R ^4' are each independently hydrogen, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, and j is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

Preferably, in some embodiments of the present invention, L is -(CH2)j, wherein 1, 2, 3 or 4 methylenes in -(CH2)j- are optionally substituted with a group selected from -NH-, -NCH3-, -NCH2CH3-, -O-, -C(CH3)2-, -CHF-, -CHCF3-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)-, -NCH3C(O)-, vinylidene, ethynylene, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylidene, oxiranylene, oxetanylene, oxolanylene, oxanylene, azridinylene, azetidinylene, azacyclopentylene, piperidinylidene, piperazinylidene, morpholinylidene, perhomomorpholinylidene, phenylene, pyrrolylidene, thienylidene, furanylidene, imidazolylidene, pyrazolilidene, triazolilidene, tetrazolylidene, oxazolilidene, isoxazolilidene, thiazolilidene, isothiazolylidene, pyridylidene, pyrimidinylidene, pyridazinylidene, pyrazinylidene, and the substituent group is optionally substituted with one or more substituents selected from halogen, oxo, -NR3'R4', -OR3' or C1-C4 alkyl, and the alkyl is optionally substituted with one or more substituents selected from halogen, -OH or -NH ₂ ; each R3' and R4' independently represents hydrogen, deuterium or C1-C4 alkyl, and j is 2, 3, 4, 5, 6, 7 or 8.

Preferably, in some embodiments of the present invention, L is -(CH2)j, wherein 1, 2, or 3 methylenes in -(CH2)j- are optionally substituted with a group selected from -NH-, -NCH3-, -NCH2CH3-, -O-, -C(CH3)2-, -CHF-, -CHCF3-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)-, -NCH3C(O)-, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylidene, oxiranylene, oxetanylene, oxolanylene, oxanylene, azridinylene, azetidinylene, azacyclopentylene, piperidinylidene, piperazinylidene, morpholinylidene, perhomomorpholinylidene, and the substituent group is optionally substituted with one or more substituents selected from F, Cl, oxo, -NR3'R4', -OR3' or C1-C4 alkyl, the alkyl optionally substituted with one or more substituents selected from halogen, -OH or -NH2; each R3' and R4' independently represents hydrogen, deuterium, methyl, ethyl, propyl, and j is 2, 3, 4, 5, 6, 7 or 8.

Preferably, in some embodiments of the present invention, L is -(CH2)j-, wherein 1, 2 or 3 methylenes in -(CH2)j- are optionally substituted with a group selected from -O-, -NH-, -NCH3-, -NCH ₂ CH3-, -C(O)-, -C(O)NH-, -NHC(O)-, -NCH3C(O)-, -C(O)NCH3-, azridinylene, azetidinylene, azacyclopentylene, piperidinylidene, piperazinylidene, and j is 2, 3, 4, 5, 6, 7, or 8.

Preferably, in some embodiments of the present invention, L is -(CH ₂ ) _j-1 C(O)-, the methylene in -(CH ₂ ) _j-1 -C(O)- is as defined in L above, and is optionally substituted with one or more groups, j is as defined in L above.

Preferably, in some embodiments of the present invention, L is selected from

Preferably, in some embodiments of the present invention, L is LA,

where in LA,

ring D is absent or represents C3-C12 cycloalkylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S, the cycloalkylene and heterocycloalkylene are optionally substituted with a substituent selected from halogen, oxo, cyano, amino, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);

ring B is absent or represents C3-C12 cycloalkylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S, the cycloalkylene and heterocycloalkylene are optionally substituted with a substituent selected from halogen, oxo, cyano, amino, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);

ring C is absent or represents C3-C12 cycloalkylene or 3-12-membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S, cycloalkylene and heterocycloalkylene are optionally substituted with a substituent selected from halogen, oxo, cyano, amino, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);

X'''' represents a bond, -NH-, _-NCH3- , -O-, -C( _CH3 ) _2- , -S-, -OC-, -OC-, -CHF-, -CHCF3-, -C( _O )-, -S(O)-, -S(O) _2- , -C(O)O-, -OC(O)-, -C(O)NH-, -C(O) _NCH3- , -NHC(O)-, or _-NCH3C (O)-;

L ₃ is -(CH ₂ ) _k , one or two methylenes in L ₃ are optionally substituted with a substituent selected from -O-, -NH-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C1-C6 hydroxyalkyl)- or -N(C3-C8 cycloalkyl)-, and k is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

Preferably, in some embodiments of the present invention, ring D is absent from LA.

Preferably, in some embodiments of the present invention, in LA, ring D is a 4-7 membered saturated monocyclic heterocycloalkylene containing 1 or 2 nitrogen heteroatoms, or a 7-11 membered spiroheterocycloalkylene or fused heterocycloalkylene containing 1 or 2 nitrogen heteroatoms.

Preferably, in some embodiments of the present invention, in LA, ring D is a 7-11 membered spiroheterocycloalkylene containing one or two nitrogen atoms.

Preferably, in some embodiments of the present invention, in LA, the D ring is Preferably, in some embodiments of the present invention, ring B is absent from LA.

Preferably, in some embodiments of the present invention, in LA, ring B is a 4-7 membered saturated monocyclic heterocycloalkylene containing 1 or 2 nitrogen heteroatoms, or a 7-11 membered spiroheterocycloalkylene or fused heterocycloalkylene containing 1 or 2 nitrogen heteroatoms.

Preferably, in some embodiments of the present invention, in LA, ring B is a 4-7 membered saturated monocyclic heterocycloalkylene containing one or two nitrogen heteroatoms.

Preferably, in some embodiments of the present invention, in LA, ring B is piperidylidene, piperazinylidene,

Preferably, in some embodiments of the present invention, in LA, ring C is a 3-7-membered saturated or partially unsaturated cycloalkylene, a 4-11-membered saturated or partially unsaturated spirocycloalkylene, a 4-11-membered saturated or partially unsaturated fused cycloalkylene, an 8-10-membered bicyclic saturated or partially unsaturated cycloalkylene, a 4-7-membered saturated or partially unsaturated heterocycloalkylene containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-11-membered saturated or partially unsaturated spiroheterocycloalkylene containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-11-membered saturated or partially unsaturated fused heterocycloalkylene containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 8-10-membered bicyclic saturated or partially unsaturated heterocycloalkylene containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Preferably, in some embodiments of the present invention, in LA, ring C is a 4-7 membered saturated monocyclic heterocycloalkylene containing 1 or 2 nitrogen heteroatoms, a 7-11 membered spiroheterocycloalkylene, or a fused heterocycloalkylene containing 1 or 2 nitrogen heteroatoms.

Preferably, in some embodiments of the present invention, in LA, ring C is a 4-7 membered saturated monocyclic heterocycloalkylene containing 1 or 2 nitrogen heteroatoms, or a 7-11 membered spiroheterocycloalkylene containing 1 or 2 nitrogen heteroatoms.

Preferably, in some embodiments of the present invention, in LA, ring C is piperidylidene, piperazinylidene,

Preferably, in some embodiments of the present invention, in LA, ring C is piperidylidene, piperazinylidene,

Preferably, in some embodiments of the present invention, in LA, X'''' is a bond or -C(O)-.

Preferably, in some embodiments of the present invention, in LA, X'''' is -C(O)-.

Preferably, in some embodiments of the present invention, in LA, L3 is -( _CH2 ) _k , and one methylene in _L3 is optionally replaced with a group selected from -O-, -NH-, _-NCH3- , or _-NCH2CH3- ; k is 1, 2, ₃ , or 4.

Preferably, in some embodiments of the present invention, in LA, ring D and ring B are absent, ring C is a 4-7-membered saturated monocyclic heterocycloalkylene containing 1 or 2 nitrogen heteroatoms, or a 7-11-membered spiroheterocycloalkylene containing 1 or 2 nitrogen heteroatoms; X'''' is -C(O)-; L ₃ is -(CH ₂ ) _k , one methylene in L ₃ is optionally substituted with a group selected from -O-, -NH-, -NCH _{3 -} , or -NCH ₂ CH ₃ -; k is 2, 3, or 4.

Preferably, in some embodiments of the present invention, formula L is selected from

Preferably, in some embodiments of the present invention, the compound of formula I and/or its stereoisomer, enantiomer, diastereomer, deuterate, metabolite, hydrate, solvate, prodrug and/or pharmaceutically acceptable salt thereof is a compound of formula IIa and/or its stereoisomer, enantiomer, diastereomer, deuterate, metabolite, hydrate, solvate, prodrug and/or pharmaceutically acceptable salt thereof,

where ring A, R _a , R _b , R _c , R _d , R _e , n are as defined in RTM-71, and Q ₁ , Q ₂ , Q ₃ , Q ₄ , Q ₅ , X'', Y'', m'', R ₁ '', R ₂ '' are as defined herein in ULM-1; L is as defined herein.

Preferably, in some embodiments of the present invention, the compound of formula I and/or its stereoisomer, enantiomer, diastereomer, deuterate, metabolite, hydrate, solvate, prodrug and/or pharmaceutically acceptable salt thereof is a compound of formula IIa-1 and/or its stereoisomer, enantiomer, diastereomer, deuterate, metabolite, hydrate, solvate, prodrug and/or pharmaceutically acceptable salt thereof,

wherein Ring A, R _a , R _b , R _c , R _d , R _e and n are as defined in RTM-71, and Q ₁ , Q ₂ , Q ₃ , Q ₄ , Q ₅ , X'', Y'', m'', R ₁ '' and R ₂ '' are as defined herein in ULM-1; L3, Ring D, Ring B, Ring C and X''' are as defined herein.

Preferably, in some embodiments of the present invention, the compound of formula I has the following structure:

The subject of the present invention is a method for producing a compound of formula I, formula Ia, formula IA, formula IA-1, formula IA-2, formula IA-3, formula IB, formula IB-1, formula IC, formula IC-1, formula IC-2, formula IC-3, formula IIa, formula IIa-1 and/or its stereoisomer, enantiomer, diastereomer, deuterate, hydrate, solvate, metabolite, prodrug and/or pharmaceutically acceptable salt.

The subject of the present invention is a pharmaceutical composition containing a therapeutically effective amount of a compound of formula I, formula Ia, formula IA, formula IA-1, formula IA-2, formula IA-3, formula IB, formula IB-1, formula IC, formula IC-1, formula IC-2, formula IC-3, formula IIa, formula IIa-1 and/or its stereoisomer, enantiomer, diastereomer, deuterate, hydrate, solvate, metabolite, prodrug and/or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent or excipient.

The subject of the present invention is a method for degrading the IRAK4 protein, comprising the step of bringing into contact a compound of formula I, formula Ia, formula IA, formula IA-1, formula IA-2, formula IA-3, formula IB, formula IB-1, formula IC, formula IC-1, formula IC-2, formula IC-3, formula IIa, formula IIa-1 and/or its stereoisomer, enantiomer, diastereomer, deuterate, hydrate, solvate, metabolite, prodrug and/or pharmaceutically acceptable salt, or a pharmaceutical composition thereof with the IRAK4 protein.

A compound of formula I, formula Ia, formula IA, formula IA-1, formula IA-2, formula IA-3, formula IB, formula IB-1, formula IC, formula IC-1, formula IC-2, formula IC-3, formula IIa, formula IIa-1 and/or its stereoisomer, enantiomer, diastereomer, deuterate, hydrate, solvate, metabolite, prodrug and/or pharmaceutically acceptable salt, or a pharmaceutical composition thereof is used as a medicine for the treatment or prevention of IRAK4-mediated diseases or conditions.

A compound of formula I, formula Ia, formula IA, formula IA-1, formula IA-2, formula IA-3, formula IB, formula IB-1, formula IC, formula IC-1, formula IC-2, formula IC-3, formula IIa, formula IIa-1 and/or its stereoisomer, enantiomer, diastereomer, deuterate, hydrate, solvate, metabolite, prodrug and/or pharmaceutically acceptable salt, or a pharmaceutical composition thereof is used as a medicine for the treatment or prevention of diseases or conditions mediated by TLRs (other than TLR3R), the IL-lα or IL-lβ receptor family (including IL-1R, IL-18R, IL-33R, IL-36R).

A compound of formula I, formula Ia, formula IA, formula IA-1, formula IA-2, formula IA-3, formula IB, formula IB-1, formula IC, formula IC-1, formula IC-2, formula IC-3, formula IIa, formula IIa-1 and/or its stereoisomer, enantiomer, diastereomer, deuterate, hydrate, solvate, metabolite, prodrug and/or pharmaceutically acceptable salt, or a pharmaceutical composition thereof is used as a medicine for the treatment or prevention of IRAK4-mediated diseases or conditions that are diseases or conditions caused by MyD88.

The subject of the present invention is the use of a compound of formula I, formula Ia, formula IA, formula IA-1, formula IA-2, formula IA-3, formula IB, formula IB-1, formula IC, formula IC-1, formula IC-2, formula IC-3, formula IIa, formula IIa-1 and/or its stereoisomer, enantiomer, diastereomer, deuterate, hydrate, solvate, metabolite, prodrug and/or pharmaceutically acceptable salt, or a pharmaceutical composition thereof in the preparation of a medicament for the treatment or prevention of IRAK4-mediated diseases or conditions.

The subject of the present invention is the use of a compound of formula I, formula Ia, formula IA, formula IA-1, formula IA-2, formula IA-3, formula IB, formula IB-1, formula IC, formula IC-1, formula IC-2, formula IC-3, formula IIa, formula IIa-1 and/or its stereoisomer, enantiomer, diastereomer, deuterate, hydrate, solvate, metabolite, prodrug and/or pharmaceutically acceptable salt, or a pharmaceutical composition thereof in the preparation of a medicament for the treatment or prevention of diseases or conditions mediated by TLRs (other than TLR3R), IL-1α or the IL-1β receptor family (including IL-1R, IL-18R, IL-33R, IL-36R).

The subject of the present invention is the use of a compound of formula I, formula Ia, formula IA, formula IA-1, formula IA-2, formula IA-3, formula IB, formula IB-1, formula IC, formula IC-1, formula IC-2, formula IC-3, formula IIa, formula IIa-1 and/or its stereoisomer, enantiomer, diastereomer, deuterate, hydrate, solvate, metabolite, prodrug and/or pharmaceutically acceptable salt, or a pharmaceutical composition thereof in the preparation of a medicament for the treatment or prevention of a disease or condition regulated by IRAK4, and an IRAK4-mediated disease or condition that is a disease or condition caused by MyD88.

The subject of the present invention is the use of a compound of formula I, formula Ia, formula IA, formula IA-1, formula IA-2, formula IA-3, formula IB, formula IB-1, formula IC, formula IC-1, formula IC-2, formula IC-3, formula IIa, formula IIa-1 and/or its stereoisomer, enantiomer, diastereomer, deuterate, hydrate, solvate, metabolite, prodrug and/or pharmaceutically acceptable salt, or a pharmaceutical composition thereof in the preparation of a medicament for the treatment or prevention of cancer, neurodegenerative diseases, viral diseases, autoimmune diseases, inflammatory diseases, hereditary diseases, hormone-mediated diseases, metabolic diseases, diseases associated with organ transplantation, immunodeficiency diseases, bone-destructive diseases, proliferative disorders, infectious diseases associated with cell death conditions, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T cell activation, cardiovascular disease, or CNS disease.

The subject of the present invention is the use of a compound of formula I, formula Ia, formula IA, formula IA-1, formula IA-2, formula IA-3, formula IB, formula IB-1, formula IC, formula IC-1, formula IC-2, formula IC-3, formula IIa, formula IIa-1 and/or its stereoisomer, enantiomer, diastereomer, deuterate, hydrate, solvate, metabolite, prodrug and/or pharmaceutically acceptable salt, or a pharmaceutical composition thereof in the preparation of a medicament for the treatment or prevention of cancer or a proliferative disease, such as brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, stomach cancer, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, genitourinary cancer, esophageal cancer, laryngeal cancer, skin cancer, bone cancer, thyroid cancer, sarcoma, neuroglioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, head and neck cancer, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, Hodgkin's and non-Hodgkin's lymphoma, breast cancer, follicular carcinoma, undifferentiated tumor, papillary tumor, seminoma, melanoma, DLBCL, Hodgkin's lymphoma, primary cutaneous T-cell lymphoma, chronic lymphocytic leukemia, smoldering indolent multiple myeloma, leukemia, diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary exudative lymphoma, Burkitt's lymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia (MB), splenic marginal zone lymphoma, multiple myeloma or plasmacytoma, or intravascular large B-cell lymphoma.

The subject of the present invention is the use of a compound of formula I, formula Ia, formula IA, formula IA-1, formula IA-2, formula IA-3, formula IB, formula IB-1, formula IC, formula IC-1, formula IC-2, formula IC-3, formula IIa, formula IIa-1 and/or its stereoisomer, enantiomer, diastereomer, deuterate, hydrate, solvate, metabolite, prodrug and/or pharmaceutically acceptable salt, or a pharmaceutical composition thereof in the preparation of a medicament for the treatment or prevention of a neurodegenerative disease, and the neurodegenerative disease is a neurodegenerative disease caused by Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia or traumatic injury, glutamate neurotoxicity, hypoxia, epilepsy, treatment of diabetes, metabolic syndrome, obesity, organ transplantation, or graft-versus-host disease.

The subject of the present invention is the use of a compound of formula I, formula Ia, formula IA, formula IA-1, formula IA-2, formula IA-3, formula IB, formula IB-1, formula IC, formula IC-1, formula IC-2, formula IC-3, formula IIa, formula IIa-1 and/or its stereoisomer, enantiomer, diastereomer, deuterate, hydrate, solvate, metabolite, prodrug and/or pharmaceutically acceptable salt, or a pharmaceutical composition thereof in the preparation of a medicament for the treatment or prevention of an inflammatory disease, and such inflammatory disease is an eye disease such as eye allergy, conjunctivitis, dry eye or vernal conjunctivitis, diseases affecting the nose, including allergic rhinitis; autoimmune hematological diseases such as hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic stomatitis, diarrhea, autoimmune inflammatory bowel disease, intestinal syndrome, celiac disease, radicular periostitis, hyaline membrane disease of the lung, nephropathy, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcomatosis, dry eye, vernal conjunctival keratitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, nephritis, vasculitis, interstitial cystitis, diverticulitis, glomerulonephritis, chronic granulomatous disease, endometriosis, leptospirosis nephropathy, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscular atrophy, catabolism, obesity, poor fetal growth, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhydromic ectodermal dysplasia, Behcet's disease, urinary incontinence, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma, acute lung injury, acute respiratory distress syndrome, eosinophilia, allergic reaction, systemic allergic reaction, sinusitis, ocular allergy, silica-induced disease, COPD, lung disease, cystic fibrosis, liver fibrosis, renal fibrosis, alcoholic fatty liver disease, nonalcoholic fatty liver disease, cardiac fibrosis, psoriasis, Crohn's disease, inflammatory bowel disease, acid-induced lung disease, pulmonary hypertension, polyneuropathy, cataract, systemic sclerosis myositis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 diabetes, type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergies, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, cystitis, lacrimal gland inflammation, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, malleolus, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, sweat gland inflammation, immunoglobulin A-related nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, focal pneumonia, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, joint inflammation, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, vulvitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, sclerosis, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired bullous laxity of the epidermis, acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, cryopyrin-associated periodic syndrome or osteoarthritis.

The invention relates to a method for treating or preventing IRAK4-mediated diseases or conditions, comprising administering a therapeutically effective amount of a compound of formula I, formula Ia, formula IA, formula IA-1, formula IA-2, formula IA-3, formula IB, formula IB-1, formula IC, formula IC-1, formula IC-2, formula IC-3, formula IIa, formula IIa-1 and/or its stereoisomer, enantiomer, diastereomer, deuterate, hydrate, solvate, metabolite, prodrug and/or pharmaceutically acceptable salt, or a pharmaceutical composition thereof to a subject in need thereof. The subject of the present invention is a method of treating or preventing IRAK4-mediated diseases or conditions, comprising administering a therapeutically effective amount of a compound of formula I, formula Ia, formula IA, formula IA-1, formula IA-2, formula IA-3, formula IB, formula IB-1, formula IC, formula IC-1, formula IC-2, formula IC-3, formula IIa, formula IIa-1 and/or its stereoisomer, enantiomer, diastereomer, deuterate, hydrate, solvate, metabolite, prodrug and/or pharmaceutically acceptable salt, or a pharmaceutical composition thereof to a subject in need thereof, and the IRAK4-mediated disease or condition is a disease or condition caused by MyD88.

The subject of the present invention is a method for the treatment or prevention of diseases or conditions mediated by TLRs (other than TLR3R) or the IL-1 receptor family (including IL-1R, IL-18R, IL-33R, IL-36R), comprising administering a therapeutically effective amount of a compound of formula I, formula Ia, formula IA, formula IA-1, formula IA-2, formula IA-3, formula IB, formula IB-1, formula IC, formula IC-1, formula IC-2, formula IC-3, formula IIa, formula IIa-1 and/or its stereoisomer, enantiomer, diastereomer, deuterate, hydrate, solvate, metabolite, prodrug and/or pharmaceutically acceptable salt, or a pharmaceutical composition thereof to a subject in need thereof.

The invention relates to a method for producing a compound of formula I and/or its stereoisomer, enantiomer, diastereomer, deuterate, hydrate, solvate, metabolite, prodrug and/or pharmaceutically acceptable salt.

Method 1:

Where is a linker moiety L; NH may be a primary amine or a secondary amine; and if represents a connection, then refers to an RTM containing an amino group; NH undergoes a reductive amination reaction with an aldehyde to give a compound of formula I, the RTM is as defined above, preferably the RTM is

wherein ring A, n, R _a , R _b , R _c , R _d and R _e are as defined in RTM-71; ULM is defined above; and reducing reagents for reductive amination include, but are not limited to, Pd/C, sodium borohydride, sodium cyanoborohydride, borane, sodium triacetylborohydride.

Method 2:

is a linker moiety L; NH may be a primary amine or a secondary amine; NH undergoes a reductive amination reaction with an aldehyde to yield a compound of formula I, PTM is as defined above, preferably PTM is

wherein ring A, n, R _a , R _b , R _c , R _d and R _e are as defined in RTM-71; ULM is defined above; and reducing reagents for reductive amination include, but are not limited to, Pd/C, sodium borohydride, sodium cyanoborohydride, borane, sodium triacetylborohydride.

Method 3:

Where is a fragment of the linker L; NH may be a primary amine or a secondary amine; NH undergoes an ester substitution reaction under basic conditions to obtain a compound of formula I, and R ₁₀₀ ' is pentafluorophenyl or p-nitrophenyl; PTM is as defined above, preferably PTM is

wherein ring A, n, R _a , R _b , R _c , R _d and R _e are as defined in RTM-71; ULM is defined above; bases in the substitution reaction include, but are not limited to, triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate, sodium bicarbonate.

DETAILED DESCRIPTION: Unless otherwise specified, the following terms used in this description and claims have the following meanings.

"Alkyl" refers to saturated aliphatic hydrocarbon groups including straight or branched alkyls; C1-C8 alkyl refers to alkyls containing 1-8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-amyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or their various branched isomers; C1-C6 alkyl is preferred; C1-C4 alkyl is more preferred. The alkyl may be substituted or unsubstituted.

"Cycloalkyl" means saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituents; "C3-C12 cycloalkyl" means cycloalkyl containing from 3 to 12 carbon atoms; "C3-C8 cycloalkyl" means cycloalkyl containing from 3 to 8 carbon atoms; "C5-C10 cycloalkyl" means cycloalkyl containing from 5 to 10 carbon atoms.

Non-limiting examples of monocycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc., preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; preferably C3-C8-membered cycloalkyl; more preferably C3-C6 cycloalkyl.

Polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls. "Spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called a spiro atom) between monocyclyls. They may contain one or more double bonds, but none of the rings contain a fully conjugated π-electron system. According to the number of spiro atoms common to the rings, spiroalkyl is classified as single spirocycloalkyl, double spirocycloalkyl, or polyspirocycloalkyl, with double spirocycloalkyl being preferred. Non-limiting examples of spirocycloalkyl include:

"Fused cycloalkyl" refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but none of them contains a completely conjugated π-electron system. It can be classified according to the number of constituent rings as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, with bicyclic fused cycloalkyl being preferred. Non-limiting examples of fused cycloalkyls include:

"Bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings contain two common carbon atoms that are not directly bonded, they may contain one or more double bonds, but neither ring contains a fully conjugated π-electron system. Based on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl. Non-limiting examples of bridged cycloalkyls include:

.

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring bound to the parent structure is cycloalkyl, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl may be optionally substituted or unsubstituted.

"Heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen, or S(O)r (where r is an integer of 0, 1, or 2), but does not contain -O-O-, -O-S-, or -S-S- ring moieties, and the remaining ring atoms are carbon. "3- to 12-membered heterocycloalkyl" refers to a cyclyl containing from 3 to 12 ring atoms, "5- to 10-membered heterocycloalkyl" refers to a cyclyl containing from 5 to 10 ring atoms, and "3- to 8-membered heterocycloalkyl" refers to a cyclyl containing from 3 to 8 ring atoms, preferably "3- to 12-membered heterocycloalkyl" containing 1 to 3 heteroatoms selected from N, O or S, more preferably 3- to 12-membered heterocycloalkyl containing 1 or 2 N atoms.

Non-limiting examples of monocyclic heterocycloalkyl include pyrrolidyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably piperidinyl and piperazinyl.

Polycyclic heterocycloalkyls include spiro, fused, and bridged heterocycloalkyls. "Spiroheterocycloalkyl" refers to a polycyclic heterocycloalkyl that contains one common atom (called a spiro atom) between single rings, wherein one or more of the ring atoms are selected from nitrogen, oxygen, or S(O)r (where r is an integer of 0, 1, 2), and the remaining ring atoms are carbon. They may contain one or more double bonds, however, none of the rings contain a fully conjugated π-electron system. According to the number of spiro atoms common to the rings, spirocycloalkyl is classified into monospiroheterocycloalkyl, bis-spiroheterocycloalkyl or polyspiroheterocycloalkyl, preferably saturated "3- to 12-membered bis-spiroheterocycloalkyl" containing 1-3 heteroatoms selected from H, O or S; more preferably saturated "3- to 12-membered bis-spiroheterocycloalkyl" containing 1 or 2 N atoms. Non-limiting examples of spiroheterocycloalkyl include:

"Fused heterocycloalkyl" refers to a polycyclic heterocycloalkyl in which each ring in the system contains a common adjacent pair of atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but none of them contains a completely conjugated π-electron system, in which one or more atoms in the ring are selected from nitrogen, oxygen or S(O)r (where r is an integer equal to 0, 1, 2), the remaining atoms of the ring are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracycline or polycyclic fused heterocycloalkyl, preferably "3- to 12-membered bicyclic fused heterocycloalkyl" containing from 1 to 3 heteroatoms selected from N, O or S; more preferably, a saturated "3- to 12-membered bicyclic fused heterocycloalkyl" containing 1 or 2 N atoms is used. Non-limiting examples of fused heterocycloalkyl include:

"Bridged heterocycloalkyl" refers to a polycyclic heterocycloalkyl in which any two rings contain two common atoms that are not directly bonded. They may contain one or more double bonds, but no ring contains a fully conjugated π-electron system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O)r (where r is an integer of 0, 1, 2), and the remaining ring atoms are carbon. Based on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl. Non-limiting examples of bridged heterocycloalkyl include:

The heterocycloalkyl ring may be fused to an aryl, heteroaryl or cycloalkyl, wherein the ring bound to the parent structure is a heterocycloalkyl, non-limiting examples include:

heterocycloalkyl may be optionally substituted or unsubstituted.

"Aryl" refers to all-carbon monocyclyls or fused polycyclyls (i.e., rings containing shared adjacent pairs of carbon atoms) and polycyclyls containing conjugated π-electron systems, and "6- to 10-membered aryl" refers to all-carbon aryls containing 6-10 carbon atoms, such as phenyl and naphthyl; phenyl is preferred. The aryl ring may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl, wherein the ring bound to the parent structure is an aryl ring, and non-limiting examples include:

aryl may be optionally substituted or unsubstituted.

"Heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, wherein the heteroatoms include nitrogen, oxygen or S(O)r (where r is an integer of 0, 1, 2), 5-6-membered heteroaryl refers to a heteroaromatic system containing from 5 to 6 ring atoms, and 5-10-membered heteroaryl refers to a heteroaromatic system containing from 5 to 10 ring atoms, 5-6-membered heteroaryl is preferred; 5-6-membered heteroaryl containing 1 or 2 N atoms is more preferred; non-limiting examples include furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, etc.; pyridyl is preferred. The heteroaryl ring may be fused to an aryl, heterocycloalkyl, or cycloalkyl, wherein the ring bound to the parent structure is a heteroaryl, and non-limiting examples include:

heteroaryl may be optionally substituted or unsubstituted.

"Alkenyl" means alkyl as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, and "C2-8 alkenyl" means linear or branched alkenyl containing 2-8 carbon atoms, including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc., preferably "C2-6 alkenyl", more preferably "C2-4 alkenyl". Alkenyl may be substituted or unsubstituted.

"Alkynyl" refers to an alkyl, as defined above, of at least two carbon atoms and at least one carbon-carbon triple bond, and "C2-8 alkynyl" refers to a linear or branched alkynyl containing 2-8 carbon atoms, including, but not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, preferably "C2-6 alkynyl", more preferably "C2-4 alkynyl". Alkynyl may be substituted or unsubstituted.

"Subgroup" refers to a divalent substituent, for example, alkylene refers to divalent alkyl, alkenylene refers to divalent alkenyl, alkynylene refers to divalent alkynyl, cycloalkylene to divalent cycloalkyl, heterocycloalkylene to divalent heterocycloalkyl, arylene to divalent aryl, heteroarylene to divalent heteroaryl, and alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, are defined above, the subgroups may be optionally substituted or unsubstituted.

"Alkoxy" refers to -O-(alkyl), where alkyl is as defined. "C1-C8 Alkoxy" refers to alkyloxy containing from 1 to 8 carbon atoms. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, etc. Alkoxy may be optionally substituted or unsubstituted.

"Cycloalkoxy" refers to -O-(unsubstituted cycloalkyl), wherein cycloalkyl is as defined. C3-C8 Cycloalkoxy refers to cycloalkyloxy containing from 3 to 8 carbon atoms. Non-limiting examples include cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, etc. Cycloalkoxy may be optionally substituted or unsubstituted.

"Haloalkyl" refers to alkyl substituted with one or more fluorine, chlorine, bromine or iodine atoms, wherein alkyl is as defined, and non-limiting examples include difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.

"Haloalkoxy" refers to a group in which the hydrogen in the alkyl is replaced by one or more fluorine, chlorine, bromine or iodine atoms, the alkoxy being as defined above. For example, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, etc.

"Hydroxyalkyl" refers to alkyl optionally substituted with one or more -OH, wherein alkyl is as defined above, and non-limiting examples include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl.

"Aminoalkyl" refers to alkyl optionally substituted with one or more -NH ₂ , wherein alkyl is as defined above, and non-limiting examples include aminomethyl, aminoethyl, aminopropyl, aminoisopropyl.

"Amino" and "amine" are known in the art and refer to substituted or unsubstituted ammonia.

"Carboxyl" or "carboxylic acid" refers to -COOH. "Oxo" refers to =O.

"Halogen" refers to fluorine, chlorine, bromine or iodine.

"Cyano" refers to -CN.

"Hydroxyl" refers to -OH.

"Raney-Ni" refers to Raney nickel (a hydrogen-activating catalytic reducing agent).

"Dess-Martin reagent" refers to 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one.

"PdCl ₂ (dppf)" refers to [1,1-bis(diphenylphosphorus)ferrocene]palladium dichloride.

"T3P" refers to 2,4,6-tripropyl-1,3,5,2,4,6-trioxytriphosphate-2,4,6-trioxide.

"HATU" refers to 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.

"DPBS" refers to Dulbecco's Phosphate Buffered Saline.

"PBS" refers to phosphate buffered saline.

"SDS-PAGE" refers to sodium dodecyl sulfate polyacrylamide gel electrophoresis.

"PVDF" refers to polyvinylidene fluoride.

"Greater" refers independently to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

"Optional" means that the subsequently described event or external factor may, but need not, occur, and the description includes the location where the event or external factor does or does not occur. For example, "heterocycloalkyl optionally substituted with alkyl" means that alkyl may, but need not, be present, and the description includes the case where the heterocycloalkyl is substituted with alkyl and the case where the heterocycloalkyl is not substituted with alkyl.

"Substituted" means that one or more hydrogen atoms, preferably not more than 5, more preferably from 1 to 3 hydrogen atoms, are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (experimentally or theoretically) possible or impossible substitutions without much effort. For example, amino or hydroxyls with free hydrogen may be unstable in combination with carbon atoms with unsaturated (e.g. olefinic) bonds.

"Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration into the body, to facilitate the absorption of the active ingredients and, thus, to exhibit biological activity.

The present invention also provides pharmaceutically acceptable salts of the compounds of formula (I). The term "pharmaceutically acceptable salt" refers to an acid addition salt or a base addition salt of a compound of the present invention that is relatively non-toxic. Acid addition salts are salts of the compounds of formula (I) of the present invention and suitable inorganic or organic acids, these salts can be obtained during the final separation and purification of the compounds or can be obtained by reacting purified compounds of formula (I) in their free base form with suitable organic or inorganic acids. Representative acid addition salts include hydrobromate, hydrochloride, sulfate, bisulfate, sulfite, acetate, oxalate, valerate, oleate, palmitic acid, stearate, lauroleate, borate, benzoate, lactate, phosphate, hydrogen phosphate, carbonate, bicarbonate, toluate, citrate, maleate, fumarate, succinate, tartrate, benzoate, mesylate, p-toluenesulfonate, gluconate, lactobionate and lauryl sulfonate, etc. The base addition salt is a salt formed by a compound of the formula (I) and a suitable inorganic or organic base, including, for example, a salt formed by alkali metal, alkaline earth metal and quaternary ammonium cations, such as sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt, tetramethyl quaternary ammonium salt, tetraethyl quaternary ammonium salt, etc.; the amine salt includes salts formed by ammonia ( _NH3 ), primary amine, secondary amine or tertiary amine, such as methylamine salt, dimethylamine salt, trimethylamine salt, triethylamine salt, ethylamine salt, etc.

The compounds of the present invention or pharmaceutically acceptable salts thereof can be administered to mammals, including humans, orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically (powder, ointment or drops) or intratumorally.

The dosage of the compound of the present invention may be about 0.05-300 mg/kg body weight/day, preferably 10-300 mg/kg body weight/day, more preferably 10-150 mg/kg body weight/day.

The compounds of the present invention or pharmaceutically acceptable salts thereof can be prepared as solid dosage forms for oral administration, including but not limited to capsules, tablets, pills, powders, granules, etc. In these solid dosage forms, the active ingredient, i.e. the compound of formula (I) of the present invention, is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with any of the following: (1) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, etc.; (2) binders, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, etc.; (3) humectants, such as glycerol, etc.; (4) disintegrating agents, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate, etc.; (5) dissolution retarders, such as paraffin, etc.; (6) absorption accelerators, such as quaternary ammonium compounds, etc.; (7) wetting agents, such as cetyl alcohol and glycerol monostearate; (8) adsorbents, such as kaolin, etc.; and (9) lubricating agents, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or a mixture thereof. Buffering agents may also be included in capsules, tablets, and pills.

Solid dosage forms such as tablets, sugar pills, capsules, pellets and granules can be coated or microencapsulated with coating and shell materials such as enteric coatings and other materials known in the art. They can contain penetration-reducing agents, and the release of the active ingredient in such a composition can be delayed in a certain part of the digestive tract. Examples of filling components that can be used are polymeric materials and wax materials. If necessary, the active ingredient can also form a microcapsule with one or more excipients described above.

The compounds of the present invention or their pharmaceutically acceptable salts can be prepared as liquid dosage forms for oral administration, including, but not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, tinctures and the like. In addition to the compounds of formula (I) or their pharmaceutically acceptable salts as active ingredients, the liquid dosage forms can contain inert diluents such as water and other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances commonly used in the art. In addition to these inert diluents, the liquid dosage forms of the present invention may also contain conventional auxiliary substances such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and spices.

The suspending agent includes, for example, ethoxylated isooctadecanol, polyoxyethylene sorbitol and dehydrated sorbitan esters, microcrystalline cellulose, aluminum methanol and agar or a mixture of these substances.

The compounds of the present invention or their pharmaceutically acceptable salts can be prepared as dosage forms for parenteral injection, including, but not limited to, physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution to obtain sterile injection solutions or dispersions. Suitable carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

The compounds of the present invention or their pharmaceutically acceptable salts can also be prepared as dosage forms for topical use, including, for example, ointments, powders, suppositories, drops, propellants, inhalants, etc. The compounds of formula (I) of the present invention or their pharmaceutically acceptable salts as an active ingredient are mixed with a physiologically acceptable carrier and, optionally, a preservative, a buffer or, if necessary, a propellant, which may require addition under sterile conditions.

The subject of the present invention is also a pharmaceutical composition comprising a compound of formula (I) according to the present invention or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier, excipient or diluent. In the preparation of pharmaceutical compositions, the compound of formula (I) or a pharmaceutically acceptable salt thereof is usually mixed with a pharmaceutically acceptable carrier, excipient or diluent.

The composition of the present invention can be prepared into a conventional pharmaceutical preparation according to a conventional preparation method. For example, tablets, pills, capsules, powders, granules, emulsions, suspensions, dispersions, solutions, syrups, elixirs, ointments, drops, suppositories, inhalants, propellants, etc.

The compound of the present invention or a pharmaceutically acceptable salt thereof can be administered alone or (if necessary) in combination with other pharmaceutically acceptable therapeutic agents, for example in combination with other antitumor agents, anti-inflammatory agents or autoimmune agents. The ingredients to be combined can be administered simultaneously or sequentially, as one formulation or as another formulation. The combination can include not only a combination of the compound of the present invention and one other active agent, but also a combination of the compound of the present invention and two or more other active agents.

The present invention proved that the compound of formula I of the present invention can effectively bind to the target protein IRAK4 or exert an inhibitory effect through the IRAK4 kinase activity testing experiment, and the compound of formula I of the present invention can effectively and specifically induce degradation of IRAK4 protein in THP-1 cells, as determined by Western blotting. It was proved by the AlphaLISA detection method that the compound of formula I of the present invention can effectively inhibit the production of IL-6 by immune cells, and the compound of the present invention has good selectivity for degradation, and the compound of formula I of the present invention and/or its stereoisomers, enantiomers, diastereomers, deuterates, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts can effectively and selectively induce degradation of IRAK4 protein to achieve the effect of preventing or treating diseases or conditions associated with IRAK4.

Examples

The present invention will now be described in more detail and fully with reference to examples, but the present invention is in no way limited to the contents of the examples. The starting materials in the examples of the present invention are known and may be commercially available or may be synthesized using or in accordance with methods known in the art. Unless otherwise specified, the present examples employ an experimental method that does not specify specific conditions, usually in accordance with conventional conditions or in accordance with conditions suggested by the manufacturer of the raw material or product.

I Examples of obtaining compounds

Intermediate 1: 2-fluoro-4-methoxy-5-nitrobenzaldehyde

Cesium carbonate (3.5 g, 10.8 mmol) and potassium iodide (1.85 g, 13.0 mmol) were added to a solution of 2-fluoro-4-hydroxy-5-nitrobenzaldehyde (2 g, 10.8 mmol) in N,N-dimethylformamide (20 mL). The reaction solution was stirred for 10 hours at room temperature, water (30 mL) was added, extracted three times with ethyl acetate, the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrate was purified by column purification to obtain 1.6 g of the desired product 2-fluoro-4-methoxy-5-nitrobenzaldehyde.

LC-MS: (ES, m/z): [M+H] ⁺ =200.1

Intermediate 2: 2-fluoro-5-nitro-4-(trifluoromethoxy)benzaldehyde

Nitric acid (1.0 mL, 65%) was added dropwise to a solution of 2-fluoro-4-(trifluoromethoxy)benzaldehyde (1.0 g, 4.8 mmol) in sulfuric acid (5 mL) while maintaining the temperature below -10 °C. After dropwise addition, the solution was poured into ice water (20 mL) and stirred for 10 min. The filtered solid was washed with water (10 mL × 3) and dried under reduced pressure to obtain 0.9 g of crude target product.

The crude product can be used for the next step without further purification.

LC-MS: (ES, m/z): [M+H] ⁺ =254.0

Intermediate 3: N-(6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Step 1: Preparation of 2-azido-4-methoxy-5-nitrobenzaldehyde

Sodium azide (1.06 g, 16.1 mmol) was added to a solution of 2-fluoro-4-methoxy-5-nitrobenzaldehyde (1.6 g, 8.04 mmol) in dimethyl sulfoxide (20 ml), stirred at room temperature for 2 hours, then the reaction solution was poured into ice-water, extracted with ethyl acetate, the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain 1.7 g of crude product, which was directly used in the next reaction without purification.

Step 2: Preparation of tert-butyl 4-(6-methoxy-5-nitro-2H-indazol-2-yl)piperidine-1-carboxylate

A solution of 2-azido-4-methoxy-5-nitrobenzaldehyde (1.7 g, 7.65 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (1.53 g, 7.65 mmol) in toluene (20 mL) was stirred and reacted at 100°C for 2 hours, cooled to room temperature, the reaction solution was concentrated, 50 mL of water was added, extracted with ethyl acetate, the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated, and the concentrate was purified by column to obtain 1.72 g of tert-butyl 4-(6-methoxy-5-nitro-2H-indazol-2-yl)piperidine-1-carboxylate.

LC-MS: (ES, m/z): [M+H] ⁺ =377.2

Step 3: Preparation of tert-butyl 4-(5-amino-6-methoxy-2H-indazol-2-yl)piperidine-1-carboxylate

Iron powder (2.85 g, 50.9 mmol) and ammonium chloride (0.13 g, 2.3 mmol) were added to a solution of tert-butyl 4-(6-methoxy-5-nitro-2H-indazol-2-yl)piperidine-1-carboxylate (1.7 g, 4.5 mmol) in ethanol (20 ml), and the reaction solution was reacted at 90°C for 2 hours. After the reaction solution was cooled to room temperature, it was filtered and concentrated to obtain 2.01 g of the crude target product, which was directly used for the next reaction.

LC-MS: (ES, m/z): [M+H] ⁺ =347.3

Step 4: Preparation of tert-butyl 4-(6-methoxy-5-(6-(trifluoromethyl)pyridine-2-amido)-2H-indazol-2-yl)piperidine-1-carboxylate

6-(Trifluoromethyl)pyridine-2-carboxylic acid (940 mg, 4.9 mmol) and N,N-diisopropylethylamine (1.9 g, 14.7 mmol) were added to a tetrahydrofuran solution of tert-butyl 4-(5-amino-6-methoxy-2H-indazol-2-yl)piperidine-1-carboxylate (1.7 g, 4.9 mmol), then _T3P (1.5 g) was added, and the reaction solution was stirred for 2 hours at room temperature. After the reaction solution was concentrated, water was added, extracted three times with ethyl acetate, and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified on a column to obtain 1.78 g of the target product tert-butyl 4-(6-methoxy-5-(6-(trifluoromethyl)pyridin-2-amide)-2H-indazol-2-yl)piperidine-1-carboxylate.

LC-MS: (ES, m/z): [M+H] ⁺ =520.2

Step 5: Preparation of N-(6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Trifluoroacetic acid (1 ml) was added to a solution of tert-butyl 4-(6-methoxy-5-(6-(trifluoromethyl)pyridine-2-amido)-2H-indazol-2-yl)piperidine-1-aryl boxylate (435 mg, 0.795 mmol) in dichloromethane. The reaction solution was stirred at room temperature for 1 h. The solvent was removed by concentration under reduced pressure to give the desired crude product (500 mg). The crude product was used directly in the next step.

LC-MS: (ES, m/z): [M+H] ⁺ =420.2

The following intermediates were prepared based on the method used to prepare intermediate 3.

Intermediate 5: N-(6-(2-hydroxyprop-2-yl)-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Step 1: Preparation of methyl 5-nitro-1H-indazole-6-carboxylate

At -10°C, concentrated nitric acid (15 ml) was slowly added to a solution of methyl 1H-indazole-6-carboxylate (9.2 g, 0.052 mol) in concentrated sulfuric acid (20 ml). The reaction solution was stirred at -10°C for 2 h. The reaction solution was poured into ice-water, and the solid was filtered off to give 10.8 g of the desired crude product as a white solid. The crude product was used directly in the next step.

LC-MS: (ES, m/z): [M+H] ⁺ =222.1

Step 2: Preparation of methyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-nitro-2H-indazole-6-carboxylate

Potassium carbonate (11.1 g, 81.3 mmol) was added to a solution of methyl 5-nitro-1H-indazole-6-carboxylate (6 g, 27.12 mmol) and tert-butyl 4-(p-toluenesulfoyloxy)piperidine-1-carboxylate (15.3 g, 43.5 mmol) in N,N-dimethylformamide (100 mL). The reaction solution was stirred at 100 °C for 10 h. The reaction solution was cooled to room temperature, water (50 mL) and ethyl acetate (100 mL) were added, and the aqueous layer was separated and extracted with ethyl acetate (100 mL × 2). The organic layers were combined, washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography to give 2.01 g of the desired product as a yellow solid.

LC-MS: (ES, m/z): [M+H] ⁺ =405.2

Step 3: Preparation of methyl 5-amino-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2H-indazole-6-carboxylate

Iron powder (2.85 g, 50.9 mmol) and ammonium chloride (0.13 g, 2.3 mmol) were added to a solution of methyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-nitro-2H-indazole-6-carboxylate (1.7 g, 4.5 mmol) in ethanol (20 mL). The reaction solution was stirred at 90 °C for 2 h. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give 2.01 g of the crude title product as an oil. The crude product was used directly in the next step.

LC-MS: (ES, m/z): [M+H] ⁺ =375.3

Step 4: Methyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-(6-(trifluoromethyl)pyridinecarboxamide)-2H-indazole-6-carboxylate

_T3P (650 mg) was added to a mixture of methyl 5-amino-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2H-indazole-6-carboxylate (170 mg, 0.45 mmol), 6-(trifluoromethyl)pyridine-2-carboxylic acid (86.8 mg, 0.45 mmol) and N,N-diisopropylethylamine (88 mg, 0.68 mmol) in tetrahydrofuran. The reaction solution was stirred at room temperature for 2 h. The solvent was removed by concentration under reduced pressure. Water (20 mL) and ethyl acetate (20 mL) were added. The aqueous layer was separated and extracted with ethyl acetate (20 mL × 2). The organic layers were combined, washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography to give 150 mg of the desired product as a yellow solid.

LC-MS: (ES, m/z): [M+H] ⁺ =548.3

Step 5: Preparation of tert-butyl 4-(6-(2-hydroxyprop-2-yl)-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)piperidine-1-carboxylate

Lithium chloride (192 mg, 4.57 mmol) was added to a solution of methyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-(6-(trifluoromethyl)pyridinecarboxylide)-2H-indazole-6-carboxylate (500 mg, 0.91 mmol) in tetrahydrofuran. The reaction solution was cooled to 0 °C and then tetrahydrofuranmethyl magnesium bromide (3.04 mL, 1 M) was added. The reaction solution was stirred at room temperature for 12 h, quenched with aqueous ammonium chloride solution, and water (30 mL) and ethyl acetate (50 mL) were added. The aqueous layers were separated and extracted with ethyl acetate (50 ml × 2), the organic layers were combined, washed with saline (50 ml × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 435 mg of the target product as a white solid.

LC-MS: (ES, m/z): [M+H] ⁺ =548.3

Step 6: Preparation of N-(6-(2-hydroxyprop-2-yl)-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

A mixture of tert-butyl 4-(6-(2-hydroxyprop-2-yl)-5-(6-(trifluoromethyl)pyridinformamido)-2H-indazole-2-yl)piperidine-1-carboxylate (435 mg, 0.79 mmol) in dichloromethane (3 ml) and trifluoroacetic acid (1 ml) was stirred and reacted at room temperature for 1 h, and the solvent was removed by concentration under reduced pressure to give 500 mg of the desired crude product as a yellow oil. The crude product was used directly in the next step.

LC-MS: (ES, m/z): [M+H] ⁺ =448.2

Intermediate 6: N-(6-(2-hydroxyprop-2-yl)-1H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Step 1: Methyl 5-amino-1H-indazole-6-carboxylate

Palladium (800 mg, 10 wt %) was added to a solution of methyl 5-nitro-1H-indazole-6-carboxylate (5.37 g, 0.024 mol) in ethyl acetate (500 mL). The reaction mixture was stirred for 16 h at room temperature under hydrogen atmosphere. The solids were filtered and washed with ethyl acetate (100 mL × 2). The filtrate was concentrated under reduced pressure to give 4.45 g of crude title product as a brown solid. The crude product was used directly for the next reaction.

LC-MS: (ES, m/z): [M+H] ⁺ =192.2.

Step 2: Methyl 5-(6-(trifluoromethyl)pyridinecarboxamide)-1H-indazole-6-carboxylate

N,N-Diisopropylethylamine (4.5 g, 0.0345 mol) was added to a solution of methyl 5-amino-1H-indazole-6-carboxylate (4.4 g, 0.023 mol) and 6-(trifluoromethyl)picolinic acid (4.4 g, 0.023 mol) in tetrahydrofuran (50 ml), the mixture was cooled to 0°C, and then T3F (18.0 g, 0.0345 mol) was added portionwise, and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed by concentration under reduced pressure, water (50 ml) and ethyl acetate (100 ml) were added, and the aqueous layer was separated and extracted with ethyl acetate (100 ml × 2). The organic layers were collected, washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography to give 7.87 g of the desired product as a yellow solid.

LC-MS: (ES, m/z): [M+H] ⁺ =365.1.

Step 3: N-(6-(2-hydroxyprop-2-yl)-1H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

A solution of methyl 5-(6-(trifluoromethyl)pyridinecarboxamido)-1H-indazole-6-carboxylate (1 g, 0.002 mol) and lithium chloride (576 mg, 0.013 mol) in tetrahydrofuran (30 mL) was cooled to -10 °C, and then methylmagnesium bromide (9.1 mL, 0.027 mol) was added under nitrogen atmosphere. After the reaction mixture was stirred at room temperature for 8 h, it was cooled to 0 °C, and saturated aqueous ammonium chloride solution (50 mL), water (50 mL), and ethyl acetate (100 mL) were added to quench the solution. The aqueous layer was separated and extracted with ethyl acetate (100 mL × 2). The organic layer was collected, washed with saturated salt water (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain 532 mg of the desired product as a yellow solid.

LC-MS: (ES, m/z): [M+H] ⁺ =365.1.

Intermediate 7: 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid

Step 1: Preparation of 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid

3-Amino-4-methoxybenzoic acid (5.0 g, 2.93 mmol) was suspended in acrylic acid (8.05 mL, 117 mmol) and stirred at 100 °C for 3 h, then the reaction solution was stirred and cooled to room temperature. Acetic acid (33 mL) was added, the stirred suspension was heated at 100 °C for 10 min, urea (11.00 g, 183 mmol) was added, and the reaction solution was stirred at 120 °C overnight. The reaction solution was added to a mixture of ice water and concentrated hydrochloric acid (37%), stirred, the resulting suspension was kept overnight in a refrigerator at 5 °C, then filtered, the solid was washed with water and dried to give a solid. The solid was triturated with hydrochloric acid solution (0.05 M), filtered, washed with methyl tert-butyl ether and dried under reduced pressure at 40°C to obtain 6.29 g of the desired product.

^1H NMR (400 MHz, DMSO) δ 12.70 (s, 1H), 10.34 (s, 1H), 7.92 (dd, J=8.6, 2.2 Hz, 1H), 7, 83 (d, J=2.2 Hz, 1H), 7.21 (d, J=8.8 Hz, 1H), 3.94-3.82 (m, 3H), 3.60 (t, J =6.7 Hz, 2H), 2.69 (s, 2H).

The following intermediates were obtained taking into account the method for preparing intermediate 7:

Intermediate 14: 3-(2,6-dioxopiperidin-3-yl)-4-fluorobenzoic acid

Step 1: Preparation of 2,6-bis(benzyloxy)pyridine

Benzyl alcohol (109.6 g, 1.01 mol) was added to a solution of sodium hydride (60% mineral oil mixture, 54.0 g, 1.35 mol) in N,N-dimethylformamide (600 mL) at 0 °C. After stirring for 30 min, 2,6-dichloropyridine (50.0 g, 0.338 mol) was added. The reaction mixture was heated to 80 °C and stirred overnight, and after cooling to room temperature, the reaction mixture was quenched with ice water (1000 mL). The solid was filtered and dried to give 75.9 g of the desired product.

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 7.68 (t, J = 8.4 Hz, 1H), 7.48-7.36 (m, 10H), 6.45 (d, J = 8.4 Hz, 2H), 5.38 (s, 4H).

LC-MS: (ES, m/z): [M+H] ⁺ =292.2.

Step 2: Preparation of 2,6-bis(benzyloxy)-3-pyridine

N-Bromosuccinimide (41.7 g, 0.23 mol) was added to a solution of 2,6-bis(benzyloxy)pyridine (75.9 g, 0.26 mol) in acetonitrile (600 mL). The reaction mixture was stirred at 80 °C for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The concentrate was diluted with ethyl acetate (500 mL) and washed with water and brine. The organic layer was collected and dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by column chromatography to obtain 75.0 g of the desired product.

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 7.88 (d, J=8.4 Hz, 1H), 7.45-7.37 (m, 10H), 6.44 (d, J=8.4 Hz, 1H), 5.42 (s, 2H), 5.33 (s, 2H).

LC-MS: (ES, m/z): [M+H] ⁺ =370.1.

Step 3: Preparation of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-4-fluorobenzoic acid

_PdCl2 (dppf)-chloroform complex (612 mg, 0.84 mmol) and sodium carbonate (1.77 g, 16.74 mmol) were added to a mixture of 2,6-bis(benzyloxy)-3-bromopyridine (3.1 g, 8.37 mmol) and 3-boro-4-fluorobenzoic acid (1.85 g, 10.05 mmol) in dioxane (31 mL) and water (7.5 mL). The reaction mixture was heated to 90 °C under nitrogen atmosphere and the reaction was maintained for 16 h. After completion of the reaction, 15% hydrochloric acid solution (20 ml) was added, extracted with ethyl acetate (100 ml × 3), washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 1.50 g of the target product.

LC-MS: (ES, m/z): [M+H] ⁺ =430.2

Step 4: Preparation of 3-(2,6-dioxopiperidin-3-yl)-4-fluorobenzoic acid

Palladium/carbon (10%, 120 mg) was added to a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-4-fluorobenzoic acid (1.50 g, 3.49 mmol) in methanol (10 mL). The reaction mixture was stirred under hydrogen atmosphere at room temperature for 48 h. After completion of the reaction, the reaction mixture was filtered through diatomite, and the filtrate was concentrated under reduced pressure. The concentrate was purified to obtain 600 mg of the desired product.

LC-MS: (ES, m/z): [M+H] ⁺ =252.1

^1H NMR (400 MHz, DMSO- _d6 ) δ 13.04 (s, 1H), 10.92 (s, 1H), 7.91-7.95 (m, 2H), 7.30-7, 34 (m, 1H), 4.15-4.19 (m, 1H), 2.70-2.79 (m, 1H), 2.53-2.57 (m, 1H), 2.23- 2.27 (m, 1H), 2.01-2.07 (m, 1H).

Intermediate 15: pentafluorophenyl 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoate

A mixture of 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid (2.0 g, 7.58 mmol), 2,3,4,5,6-pentafluorophenol (1.67 g, 9.09 mmol) and N,N'-dicyclohexylcarbimide (1.87 g, 9.09 mmol) in N,N-dimethylformamide (20 mL) was stirred for 3 h at room temperature. The reaction solution was poured into water (200 mL) and stirred for 0.5 h. The solution was extracted with ethyl acetate (3 x 200 mL). The organic phase was collected, washed with water (2 x 500 mL) and brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by column chromatography to give 3.0 g of the desired product as a brown solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =431.1

The following intermediates were prepared taking into account the method for preparing intermediate 15:

Intermediate 23: 1-(2-methoxy-5-(3,9-diazaspiro[5,5]undecyl-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1: Preparation of tert-butyl 9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5,5]undecyl-3-carboxylate

At room temperature under nitrogen blanket, HATU (1.66 g, 4.37 mmol), tert-butyl 3,9-diazaspiro[5,5]undecyl-3-carboxylate (0.96 g, 3.78 mmol), and N-methylmorpholine (0.8 g, 7.92 mmol) were added to a solution of 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid (1.0 g, 3.78 mmol) in N,N-dimethylformamide (10 mL). After stirring for 2 h, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was collected and washed with saturated brine (3×50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by column chromatography to give 1.55 g of the desired product as a white solid.

LC-MS: (ES, m/z): [M+H] ⁺ =501.2

Step 2: Preparation of 1-(2-methoxy-5-(3,9-diazaspiro[5,5]undecyl-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

A reaction solution of tert-butyl 9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5,5]undecyl-3-carboxylate (1.55 g, 3.1 mmol) in trifluoroacetic acid/dichloromethane (2.5 mL/5 mL) was stirred at room temperature for 4 h. The reaction solution was concentrated under reduced pressure to give 2.7 g of crude title compound as a yellow oil. The crude product was used directly for the next reaction.

LC-MS: (ESI, m/z): [M+H] ⁺ =401.1

The following intermediates were prepared according to the method for the preparation of intermediate 23:

Intermediate 27: 2-(9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5,5]undec-3-yl)acetaldehyde

Step 1: Preparation of 1-(5-(9-(2,2-dimethoxyethyl)-3,9-diazaspiro[5,5]undecyl-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

2-Bromo-1,1-dimethoxyethane (46 mg, 0.3 mmol) was added to a mixture of 1-(2-methoxy-5-(3,9-diazaspiro[5,5]undecyl-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (200 mg, 0.25 mmol), potassium carbonate (155 mg, 1.25 mmol) and potassium iodide (19 mg, 0.11 mmol) in acetone (4 mL). The reaction mixture was stirred at 80 °C for 3 h and then concentrated under reduced pressure. The concentrate was purified by column chromatography to give 120 mg of the title compound as a white solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =489.3

Step 2: Preparation of 2-(9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5,5]undec-3-yl)acetaldehyde

A mixture of 1-(5-(9-(2,2-dimethoxyethyl)-3,9-diazaspiro[5,5]undecyl-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (120 mg, 0.246 mmol) in trifluoroacetic acid/dichloromethane (1 mL/2 mL) was stirred and reacted at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure. The concentrate was purified by column chromatography to give 100 mg of the title compound as a white solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =443.1

The following intermediates were obtained relative to intermediate 27:

Intermediate 32: 4-(9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5,5]undec-3-yl)butyraldehyde

Step 1: Preparation of 1-(5-(9-(3-(1,3-dioxan-2-yl)propyl)-3,9-diazaspiro[5,5]undecyl-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

2-(3-Bromopropyl)-1,3-dioxane (58 mg, 0.3 mmol) was added to a mixture of 1-(2-methoxy-5-(3,9-diazaspiro[5,5]undecyl-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (200 mg, 0.25 mmol), potassium carbonate (160 mg, 1.25 mmol) and potassium iodide (19 mg, 0.125 mmol) in acetone (10 mL). The reaction solution was stirred at 80 °C for 3 h, and the resulting mixture was concentrated under reduced pressure. The concentrate was purified by column chromatography to give 70 mg of the title compound as a white solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =515.1

Step 2: Preparation of 4-(9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5,5]undec-3-yl)butyraldehyde

A mixture of 1-(5-(9-(3-(1,3-dioxacyclopentan-2-yl)propyl)-3,9-diazaspiro[5,5]undecyl-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (70 mg, 0.136 mmol) in trifluoroacetic acid/dichloromethane (1 mL/2 mL) was stirred for 4 h at room temperature. The reaction solution was concentrated under reduced pressure. The concentrate was purified by column chromatography to give 60 mg of the title compound as a white solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =471.1

Intermediate 33: 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxy-N-methyl-N-(5-oxopentyl)benzamide

Step 1: Preparation of tert-butyl (5-((tetrahydro-2H-pyran-2-yl)oxy)pentyl)carbamate

In a 50 mL round bottom flask were added tert-butyl (5-hydroxypentyl)carbamate (1.0 g, 4.92 mmol), dichloromethane (10.0 mL), p-toluenesulfonic acid (99.47 mg, 0.49 mmol), then 3,4-dihydro-2H-pyran (496.0 mg, 5.90 mmol). The reaction mixture was stirred at room temperature overnight. 30 mL of water was added to quench the reaction, extracted with dichloromethane (2×30 mL), the organic layers were combined and washed with saturated brine (30 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was purified by column chromatography to give 900 mg of the desired product.

LC-MS: (ES, m/z): [M+H] ⁺ =288.2

Step 2: Preparation of tert-butylmethyl (5-((tetrahydro-2H-pyran-2-yl)oxy)pentyl)carbamate

Tert-Butyl (5-((tetrahydro-2H-pyran-2-yl)oxy)pentyl)carbamate (900.0 mg, 3.13 mmol), N,N-dimethylformamide (5.0 mL), and tetrahydrofuran (5.0 mL) were added to a 50 mL round bottom flask and placed in an ice water bath, followed by the addition of sodium hydride (60% mineral oil mixture, 137.72 mg, 3.44 mmol). The reaction mixture was stirred at 0 °C for 0.5 h. Then potassium iodide (533.35 mg, 3.75 mmol) was added and stirred overnight at room temperature. Water (30 mL) was added to quench the reaction, extracted with ethyl acetate (2×30 mL), the organic layers were combined and washed with water (30 mL) and brine (30 mL). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain 400 mg of the target product.

LC-MS: [M+Na] ⁺ =324.2

Step 3: Obtaining 5-(methylamino)pentyl-1-ol

In a 25 mL round-bottomed flask, tert-butylmethyl (5-((tetrahydro-2H-pyran-2-yl)oxy)pentyl)carbamate (400 mg, 1.33 mmol) and dichloromethane (5.00 mL) were added, followed by trifluoroacetic acid (3.0 mL), and the reaction mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain 500 mg of the desired product. The desired product was directly used in the next reaction.

Step 4: Preparation of 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-N-(5-hydroxypentyl)-4-methoxy-N-methylbenzamide

5-(methylamino)pentyl-1-ol (500 mg crude product, 1.33 mmol), dimethyl sulfoxide (5.0 mL) and N,N-diisopropylethylamine (686.28 mg, 5.32 mmol) were added into a 50 mL round-bottomed flask, then pentafluorophenyl 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoate (430.0 mg, 1.0 mmol) was added, and the mixed reaction solution was stirred at room temperature overnight. 10 mL water was added to quench the reaction. The mixture was extracted with ethyl acetate (2×20 mL), and the organic layers were combined and washed with 10 mL water and 20 mL saturated brine. The mixture was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain 100 mg of the desired product.

Step 5: Preparation of 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxy-N-methyl-N-(5-oxopentyl)benzamide

3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-N-(5-hydroxypentyl)-4-methoxy-N-methylbenzamide (100 mg, 0.27 mmol) and dichloromethane (5.0 mL) were added to a 25 mL round bottom flask and placed in an ice water bath, followed by the addition of Dess-Martin oxidizer (137.37 mg, 0.32 mmol), and the reaction mixture was stirred at room temperature for 2 h. 5 mL of saturated sodium thiosulfate and 5 mL of saturated sodium bicarbonate were added to quench the reaction, and then the mixture was continued to stir for 20 min. The mixture was extracted with dichloromethane (2×20 mL), and the organic layers were combined and washed with 20 mL of saturated brine. The organic layer was collected and dried over anhydrous sodium sulfate, then concentrated under reduced pressure to obtain 110.0 mg of the desired crude product.

LC-MS: (ES, m/z): [M+H] ⁺ =362.2

Intermediate 34: 2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)acetaldehyde

Step 1: Preparation of 2-(piperidin-4-yl)acetaldehyde

Trifluoroacetic acid (1.5 ml) was added to a solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (580 mg, 2.72 mol) in dichloromethane (10 ml). The reaction solution was stirred at room temperature for 2 hours. The reactants were concentrated under reduced pressure to give 320 mg of oil, which was directly used in the next reaction.

LC-MS: (ES, m/z): [M+H] ⁺ =128.2

Step 2: Preparation of 2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)acetaldehyde

Triethylamine (406 mg, 3.98 mmol) and HATU (605 mg, 1.59 mmol) were added to a mixture of 2-(piperidin-4-yl)acetaldehyde (320 mg, 1.33 mmol) and 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid (150 mg, 1.33 mmol) in N,N-dimethylformamide (5 mL). The reaction solution was stirred at room temperature for 12 hours. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL × 2), and the organic layer was collected, washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified on a column to give 120 mg of the desired product as a yellow solid.

LC-MS: (ES, m/z): [M+H] ⁺ =374.2

Intermediate 35: 2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl)acetaldehyde

Step 1: Preparation of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-carboxylate

To a mixture of 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid (300 mg, 1.14 mmol) and tert-butyl piperazine-1-carboxylate (212 mg, 1.14 mmol) in N,N-dimethylformamide (10 mL) were added N,N-diisopropylethylamine (440 mg, 9.3 mmol) and HATU (520 mg, 1.36 mmol). The reaction solution was stirred at room temperature for 2 hours, then the reaction solution was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 2). The organic layers were combined, washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified on a column to give 400 mg of the desired product as a yellow solid.

LC-MS: (ES, m/z): [M+H] ⁺ =433.2

Step 2: Preparation of 1-(2-methoxy-5-(piperazine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

Trifluoroacetic acid (1.5 ml) was added to a solution of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-carboxylate (400 mg, 0.93 mmol) in dichloromethane (10 ml). The reaction solution was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure to give 300 mg of crude title product as an oil. The crude product was used directly in the next step.

LC-MS: (ES, m/z): [M+H] ⁺ =333.2

Step 3: Preparation of 1-(5-(4-(2,2-dimethoxyethyl)piperazine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

To a mixture of 1-(2-methoxy-5-(piperazine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (300 mg, 0.9 mmol) and 2-bromo-1,1-dimethoxyethane (305 mg, 1.81 mmol) in acetone (20 mL) were added potassium carbonate (371 mg, 2.71 mmol) and potassium iodide (15 mg, 0.01 mmol). The reaction solution was stirred at 80 °C for 12 h. The reaction solution was concentrated under reduced pressure to remove the solvent, and water (10 mL) and ethyl acetate (10 mL) were added. The aqueous layers were separated and extracted with ethyl acetate (10 ml × 2), and the organic layers were combined, washed with brine (10 ml × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column to give 120 mg of the desired product as an oil.

LC-MS: (ES, m/z): [M+H] ⁺ =421.2

Step 4: Preparation of 2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperazin-1-yl)acetaldehyde

Trifluoroacetic acid (6 ml) was added to a solution of 1-(5-(4-(2,2-dimethoxyethyl)piperazine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (120 mg, 0.27 mmol) in dichloromethane (10 ml). The reaction solution was stirred at room temperature for 12 h. The solvent was removed by concentration under reduced pressure to obtain 53 mg of crude target product. The crude product was used directly in the next step.

LC-MS: (ES, m/z): [M+H] ⁺ =375.1

Intermediate 36: 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxy-N-(2-(2-(2-(2-oxoethoxy)ethoxy)ethyl)benzamide

Step 1: Preparation of 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-N-(2-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)-4-methoxybenzamide

A mixture of 2-(2-(2-aminoethoxy)ethoxy)ethan-1-ol (200 mg, 0.75 mmol), 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid (135 mg, 0.91 mmol), HATU (432 mg, 1.14 mmol) and N,N-diisopropylethylamine (293 mg, 2.27 mmol) in N,N-dimethylformamide (5 mL) was stirred for 16 h at room temperature. The reactants were poured into water (30 mL) and extracted with ethyl acetate (3 x 30 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography to give 190 mg of the product as a yellow solid.

LC-MS-3: (ES, m/z): [M-H] ^- =394.1

Step 2: Preparation of 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxy-N-(2-(2-(2-(2-oxoethoxy)ethoxy)ethyl)benzamide

Dess-Martin reagent (408 mg, 0.96 mmol) was added to a mixture of 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-N-(2-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-4-methoxybenzamide (190 mg, 0.48 mmol) in dichloromethane (5 mL) at 0 °C. The reaction solution was stirred for 2 h at room temperature, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography to give 100 mg of the desired product as a yellow solid.

LC-MS-4: (ES, m/z): [M-H] ^- =394.1

Intermediate 37: 5-((tert-butoxycarbonyl)amino)pentyl 4-methylbenzenesulfonate

A mixture of tert-butyl (5-hydroxypentyl)aminocarboxylate (500 mg, 2.463 mmol), p-toluenesulfonyl chloride (706 mg, 3.695 mmol) and 4-dimethylaminopyridine (154 mg, 1.232 mmol) in pyridine (5 mL) was stirred for 3 h at room temperature. The resulting reaction solution was diluted with water (50 mL), extracted with ethyl acetate (3 x 50 mL) and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 400 mg of crude title product as a light yellow oil. The crude product was used directly in the next step.

LC-MS: (ESI, m/z): [M+H] ⁺ =358.2

Intermediate 38: tert-butyl 9-(2-hydroxyethyl)-3-azaspiro[5,5]undecyl-3-carboxylate

Step 1: tert-butyl 9-(2-ethoxy-2-oxoethylene)-3-azaspiro[5,5]undecyl-3-carboxylate

At 0°C, sodium hydride (60% mineral oil mixture, 224 mg, 5.6 mmol) was added to a solution of 2-(diethoxyphosphoryl)ethyl acetate (1.26 g, 5.63 mmol) in N,N-dimethylformamide (15 mL) and stirred at 0°C for 0.5 h, then tert-butyl 9-oxo-3-azaspiro[5.5]undecyl-3-carboxylate (1.0 g, 3.75 mmol) was added. The reaction mixture was stirred at 0°C for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×30 mL). The organic layer was collected and washed with water (2 x 20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 0.7 g of crude title product. The crude product was used directly in the next step.

Step 2: tert-butyl 9-(2-ethoxy-2-oxoethyl)-3-azaspiro[5,5]undecyl-3-carboxylate

The reaction mixture of tert-butyl 9-(2-ethoxy-2-oxoethylene)-3-azaspiro[5,5]undecyl-3-carboxylate (0.7 g, 2.08 mmol) and palladium hydroxide (0.2 g, 1.43 mmol) in ethanol (10 mL) was stirred at room temperature for 16 h under hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give 0.5 g of crude title product. The crude product was used directly in the next step.

¹ H NMR (400 MHz, CDCl ₃ ) δ 4.12 (q, J = 7.1 Hz, 2H), 3.35 (ddd, J = 7.6, 6.8, 5.0 Hz, 4H), 2.20 (d, J = 7.1 Hz, 2H), 1.70-1.63 (m, 2H), 1.58 (dd, J = 12.7, 7.1 Hz, 2H), 1.45 (s, 9H), 1.27 (dt, J = 14.3, 6.5 Hz, 6H), 1.18-1.10 (m, 4H), 0.86 (dd, J = 13.4, 6.3 Hz, 2H).

Step 3: tert-butyl 9-(2-hydroxyethyl)-3-azaspiro[5,5]undecyl-3-carboxylate

A reaction mixture of tert-butyl 9-(2-ethoxy-2-oxoethyl)-3-azaspiro[5,5]undecyl-3-carboxylate (0.5 g, 1.47 mmol) and lithium borohydride (0.13 g, 5.9 mmol) in tetrahydrofuran (5 mL) was refluxed overnight. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The organic layer was collected and washed with water (2 x 20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 0.4 g of crude title product.

LC-MS: (ESI, m/z): [M+H] ⁺ =298.2

^1H NMR (400 MHz, MeOD) δ 3.58 (t, J=6.6 Hz, 2H), 3.43-3.28 (m, 5H), 1.77-1.66 (m, 2H ), 1.62-1.52 (m, 2H), 1.52-1.41 (m, 13H), 1.29 (t, J=5.6 Hz, 3H), 1.12 (dd, J=19.2, 11.5 Hz, 4H).

The following intermediates were prepared taking into account the method used to prepare intermediate 38:

Intermediate 40: N-(2-(1-(5-aminopentyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Step 1: Preparation of tert-butyl (5-(4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)piperidin-1-yl)pentyl)carbamate

A mixture of N-(6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (387 mg, 0.924 mmol), 5-((tert-butoxycarbonyl)amino)pentyl 4-methylbenzenesulfonate (330 mg, 0.924 mmol) and potassium carbonate (638 mg, 4.622 mmol) in N,N-dimethylformamide (10 mL) was stirred at 75 °C for 3 h, and the reaction solution was poured into water (100 mL), extracted with ethyl acetate (3×100 mL), the organic phase was collected, washed with water (2×200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by column chromatography to give a yellow oily product (60 mg, yield=11%).

LC-MS: (ESI, m/z): [M+H] ⁺ =605.3

Step 2: Preparation of N-(2-(1-(5-aminopentyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

A mixture of tert-butyl (5-(4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)piperidin-1-yl)pentyl)carbamate (60 mg, 0.0993 mmol) in trifluoroacetic acid/dichloromethane (1 mL, 1:1) was stirred and reacted overnight at room temperature, and the reactants were concentrated under reduced pressure to give 160 mg of the crude title product as a yellow oil, and the crude product was used directly for the next step.

LC-MS: (ESI, m/z): [M+H] ⁺ =505.2

Intermediate 41: N-(2-(1-(2-(2-aminoethoxy)ethyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Step 1: Preparation of tert-butyl (2-(2-(4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)piperidin-1-yl)ethoxy)ethyl)carbamate

A solution of N-(6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (500 mg, 1.193 mmol), tert-butyl (2-(2-bromoethoxy)ethyl)carbamate (610 mg, 2.864 mmol), potassium carbonate (823 mg, 5.967 mmol) and potassium iodide (99 mg, 0.597 mmol) in acetonitrile (10 mL) was stirred at 80 °C and reacted for 5 h. The resulting reaction solution was diluted with ethyl acetate (50 mL), the organic phase was collected, washed with water (2×50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by column chromatography to give 330 mg of a yellow oily product.

LC-MS: (ESI, m/z): [M+H] ⁺ =607.3

Step 2: Preparation of N-(2-(1-(2-(2-aminoethoxy)ethyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

A mixture of tert-butyl (2-(2-(4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)piperidin-1-yl)ethoxy)ethyl)carbamate (140 mg, 0.231 mmol) in trifluoroacetic acid/dichloromethane (3 mL, 1:1) was stirred and reacted overnight at room temperature. The reactants were concentrated under reduced pressure to give 270 mg of crude product as a yellow oil. The crude product was used directly in the next step.

LC-MS: (ESI, m/z): [M+H] ⁺ =507.3

Intermediate 42: N-(6-methoxy-2-(1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Step 1: Preparation of tert-butyl 4-(2-(4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)piperidin-1-yl)ethyl)piperidine-1-formate

Sodium triacetoxyborohydride (1.518 g, 7.160 mmol) was added to a mixture of N-(6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (1.0 g, 2.386 mmol) and tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (0.813 g, 3.581 mmol) in tetrahydrofuran (20 mL). The reaction solution was stirred for reaction overnight at room temperature. The reaction solution was diluted with ethyl acetate (50 mL), washed with water (2×50 mL) and saturated brine (50 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by column chromatography to give 700 mg of the desired product as a yellow solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =631.3

Step 2: Preparation of N-(6-methoxy-2-(1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

A mixture of tert-butyl 4-(2-(4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)piperidin-1-yl)ethyl)piperidine-1-formate (700 mg, 1.11 mmol) in hydrochloric acid/ethyl acetate (1 M, 20 mL) was stirred and reacted overnight at room temperature. The reactants were concentrated under reduced pressure to give 650 mg of crude title product as a yellow oil. The crude product was used directly in the next step.

LC-MS: (ESI, m/z): [M+H] ⁺ =531.3

Intermediate 43: N-(6-methoxy-2-(1-(2-oxoethyl)piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Step 1: Preparation of N-(2-(1-(2,2-dimethoxyethyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Potassium carbonate (1.235 g, 8.95 mmol) and potassium iodide (149 mg, 0.89 mmol) were added to a mixture of N-(6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (750 mg, 1.79 mmol) and 2-bromo-1,1-dimethoxyethane (46 mg, 0.3 mmol) in acetonitrile (20 mL). The reaction solution was stirred at 80 °C overnight. The reaction solution was concentrated under reduced pressure to remove the solvent, water (20 mL) was added, extracted with ethyl acetate (20 mL × 3), and the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified on a column to obtain 500 mg of the target product as an oil.

LC-MS: (ESI, m/z): [M+H] ⁺ =508.1

Step 2: Preparation of N-(6-methoxy-2-(1-(2-oxoethyl)piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

A mixture of N-(2-(1-(2,2-dimethoxyethyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (500 mg, 0.99 mmol) in hydrochloric acid (4 mL)/dioxane (5 mL) was stirred and reacted overnight at 50 °C. The reaction solution was concentrated under reduced pressure to remove the solvent, water (20 mL) was added, extracted with ethyl acetate (20 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column to give 300 mg of the desired product as an oil.

LC-MS: (ESI, m/z): [M+H] ⁺ =462.1

The following intermediates were prepared taking into account the method used to prepare intermediate 43:

Intermediate 45: N-(6-methoxy-2-(1-(3-piperidin-4-yl)propyl)piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Step 1: tert-butyl 4-(3-(p-toluenesulfonyloxy)propyl)piperidine-1-formate

To a stirred solution of tert-butyl 4-(3-hydroxypropyl)piperidine-1-formate (1.0 g, 4.1 mmol) in dichloromethane (30 mL) were added triethylamine (2.1 g, 20.6 mmol) and p-toluenesulfonyl chloride (1.2 g, 6.1 mmol). After stirring the reaction mixture at 25 °C overnight, the reaction was quenched with saturated ammonium chloride solution (50 mL) and extracted with dichloromethane (2 x 50 mL). The organic layer was collected and concentrated under reduced pressure. The concentrate was purified by column chromatography to give 1.1 g of the desired product.

LC-MS: (ESI, m/z): [M+H] ⁺ =398.2

Step 2: tert-butyl 4-(3-(4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido))-2H-indazol-2-yl)piperidin-1-yl)propyl)piperidine-1-formate

N-(6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (1.2 g, 2.9 mmol) and potassium carbonate (2.0 g, 14.5 mmol) were added to a stirred solution of tert-butyl 4-(3-(p-toluenesulfonyloxy)propyl)piperidine-1-formate (1.1 g, 2.9 mmol) in N,N-dimethylformamide (15 mL). The reaction mixture was stirred at 75 °C for 3 h. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layer was collected, washed with brine (100 mL), and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain 1.2 g of the desired product.

LC-MS: (ESI, m/z): [M+H] ⁺ =645.3

Step 3: N-(6-methoxy-2-(1-(3-piperidin-4-yl)propyl)piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

To a stirred solution of tert-butyl 4-(3-(4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido))-2H-indazol-2-yl)piperidin-1-yl)propyl)piperidine-1-formate (1.4 g, 2.1 mmol) in dichloromethane (20.0 mL) was added trifluoroacetic acid (4.0 mL). The reaction mixture was stirred at 25 °C for 2 h, then concentrated under reduced pressure to give 1.1 g of crude title product. The crude product was used directly in the next step.

LC-MS: (ESI, m/z): [M+H] ⁺ =545.2

The following intermediates were prepared taking into account the method used to prepare intermediate 45:

Intermediate 53: N-(6-methoxy-2-(1-(2-(piperidin-4-yloxy)ethyl)piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Step 1: tert-butyl 4-(allyloxy)piperidine-1-carboxylate

Sodium hydride (60% mineral oil mixture, 360 mg, 12 mmol) was added to a stirred solution of tert-butyl 4-hydroxypiperidine-1-formate (2.0 g, 10 mmol) in tetrahydrofuran (50 mL) at 0 °C, followed by stirring for 1 h at 0 °C. Then 3-bromoprop-1-ene (1.44 g, 12 mmol) was added. After stirring the reaction mixture for 4 h, the reaction was quenched with water (300 mL) and extracted with ethyl acetate (3 x 200 mL). The organic phase was collected and concentrated under reduced pressure. The concentrate was purified by silica gel column to give 2.2 g of the desired product.

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.02-5.81 (m, 1H), 5.23 (dddd, J=42.1, 10.4, 3.1, 1.5 Hz, 2H), 4.02 (dt, J=5.5, 1.4 Hz, 2H), 3.86-3.71 (m, 2H), 3.49 (dt, J=12.0, 4.1 Hz, 1H), 3.15-2.97 (m, 2H), 1.91-1.74 (m, 2H), 1.60-1.36 (m, 11H).

Step 2: tert-butyl 4-(2-oxoethoxy)piperidine-1-carboxylate

Under ozone atmosphere, tert-butyl 4-(allyloxy)piperidine-1-carboxylate (1 g, 4.15 mmol) in dichloromethane (30 mL) was reacted at -78°C for 30 min, and then quenched with dimethyl sulfide (10 mL), concentrated under reduced pressure, and the concentrate was purified by column chromatography to give 300 mg of the desired product.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.74 (t, J=0.8 Hz, 1H), 4.68 (m, 1H), 4.51-4.43 (m, 1H), 3 .56-3.52 (m, 2H), 3.29 (m, 2H), 3.21 (m, 1H), 2.31-2.19 (m, 2H), 1.82-1.68 (m, 2H), 1.46 (s, 9H).

Step 3: tert-butyl 4-(2-(4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido))-2H-indazol-2-yl)piperidin-1-yl)ethoxy)piperidin-1 -carboxylate

To a stirred solution of N-(6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (200 mg, 0.477 mmol) and tert-butyl 4-(2-oxoethoxy)piperidine-1-carboxylate (174 mg, 0.716 mmol) in tetrahydrofuran (15 mL) were added sodium triacetoxyborohydride (303 mg, 1.40 mmol) and three drops of acetic acid, and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with ethyl acetate (60 mL) and washed with water (2 x 60 mL) and brine (60 mL). The organic phase was collected and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified on a silica gel column to obtain 260 mg of the target product.

LC-MS: (ESI, m/z): [M+H] ⁺ =647.1

Step 4: N-(6-methoxy-2-(1-(2-(piperidin-4-yloxy)ethyl)piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

A reaction mixture of tert-butyl 4-(2-(4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido))-2H-indazol-2-yl)piperidin-1-yl)ethoxy)piperidine-1-formate (260 mg, 0.402 mmol) in trifluoroacetic acid/dichloromethane (4 mL, 1:1) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give 500 mg of crude title product. The crude product was used directly in the next step.

LC-MS: (ESI, m/z): [M+H] ⁺ =547.3

The following intermediates were prepared taking into account the method used to prepare intermediate 53:

Intermediate 55: N-(2-(1-((3-azaspiro[5,5]undec-9-yl)methyl)piperidin-4-yl)-6-(2-hydroxyprop-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Step 1: tert-butyl 9-((4-(6-(2-hydroxyprop-2-yl)-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)piperidin-1-yl)methyl)-3-azaspiro[5,5]undecyl-3-carboxylate

At room temperature, sodium triacetylborohydride (212 mg, 1 mmol) was added to a mixture of N-(6-(2-hydroxyprop-2-yl)-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (223 mg, 0.5 mmol) and tert-butyl 9-formyl-3-azaspiro[5,5]undecyl-3-carboxylate (140 mg, 0.5 mmol) in tetrahydrofuran (5 mL), followed by stirring and reaction for 2 hours. The solution was diluted with water (20 mL) and extracted with dichloromethane (10 mL × 3). The organic layer was collected, concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 260 mg of the intended product.

LC-MS: (ESI, m/z): [M+H] ⁺ =713.1

^1H NMR (400 MHz, DMSO) δ 12.37 (s, 1H), 8.72 (s, 1H), 8.45 (d, J=7.7 Hz, 1H), 8.37 (dd, J=14.8, 7.0 Hz, 2H), 8.16 (dd, J=7.8, 0.8 Hz, 1H), 7.57 (s, 1H), 5.95 (s, 1H ), 4.44 (s, 1H), 3.28 (s, 4H), 2.96 (s, 2H), 2.08 (d, J=10.9 Hz, 7H), 1.70-1 .44 (m, 12H), 1.39 (s, 11H), 1.22 (d, J=6.0 Hz, 2H), 1.07 (d, J=9.7 Hz, 4H).

Step 2: N-(2-(1-((3-azaspiro[5,5]undec-9-yl)methyl)piperidin-4-yl)-6-(2-hydroxyprop-2-yl)-2H- indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Tert-butyl 9-((4-(6-(2-hydroxyprop-2-yl)-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)piperidin-1-yl)methyl)-3-azaspiro[5,5]undecyl-3-carboxylate (260 mg, 0.365 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added at 0 °C. The reaction mixture was stirred and reacted at 0 °C for 2 h. N,N-diisopropylethylamine was slowly added at 0-5 °C until the pH of the reaction solution was >9, the solution was concentrated under reduced pressure at room temperature, and the crude product was directly used for the next step without further purification.

LC-MS: (ESI, m/z): [M+H] ⁺ =613.1

The following intermediates were prepared taking into account the method used to prepare intermediate 55:

Intermediate 60: N-(6-methoxy-2-(1-(2-(piperazin-1-yl)ethyl)piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Step 1: Preparation of tert-butyl 4-(2-(4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido))-2H-indazol-2-yl)piperidin-1-yl)ethyl)piperazine-1-carboxylate

Sodium triacetoxyborohydride (110 mg, 0.521 mmol) was added to a mixture of N-(6-methoxy-2-(1-(2-oxoethyl)piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (80 mg, 0.174 mmol) and tert-butyl piperazine-1-formate (32 mg, 0.174 mmol) in tetrahydrofuran (2 mL). The reaction solution was stirred and reacted overnight at room temperature, and the resulting reaction solution was diluted with ethyl acetate (20 mL), washed with water (2×20 mL) and saturated brine (20 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by column chromatography to give 80 mg of the desired product as a yellow oil.

LC-MS: (ESI, m/z): [M+H] ⁺ =632.1

Step 2: N-(6-methoxy-2-(1-(2-(piperazin-1-yl)ethyl)piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

A mixture of tert-butyl 4-(2-(4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido))-2H-indazol-2-yl)piperidin-1-yl)ethyl)piperazine-1-carboxylate (80 mg, 0.127 mmol) in trifluoroacetic acid/dichloromethane (2 mL, 1:1) was stirred and reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure to give 120 mg of crude title product as a yellow oil. The crude product was used directly in the next step.

LC-MS: (ESI, m/z): [M+H] ⁺ =532.3

The following intermediates were prepared taking into account the method used to prepare intermediate 60:

Intermediate 69: N-(6-methoxy-2-(1-(2-(piperidin-4-yl)methyl)piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Step 1: Preparation of tert-butyl 4-(2-(4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)piperidin-1-yl)methyl)piperidine-1-formate

Sodium triacetoxyborohydride (1.518 g, 7.160 mmol) was added to a mixture of N-(6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (1.0 g, 2.386 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (0.763 g, 3.581 mmol) in tetrahydrofuran (20 mL). The reaction solution was stirred for reaction overnight at room temperature. The reaction solution was diluted with ethyl acetate (50 mL), washed with water (2 × 50 mL) and saturated brine (50 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by column chromatography to give 550 mg of the desired product as a yellow solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =617.3

Stage 2: Receiving

N-(6-methoxy-2-(1-(2-(piperidin-4-yl)methyl)piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

The tert-butyl mixture was stirred

4-(2-(4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)piperidin-1-yl)methyl)piperidine-1-formate (573 mg, 1.11 mmol) in hydrochloric acid/ethyl acetate (1 M, 20 mL) and reacted overnight at room temperature. The reactants were concentrated under reduced pressure to give 400 mg of crude title product as a yellow oil. The crude product was used directly in the next step.

LC-MS: (ESI, m/z): [M+H] ⁺ =517.2

Intermediate connection 70:

N-(6-methoxy-2-(1-(2-(piperidin-4-yl)methyl)piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Step 1: Preparation of tert-butyl 4-(2-(4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)piperidin-1-yl)methyl)piperidine-1-formate

Sodium triacetoxyborohydride (1.518 g, 7.160 mmol) was added to a mixture of N-(6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (1.0 g, 2.386 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (0.763 g, 3.581 mmol) in tetrahydrofuran (20 mL). The reaction solution was stirred for reaction overnight at room temperature. The reaction solution was diluted with ethyl acetate (50 mL), washed with water (2 × 50 mL) and saturated brine (50 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by column chromatography to give 550 mg of the desired product as a yellow solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =617.3

Stage 2: Receiving

N-(6-methoxy-2-(1-(2-(piperidin-4-yl)methyl)piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

The tert-butyl mixture was stirred

4-(2-(4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)piperidin-1-yl)methyl)piperidine-1-formate (573 mg, 1.11 mmol) in hydrochloric acid/ethyl acetate (1 M, 20 mL) and reacted overnight at room temperature. The reactants were concentrated under reduced pressure to give 400 mg of crude title product as a yellow oil. The crude product was used directly in the next step.

LC-MS: (ESI, m/z): [M+H] ⁺ =517.2

Intermediate 71: N-(2-((1R,4R)-4-formylcytohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Step 1: Preparation of ((1R,4R)-4-(6-methoxy-5-nitro-2H-indazol-2-yl)cyclohexyl)methanol

A mixture of 2-azido-4-methoxy-5-nitrobenzaldehyde (1.33 g, 6 mmol) and ((1r,4r)-4-aminocyclohexyl)methanol (774 mg, 6 mmol) in toluene (50 mL) was heated to 100 °C and stirred to react overnight. The reaction mixture was concentrated under reduced pressure, and the concentrate was purified by column chromatography to give 1.5 g of the desired product as a brown solid.

^1H NMR (400 MHz, DMSO) δ 8.60 (s, 1H), 8.39 (s, 1H), 7.27 (s, 1H), 4.54-4.40 (m, 2H), 3.91 (s, 3H), 3.29 (t, J=5.8 Hz, 2H), 2.20-2.09 (m, 2H), 1.96-1.82 (m, 4H), 1.47 (dtd, J=11.9, 6.0, 3.0 Hz, 1H), 1.22-1.04 (m, 2H).

Step 2: ((1R,4R)-4-(5-amino-6-methoxy-2H-indazol-2-yl)cyclohexyl)methanol

Hydrazine hydrate (2 ml) and Raney nickel (150 mg) were added to a solution of ((1R,4R)-4-(6-methoxy-5-nitro-2H-indazol-2-yl)cyclohexyl)methanol (1.5 g, 5.0 mmol) in ethanol (50 ml). The reaction mixture was stirred at room temperature for 2 h. The filtered solid was washed with ethanol (10 ml × 1). The filtrate was collected and concentrated under reduced pressure to give 1.4 g of crude product as a brown gel.

LC-MS: (ESI, m/z): [M+H] ⁺ =276.3

Step 3: N-(2-((1R,4R)-4-(hydroxymethyl)cyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

To a solution of ((1R,4R)-4-(5-amino-6-methoxy-2H-indazol-2-yl)cyclohexyl)methanol (1.4 g, 5.07 mmol) in N,N-dimethylformamide (20 mL) were added 6-(trifluoromethyl)picolinic acid (0.97 g, 5.07 mmol), N,N-diisopropylethylamine (1.96 g, 15.21 mmol) and HATU (2.5 g, 6.59 mmol). After stirring the reaction mixture at room temperature for 2 h, the reaction was quenched with water and extracted with ethyl acetate to collect the organic layer. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography to give 1.2 g of the desired product as a brown solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =449.2

Step 4: N-(2-((1R,4R)-4-formylcyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

2-Iodoacylbenzoic acid (404 mg, 1.0 mmol) was added to a mixture of N-(2-((1R,4R)-4-(hydroxymethyl)cyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (224 mg, 0.5 mmol) in acetonitrile (10 mL), and the reaction mixture was heated to 80 °C and stirred for 2 h. The reaction solution was concentrated under reduced pressure, and the concentrate was purified by column chromatography to give 180 mg of the desired product as a brown solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =447.1

The following intermediates were prepared taking into account the method used to prepare intermediate 71:

Intermediates 74: N-(2-((1r,4r)-4-formylcytohexanyl)-6-(2-hydroxyprop-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Step 1: Ethyl (1s,4s)-4-hydroxycyclohexane-1-carboxylate

Sulfuric acid (0.25 ml) was added to a solution of (1s,4s)-4-hydroxycyclohexane-1-carboxylic acid (10 g, 69.4 mmol) in ethanol (50 ml), and the reaction mixture was stirred at 70 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give 11.6 g of crude title product. The crude product was used directly in the next step.

Step 2: Ethyl (1s,4s)-4-(toluenesulfonyloxy)cyclohexane-1-carboxylate

p-Toluenesulfonyl chloride (12 g, 62 mmol), TEA (16 g, 156 mmol) and 4-dimethylaminopyridine (61 mg, 0.5 mmol) were added to a mixture of ethyl (1s,4s)-4-hydroxycyclohexane-1-carboxylate (9.0 g, 12 mmol) in dichloromethane (150 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the concentrate was purified by column chromatography to give 11 g of the title compound as a yellow solid.

LC-MS: (ES, m/z): [M+NH4] ⁺ = 344.2.

Step 3: (1s,4s)-4-(hydroxymethyl)cyclohexyl-4-methylbenzenesulfonate

Lithium aluminum hydride (24 mL) was added to a solution of ethyl (1s,4s)-4-(toluenesulfonyloxy)cyclohexane-1-carboxylate (5.0 g, 15.3 mmol) in tetrahydrofuran (50 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. Sodium sulfate decahydrate was added, filtered, and the filtrate was concentrated to give 3.6 g of the title compound as a colorless solid.

LC-MS: (ES, m/z): [M+HN ₄ ] ⁺ =302.1.

Step 4: N-(2-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-6-(2-hydroxyprop-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

To a mixture of N-(6-(2-hydroxyprop-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (3.4 g, 9 mmol) in N,N-dimethylformamide (50 mL) were added (1s,4s)-4-(hydroxymethyl)cyclohexyl 4-methylbenzenesulfonate (2.65 g, 9 mmol) and cesium carbonate (8.8 g, 27 mmol). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with water (100 mL) and the solution was extracted with ethyl acetate (3 × 30 mL). The organic layer was collected, washed with water (2 × 20 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by column chromatography to give 500 mg of the title compound as a yellow solid.

LC-MS: (ES, m/z): [M+H] ⁺ =477.1

Step 5: N-(2-((1r,4r)-4-formylcyclohexanyl)-6-(2-hydroxyprop-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Dess-Martin reagent (213 mg, 0.50 mmol) was added to a mixture of N-(2-(1r,4r)-4-(hydroxymethyl)cyclohexyl)-6-(2-hydroxyprop-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (200 mg, 0.42 mmol) in 5 mL of dichloromethane. After stirring the reaction mixture at room temperature for 16 h, the reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (3 x 10 mL). The organic layer was collected, washed with water (2 x 2 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by column chromatography to give 50 mg of the title compound as a yellow solid.

LC-MS: (ES, m/z): [M+H] ⁺ =475.0.

Intermediate 75: N-(6-methoxy-2-((1R,4R)-4-((methyl(2-(piperidin-4-yl)ethyl)amino)methyl)cyclohexyl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Step 1: tert-Butyl 4-(2-((((1R,4R)-4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)cyclohexyl)methyl)amino)ethyl)piperidine-1-formate

Sodium triacetoxyborohydride (424 mg, 2 mmol) was added to a mixture of N-(2-((1R,4R)-4-formylcyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (180 mg, 0.4 mmol) and butyl 4-(2-aminoethyl)piperidine-1-formate (91 mg, 0.4 mmol) in tetrahydrofuran (10 mL), and then the reaction mixture was stirred overnight at room temperature. Water (20 mL) was added, extracted with ethyl acetate (20 mL × 3), the organic layer was collected, washed with saturated brine (20 mL × 1), the organic layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by column chromatography to give 170 mg of the desired product as a white solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =659.4.

Step 2: tert-Butyl 4-(2-((((1R,4R)-4-(6-methoxy-5-(6-(trifluoromethyl)pyridinformyl)-2H-indazol-2-yl)cyclohexyl)methyl)(methyl)amino)ethyl)piperidine-1-carboxylate

At room temperature, sodium triacetoxyborohydride (276 mg, 1.3 mmol) was added to a mixture of tert-butyl 4-(2-((((1R,4R)-4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)cyclohexyl)methyl)amino)ethyl)piperidine-1-formate (170 mg, 0.26 mmol) and formaldehyde (37 wt % aqueous solution, 162 mg, 2 mmol) in tetrahydrofuran (10 mL), and the reaction mixture was stirred overnight. Water (20 ml) was added to the reaction mixture, extracted with ethyl acetate (20 ml × 3), the organic layer was collected, washed with saturated brine (20 ml × 1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 135 mg of the target product as a white solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =673.4.

Step 3: N-(6-methoxy-2-((1R,4R)-4-((methyl(2-(piperidin-4-yl)ethyl)amino)methyl)cyclohexyl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

At room temperature, trichloroacetic acid (4 ml) was added to a mixture of tert-butyl 4-(2-((((1R,4R)-4-(6-methoxy-5-(6-(trifluoromethyl)pyridinformyl)-2H-indazol-2-yl)cyclohexyl)methyl)(methyl)amino)ethyl)piperidine-1-carboxylate (135 mg, 0.20 mmol) in dichloromethane (10 ml), and the mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure to give 130 mg of crude product as a brown gel. The crude product can be used directly for the next step without further purification.

LC-MS: (ESI, m/z): [M+H] ⁺ =573.4.

The following intermediates were prepared taking into account the method used to prepare intermediate 75:

Intermediate 83: N-(6-methoxy-2-((1r,4r)-4-((methyl(piperidin-4-ylmethyl)amino)methyl)cyclohexyl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Step 1: tert-Butyl 4-(((((1r,4r)-4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)cyclohexyl)methyl)(methyl)amino)methyl)piperidine-1-formate

A mixture of N-(2-((1r,4r)-4-formylcyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (100 mg, 0.22 mmol), tert-butyl 4-((methylamino)methyl)piperidine-1-formate (51 mg, 0.22 mmol) and sodium triacetoxyborohydride (142 mg, 0.67 mmol) in tetrahydrofuran (10 mL) was stirred overnight at room temperature. The reaction mixture was quenched with water (50 mL) and extracted with dichloromethane (3 x 20 mL), the organic layer was collected, washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by column chromatography to give 120 mg of the desired product as a light yellow solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =659.4.

Step 2: N-(6-methoxy-2-((1r,4r)-4-((methyl(piperidin-4-ylmethyl)amino)methyl)cyclohexyl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

To a mixture of tert-butyl 4-((((1r,4r)-4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)cyclohexyl)methyl)(methyl)amino)methyl)piperidine-1-formate (120 mg, 0.18 mmol) in dichloromethane (5 mL) was added trichloroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to give 200 mg of crude title product as a light yellow solid. The crude product was used directly in the next step.

LC-MS: (ESI, m/z): [M+H] ⁺ =559.2.

Intermediate 84: tert-butyl 9-amino-3-azaspiro[5,5]undecyl-3-carboxylate

Step 1: tert-butyl 9-(benzylamino)-3-azaspiro[5,5]undecyl-3-carboxylate

A mixture of tert-butyl 9-oxo-3-azaspiro[5,5]undecyl-3-carboxylate (267 mg, 1.0 mmol), benzylamine (321 mg, 3.0 mmol) and sodium triacetoxyborohydride (2.10 g, 10.0 mmol) in tetrahydrofuran (30 mL) was stirred for 2 h at room temperature. The reaction mixture was quenched with water (100 mL) and extracted with dichloromethane (3 x 50 mL). The organic layer was collected and washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the concentrate was purified by column chromatography to give 310 mg of the title compound as a colorless oil.

LC-MS: (ESI, m/z): [M+H] ⁺ =359.2

Step 2: tert-butyl 9-amino-3-azaspiro[5,5]undecyl-3-carboxylate

Palladium hydroxide/carbon (303 mg) was added to a mixture of tert-butyl 9-(benzylamino)-3-azaspiro[5,5]undecyl-3-carboxylate (310 mg, 0.86 mmol) in methanol (30 mL). The reaction mixture was stirred overnight at room temperature under hydrogen atmosphere. The reaction mixture was filtered through a diatomaceous earth pad and the filtrate was concentrated to give 200 mg of the desired crude product as a colorless oil. The crude mixture was used directly in the next step.

LC-MS: (ESI, m/z): [M+H] ⁺ =269.3.

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.49 (s, 1H), 3.35 (d, J=3.3 Hz, 4H), 3.15 (s, 1H), 1.97 (d , J=12.3 Hz, 2H), 1.83-1.65 (m, 5H), 1.45 (s, 9H), 1.36-1.12 (m, 6H).

Intermediate connection 85:

N-(6-methoxy-2-((1r,4r)-4-(methyl(3-azaspiro[5,5]undec-9-yl)amino)cyclohexyl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Step 1: tert-butyl ((1r,4r)-4-(6-methoxy-5-nitro-2H-indazol-2-yl)cyclohexyl)carbamate

Tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (1.03 g, 4.8 mmol) was added to a solution of 2-azido-4-methoxy-5-nitrobenzaldehyde (1.07 g, 4.8 mmol) in toluene (50 mL), and the mixture was heated to 110 °C and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the concentrate was purified by column chromatography to give 1.5 g of the desired product as a yellow solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =391.2.

Step 2: tert-butyl ((1r,4r)-4-(5-amino-6-methoxy-2H-indazol-2-yl)cyclohexyl)carbamate

To a mixture of tert-butyl ((1r,4r)-4-(6-methoxy-5-nitro-2H-indazol-2-yl)cyclohexyl)carbamate (1.5 g, 3.85 mmol) in ethanol (20 mL) were added hydrazine hydrate (85%, 1.5 mL) and Raney nickel (100 mg). The reaction mixture was stirred at room temperature for 2 h, filtered, and the filtrate was concentrated under reduced pressure to give 1.15 g of crude title product as a yellow gel, which could be used in the next step without further purification.

LC-MS: (ESI, m/z): [M+H] ⁺ =361.2.

Step 3: tert-butyl ((1r,4r)-4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)cyclohexyl)carbamate

To a mixture of tert-butyl ((1r,4r)-4-(5-amino-6-methoxy-2H-indazol-2-yl)cyclohexyl)carbamate (1.15 g, 3.19 mmol) in N,N-dimethylformamide (10 mL) were added 6-(trifluoromethyl)picolinic acid (609 mg, 3.19 mmol), HATU (1.5 g, 4.0 mmol), and N,N-diisopropylethylamine (1.2 g, 9.3 mmol). The reaction mixture was stirred at room temperature for 2 h, and the reaction was quenched with water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The organic layers were collected and washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by column chromatography to give 1.3 g of crude target product as a yellow solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =534.3.

Step 4: N-(2-((1r,4r)-4-aminocyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

A mixture of tert-butyl ((1r,4r)-4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)cyclohexyl)carbamate (400 mg, 0.75 mmol) in trifluoroacetic acid/dichloromethane (8 mL, 1:3) was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give 430 mg of crude title product as a brown oil. The crude product was used directly for the next reaction.

LC-MS: (ESI, m/z): [M+H] ⁺ =434.2.

Step 5: tert-Butyl 9-(((1r,4r)-4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)cyclohexyl)amino)-3-azaspiro[5,5]undecyl-3-carboxylate

A mixture of N-(2-((1r,4r)-4-aminocyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (430 mg, crude), tert-butyl 9-oxo-3-azaspiro[5,5]undecyl-3-carboxylate (210 mg, 0.79 mmol), and sodium triacetoxyborohydride (835 mg, 3.93 mmol) in tetrahydrofuran (10 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The organic layer was collected, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by column chromatography to give 400 mg of the desired product as a light yellow solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =685.4

Step 6: tert-Butyl 9-(((1r,4r)-4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)cyclohexyl)(methyl)amino)-3-azaspiro[5,5]undecyl-3-carboxylate

A mixture of tert-butyl 9-(((1r,4r)-4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)cyclohexyl)amino)-3-azaspiro[5,5]undecyl-3-carboxylate (400 mg, 0.58 mmol), formaldehyde (0.5 mL), and sodium triacetoxyborohydride (615 mg, 2.9 mmol) in tetrahydrofuran (10 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The organic layer was collected, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by column chromatography to give 300 mg of the desired product as a yellow oil.

LC-MS: (ESI, m/z): [M+H] ⁺ =699.3.

Step 7: N-(6-methoxy-2-((1r,4r)-4-(methyl(3-azaspiro[5,5]undec-9-yl)amino)cyclohexyl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

A mixture of tert-butyl 9-(((1r,4r)-4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)cyclohexyl)(methyl)amino)-3-azaspiro[5,5]undecyl-3-carboxylate (300 mg, 0.43 mmol) in trifluoroacetic acid/dichloromethane (6 mL, 1:2) was stirred and reacted at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give 330 mg of crude title product as a brown oil. The crude product was used directly in the next step.

LC-MS: (ESI, m/z): [M+H] ⁺ =599.4.

The following intermediates were prepared taking into account the preparation of intermediate 85.

Intermediate compound 87:

N-(6-methoxy-2-(3-(piperidin-4-ylmethyl)-3-azaspiro[5,5]undec-9-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Step 1: tert-butyl 9-(6-methoxy-5-nitro-2H-indazol-2-yl)-3-azaspiro[5,5]undecyl-3-carboxylate

Tert-butyl 9-amino-3-azaspiro[5,5]undecyl-3-carboxylate (498 mg, 1.85 mmol) was added to a solution of 2-azido-4-methoxy-5-nitrobenzaldehyde (416 mg, 1.85 mmol) in toluene (50 mL). The reaction mixture was heated to 110 °C and stirred to react overnight. The reaction mixture was concentrated under reduced pressure, and the concentrate was purified by column chromatography to give 600 mg of the desired product as a yellow solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =445.2.

Step 2: tert-butyl 9-(5-amino-6-methoxy-2H-indazol-2-yl)-3-azaspiro[5,5]undecyl-3-carboxylate

To a mixture of tert-butyl 9-(6-methoxy-5-nitro-2H-indazol-2-yl)-3-azaspiro[5,5]undecyl-3-carboxylate (600 mg, 1.35 mmol) in ethanol (20 mL) were added Raney nickel (60 mg) and hydrazine hydrate (85%, 1 mL). The reaction mixture was stirred at room temperature for 2 h, filtered and concentrated under reduced pressure to give 450 mg of crude title product as a yellow gel. The crude product can be used for the next step without further purification.

LC-MS: (ESI, m/z): [M+H] ⁺ =415.2.

Step 3: tert-butyl 9-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)-3-azaspiro[5,5]undecyl-3-carboxylate

To a mixture of tert-butyl 9-(5-amino-6-methoxy-2H-indazol-2-yl)-3-azaspiro[5,5]undecyl-3-carboxylate (450 mg, 1.09 mmol) in N,N-dimethylformamide (10 mL) were added 6-(trifluoromethyl)picolinic acid (208 mg, 1.09 mmol), HATU (538 mg, 1.42 mmol), and N,N-diisopropylethylamine (554 mg, 4.26 mmol), and the reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The organic layer was collected and washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by chromatography to give 600 mg of the desired product as a light yellow solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =588.2.

Step 4: N-(6-methoxy-2-(3-azaspiro[5,5]undec-9-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Trifluoroacetic acid (2 ml) was added to a mixture of tert-butyl 9-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)-3-azaspiro[5,5]undecyl-3-carboxylate (200 mg, 0.34 mmol) in dichloromethane (5 ml). The reaction mixture was stirred at room temperature for 2 h and concentrated under reduced pressure to give 270 mg of the desired crude title product as a pale yellow solid, which was directly used in the next step.

LC-MS: (ESI, m/z): [M+H] ⁺ =488.3.

Step 5: tert-Butyl 4-((9-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)-3-azaspiro[5,5]undec-3-yl)methyl)piperidine-1-carboxylate

A reaction mixture of N-(6-methoxy-2-(3-azaspiro[5,5]undec-9-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (270 mg, crude), tert-butyl 4-formylpiperidine-1-carboxylate (130 mg, 0.61 mmol) and sodium triacetoxyborohydride (643 mg, 3.05 mmol) in tetrahydrofuran (10 mL) was stirred and reacted overnight at 60 °C. The reaction was quenched with water (50 mL) and extracted with dichloromethane (3 × 20 mL), and the organic layer was collected, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by column chromatography to give 130 mg of the desired product as a light yellow solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =685.6.

Step 6: N-(6-methoxy-2-(3-(piperidin-4-ylmethyl)-3-azaspiro[5,5]undec-9-yl)-2H-indazol-5-yl)-6-( trifluoromethyl)pyridinecarboxamide

Trifluoroacetic acid (2 ml) was added to a stirred mixture of tert-butyl 4-((9-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)-3-aza spiro[5,5]undec-3-yl)methyl)piperidine-1-carboxylate (130 mg, 0.19 mmol) in dichloromethane (5 ml). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to give 220 mg of crude title product as a light yellow solid, and the crude product was used directly in the next step.

LC-MS: (ESI, m/z): [M+H] ⁺ =585.3.

Intermediate 88: tert-butyl 9-(4-(6-methoxy-5-nitro-2H-indazol-2-yl)cyclohexyl)-3,9-diazaspiro[5,5]undecyl-3-carboxylate

Step 1: 4-aminocyclohexyl-1-one

Trifluoroacetic acid (5 ml) was added to a solution of tert-butyl (4-oxocyclohexyl)carbamate (2.13 g, 10 mmol) in dichloromethane (20 ml), and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure to give 2.1 g of crude title product, which could be used in the next step without further purification.

Step 2: 4-(6-methoxy-5-nitro-2H-indazol-2-yl)cyclohexyl-1-one

2-Azido-4-methoxy-5-nitrobenzaldehyde (2.22 g, 10 mmol) was added to the reaction mixture of 4-aminocyclohexyl-1-one (crude, 2.1 g) in toluene (50 mL), and the reaction mixture was heated to 100 °C, stirred for reaction overnight, and concentrated under reduced pressure. The concentrate was purified by column chromatography to give 1.5 g of the title compound as a yellow solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =290.1

Step 3: tert-butyl 9-(4-(6-methoxy-5-nitro-2H-indazol-2-yl)cyclohexyl)-3,9-diazaspiro[5,5]undecyl-3-carboxylate

A reaction mixture of 4-(6-methoxy-5-nitro-2H-indazol-2-yl)cyclohexyl-1-one (500 mg, 1.73 mmol), tert-butyl 3,9-diazaspiro[5,5]undecyl-3-carboxylate (484 mg, 1.90 mmol), sodium triacetoxyborohydride (4.00 g, 18.95 mmol), and acetic acid (12 mg, 0.19 mmol) in dichloroethane (100 mL) was heated at reflux overnight. The reaction mixture was quenched with water (100 mL) and extracted with dichloromethane (3 x 50 mL). The organic layer was collected, washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by column chromatography to give the desired products P1: 150 mg and P2: 160 mg as light yellow solids.

P1: tert-butyl 9-((1r,4r)-4-(6-methoxy-5-nitro-2H-indazol-2-yl)cyclohexyl)-3,9-diazaspiro[5,5]undecyl-3-carboxylate

LC-MS-R1: (ESI, m/z): [M+H] ⁺ =528.3.

P2: tert-butyl 9-((1s,4s)-4-(6-methoxy-5-nitro-2H-indazol-2-yl)cyclohexyl)-3,9-diazaspiro[5,5]undecyl-3-carboxylate

LC-MS-R2: (ESI, m/z): [M+H] ⁺ = 528.3.

Intermediate 89: N-(2-((1s,4s)-4-(3,9-diazaspiro[5,5]undec-3-yl)cyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Step 1: tert-butyl 9-((1s,4s)-4-(5-amino-6-methoxy-2H-indazol-2-yl)cyclohexyl)-3,9-diazaspiro[5,5]undecyl-3-carboxylate

Palladium/carbon (100 mg) was added to a solution of tert-butyl 9-(4-(6-methoxy-5-nitro-2H-indazol-2-yl)cyclohexyl)-3,9-diazaspiro[5,5]undecyl-3-carboxylate (P2, 160 mg, 0.30 mmol) in methanol (10 mL). The resulting mixture was stirred for 4 h at room temperature under hydrogen atmosphere. The reaction mixture was filtered through diatomite, and the filtrate was concentrated to give 140 mg of crude title product as a light yellow solid. The crude mixture was used directly in the next step.

LC-MS: (ESI, m/z): [M+H] ⁺ =498.3.

Step 2: tert-butyl 9-((1s,4s)-4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)cyclohexyl)-3,9-diazaspiro[5,5]undecyl-3-carboxylate

To a stirred solution of tert-butyl 9-((1s,4s)-4-(5-amino-6-methoxy-2H-indazol-2-yl)cyclohexyl)-3,9-diazaspiro[5,5]undecyl-3-carboxylate (140 mg, 0.23 mmol) in N,N-dimethylformamide (3 ml) were added 6-(trifluoromethyl)picolinic acid (58 mg, 0.30 mmol), HATU (149 mg, 0.39 mmol), and N,N-diisopropylethylamine (117 mg, 0.90 mmol). The resulting reaction mixture was stirred for 2 h at room temperature. The reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (3 x 20 ml). The organic layers were collected and washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by column chromatography to give 90 mg of the desired product as a light yellow solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =671.3.

Step 3: N-(2-((1s,4s)-4-(3,9-diazaspiro[5,5]undec-3-yl)cyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Trifluoroacetic acid (2 ml) was added to a solution of tert-butyl 9-((1s,4s)-4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)cyclohexyl)-3,9-diazaspiro[5,5]undecyl-3-carboxylate (90 mg, 0.13 mmol) in dichloromethane (5 ml). The resulting reaction mixture was stirred for 2 h at room temperature. The reaction mixture was concentrated to give 120 mg of crude title product as a light yellow solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =571.3

The following intermediates were prepared based on the method used to prepare intermediate 89.

Intermediate 91: N-(6-methoxy-2-((1r,4r)-4-((2-(piperidin-4-yl)ethoxy)methyl)cyclohexyl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Step 1: Benzyl 4-(2-hydroxyethyl)piperidine-1-carboxylate

Benzylcarbonyl chloride (5.06 g, 29.8 mmol) was added to a mixture of 2-(piperidin-4-yl)ethyl-1-ol (3.2 g, 24.8 mmol) in saturated aqueous sodium bicarbonate (30 mL) and water (30 mL). The reaction mixture was stirred overnight at room temperature and extracted with ethyl acetate (3 x 100 mL). The organic layer was collected, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by column chromatography to give 6.0 g of the desired product as a yellow oil.

LC-MS: (ESI, m/z): [M+H] ⁺ =264.3.

Step 2: Benzyl 4-(2-(toluenesulfonyloxy)ethyl)piperidine-1-carboxylate

A mixture of benzyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (6.0 g, 22.8 mmol), p-toluenesulfonyl chloride (5.23 g, 27.4 mmol), triethylamine (6.9 g, 68.4 mmol), and 4-dimethylaminopyridine (0.278 g, 2.28 mmol) in dichloromethane (100 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (3 x 100 mL). The organic layers were collected and washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by column chromatography to give 8.0 g of the title product as a white solid.

¹ H NMR (400 MHz, DMSO) δ 7.85-7.75 (m, 2H), 7.49 (d, J=8.0 Hz, 2H), 7.43-7.24 (m, 5H ), 5.05 (s, 2H), 4.08-4.02 (m, 2H), 3.92 (d, J=13.2 Hz, 2H), 2.68 (s, 2H), 2.42 (s, 3H), 1.55-1.38 (m, 5H), 1.01-0.85 (m , 2H).

Step 3: benzyl 4-(2-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methoxy)ethyl)piperidine-1-carboxylate

At 0°C, sodium hydride (60%, 210 mg) was added to a solution of tert-butyl ((1r,4r)-4-(hydroxymethyl)cyclohexyl)carbamate (1.0 g, 4.37 mmol) in anhydrous tetrahydrofuran (20 mL), and the reaction mixture was stirred at this temperature for 1 hour, benzyl 4-(2-(toluenesulfonyloxy)ethyl)piperidine-1-carboxylate (2.0 g, 4.80 mmol) was added, the reaction mixture was heated to 60°C, refluxed overnight. Water (50 ml) was slowly added thereto, extracted with ethyl acetate (100 ml * 3), the organic layer was collected, washed with saturated brine (50 ml), concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 1.2 g of the target product as a colorless oil.

LC-MS: (ESI, m/z): [M+H] ⁺ =475.3.

Step 4: benzyl 4-(2-(((1r,4r)-4-aminocyclohexyl)methoxy)ethyl)piperidine-1-carboxylate

Trifluoroacetic acid (20 ml) was added to a solution of benzyl 4-(2-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methoxy)ethyl)piperidine-1-carboxylate (1.4 g 2.95 mmol) in dichloromethane (50 ml), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give 1.4 g of crude target product. It can be used for the next step without further purification.

LC-MS: (ESI, m/z): [M+H] ⁺ =375.3.

Step 5: benzyl 4-(2-(((1r,4r)-4-(6-methoxy-5-nitro-2H-indazol-2-yl)cyclohexyl)methoxy)ethyl)piperidine-1-carboxylate

Benzyl 4-(2-(((1r,4r)-4-aminocyclohexyl)methoxy)ethyl)piperidine-1-carboxylate (1.4 g, 2.95 mmol) was added to a solution of 2-azido-4-methoxy-5-nitrobenzaldehyde (661 mg, 2.95 mmol) in toluene (50 mL), the reaction mixture was heated to 110 °C and stirred overnight, concentrated under reduced pressure, and the concentrate was purified by column chromatography to give 0.9 g of the desired product as a yellow solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =551.2.

Step 6: benzyl 4-(2-(((1r,4r)-4-(5-amino-6-methoxy-2H-indazol-2-yl)cyclohexyl)methoxy)ethyl)piperidine-1-carboxylate

To a mixture of benzyl 4-(2-(((1r,4r)-4-(6-methoxy-5-nitro-2H-indazol-2-yl)cyclohexyl)methoxy)ethyl)piperidine-1-carboxylate (570, 1.0 mmol) in ethanol (20 mL) were added Raney nickel (100 mg) and hydrazine hydrate (85%, 1 mL), the reaction mixture was stirred for 2 hours at room temperature, filtered, and the filtrate was concentrated under reduced pressure to give 500 mg of crude target product as a yellow gel. The crude product can be used for the next step without further purification.

LC-MS: (ESI, m/z): [M+H] ⁺ =521.4.

Step 7: Benzyl 4-(2-(((1r,4r)-4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)cyclohexyl)methoxy)ethyl)piperidine-1-carboxylate

To a mixture of benzyl 4-(2-(((1r,4r)-4-(5-amino-6-methoxy-2H-indazol-2-yl)cyclohexyl)methoxy)ethyl)piperidine-1-carboxylate (500 mg, 0.96 mmol) in N,N-dimethylformamide (10 mL) were added 6-(trifluoromethyl)picolinic acid (184 mg, 0.96 mmol), HATU (474 mg, 1.25 mmol) and N,N-diisopropylethylamine (372 mg, 2.88 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with water (20 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The organic layers were collected and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by column chromatography to give 700 mg of the desired product as a yellow solid, ¹ H-NMR showed that the desired product contained N,N-dimethylformamide.

LC-MS: (ESI, m/z): [M+H] ⁺ =694.2.

Step 8: N-(6-methoxy-2-((1r,4r)-4-((2-(piperidin-4-yl)ethoxy)methyl)cyclohexyl)-2H-indazol-5-yl)-6- (trifluoromethyl)pyridinecarboxamide

Palladium/carbon (10%, 70 mg) was added to a mixture of benzyl 4-(2-(((1r,4r)-4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)cyclohexyl)methoxy)ethyl)piperidine-1-carboxylate (700 mg, 0.96 mmol) in ethyl acetate (20 mL), the reaction mixture was stirred overnight at room temperature under hydrogen atmosphere, filtered, the solid was washed with ethyl acetate (20 mL), and the organic layer was collected, concentrated under reduced pressure to give 550 mg of crude title product. The crude product can be used for the next step without further purification.

LC-MS: (ESI, m/z): [M+H] ⁺ = 560.3.

Intermediate 92: N-(2-((1r,4r)-4-(([1,4'-bipiperidin]-4-yl(methyl)amino)methyl)cyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Step 1: tert-Butyl 4-(((1r,4r)-4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)cyclohexyl)methyl)(methyl)amino)-[1,4'-bipiperidine]-1'-carboxylate

N-(6-methoxy-2-((1r,4r)-4-((methyl(piperidin-4-yl)amino)methyl)cyclohexyl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (280 mg, 0.40 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (88 mg, 0.44 mmol) were dissolved in 1,2-dichloroethane (20 ml), the temperature was raised to 70 °C, three drops of acetic acid were added, sodium triacetoxyborohydride (844 mg, 4.0 mmol) was divided into five parts, one part was added to the reaction solution every 1 hour and stirred overnight at 70 °C. The reaction solution was cooled to room temperature, water (30 ml) was added, extracted with dichloromethane (3 × 20 ml), and the organic phase was washed with saturated brine (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography to give 70 mg of the desired product as a light yellow solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =728.4.

Stage 2:

N-(2-((1r,4r)-4-(([1,4'-bipiperidin]-4-yl(methyl)amino)methyl)cyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Tert-butyl 4-((((1r,4r)-4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)cyclohexyl)methyl)(methyl)amino)-[1,4'-biperidine]-1'-carboxylate (70 mg, 0.096 mmol) was dissolved in dichloromethane (5 ml), trifluoroacetic acid (2 ml) was added and stirred at room temperature for 2 hours, directly concentrated under reduced pressure to give 100 mg of crude target product as a yellow solid, which was directly used for the next reaction without purification.

LC-MS: (ESI, m/z): [M+H] ⁺ =628.3.

Intermediate compound 93:

N-(2-(1-((3-azaspiro[5,5]undec-9-yl)methyl)piperidin-4-yl)-6-(difluoromethoxy)-2H-indazol-5-yl)-6- (trifluoromethyl))pyridinecarboxamide

Step 1: tert-butyl 4-(6-hydroxy-5-nitro-2H-indazol-2-yl)piperidine-1-carboxylate

Tert-butyl 4-(6-methoxy-5-nitro-2H-indazol-2-yl)piperidine-1-carboxylate (5.0 g, 13.29 mmol) was dissolved in aqueous hydrogen bromide (48%, 60 mL), heated to 110 °C, stirred for 48 h, the reaction solution was adjusted to pH 9-10 with aqueous sodium hydroxide solution and di-tert-butyl dicarbonate (3.73 g, 13.29 mmol) and 4-dimethylaminopyridine (324 mg, 2.65 mmol) were added, stirred overnight at room temperature, extracted with ethyl acetate (3 x 100 mL), the organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain 530 mg of the title compound as an orange-red solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =363.1.

^1H NMR (400 MHz, DMSO) δ 10.47 (s, 1H), 8.62 (s, 1H), 8.42 (s, 1H), 7.02 (s, 1H), 4.68 ( tt, J=11.4,4.0 Hz, 1H), 4.18-3.98 (m, 2H), 2.94 (m, 2H), 2.10 (d, J=10.1 Hz, 2H), 1.92 (cd, J=12.3,4.3 Hz, 2H), 1.43 (s, 9H) .

Step 2: tert-butyl 4-(6-(difluoromethoxy)-5-nitro-2H-indazol-2-yl)piperidine-1-carboxylate

Sodium hydroxide (1.17 g, 29.2 mmol) was dissolved in water (10 mL) and acetonitrile (10 mL), cooled to -20 °C, tert-butyl 4-(6-hydroxy-5-nitro-2H-indazol-2-yl)piperidine-1-carboxylate (530 mg, 1.46 mmol) was added, diethyl (bromodifluoromethyl)phosphonate (782 mg, 2.92 mmol) was slowly added, stirred at -20 °C for 3 h, extracted with ethyl acetate (3 × 30 mL), the organic phase was washed with saturated brine (90 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified to obtain 420 mg of the desired product.

LC-MS: (ESI, m/z): [M-55] ⁺ =357.2.

^1H NMR (400 MHz, DMSO) δ 8.84 (s, 1H), 8.68 (s, 1H), 7.64 (s, 1H), 7.31 (t, J=73.2 Hz, 1H), 4.89-4.75 (m, 1H), 4.11 (d, J=12.0 Hz, 2H), 2.97 (s, 2H), 2.13 (d, J=10.5 Hz, 2H), 2.02-1.89 (m, 3H), 1.44 (s, 9H).

Step 3: tert-butyl 4-(5-amino-6-(difluoromethoxy)-2H-indazol-2-yl)piperidine-1-carboxylate

To ethanol (20 ml) were added tert-butyl 4-(6-(difluoromethoxy)-5-nitro-2H-indazol-2-yl)piperidine-1-carboxylate (420 mg, 1.02 mmol), Raney nickel (0.5 ml) and hydrazine hydrate (0.5 ml) with stirring, stirred for 2 hours at room temperature, filtered, and the filter cake was washed twice with ethanol (5 ml × 2), concentrated under reduced pressure to obtain 380 mg of the target compound, which can be directly used in the next reaction without purification.

LC-MS: (ESI, m/z): [M+H] ⁺ =383.1

Step 4: tert-butyl 4-(6-(difluoromethoxy)-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl) piperidine-1-carboxylate

Tert-butyl 4-(5-amino-6-(difluoromethoxy)-2H-indazol-2-yl)piperidine-1-carboxylate (380 mg, 0.99 mmol) was dissolved in N,N-dimethylformamide (5 mL), 6-(trifluoromethyl)picolinic acid (229 mg, 1.2 mmol), HATU (494 mg, 1.3 mmol) and N,N-diisopropylethylamine (387 mg, 3.0 mmol) were added, stirred at room temperature for 2 hours, water (20 mL) was added, filtered, the filter cake was washed twice with water (10 mL × 2) to obtain a crude product, and the crude product was purified by column chromatography to obtain 400 mg of the title compound.

LC-MS: (ESI, m/z): [M-55] ⁺ =556.0.

^1H NMR (400 MHz, DMSO) δ 10.51 (s, 1H), 8.69 (s, 1H), 8.46 (d, J=7.4 Hz, 1H), 8.41 (t, J=7.8 Hz, 1H), 8.35 (s, 1H), 8.22 (dd, J=7.7, 1.0 Hz, 1H), 7.15 (s, 1H), 4.39 (ddd, J=11.7, 8.0, 3.8 Hz, 1H), 3.97 (d, J=14.3 Hz , 5H), 3.04 (s, 1H), 2.76 (d, J=6.1 Hz, 4H), 2.17 (d, J=10.1 Hz, 2H), 2.00 (d, J=8.7 Hz, 4H), 1.93-1.84 (m, 2H), 1.73 (s, 1H), 1.39 (d, J=15.8 Hz, 11H), 1, 21 (dt, J=14.3, 9.8 Hz, 2H).

Step 5: N-(6-(difluoromethoxy)-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Tert-butyl 4-(6-(difluoromethoxy)-5-(6-(trifluoromethyl)pyridinecarboxamide)-2H-indazol-2-yl)piperidine-1-carboxylate (200 mg, 0.36 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added and stirred at room temperature for 2 hours, directly concentrated under reduced pressure to obtain 220 mg of crude target product, which was directly used for the next reaction without purification.

LC-MS: (ESI, m/z): [M+H] ⁺ =456.1.

Step 6: tert-Butyl 9-((4-(6-(difluoromethoxy)-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)piperidin-1-yl)methyl)-3-azaspiro[5,5]undecyl-3-carboxylate

N-(6-(difluoromethoxy)-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (220 mg) and tert-butyl 9-formyl-3-azaspiro[5,5]undecyl-3-carboxylate (109 mg, 0.38 mmol) were dissolved in tetrahydrofuran (10 mL), stirred at room temperature, sodium triacetoxyborohydride (371 mg, 1.76 mmol) was added and stirred at room temperature for 2 h, water (30 mL) was added, extracted with dichloromethane (3 × 30 mL), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography with obtaining 100 mg of the target product.

LC-MS: (ESI, m/z): [M+H] ⁺ =721.7.

Step 7: N-(2-(1-((3-azaspiro[5,5]undec-9-yl)methyl)piperidin-4-yl)-6-(difluoromethoxy)-2H-and ndazol-5-yl )-6-(trifluoromethyl))pyridinecarboxamide

Tert-butyl 9-((4-(6-(difluoromethoxy)-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)piperidin-1-yl)methyl)-3-azaspiro[5,5]undecyl-3-carboxylate (100 mg, 0.138 mmol) was dissolved in dichloromethane (5 ml), trifluoroacetic acid (2 ml) was added and stirred at room temperature for 2 hours and directly concentrated under reduced pressure to obtain 120 mg of the desired crude product, which was directly used for the next reaction without purification.

LC-MS: (ESI, m/z): [M+H] ⁺ = 621.2.

Intermediate 94: tert-butyl 4-(4-aminobutyl)piperidine-1-carboxylate

Step 1: tert-butyl 4-(4-(1,3-dioxoisoindolin-2-yl)butyl)piperidine-1-carboxylate

Tert-butyl 4-(4-hydroxybutyl)piperidine-1-carboxylate (1.2 g, 4.73 mmol), phthalimide (0.82 g, 5.52 mmol) and triphenylphosphine (1.45 g, 5.52 mmol) were dissolved in anhydrous tetrahydrofuran (25 mL), the reaction solution was stirred at room temperature under nitrogen protection for 10 minutes and then cooled to 0 °C, diethyl azodicarboxylate (0.87 mL, 5.52 mmol) was slowly added dropwise to the reaction solution at 0 °C, the ice bath was removed, stirred at room temperature for 7 hours, the solvent was removed by concentration under reduced pressure, and the concentrate was purified by column chromatography (20% ethyl acetate/petroleum ether) to obtain 1.5 g of the title compound as a white solid. colors.

LC-MS: (ESI, m/z): [M-99] ⁺ =387.2.

Step 2: tert-butyl 4-(4-aminobutyl)piperidine-1-carboxylate

Tert-butyl 4-(4-hydroxybutyl)piperidine-1-carboxylate (1.5 g, 3.88 mmol) and hydrazine hydrate (5 ml) were added to ethanol (20 ml), heated and refluxed overnight, cooled to room temperature, filtered, the filter cake was washed twice with ethanol (5 ml × 2) and concentrated under reduced pressure to give 1.0 g of the title compound as a colorless oil, which could be directly used in the next reaction without purification.

¹ H NMR (400 MHz, DMSO) δ 3.95 (t, J=27.6 Hz, 2H), 2.64 (s, 2H), 2.57-2.52 (m, 2H), 1.60 (d, J=12.4 Hz, 2H), 1.48-1.21 (m, 14H), 1.17 (dd, J=13.9, 6.3 Hz, 2H), 0.92 (ad, J-12.5, 4.2 Hz, 2H).

Intermediate 95: N-(2-(1-((3-azaspiro[5,5]undec-9-yl)methyl)piperidin-4-yl)-6-(2-methoxyethoxy)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Step 1: 5-nitro-2-(piperidin-4-yl)-2H-indazol-6-ol

Tert-butyl 4-(6-hydroxy-5-nitro-2H-indazol-2-yl)piperidine-1-carboxylate (1.4 g, crude product) was dissolved in 4 M hydrochloric acid-1,4-dioxane (20 ml), stirred for 3 h at room temperature and concentrated directly under reduced pressure to give 800 mg of crude title product as a light yellow solid. The crude product was directly used for the next reaction without purification.

LC-MS: (ESI, m/z): [M+H] ⁺ =263.1.

Step 2: tert-butyl 9-((4-(6-hydroxy-5-nitro-2H-indazol-2-yl)piperidin-1-yl)methyl)-3-azaspiro[5,5]undecyl-3-carboxylate

5-Nitro-2-(piperidin-4-yl)-2H-indazol-6-ol (500 mg) and tert-butyl 9-formyl-3-azaspiro[5,5]undecyl-3-carboxylate (536 mg, 1.9 mmol) were dissolved in tetrahydrofuran (20 mL), stirred at room temperature, sodium triacetoxyborohydride (1.2 g, 5.7 mmol) was added and stirred at room temperature for 2 hours, water (50 mL) was added, extracted with dichloromethane (3 × 30 mL), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography to give 440 mg of the title compound as a yellow solid. LC-MS: (ESI, m/z): [M+H] ⁺ =528.2.

Step 3: tert-butyl 9-((4-(6-(2-methoxyethoxy)-5-nitro-2H-indazol-2-yl)piperidin-1-yl)methyl)-3-azaspiro[5,5]undecyl-3-carboxylate

Tert-butyl 9-((4-(6-hydroxy-5-nitro-2H-indazol-2-yl)piperidin-1-yl)methyl)-3-azaspiro[5,5]undecyl-3-carboxylate (440 mg, 0.8 mmol) and 1-bromo-2-methoxyethane (1.15 g, 8.0 mmol) were dissolved in acetonitrile (20 mL), anhydrous potassium carbonate (331 mg, 2.4 mmol) was added and heated to 80 °C, stirred for 2 h, water (50 mL) was added, extracted with ethyl acetate (3 × 30 mL), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography to give 110 mg of the target compound as a yellow solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =586.5.

Step 4: tert-butyl 9-((4-(5-amino-6-(2-methoxyethoxy)-2H-indazol-2-yl)piperidin-1-yl)methyl)-3-azaspir[5,5]undecyl-3-carboxylate

Tert-butyl 9-((4-(6-(2-methoxyethoxy)-5-nitro-2H-indazol-2-yl)piperidin-1-yl)methyl)-3-azaspiro[5,5]undecyl-3-carboxylate (110 mg, 0.18 mmol) was added to ethanol (10 ml), Raney nickel (0.5 ml) and hydrazine hydrate (0.5 ml) were added with stirring, stirred for 2 hours at room temperature, filtered, and the filter cake was washed twice with ethanol (5 ml×2) and concentrated under reduced pressure to obtain 100 mg of the title compound as a yellow solid, which can be directly used in the next reaction without purification.

LC-MS: (ESI, m/z): [M+H] ⁺ =556.5.

Step 5: tert-Butyl 9-((4-(6-(2-methoxyethoxy))-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)piperidin-1-yl)methyl)-3-azaspiro[5,5]undecyl-3-carboxylate

Tert-butyl 9-((4-(5-amino-6-(2-methoxyethoxy)-2H-indazol-2-yl)piperidin-1-yl)methyl)-3-azaspiro[5,5]undecyl-3-carboxylate (100 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (5 mL), 6-(trifluoromethyl)picolinic acid (41 mg, 0.21 mmol), HATU (89 mg, 0.23 mmol) and N,N-diisopropylethylamine (70 mg, 0.54 mmol) were added, stirred for 2 h at room temperature, water (20 mL) was added, extracted with ethyl acetate (3 × 20 mL), the organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography to give 80 mg of the desired product as a yellow solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =729.1.

^1H NMR (400 MHz, DMSO) δ 10.57 (s, 1H), 8.74 (s, 1H), 8.48 (d, J=7.8 Hz, 1H), 8.41 (t, J=7.8 Hz, 1H), 8.37 (s, 1H), 8.22 (d, J=7.7 Hz, 1H), 7.17 (s, 1H), 4.37 (m, 1H), 4.32-4.26 (m, 2H), 3.86-3.77 (m, 2H), 3.27 (m, 5H), 2.94 (m, 2H), 2.17 (m, J=5.6 Hz, 2H), 2.07 (m, J=5.3 Hz, 6H), 1.64 (d, J=7.7 Hz, 2H), 1.56 (d, J=9.3 Hz, 2H), 1.53-1.32 (m, 14H), 1.22 (d, J=7.0 Hz, 2H), 1.12-0.98 (m, 4H).

Step 6: N-(2-(1-((3-azaspiro[5,5]undec-9-yl)methyl)piperidin-4-yl)-6-(2-methoxyethoxy)-2H-indazol-5- yl)-6-(trifluoromethyl)pyridinecarboxamide

Tert-butyl 9-((4-(5-amino-6-(2-methoxyethoxy)-2H-indazol-2-yl)piperidin-1-yl)methyl)-3-azaspiro[5,5]undecyl-3-carboxylate (80 mg, 0.110 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added and stirred at room temperature for 2 hours, directly concentrated under reduced pressure to obtain 105 mg of crude title compound, which was directly used for the next reaction without purification.

LC-MS: (ESI, m/z): [M+H] ⁺ =629.1.

The following intermediates were prepared based on the method used to prepare intermediate 95.

Intermediate 97: benzyl 4-((((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methoxy)methyl)piperidine-1-carboxylate

Step 1: tert-butyl ((1r,4r)-4-((pyridin-4-ylmethoxy)methyl)cyclohexyl)carbamate

Sodium hydride (211 mg, 8.8 mmol) was added to tert-butyl ((1r,4r)-4-(hydroxymethyl)cyclohexyl)carbamate (1.0 g, 4.4 mmol) in tetrahydrofuran (20 mL) at 0 °C, stirred at 0 °C for 30 min, continued stirring at room temperature for 30 min, 4-bromomethylpyridine (1.1 g, 4.4 mmol) was added and stirred at room temperature overnight, water (30 mL) was added, extracted with ethyl acetate (3 × 50 mL), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography (50% EA/PE) to give 1.0 g of the desired product as white solid substance.

LC-MS: (ESI, m/z): [M+H] ⁺ =321.1.

Step 2: tert-butyl ((1r,4r)-4-((piperidin-4-ylmethoxy)methyl)cyclohexyl)carbamate

Tert-butyl ((1r,4r)-4-((pyridin-4-ylmethoxy)methyl)cyclohexyl)carbamate (1.0 g, 3.1 mmol) was dissolved in isopropanol (30 mL) and water (35 mL), palladium/carbon (0.5 g) was added, stirred at 75 °C for 72 h under hydrogen atmosphere, filtered, concentrated and dried to give 1.0 g of crude title product as a white solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =327.2.

Step 3: benzyl 4-((((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methoxy)methyl)piperidine-1-carboxylate

Saturated sodium bicarbonate solution (30 mL) and benzyl chloroformate (680 mg, 3.98 mmol) were added to tert-butyl ((1r,4r)-4-((piperidin-4-ylmethoxy)methyl)cyclohexyl)carbamate (1.0 g, 3.06 mmol) in ethyl acetate (30 mL), stirred overnight at room temperature, water (30 mL) was added, extracted with ethyl acetate (3 x 50 mL), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography to give 400 mg of the desired product as a white solid. LC-MS: (ESI, m/z): [M+H] ⁺ = 461.2.

The following intermediates were prepared based on the method used to prepare intermediate 91.

Example 1: N-(2-(1-(2-(9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5,5] undec-3-yl)ethyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)-2-pyridinecarboxamide

To a mixture of 2-(9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5,5]undec-3-yl)acetaldehyde (100 mg, 0.226 mmol) and sodium cyanoborohydride (28 mg, 0.452 mmol) in methanol/acetic acid (4 mL, 10:1) was added N-(6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (95 mg, 0.226 mmol). The mixture was stirred at room temperature for 4 h, concentrated under reduced pressure, and the concentrate was purified by preparative HPLC to give 11.23 mg of the title compound as a light yellow solid.

LC-MS: (ESI, m/z): [M+H] ⁺ = 846.3

1H NMR (400 MHz, MeOD) δ 8.85 (s, 1H), 8.50-8.42 (m, 2H), 8.32 (t, J=7.9 Hz, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.49-7.39 (m, 2H), 7.20 (d, J=8.6 Hz, 1H), 7.13 (s, 1H) , 4.94 (s, 1H), 4.09 (s, 3H), 3.97 (s, 1H), 3.93 (s, 3H), 3.82-3.36 (m, 16H), 3.26-3.18 (m, 1H), 2.81 (t, J=6.7 Hz, 2H), 2.63 (m, J=35.7, 11.9 Hz, 4H), 2.12-1.52 (m, 8H).

The following compounds were obtained using the method from Example 1:

Example 4: N-(2-(1-(5-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzamido)pentyl)piperidin-4-yl)-6-methoxy-2H -indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

A mixture of N-(2-(1-(5-aminopentyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (160 mg, 0.317 mmol), 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid (26 mg, 0.0985 mmol), HATU (49 mg, 0.129 mmol) and N,N-diisopropylethylamine (64 mg, 0.496 mmol) in N,N-dimethylformamide (3 mL) was stirred for 3 h at room temperature. The reaction solution was poured into water (20 mL) and extracted with ethyl acetate (3 × 20 mL), the organic phase was collected, washed with water (2 × 50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by preparative HPLC to give 19.97 mg of the desired product as a light yellow solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =751.2.

1H NMR (400 MHz, DMSO) δ 10.50 (s, 1H), 10.35 (s, 1H), 8.69 (s, 1H), 8.49-8.32 (m, 4H), 8 .22 (d, J-7.6 Hz, 1H), 7.86 (d, J-8.8 Hz, 1H), 7.79 (d, J-6.2 Hz, 1H), 7.18 (d, J -8.8 Hz, 2H), 4.45-4.30 (m, 1H), 3.98 (s, 3H), 3.85 (s, 3H), 3.62-3, 55 (m, 2H), 3.29 -3.23 (d, J=6.2 Hz, 2H), 3.05-2.95 (m, 2H), 2.72-2.65 (m, 2H), 2.38-2.29 (m, 2H), 2.15-1.98 (m, 6H), 1.60-1 .44 (m, 4H), 1.38-1.28 (m, 2H).

The following compounds were obtained using the method from Example 4:

Example 7: N-(2-(1-(2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)ethyl)piperidin-4 -yl)-6-(2-hydroxyprop-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

STAB (71 mg, 0.33 mmol) was added to a mixture of 2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)acetaldehyde (80 mg, 0.22 mmol) and N-(6-(2-hydroxyprop-2-yl)-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (50 mg, 0.11 mmol) in tetrahydrofuran (10 mL). The reaction solution was stirred at room temperature for 2 h. Water (10 mL) and ethyl acetate (10 mL) were added. The aqueous layer was separated and extracted with ethyl acetate (10 mL × 2). The organic layers were combined, washed with brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by preparative HPLC to give 9.8 mg of the desired product as a yellow solid.

LC-MS: (ES, m/z): [M+H] ⁺ =805.3

^1H NMR (400 MHz, MeOD) δ 8.72 (s, 1H), 8.47 (d, J=7.8 Hz, 2H), 8.32-8.24 (m, 2H), 8, 02 (d, J=7.8 Hz, 1H), 7.67 (s, 1H), 7.45 (dd, J=8.5, 2.1 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H), 7.19 (d, J=8.6 Hz, 1H), 5.02-4.96 (m, 1H), 4.59-4.56 (m, 2H), 3.92 (s, 3H), 3.73 (s, 2H), 2.81 (t, J=6.7 Hz, 3H), 2.73-2.69 (m, 2H), 2.53-2.49 (m, 2H), 2.33-2.29 (m, 4H), 1.95-1.55 (m, 12H ), 1.29-1.25 (m, 2H).

The following examples were obtained using the method in Example 7:

Example 9: N-(2-(1-(5-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxy-N-methylbenzamido)pentyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxy-N-methyl-N-(5-oxopentyl)benzamide (100 mg, 0.27 mmol), dichloroethane (2 mL), methanol (2 mL), N-(6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (113.13 mg, 0.27 mmol), acetic acid (1 drop) and sodium triacetateborohydride (114.48 mg, 0.54 mmol) were added to a 25 mL round-bottomed flask, and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with 10 mL of water, extracted with dichloromethane (2 x 20 mL), the organic layers were combined and washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by preparative HPLC to give 36.5 mg of the desired product as a white solid.

LC-MS: (ES, m/z): [M+H] ⁺ =765.4

^1H NMR (400 MHz, DMSO- _d6 ) δ 10.51 (s, 1H), 10.34 (s, 1H), 8.69 (s, 1H), 8.49-8.38 (m, 2H), 8.36 (s, 1H), 8.22 (d, J=8.6 Hz, 2H), 7.44-7.27 (m, 2H), 7.16 (d, J=8.4 Hz, 2H), 4.39-4.35 (m, 1H), 3.98 (s, 3H) , 3.84 (s, 3H), 3.59 (t, J=6.6 Hz, 3H), 2.97-2.90 (m, 6H), 2.68 (t, J=6.1 Hz, 2H), 2.35-2.31 (m, 2H), 2.11-2.05 (m, 6H), 1.64-1.16 (m, 6H).

Example 10: N-(2-(1-(2-(9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5,5] undec-3-yl)ethyl)piperidin-4-yl)-6-(2-hydroxyprop-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

2-(9-(3-(2,4-dioctetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5,5]undec-3-yl)acetaldehyde (150 mg, 0.336 mmol) was added to a mixture of N-(6-(2-hydroxyprop-2-yl)-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (50 mg, 0.112 mmol) and sodium cyanoborohydride (21 mg, 0.336 mmol) in methanol/acetic acid (4 mL, 10:1). The reaction mixture was stirred at room temperature for 4 h. It was then concentrated under reduced pressure, and the concentrate was purified by preparative HPLC to give 26.96 mg of crude target product.

LC-MS: (ESI, m/z): [M+H] ⁺ =874.4

^1H NMR (400 MHz, DMSO) δ 12.37 (s, 1H), 10.34 (s, 1H), 8.71 (s, 1H), 8.46-8.34 (m, 3H), 8.16 (dd, J=7.8, 0.8 Hz, 1H), 7.57 (s, 1H), 7.43-7.26 (m, 2H), 7.15 (d, J=8.6 Hz, 1H), 5.95 (s, 1H), 4.44-4.42 (m, 1H) , 3.84 (s, 3H), 3.61-3.35 (m, 6H), 3.01 (d, J=10.5 Hz, 2H), 2.68 (t, J=6.6 Hz, 2H), 2.49-2.31 (m, 8H), 2.21-2.03 (m, 6H), 1.62 (s, 6H), 1.48-1.27 (m, 8H).

The compounds in the following table were prepared using the method of Example 10.

Example 14: N-(2-(1-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperazin-1-yl)ethyl)piperidin-4 -yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

A mixture of N-(6-methoxy-2-(1-(2-(piperazin-1-yl)ethyl)piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (120 mg, 0.226 mmol), pentafluorophenyl 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoate (49 mg, 0.113 mmol) and N,N-diisopropylethylamine (291 mg, 2.26 mmol) in dimethyl sulfoxide (3 ml) was stirred for 2 h at room temperature. The reaction solution was poured into water (50 mL) and stirred for 0.5 h, the solution was extracted with ethyl acetate (3 x 50 mL), and the organic phase was collected, washed with water (2 x 100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by preparative HPLC to give 28.57 mg of the desired product as a yellow solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =778.2

^1H NMR (400 MHz, CDCl3) δ 10.71 (s, 1H), 8.82 (s, 1H), 8.50 (d, J=7.9 Hz, 1H), 8.12 (t, J=7.8 Hz, 1H), 7.93-7.81 (m, 2H), 7.71 (s, 1H), 7.50-7.33 (m, 2H), 7.14-6.93 (m, 2H), 4.52-4.42 (m, 1H), 4.03 (s, 3H), 3. 90 (s, 3H), 3.82-3.53 (m, 6H), 3.33 (d, J=11.7 Hz, 2H), 2.82 (t, J=6.6 Hz, 4H), 2.72 (t, J=6.2 Hz, 2H), 2.55-2.43 (m, 6H), 2.35-2.28 (m, 4H).

The following examples were obtained using the method in Example 14:

Example 71: methyl (3-(2-chloro-5-(9-(2-(4-(6-(2-hydroxyprop-2-yl)-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)piperidin-1-yl)ethyl)-3-azaspiro[5,5]undecyl-3-carbonyl)phenyl)-2,6-dioxotetrahydropyrimidin-1(2H)-yl)pivalate

To a mixture of N-(2-(1-(2-(3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3-azaspiro[5,5]undec-9-yl)ethyl)piperidin-4-yl)-6-(2-hydroxyprop-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (182 mg, 0.208 mmol) in acetonitrile (5 mL) were added cesium carbonate (82 mg, 0.249 mmol) and chloromethyl pivalate (63 mg, 0.416 mmol). The reaction mixture was stirred at room temperature for 4 h, filtered, and the filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by preparative HPLC to give 50 mg of the desired product as a light yellow solid.

LC-MS: (ESI, m/z): [M+H] ⁺ =991.1

^1H NMR (400 MHz, DMSO) δ 12.37 (s, 1H), 8.71 (s, 1H), 8.45 (d, J=7.9 Hz, 1H), 8.40-8, 33 (m, 2H), 8.16 (d, J=7.8 Hz, 1H), 7.66 (d, J=8.2 Hz, 1H), 7.61-7.54 (m, 2H), 7.42 (d, J=8.3 Hz, 1H), 5.94 (s, 1H), 5.69 (s, 2H ), 4.49-4.36 (m, 1H), 3.84-3.63 (m, 2H), 3.62-3.50 (m, 2H), 3.30-3.20 (m, 2H), 2.97 (dt, J=16.7, 7.9 Hz, 4H), 2.40-2.35 (m, 2H), 2.10-1.96 (m, 6H), 1 .75-1.67 (m, 2H), 1.62 (s, 6H), 1.58-1.47 (m, 3H), 1.47-1.32 (m, 4H), 1.31-1.22 (m, 2H), 1.18-1.04 (m, 13H).

Control group 1: N-(2-(1-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)oxy)ethoxy)ethyl) piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Step 1: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-hydroxyethoxy)ethoxy)isoindolin-1,3-dione

To a mixture of 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindolin-1,3-dione (500 mg, 0.0018 mol) and 2-(2-chloroethoxy)ethyl-1-ol (227 mg, 0.0018 mol) in dimethyl sulfoxide (20 ml) were added dropwise N,N-diisopropylethylamine (706.2 mg, 0.0055 mol) and potassium iodide (30 mg, 0.0002 mol). The reaction solution was stirred at 100 °C for 10 h. Water (30 ml) and ethyl acetate (100 ml) were added, and the aqueous layer was separated and extracted with ethyl acetate (100 ml × 2). The organic phases were combined and washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography to give 612 mg of the desired product as a white solid.

LC-MS: (ES, m/z): [M+H] ⁺ =363.0

Step 2: Preparation of 2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)acetaldehyde

Dess-Martin oxidizer (393 mg, 0.88 mmol) was added to a mixture of 2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-hydroxyethoxy)ethoxy)isoindolin-1,3-dione (162 mg, 0.44 mmol) in tetrahydrofuran (10 mL) at 0 °C, and the resulting reaction solution was stirred for 16 h at room temperature. The reaction solution was quenched with water (30 mL) and dichloromethane (50 mL). The aqueous layer was separated and extracted with dichloromethane (50 mL × 2). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography to give 32 mg of the desired product as a white solid.

LC-MS: (ES, m/z): [M+H] ⁺ =361.0

Step 3: Preparation of N-(2-(1-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)oxy)ethoxy)ethyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Sodium triacetoxyborohydride (36 mg, 0.17 mmol) was added to a mixture of N-(6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (24 mg, 0.05 mmol) and 2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)oxy)ethoxy)acetaldehyde (40 mg, 0.11 mmol) in 1,2-dichloroethane (5 mL). The reaction solution was stirred at room temperature for 2 h. The solvent was removed by concentration under reduced pressure, and the concentrate was purified by HPLC to give 3.25 mg of the desired product as a white solid.

LC-MS: (ES, m/z): [M+H] ⁺ =764.3

¹ H-NMR-LT-002-007: ¹ H NMR (400 MHz, CD ₃ OD_SPE) δ 8.77 (s, 1H), 8.47 (d, J=8.0 Hz, 3H), 8.31 (t, J=7.8 Hz, 1H), 8.18 (s, 1H), 8.05 (d, J=7.4 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.47 (d, J=1.9 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.07 (s, 1H), 5.12-5.07 (m, 1H), 4.51 (s, 1H), 4.37 (s, 2H), 4.05 (s, 3H), 3.91 (s, 2H), 3.82 (t, J=5.0 Hz, 2H), 3.37 (s, 2H), 2.96 (s, 2H), 2.90-2.77 (m, 1H), 2.77-2.60 (m, 4H), 2.26 (s, 4H), 2.08 (d, J=5.2 Hz, 1H).

Control group 2: N-(2-(1-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)oxy)ethyl)piperidine -4-yl)methyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

Step 1: Preparation of 5-(allyloxy)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione

Under nitrogen protection, 3-bromoprop-1-ene (470 mg, 3.89 mmol) was added to a mixture of 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindolin-1,3-dione (1 g, 3.65 mmol) and potassium carbonate (1.01 g, 7.29 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred overnight at 50 °C. At 0 °C, the reaction was quenched with water (60 mL) and extracted with ethyl acetate (30 mL × 3). The organic phase was collected and washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography to give 0.85 g of the desired product.

LC-MS: (ES, m/z): [M+H] ⁺ =315.1

Step 2: 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetaldehyde

Ozone was introduced into a solution of 5-(allyloxy)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (0.7 g, 2.23 mmol) in methylene chloride (200 mL) at -78 °C until the reaction solution became blue. Then, nitrogen was introduced until the reaction solution became colorless. Dimethyl sulfide (7.61 g, 123 mmol) was added at -78 °C under nitrogen atmosphere, and the reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated, and the concentrate was purified by column chromatography to obtain the desired product.

LC-MS: (ES, m/z): [M+H] ⁺ =317.1

Step 3: Preparation of N-(2-(1-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)oxy)ethyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

It was synthesized taking into account the method of stage 3 of control group 1.

LC-MS: (ESI, m/z): [M+H] ⁺ =817.1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.11 (s, 1H), 10.50 (s, 1H), 8.69 (s, 1H), 8.46 (d, J=7.6 Hz, 1H), 8.41 (t, J=7.8 Hz, 1H), 8.37 (s, 1H), 8.22 (d, J=8.6 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.47 (d, J=2.2 Hz, 1H), 7.37 (dd, J=8.3, 2.3 Hz, 1H), 7.16 (s, 1H), 5.12(dd, J=12.8, 5.3 Hz, 1H), 4.43-4.34 (m, 1H), 4.29 (t, J=5.5 Hz, 2H), 3.00-2.91 (m, 5H), 2.78-2.70 (m, 2H), 2.64-2.54 (m, 2H), 2.22-2.16 (m, 3H), 2.13-2.02 (m, 9H), 1.74-1.66 (m, 2H), 1.58-1.44 (m, 1H), 1.18-1.08 (m, 2H).

Control group 3: N-(2-((1r,4r)-4-((((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)(methyl)amino)methyl)cyclohexyl)-6-(2-hydroxyprop-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

It was obtained taking into account the method for obtaining compound 1-317 in WO 2020113233

LC-MS: (ESI, m/z): [M+H] ⁺ =843.3

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.36 (s, 1H), 11.08 (s, 1H), 8.71 (s, 1H), 8.45 (d, J=7, 8 Hz, 1H), 8.41-8.32 (m, 2H), 8.16 (d, J=7.8 Hz, 1H), 7.74-7.62 (m, 1H), 7.57 (s, 1H), 7.42-7.17 (m, 2H), 5.94 (s, 1H), 5.09 (dd, J=12.8, 5.3 Hz, 1H), 4.47-4.36 (m, 1H), 3.70 (d, J=10.0 Hz, 2H), 2.90 (d, J=12.7 Hz, 3H), 2.65-2.52 (m, 2H), 2.25-2.10 (m, 9H), 2.05-1.81 (m, 7H ), 1.74-1.55 (m, 8H), 1.32 (d, J=11.6 Hz, 2H), 1.11 (d, J=11.9 Hz, 2H).

II Example of biological activity tests

Test Example 1: IRAK4 Kinase Activity Test

KinEASE-STK S1 Serine/Threonine Kinase Kit (Cisbio) was used to detect the inhibitory effect of the compound on the IRAK4 kinase activity. The specific method was as follows: the compound was dissolved in dimethyl sulfoxide and then diluted with the kit buffer solution by an equal gradient to make the final concentration range of the test compound in the reaction system from 10,000 nM to 0.038 nM, then 2.5 nM kinase, 1 μM biotinylated polypeptide substrate and 7 μM adenosine triphosphate (ATP) were added sequentially and incubated at 37°C for 120 min. After that, anti-phosphorylated serine/threonine antibody linked to europium element compound and modified streptavidin XL665 were added to the reaction system to stop the reaction. After incubation at room temperature for 1 h, the fluorescence intensity of each well was determined at emission wavelengths of 620 nm and 665 nm and excitation wavelength of 337 nm in HTRF mode on an En Vision microplate reader (PerkinElmer), and the ratio value was calculated using the formula: Ratio = (665 nm / 620 nm) × 10 ⁴ . By comparing with the fluorescence intensity ratio of the control group, the inhibition rate of the compound at each concentration was calculated, and then the IC ₅₀ value of the compound was obtained by fitting a nonlinear logarithmic concentration-inhibition rate curve using GraphPad Prism 7.

Experimental results: The compound of the invention can effectively bind to the target protein and inhibit the activity of IRAK4 kinase.

Test Example 2: Degradation of IRAK4 in THP-1 Cells by the Compounds of the Invention Each well of a 24-well cell culture plate was inoculated with 0.95 ml of THP-1 cells (Stem Cell Bank of Chinese Academy of Sciences) at a cell seeding density of 5× ¹⁰⁵ cells/well. The cell plate was placed in an incubator with 5% carbon dioxide and cultured overnight at 37°C, and then 50 μl of the compound in dimethyl sulfoxide was added. The final concentration of the compound was in the range of 1-3000 nM. After continuous culture for 24 hours, the cells were collected in a 1.5 ml centrifuge tube, centrifuged at 1000 rpm and 4°C for 5 minutes. The cell pellet was cleared twice with 1×DPBS, the resuspended cells were lysed with 200 μl of lysate (cell lysate was Western and IP cell lysate (Beyotime) supplemented with 1 mM phenylmethylsulfonyl fluoride and protease inhibitor mixture (Beyotime)), kept on ice for 30 min, then centrifuged at 14000g at 4°C for 10 min, and the supernatant was taken for determination of IRAK4 protein level by Western blotting. Western blotting (WB) method: The total protein concentration in the supernatant after cell lysis was determined using BCA protein quantification kit (Tiangen). According to the total protein concentration detected by the BCA kit, the supernatant was adjusted to 0.2 μg/μl with PBS and 5× SDS-PAGE protein loading buffer (Beyotime), kept in a water bath at 100°C for 10 min, then placed in an ice bath for 5 min, centrifuged at 14000g and 4°C for 5 min, and then collected as a sample for WB loading. Ready-to-use adhesive (KeyGEN) was used for protein electrophoresis with a loading volume of 10 μl (total protein 2 μg). After keeping in Tris-MOPS-SDS solution (Adamas), electrophoresis was performed at a constant voltage of 120 V. After electrophoresis, the protein on the adhesive strip was transferred to a PVDF membrane and kept at a constant voltage of 250 V for 50 min. After transfer, the membrane was placed in 1× QuickBlock blocking buffer (Beyotime) and incubated for 30 min at room temperature. After blocking, PVDF membranes were incubated with IRAK4 primary antibody (Abcam) overnight at 4°, membranes were washed with TBST buffer (2.4 g Tris, 8.8 g NaCl, 1.5 ml Tween 20, adjusted to pH 7.4, constant volume to 1 L) for 30 min, incubated with secondary antibodies (Abcam) for 2 h at room temperature, finally incubated with Clarity Western ECL Substrate (BIO-RAD) for 5 min to develop luminescence, a chemiluminescence imaging system (Clinx, chemi Scope 6200 Touch) was used for development and photographic mapping of proteins. The protein map was analyzed using Clinx chemiluminescence analysis software to obtain a gray scale. Using the formula: gray scale correction value = (gray scale value of the target protein / corresponding gray scale value of the internal standard) × 10 ³ , the gray scale correction value for each sample was calculated. The degradation rate was calculated by comparing with the gray scale correction value of the control group. In addition, the DC ₅₀ and D _max values of the compound were obtained by nonlinear curve fitting of the logarithmic concentration-rate of inhibition using GraphPad Prism 7.

Experimental results: The compound of the present invention can effectively induce degradation of IRAK4 kinase protein in THP-1 cells and has excellent degradation activity.

Test Example 3: Degradation of IKZF1 and IKZF3 in L363 cells by the compound of the invention

A 24-well cell culture plate was inoculated with 0.95 ml L363 cells (Nanjing Co-bioer) per well at a cell seeding density of 6 × 10 ⁵ cells/well. The cell plate was placed in an incubator with 5% carbon dioxide and cultured at 37 °C for 8 h, then 50 μl of the compound solution was added. The final concentration of the compound was 1000 nM. After continuing the culture for 16 h, the cells were collected in a 1.5 ml centrifuge tube and centrifuged at 3000 rpm and 4 °C for 5 min. The cell pellet was cleared twice with 1×DPBS, the resuspended cells were lysed with 100 μl of lysate (cell lysate was Western and IP cell lysate (Beyotime) supplemented with 1 mM phenylmethylsulfonyl fluoride and protease inhibitor mixture (Beyotime)), kept on ice for 30 min, then centrifuged at 14000g at 4°C for 10 min, and the supernatant was taken for determination of IKZF1 and IKZF3 protein levels by Western blotting. The total protein concentration in the supernatant after cell lysis was determined using a BCA protein quantification kit (Tiangen). According to the total protein concentration detected by the BCA kit, the supernatant was adjusted to 0.2 μg/μl with PBS and 5× SDS-PAGE protein loading buffer (Beyotime), kept in a water bath at 100°C for 10 min, then placed in an ice bath for 5 min, centrifuged at 14000g and 4°C for 5 min, and then collected as a sample for WB loading. Ready-to-use adhesive (KeyGEN) was used for protein electrophoresis with a loading volume of 10 μl (total protein 2 μg). After keeping in Tris-MOPS-SDS solution (Adamas), electrophoresis was performed at a constant voltage of 120 V. After electrophoresis, the protein on the adhesive strip was transferred to a PVDF membrane and kept at a constant voltage of 250 V for 50 min. After transfer, the membrane was incubated in 5% bovine serum albumin for 2 hours at room temperature. After blocking, PVDF membranes were incubated with IKZF1 primary antibodies (CST) and IKZF3 primary antibodies (Abcam) overnight at 4°, the membranes were washed with TBST buffer (2.4 g Tris, 8.8 g NaCl, 1.5 ml Tween 20, pH adjusted to 7.4, constant volume to 1 L) for 30 minutes, incubated with secondary antibodies (Abcam) for 2 hours at room temperature, finally incubated with Clarity Western ECL Substrate (BIO-RAD) for 5 minutes to develop luminescence, a chemiluminescence imaging system (Clinx, chemi Scope 6200 Touch) was used for development and photographic mapping of proteins. The protein map was analyzed using Clinx chemiluminescence analysis software to obtain a gray scale. Using the formula: gray scale correction value = (gray scale value of the target protein / corresponding gray scale value of the internal standard) × 10 ³ , the gray scale correction value for each sample was calculated. The degradation rate was calculated by comparing with the gray scale correction value of the control group.

The experimental results show that the compound of the present invention has good degradation selectivity, no or little degradation for IKZF1 and IKZF3, and little toxic side effects, which gives advantages to the patented drug.

Test Example 4: Determination of Cytokine Concentrations in LPS-Induced Secretion of Human PBMCs

Frozen human peripheral blood mononuclear cells (PBMC) (Milestone, PB010C) were resuspended in RPMI 1640 medium (Gibco, A1049101) after its reconstitution with 10% fetal bovine serum (Gibco, 10099141), 100 U/ml penicillin and 100 μg/ml streptomycin (Gibco, 15140122). On the same day, 150 μl of PBMC were added to each well of a 96-well clear cell plate (Labserv, 310109008) so that the cell seeding density was 2 × 10 ⁵ cells/well. Then, 50 μl of the diluted compound solution were added to the corresponding cell-coated wells to achieve a final compound concentration in the range of 0.026-10000 nM. The final DMSO concentration was 0.25%. After culturing the drug-treated cell plate at 37°C for 1 h or 20 h in a 5% _CO2 incubator, 10 μl of lipopolysaccharide (LPS) (0111:B4) (Sigma, L4391) was added at a final concentration of 100 ng/ml. The cell plate was again placed in a 5% _CO2 incubator at 37°C for 5 hours, centrifuged at 2000 rpm for 10 minutes, 100 μl of cell supernatant was collected from each well and transferred to a new 96-well clear cell plate for cytokine concentration assay, the plate was frozen at -80°C for testing.

Detection of interleukin-6 (IL-6) by the AlphaLISA kit

The IL-6 concentration in the supernatant of human PBMCs induced by LPS was determined using the AlphaLISA interleukin-6 (IL-6) detection kit (PerkinElmer, AL223 C).

According to the instruction of the kit, standard solutions of IL-6 with different concentrations in the concentration range of 0-100000 pg/mL were prepared. 2 μL of the standard solution of IL-6 at different concentrations and a sample of the tested cell supernatant were taken and added to white 384-well plates (PerkinElmer, 6007299) respectively, then a mixed solution of 8 μL of 5 × anti-IL-6 receptor antibody beads (final concentration: 10 μg/mL) and biotin-labeled anti-IL-6 antibody (final concentration 1 nM) was added to each well and incubated at 23°C for 60 minutes. Finally, 10 μl of 2× streptavidin-labeled donor beads (final concentration: 40 μg/ml) were added to each well and incubated at 23°C for 30 min in the absence of light. After incubation, the AlphaLISA signal value was determined in the standard AlphaScreen setting mode of the En Vision microplate reader (PerkinElmer, 2105). A standard curve was constructed from the AlphaLISA signal value for each concentration of the IL-6 standard solution, and then the IL-6 concentration in the supernatant of each cell lysate was determined based on the corresponding concentration on the standard curve for the AlphaLISA signal value of the test sample. Compared with the IL-6 concentration in the control group, the inhibition rate of the compound at each concentration was calculated, and then the _IC50 value of the compound was calculated by fitting a nonlinear logarithmic concentration-inhibition rate curve using GraphPad Prism 7.

Experimental results: The compounds of the present invention have a good inhibitory effect on the production of IL-6 by immune cells.

Claims (120)

1. Compound of formula I PTM-L-ULM I, where ULM has the following structure: where in ULM-1: X'' represents CH or N; Y'' represents N; Q ₁ , Q ₂ , Q ₃ , Q ₄ and Q ₅ each independently represent CR ₃ ''; R ₃ '' each independently represents hydrogen, halogen, C1-C6 alkyl, -O(C1-C6 alkyl); and alkyl is optionally substituted with 1-3 groups independently selected from halogen; m'' is equal to 2; R ₁ '' each independently represents hydrogen; R ₂ '' is hydrogen or C1-C6 alkyl, C1-C6 alkyl optionally substituted with 1 group selected from -O-(C=O)-(C1-C6 alkyl); PTM is where in PTM-71: ring A is a 6-membered heteroaryl; R _d each independently represents hydrogen, halogen or C1-C6 alkyl; and the alkyl is optionally substituted with one or more groups selected from halogen or hydroxyl; n represents 1; R _e represents hydrogen; R _c is hydrogen, -O-(C1-C6 alkyl), -O-(3-8 membered heterocycloalkyl), C1-C6 alkyl; and alkyl, heterocycloalkyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen or -O-(C1-C6 alkyl); R _b is hydrogen, -O-(C1-C6 alkyl) or C1-C6 alkyl; and the alkyl is optionally substituted with one or more groups independently selected from hydroxyl or halogen; R _a represents hydrogen, 3-8-membered heterocycloalkyl, C3-C8 cycloalkyl; L is -(CH2) _j -, and one or more methylenes in -(CH2) _j - are optionally replaced by a group selected from -NR ^3' -, -O-, -C(O)-, -C(O)NR ^3' -, -NR ^3' C(O)- , C3-C12 cycloalkylene or 3-12 membered heterocycloalkylene containing one or two N heteroatoms; R ^3' each independently represents hydrogen or C1-C6 alkyl; j is equal to 3, 4, 5, 6, 7, 8, 9, 10; heteroaryl contains 1 heteroatom selected from N, O; 3-8-membered heterocycloalkyl contains 1 heteroatom selected from N, O. 2. A compound of formula I according to claim 1, wherein R ₃ '' in ULM-1, each independently, is hydrogen, halogen, -O(C1-C6 alkyl) or C1-C6 alkyl and the alkyl is optionally substituted with 1 to 3 halogens; preferably, each R ₃ '' independently is hydrogen, F, Cl, methyl, methoxy, ethoxy, trifluoromethoxy or trifluoromethyl. 3. A compound of formula I according to claim 1, wherein ULM is selected from the group consisting of: where Q ₁ , Q ₂ , Q ₃ , Q ₄ , Q ₅ , R ₁ '', R ₂ '', R ₃ '' and m'' are defined as specified in paragraph 1. 4. A compound of formula I according to claim 1, wherein ULM is selected from the group consisting of: where Q ₁ , Q ₂ , Q ₃ , Q ₄ , Q ₅ , R ₁ '', R ₂ '', R ₃ '' and m'' are defined as specified in paragraph 1. 5. A compound of formula I according to claim 3, wherein ULM is selected from: 6. A compound of formula I according to claim 4, wherein ULM is selected from: 7. A compound of formula I according to claim 1, wherein PTM is where in PTM-71: ring A is pyridyl; R _d each independently represents hydrogen, halogen or C1-C6 alkyl; and the alkyl is optionally substituted with one or more groups selected from halogen or hydroxyl; n is equal to 1; R _e represents hydrogen; R _c is hydrogen, -O(C1-C6 alkyl), C1-C6 alkyl, or -O(3-6 membered heterocycloalkyl); both alkyl and heterocycloalkyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, or -O-(C1-C6 alkyl); R _b is hydrogen or C1-C6 alkyl and the alkyl is optionally substituted with one or more groups independently selected from hydroxyl or halogen; R _a represents hydrogen, 3-8 membered heterocycloalkyl, C3-C8 cycloalkyl. 8. A compound of formula I according to claim 7, wherein R _d is hydrogen, F, methyl, difluoromethyl, trifluoromethyl or 2-hydroxypropyl. 9. A compound of formula I according to claim 7, wherein R _c in PTM-71 is C1-C6 alkyl and the alkyl is optionally substituted with one or more groups independently selected from hydroxyl and halogen; preferably R _c is difluoromethyl or 2-hydroxypropyl. 10. A compound of formula I according to claim 9, wherein R _c in PTM-71 is C1-C6 alkyl and the alkyl is substituted with hydroxyl. 11. A compound of formula I according to claim 7, wherein R _c in PTM-71 is -O(C1-C6 alkyl) and the alkyl is optionally substituted with one or more groups independently selected from hydroxyl, halogen or -OCH ₃ ; preferably R _c is methoxy, ethoxy, isopropoxy, -OCH ₂ CH ₂ OCH ₃ , difluoromethoxy or trifluoromethoxy. 12. A compound of formula I according to claim 7, wherein R _c in PTM-71 is -O-(3- to 6-membered heterocycloalkyl containing one or two heteroatoms selected from N or O); preferably . 13. A compound of formula I according to claim 7, wherein R _b in PTM-71 is hydrogen or methyl. 14. A compound of formula I according to claim 7, wherein R _a in PTM-71 is piperidinyl. 15. A compound of formula I according to claim 7, wherein R _a in PTM-71 is cyclohexane. 16. A compound of formula I according to claim 7, wherein PTM is or . 17. A compound of formula I according to claim 1, wherein L is -( _CH2 ) _j , 1, 2, 3 or 4 methylenes in -( _CH2 ) _j- are optionally substituted with a group selected from -NH-, _-NCH3- , _-NCH2CH3- , _-O- , -C(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)-, _-NCH3C (O)-, cyclopropylene, cyclobutylene, _{cyclopentylene} , cyclohexylidene, aziridinylene, azetidinylene, azacyclopentylene, piperidinylidene, piperazinylidene, , , , , , , , , or , and j is 3, 4, 5, 6, 7, or 8. 18. A compound of formula I according to claim 1, wherein L is -( _CH2 ) _j- , 1, 2 or 3 methylenes _in -( _CH2 ) _j- are optionally substituted with a group selected from -O-, -NH-, -NCH3-, _-NCH2CH3- , -C(O)-, _-C (O)NH-, -NHC(O)-, -NCH3C(O)-, -C(O) _NCH3- , aziridinylene, _{azetidinylene} , azacyclopentylene, piperidinylidene, piperazinylidene, , , , , , or , j is 3, 4, 5, 6, 7 or 8. 19. A compound of formula I according to claim 1, wherein L is -(CH ₂ ) _j-1 -C(O)-, wherein the methylene in -(CH ₂ ) _j-1 -C(O)- is as defined in claim 1, optionally substituted with one or more groups, j is as defined in claim 1. 20. A compound of formula I according to claim 1, wherein L is LA LA, where in LA: ring D is absent or represents a 3-12-membered heterocycloalkylene containing 1-2 N heteroatoms; ring B is absent or represents a 3-12-membered heterocycloalkylene containing 1-2 N heteroatoms; ring C is absent or represents a 3-12-membered heterocycloalkylene containing 1-2 N heteroatoms; X'''' represents -C(O)-, -NHC(O)-, or _-NCH3C (O)-; L ₃ is -(CH ₂ ) _k , one or two methylenes in L ₃ are optionally substituted with a substituent selected from -O-, -NH- or -N(C1-C6 alkyl)-, k is 0, 1, 2, 3, 4, 5, 6, 7, 8. 21. A compound of formula I according to claim 1, wherein L is LA LA, where in LA: Ring D and Ring B are absent, Ring C is a 4- to 7-membered saturated monocyclic heterocycloalkylene containing 1 or 2 nitrogen heteroatoms or a 7- to 11-membered spiroheterocycloalkylene containing 1 or 2 nitrogen heteroatoms; X'''' is -C(O)-; L ₃ is -(CH ₂ ) _k , one methylene in L ₃ is optionally substituted with a group selected from -O-, -NH-, -NCH ₃ - or -NCH ₂ CH ₃ -; and k is 2, 3 or 4. 22. A compound of formula I according to claim 1, wherein L is: or . 23. A compound, where the compound is: or . 24. A pharmaceutical composition for the treatment and/or prevention of IRAK4-mediated diseases or conditions, comprising a compound according to any one of claims 1-23 and a pharmaceutically acceptable carrier, diluent or excipient. 25. Use of a compound according to any one of claims 1 to 23 in the manufacture of a medicament for the treatment and/or prevention of IRAK4-mediated diseases or conditions; wherein the IRAK4-mediated diseases or conditions are selected from the group consisting of autoimmune diseases and inflammatory diseases. 26. The use according to claim 25, wherein the IRAK4-mediated diseases or conditions are selected from the group consisting of autoimmune hematological diseases, systemic lupus erythematosus, rheumatoid arthritis, scleroderma, dermatomyositis, autoimmune inflammatory bowel disease, multiple sclerosis, systemic juvenile idiopathic arthritis, acute respiratory distress syndrome, lung diseases, allergies, dermatitis, enteritis, purulent inflammation of the sweat glands, psoriasis, pericarditis, pneumonia, uveitis, focal alopecia, acute and chronic gout, juvenile rheumatoid arthritis or diseases of the osteoarthritic group. 27. The use according to claim 26, wherein enteritis is selected from the group consisting of Crohn's disease, inflammatory bowel disease and ulcerative colitis. 28. Use according to claim 26, wherein the pneumonia is focal pneumonia. 29. The use according to claim 26, wherein the lung disease is selected from the group consisting of interstitial lung disease, asthma, acute lung injury, COPD and interstitial pulmonary fibrosis. 30. The use according to claim 26, wherein the acute and chronic gout is chronic gouty arthritis.